ALBERT

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kupferschmidt, Kai -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1143. doi: 10.1126/science.351.6278.1143.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965608" target="_blank"〉PubMed〈/a〉

Description: Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barrera, Luis A -- Vedenko, Anastasia -- Kurland, Jesse V -- Rogers, Julia M -- Gisselbrecht, Stephen S -- Rossin, Elizabeth J -- Woodard, Jaie -- Mariani, Luca -- Kock, Kian Hong -- Inukai, Sachi -- Siggers, Trevor -- Shokri, Leila -- Gordan, Raluca -- Sahni, Nidhi -- Cotsapas, Chris -- Hao, Tong -- Yi, Song -- Kellis, Manolis -- Daly, Mark J -- Vidal, Marc -- Hill, David E -- Bulyk, Martha L -- P50 HG004233/HG/NHGRI NIH HHS/ -- R01 HG003985/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1450-4. doi: 10.1126/science.aad2257. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. ; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. ; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013732" target="_blank"〉PubMed〈/a〉

Description: p97 is a hexameric AAA+ adenosine triphosphatase (ATPase) that is an attractive target for cancer drug development. We report cryo-electron microscopy (cryo-EM) structures for adenosine diphosphate (ADP)-bound, full-length, hexameric wild-type p97 in the presence and absence of an allosteric inhibitor at resolutions of 2.3 and 2.4 angstroms, respectively. We also report cryo-EM structures (at resolutions of ~3.3, 3.2, and 3.3 angstroms, respectively) for three distinct, coexisting functional states of p97 with occupancies of zero, one, or two molecules of adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) per protomer. A large corkscrew-like change in molecular architecture, coupled with upward displacement of the N-terminal domain, is observed only when ATPgammaS is bound to both the D1 and D2 domains of the protomer. These cryo-EM structures establish the sequence of nucleotide-driven structural changes in p97 at atomic resolution. They also enable elucidation of the binding mode of an allosteric small-molecule inhibitor to p97 and illustrate how inhibitor binding at the interface between the D1 and D2 domains prevents propagation of the conformational changes necessary for p97 function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerjee, Soojay -- Bartesaghi, Alberto -- Merk, Alan -- Rao, Prashant -- Bulfer, Stacie L -- Yan, Yongzhao -- Green, Neal -- Mroczkowski, Barbara -- Neitz, R Jeffrey -- Wipf, Peter -- Falconieri, Veronica -- Deshaies, Raymond J -- Milne, Jacqueline L S -- Huryn, Donna -- Arkin, Michelle -- Subramaniam, Sriram -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):871-5. doi: 10.1126/science.aad7974. Epub 2016 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA. ; Small Molecule Discovery Center, Pharmaceutical Chemistry, School of Pharmacy, University of California, San Francisco, CA 94143, USA. ; University of Pittsburgh Chemical Diversity Center, University of Pittsburgh, Pittsburgh, PA 15260, USA. ; Leidos Biomedical Research Inc., Frederick, MD 21702, USA. ; Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD 20892, USA. ; Division of Biology and Biological Engineering and Howard Hughes Medical Institute, California Institute of Technology, Pasadena, CA 91107, USA. ; Laboratory of Cell Biology, National Cancer Institute, Bethesda, MD 20892, USA. ss1@nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26822609" target="_blank"〉PubMed〈/a〉

Description: The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Sheng-Hong -- Forrester, William -- Lahav, Galit -- F32GM105205/GM/NIGMS NIH HHS/ -- GM083303/GM/NIGMS NIH HHS/ -- R01 GM083303/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1204-8. doi: 10.1126/science.aac5610. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, MA, USA. ; Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965628" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2016 Jan 7;529(7584):12. doi: 10.1038/529012a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738576" target="_blank"〉PubMed〈/a〉

Description: Eukaryotic cells restrict protein synthesis under various stress conditions, by inhibiting the eukaryotic translation initiation factor 2B (eIF2B). eIF2B is the guanine nucleotide exchange factor for eIF2, a heterotrimeric G protein consisting of alpha-, beta- and gamma-subunits. eIF2B exchanges GDP for GTP on the gamma-subunit of eIF2 (eIF2gamma), and is inhibited by stress-induced phosphorylation of eIF2alpha. eIF2B is a heterodecameric complex of two copies each of the alpha-, beta-, gamma-, delta- and epsilon-subunits; its alpha-, beta- and delta-subunits constitute the regulatory subcomplex, while the gamma- and epsilon-subunits form the catalytic subcomplex. The three-dimensional structure of the entire eIF2B complex has not been determined. Here we present the crystal structure of Schizosaccharomyces pombe eIF2B with an unprecedented subunit arrangement, in which the alpha2beta2delta2 hexameric regulatory subcomplex binds two gammaepsilon dimeric catalytic subcomplexes on its opposite sides. A structure-based in vitro analysis by a surface-scanning site-directed photo-cross-linking method identified the eIF2alpha-binding and eIF2gamma-binding interfaces, located far apart on the regulatory and catalytic subcomplexes, respectively. The eIF2gamma-binding interface is located close to the conserved 'NF motif', which is important for nucleotide exchange. A structural model was constructed for the complex of eIF2B with phosphorylated eIF2alpha, which binds to eIF2B more strongly than the unphosphorylated form. These results indicate that the eIF2alpha phosphorylation generates the 'nonproductive' eIF2-eIF2B complex, which prevents nucleotide exchange on eIF2gamma, and thus provide a structural framework for the eIF2B-mediated mechanism of stress-induced translational control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kashiwagi, Kazuhiro -- Takahashi, Mari -- Nishimoto, Madoka -- Hiyama, Takuya B -- Higo, Toshiaki -- Umehara, Takashi -- Sakamoto, Kensaku -- Ito, Takuhiro -- Yokoyama, Shigeyuki -- England -- Nature. 2016 Mar 3;531(7592):122-5. doi: 10.1038/nature16991. Epub 2016 Feb 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. ; RIKEN Systems and Structural Biology Center, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Center for Life Science Technologies, Tsurumi-ku, Yokohama 230-0045, Japan. ; RIKEN Structural Biology Laboratory, Tsurumi-ku, Yokohama 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26901872" target="_blank"〉PubMed〈/a〉

Description: The palaeobiological record of 12 million to 7 million years ago (Ma) is crucial to the elucidation of African ape and human origins, but few fossil assemblages of this period have been reported from sub-Saharan Africa. Since the 1970s, the Chorora Formation, Ethiopia, has been widely considered to contain ~10.5 million year (Myr) old mammalian fossils. More recently, Chororapithecus abyssinicus, a probable primitive member of the gorilla clade, was discovered from the formation. Here we report new field observations and geochemical, magnetostratigraphic and radioisotopic results that securely place the Chorora Formation sediments to between ~9 and ~7 Ma. The C. abyssinicus fossils are ~8.0 Myr old, forming a revised age constraint of the human-gorilla split. Other Chorora fossils range in age from ~8.5 to 7 Ma and comprise the first sub-Saharan mammalian assemblage that spans this period. These fossils suggest indigenous African evolution of multiple mammalian lineages/groups between 10 and 7 Ma, including a possible ancestral-descendent relationship between the ~9.8 Myr old Nakalipithecus nakayamai and C. abyssinicus. The new chronology and fossils suggest that faunal provinciality between eastern Africa and Eurasia had intensified by ~9 Ma, with decreased faunal interchange thereafter. The Chorora evidence supports the hypothesis of in situ African evolution of the Gorilla-Pan-human clade, and is concordant with the deeper divergence estimates of humans and great apes based on lower mutation rates of ~0.5 x 10(-9) per site per year (refs 13 - 15).〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Katoh, Shigehiro -- Beyene, Yonas -- Itaya, Tetsumaru -- Hyodo, Hironobu -- Hyodo, Masayuki -- Yagi, Koshi -- Gouzu, Chitaro -- WoldeGabriel, Giday -- Hart, William K -- Ambrose, Stanley H -- Nakaya, Hideo -- Bernor, Raymond L -- Boisserie, Jean-Renaud -- Bibi, Faysal -- Saegusa, Haruo -- Sasaki, Tomohiko -- Sano, Katsuhiro -- Asfaw, Berhane -- Suwa, Gen -- England -- Nature. 2016 Feb 11;530(7589):215-8. doi: 10.1038/nature16510.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Natural History, Hyogo Museum of Nature and Human Activities, Sanda 669-1546, Japan. ; Association for Conservation of Culture Awassa, PO Box 6686, Addis Ababa, Ethiopia. ; Centre francais des etudes ethiopiennes (CFEE), USR CNRS 3137, French Ministry for Foreign Affairs, PO Box 5554, Addis Ababa, Ethiopia. ; Research Institute of Natural Sciences, Okayama University of Science, Okayama 700-0005, Japan. ; Research Center for Inland Seas, Kobe University, Kobe 657-8501, Japan. ; Hiruzen Institute for Geology and Chronology, Okayama 703-8252, Japan. ; EES-14/MS D462, Los Alamos National Laboratory, Los Alamos, New Mexico 87545, USA. ; Department of Geology and Environmental Earth Science, Miami University, 133 Culler Hall, Oxford, Ohio 45056, USA. ; Department of Anthropology, University of Illinois, Urbana, Illinois 61801, USA. ; Department of Earth and Environmental Sciences, Kagoshima University, Kagoshima 890-0065, Japan. ; Department of Anatomy, Howard University, Washington DC 20059, USA. ; Institut de Paleoprimatologie, Paleontologie Humaine : Evolution et Paleoenvironnements (IPHEP), UMR CNRS 7262, Universite de Poitiers, 86022 Poitiers, France. ; Museum fur Naturkunde - Leibniz Institute for Evolution and Biodiversity Science, Invalidenstrasse 43, 10115 Berlin, Germany. ; Institute of Natural and Environmental Sciences, University of Hyogo, Sanda 669-1546, Japan. ; The University Museum, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; Rift Valley Research Service, PO Box 5717, Addis Ababa, Ethiopia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863981" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bender, Eric -- England -- Nature. 2016 May 11;533(7602):S62-4. doi: 10.1038/533S62a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27167394" target="_blank"〉PubMed〈/a〉

Description: Sex and recombination are pervasive throughout nature despite their substantial costs. Understanding the evolutionary forces that maintain these phenomena is a central challenge in biology. One longstanding hypothesis argues that sex is beneficial because recombination speeds adaptation. Theory has proposed several distinct population genetic mechanisms that could underlie this advantage. For example, sex can promote the fixation of beneficial mutations either by alleviating interference competition (the Fisher-Muller effect) or by separating them from deleterious load (the ruby in the rubbish effect). Previous experiments confirm that sex can increase the rate of adaptation, but these studies did not observe the evolutionary dynamics that drive this effect at the genomic level. Here we present the first, to our knowledge, comparison between the sequence-level dynamics of adaptation in experimental sexual and asexual Saccharomyces cerevisiae populations, which allows us to identify the specific mechanisms by which sex speeds adaptation. We find that sex alters the molecular signatures of evolution by changing the spectrum of mutations that fix, and confirm theoretical predictions that it does so by alleviating clonal interference. We also show that substantially deleterious mutations hitchhike to fixation in adapting asexual populations. In contrast, recombination prevents such mutations from fixing. Our results demonstrate that sex both speeds adaptation and alters its molecular signature by allowing natural selection to more efficiently sort beneficial from deleterious mutations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855304/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855304/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McDonald, Michael J -- Rice, Daniel P -- Desai, Michael M -- GM104239/GM/NIGMS NIH HHS/ -- R01 GM104239/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 10;531(7593):233-6. doi: 10.1038/nature17143. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Department of Physics, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909573" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2016 Feb 18;530(7590):266. doi: 10.1038/nature.2016.19336.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887473" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2016 Mar 31;531(7596):562. doi: 10.1038/531562a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029259" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2016 Mar 24;531(7595):425-6. doi: 10.1038/531425a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27008947" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Melott, Adrian L -- England -- Nature. 2016 Apr 7;532(7597):40-1. doi: 10.1038/532040a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physics and Astronomy, University of Kansas, Lawrence, Kansas 66045, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078562" target="_blank"〉PubMed〈/a〉

Description: Plant respiration results in an annual flux of carbon dioxide (CO2) to the atmosphere that is six times as large as that due to the emissions from fossil fuel burning, so changes in either will impact future climate. As plant respiration responds positively to temperature, a warming world may result in additional respiratory CO2 release, and hence further atmospheric warming. Plant respiration can acclimate to altered temperatures, however, weakening the positive feedback of plant respiration to rising global air temperature, but a lack of evidence on long-term (weeks to years) acclimation to climate warming in field settings currently hinders realistic predictions of respiratory release of CO2 under future climatic conditions. Here we demonstrate strong acclimation of leaf respiration to both experimental warming and seasonal temperature variation for juveniles of ten North American tree species growing for several years in forest conditions. Plants grown and measured at 3.4 degrees C above ambient temperature increased leaf respiration by an average of 5% compared to plants grown and measured at ambient temperature; without acclimation, these increases would have been 23%. Thus, acclimation eliminated 80% of the expected increase in leaf respiration of non-acclimated plants. Acclimation of leaf respiration per degree temperature change was similar for experimental warming and seasonal temperature variation. Moreover, the observed increase in leaf respiration per degree increase in temperature was less than half as large as the average reported for previous studies, which were conducted largely over shorter time scales in laboratory settings. If such dampening effects of leaf thermal acclimation occur generally, the increase in respiration rates of terrestrial plants in response to climate warming may be less than predicted, and thus may not raise atmospheric CO2 concentrations as much as anticipated.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reich, Peter B -- Sendall, Kerrie M -- Stefanski, Artur -- Wei, Xiaorong -- Rich, Roy L -- Montgomery, Rebecca A -- England -- Nature. 2016 Mar 31;531(7596):633-6. doi: 10.1038/nature17142. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Forest Resources, University of Minnesota, Minnesota 55108, USA. ; Hawkesbury Institute for the Environment, Western Sydney University, Penrith, New South Wales 2753, Australia. ; State Key Laboratory of Soil Erosion and Dryland Farming on the Loess Plateau, Northwest A&F University, Yangling 712100, China. ; Smithsonian Environmental Research Center, Edgewater, Maryland 20137, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982730" target="_blank"〉PubMed〈/a〉

Description: Nonribosomal peptide synthetases (NRPSs) are very large proteins that produce small peptide molecules with wide-ranging biological activities, including environmentally friendly chemicals and many widely used therapeutics. NRPSs are macromolecular machines, with modular assembly-line logic, a complex catalytic cycle, moving parts and many active sites. In addition to the core domains required to link the substrates, they often include specialized tailoring domains, which introduce chemical modifications and allow the product to access a large expanse of chemical space. It is still unknown how the NRPS tailoring domains are structurally accommodated into megaenzymes or how they have adapted to function in nonribosomal peptide synthesis. Here we present a series of crystal structures of the initiation module of an antibiotic-producing NRPS, linear gramicidin synthetase. This module includes the specialized tailoring formylation domain, and states are captured that represent every major step of the assembly-line synthesis in the initiation module. The transitions between conformations are large in scale, with both the peptidyl carrier protein domain and the adenylation subdomain undergoing huge movements to transport substrate between distal active sites. The structures highlight the great versatility of NRPSs, as small domains repurpose and recycle their limited interfaces to interact with their various binding partners. Understanding tailoring domains is important if NRPSs are to be utilized in the production of novel therapeutics.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reimer, Janice M -- Aloise, Martin N -- Harrison, Paul M -- Schmeing, T Martin -- 106615/Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Jan 14;529(7585):239-42. doi: 10.1038/nature16503.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, McGill University, 3649 Promenade Sir-William-Osler, Montreal, Quebec H3G 0B1, Canada. ; Department of Biology, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec H3A 1B1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762462" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kraus, Robert H S -- England -- Nature. 2016 Mar 24;531(7595):448. doi: 10.1038/531448e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Konstanz, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27008959" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 11;530(7589):129-30. doi: 10.1038/530130a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863944" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 11;530(7589):129. doi: 10.1038/530129a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863943" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heffernan, Olive -- England -- Nature. 2016 Feb 4;530(7588):20-2. doi: 10.1038/530020a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842039" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neuberger, David -- England -- Nature. 2016 Mar 3;531(7592):9. doi: 10.1038/531009a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935661" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Laursen, Lucas -- England -- Nature. 2016 May 11;533(7602):S68-9. doi: 10.1038/533S68a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27167396" target="_blank"〉PubMed〈/a〉

Description: Polar temperatures over the last several million years have, at times, been slightly warmer than today, yet global mean sea level has been 6-9 metres higher as recently as the Last Interglacial (130,000 to 115,000 years ago) and possibly higher during the Pliocene epoch (about three million years ago). In both cases the Antarctic ice sheet has been implicated as the primary contributor, hinting at its future vulnerability. Here we use a model coupling ice sheet and climate dynamics-including previously underappreciated processes linking atmospheric warming with hydrofracturing of buttressing ice shelves and structural collapse of marine-terminating ice cliffs-that is calibrated against Pliocene and Last Interglacial sea-level estimates and applied to future greenhouse gas emission scenarios. Antarctica has the potential to contribute more than a metre of sea-level rise by 2100 and more than 15 metres by 2500, if emissions continue unabated. In this case atmospheric warming will soon become the dominant driver of ice loss, but prolonged ocean warming will delay its recovery for thousands of years.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeConto, Robert M -- Pollard, David -- England -- Nature. 2016 Mar 31;531(7596):591-7. doi: 10.1038/nature17145.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geosciences, University of Massachusetts, Amherst, Massachusetts 01003, USA. ; Earth and Environmental Systems Institute, Pennsylvania State University, University Park, Pennsylvania 16802, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029274" target="_blank"〉PubMed〈/a〉

Description: Somatic mutations are the driving force of cancer genome evolution. The rate of somatic mutations appears to be greatly variable across the genome due to variations in chromatin organization, DNA accessibility and replication timing. However, other variables that may influence the mutation rate locally are unknown, such as a role for DNA-binding proteins, for example. Here we demonstrate that the rate of somatic mutations in melanomas is highly increased at active transcription factor binding sites and nucleosome embedded DNA, compared to their flanking regions. Using recently available excision-repair sequencing (XR-seq) data, we show that the higher mutation rate at these sites is caused by a decrease of the levels of nucleotide excision repair (NER) activity. Our work demonstrates that DNA-bound proteins interfere with the NER machinery, which results in an increased rate of DNA mutations at the protein binding sites. This finding has important implications for our understanding of mutational and DNA repair processes and in the identification of cancer driver mutations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sabarinathan, Radhakrishnan -- Mularoni, Loris -- Deu-Pons, Jordi -- Gonzalez-Perez, Abel -- Lopez-Bigas, Nuria -- England -- Nature. 2016 Apr 14;532(7598):264-7. doi: 10.1038/nature17661.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Doctor Aiguader 88, 08003 Barcelona, Spain. ; Institucio Catalana de Recerca i Estudis Avancats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075101" target="_blank"〉PubMed〈/a〉

Description: (beta-)Arrestins are important regulators of G-protein-coupled receptors (GPCRs). They bind to active, phosphorylated GPCRs and thereby shut off 'classical' signalling to G proteins, trigger internalization of GPCRs via interaction with the clathrin machinery and mediate signalling via 'non-classical' pathways. In addition to two visual arrestins that bind to rod and cone photoreceptors (termed arrestin1 and arrestin4), there are only two (non-visual) beta-arrestin proteins (beta-arrestin1 and beta-arrestin2, also termed arrestin2 and arrestin3), which regulate hundreds of different (non-visual) GPCRs. Binding of these proteins to GPCRs usually requires the active form of the receptors plus their phosphorylation by G-protein-coupled receptor kinases (GRKs). The binding of receptors or their carboxy terminus as well as certain truncations induce active conformations of (beta-)arrestins that have recently been solved by X-ray crystallography. Here we investigate both the interaction of beta-arrestin with GPCRs, and the beta-arrestin conformational changes in real time and in living human cells, using a series of fluorescence resonance energy transfer (FRET)-based beta-arrestin2 biosensors. We observe receptor-specific patterns of conformational changes in beta-arrestin2 that occur rapidly after the receptor-beta-arrestin2 interaction. After agonist removal, these changes persist for longer than the direct receptor interaction. Our data indicate a rapid, receptor-type-specific, two-step binding and activation process between GPCRs and beta-arrestins. They further indicate that beta-arrestins remain active after dissociation from receptors, allowing them to remain at the cell surface and presumably signal independently. Thus, GPCRs trigger a rapid, receptor-specific activation/deactivation cycle of beta-arrestins, which permits their active signalling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nuber, Susanne -- Zabel, Ulrike -- Lorenz, Kristina -- Nuber, Andreas -- Milligan, Graeme -- Tobin, Andrew B -- Lohse, Martin J -- Hoffmann, Carsten -- 1 R01 DA038882/DA/NIDA NIH HHS/ -- BB/K019864/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- England -- Nature. 2016 Mar 31;531(7596):661-4. doi: 10.1038/nature17198. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Pharmacology and Toxicology, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Rudolf Virchow Center, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Comprehensive Heart Failure Center, University of Wurzburg, Versbacher Str. 9, 97078 Wurzburg, Germany. ; Molecular Pharmacology Group, Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK. ; MRC Toxicology Unit, University of Leicester, Hodgkin Building, Lancaster Road, Leicester LE1 9HN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007855" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2016 Mar 17;531(7594):286. doi: 10.1038/531286a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26983523" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scheuermann, Richard H -- England -- Nature. 2016 Mar 10;531(7593):173. doi: 10.1038/531173a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉J. Craig Venter Institute, La Jolla, California, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961650" target="_blank"〉PubMed〈/a〉

Description: In recent years, several extreme weather disasters have partially or completely damaged regional crop production. While detailed regional accounts of the effects of extreme weather disasters exist, the global scale effects of droughts, floods and extreme temperature on crop production are yet to be quantified. Here we estimate for the first time, to our knowledge, national cereal production losses across the globe resulting from reported extreme weather disasters during 1964-2007. We show that droughts and extreme heat significantly reduced national cereal production by 9-10%, whereas our analysis could not identify an effect from floods and extreme cold in the national data. Analysing the underlying processes, we find that production losses due to droughts were associated with a reduction in both harvested area and yields, whereas extreme heat mainly decreased cereal yields. Furthermore, the results highlight ~7% greater production damage from more recent droughts and 8-11% more damage in developed countries than in developing ones. Our findings may help to guide agricultural priorities in international disaster risk reduction and adaptation efforts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lesk, Corey -- Rowhani, Pedram -- Ramankutty, Navin -- England -- Nature. 2016 Jan 7;529(7584):84-7. doi: 10.1038/nature16467.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Geography, McGill University, Montreal H3A 0B9, Canada. ; Department of Geography, University of Sussex, Brighton BN1 9QJ, UK. ; Liu Institute for Global Issues and Institute for Resources, Environment and Sustainability, University of British Columbia, Vancouver V6T 1Z2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738594" target="_blank"〉PubMed〈/a〉

Description: As climate change unfolds, weather systems in the United States have been shifting in patterns that vary across regions and seasons. Climate science research typically assesses these changes by examining individual weather indicators, such as temperature or precipitation, in isolation, and averaging their values across the spatial surface. As a result, little is known about population exposure to changes in weather and how people experience and evaluate these changes considered together. Here we show that in the United States from 1974 to 2013, the weather conditions experienced by the vast majority of the population improved. Using previous research on how weather affects local population growth to develop an index of people's weather preferences, we find that 80% of Americans live in counties that are experiencing more pleasant weather than they did four decades ago. Virtually all Americans are now experiencing the much milder winters that they typically prefer, and these mild winters have not been offset by markedly more uncomfortable summers or other negative changes. Climate change models predict that this trend is temporary, however, because US summers will eventually warm more than winters. Under a scenario in which greenhouse gas emissions proceed at an unabated rate (Representative Concentration Pathway 8.5), we estimate that 88% of the US public will experience weather at the end of the century that is less preferable than weather in the recent past. Our results have implications for the public's understanding of the climate change problem, which is shaped in part by experiences with local weather. Whereas weather patterns in recent decades have served as a poor source of motivation for Americans to demand a policy response to climate change, public concern may rise once people's everyday experiences of climate change effects start to become less pleasant.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Egan, Patrick J -- Mullin, Megan -- England -- Nature. 2016 Apr 21;532(7599):357-60.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127821" target="_blank"〉PubMed〈/a〉

Description: The human sigma1 receptor is an enigmatic endoplasmic-reticulum-resident transmembrane protein implicated in a variety of disorders including depression, drug addiction, and neuropathic pain. Recently, an additional connection to amyotrophic lateral sclerosis has emerged from studies of human genetics and mouse models. Unlike many transmembrane receptors that belong to large, extensively studied families such as G-protein-coupled receptors or ligand-gated ion channels, the sigma1 receptor is an evolutionary isolate with no discernible similarity to any other human protein. Despite its increasingly clear importance in human physiology and disease, the molecular architecture of the sigma1 receptor and its regulation by drug-like compounds remain poorly defined. Here we report crystal structures of the human sigma1 receptor in complex with two chemically divergent ligands, PD144418 and 4-IBP. The structures reveal a trimeric architecture with a single transmembrane domain in each protomer. The carboxy-terminal domain of the receptor shows an extensive flat, hydrophobic membrane-proximal surface, suggesting an intimate association with the cytosolic surface of the endoplasmic reticulum membrane in cells. This domain includes a cupin-like beta-barrel with the ligand-binding site buried at its centre. This large, hydrophobic ligand-binding cavity shows remarkable plasticity in ligand recognition, binding the two ligands in similar positions despite dissimilar chemical structures. Taken together, these results reveal the overall architecture, oligomerization state, and molecular basis for ligand recognition by this important but poorly understood protein.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Hayden R -- Zheng, Sanduo -- Gurpinar, Esin -- Koehl, Antoine -- Manglik, Aashish -- Kruse, Andrew C -- T32GM007226/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 28;532(7600):527-30. doi: 10.1038/nature17391. Epub 2016 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27042935" target="_blank"〉PubMed〈/a〉

Description: The identification of properties that contribute to the persistence and resilience of ecosystems despite climate change constitutes a research priority of global relevance. Here we present a novel, empirical approach to assess the relative sensitivity of ecosystems to climate variability, one property of resilience that builds on theoretical modelling work recognizing that systems closer to critical thresholds respond more sensitively to external perturbations. We develop a new metric, the vegetation sensitivity index, that identifies areas sensitive to climate variability over the past 14 years. The metric uses time series data derived from the moderate-resolution imaging spectroradiometer (MODIS) enhanced vegetation index, and three climatic variables that drive vegetation productivity (air temperature, water availability and cloud cover). Underlying the analysis is an autoregressive modelling approach used to identify climate drivers of vegetation productivity on monthly timescales, in addition to regions with memory effects and reduced response rates to external forcing. We find ecologically sensitive regions with amplified responses to climate variability in the Arctic tundra, parts of the boreal forest belt, the tropical rainforest, alpine regions worldwide, steppe and prairie regions of central Asia and North and South America, the Caatinga deciduous forest in eastern South America, and eastern areas of Australia. Our study provides a quantitative methodology for assessing the relative response rate of ecosystems--be they natural or with a strong anthropogenic signature--to environmental variability, which is the first step towards addressing why some regions appear to be more sensitive than others, and what impact this has on the resilience of ecosystem service provision and human well-being.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seddon, Alistair W R -- Macias-Fauria, Marc -- Long, Peter R -- Benz, David -- Willis, Kathy J -- England -- Nature. 2016 Mar 10;531(7593):229-32. doi: 10.1038/nature16986. Epub 2016 Feb 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, University of Bergen, Allegaten 41, N-500 Bergen, Norway. ; School of Geography and the Environment, South Parks Road, University of Oxford, Oxford OX1 3QY, UK. ; Long-Term Ecology Laboratory, Biodiversity Institute, Oxford Martin School, Department of Zoology, South Parks Road, University of Oxford, Oxford OX1 3PS, UK. ; Royal Botanic Gardens, Kew, Richmond, Surrey TW9 3AB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26886790" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Mar 10;531(7593):139. doi: 10.1038/531139a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961619" target="_blank"〉PubMed〈/a〉

Description: Hydrophobic signal sequences target secretory polypeptides to a protein-conducting channel formed by a heterotrimeric membrane protein complex, the prokaryotic SecY or eukaryotic Sec61 complex. How signal sequences are recognized is poorly understood, particularly because they are diverse in sequence and length. Structures of the inactive channel show that the largest subunit, SecY or Sec61alpha, consists of two halves that form an hourglass-shaped pore with a constriction in the middle of the membrane and a lateral gate that faces lipid. The cytoplasmic funnel is empty, while the extracellular funnel is filled with a plug domain. In bacteria, the SecY channel associates with the translating ribosome in co-translational translocation, and with the SecA ATPase in post-translational translocation. How a translocating polypeptide inserts into the channel is uncertain, as cryo-electron microscopy structures of the active channel have a relatively low resolution (~10 A) or are of insufficient quality. Here we report a crystal structure of the active channel, assembled from SecY complex, the SecA ATPase, and a segment of a secretory protein fused into SecA. The translocating protein segment inserts into the channel as a loop, displacing the plug domain. The hydrophobic core of the signal sequence forms a helix that sits in a groove outside the lateral gate, while the following polypeptide segment intercalates into the gate. The carboxy (C)-terminal section of the polypeptide loop is located in the channel, surrounded by residues of the pore ring. Thus, during translocation, the hydrophobic segments of signal sequences, and probably bilayer-spanning domains of nascent membrane proteins, exit the lateral gate and dock at a specific site that faces the lipid phase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855518/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855518/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Long -- Park, Eunyong -- Ling, JingJing -- Ingram, Jessica -- Ploegh, Hidde -- Rapoport, Tom A -- GM052586/GM/NIGMS NIH HHS/ -- R01 GM052586/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 17;531(7594):395-9. doi: 10.1038/nature17163. Epub 2016 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Harvard Medical School, Department of Cell Biology, 240 Longwood Avenue, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26950603" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Evans Ogden, Lesley -- England -- Nature. 2016 May 5;533(7601):26-8. doi: 10.1038/533026a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147016" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Mar 3;531(7592):7-8. doi: 10.1038/531007b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935658" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sherkow, Jacob S -- England -- Nature. 2016 Apr 14;532(7598):172-3. doi: 10.1038/532172a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Innovation Center for Law and Technology, New York Law School, New York, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075081" target="_blank"〉PubMed〈/a〉

Description: Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behaviour and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes. A fundamental knowledge gap exists, however, between circadian gene expression cycles and the biochemical mechanisms that ultimately facilitate circadian regulation of cell biology. Here we report circadian rhythms in the intracellular concentration of magnesium ions, [Mg(2+)]i, which act as a cell-autonomous timekeeping component to determine key clock properties both in a human cell line and in a unicellular alga that diverged from each other more than 1 billion years ago. Given the essential role of Mg(2+) as a cofactor for ATP, a functional consequence of [Mg(2+)]i oscillations is dynamic regulation of cellular energy expenditure over the daily cycle. Mechanistically, we find that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression. The global regulation of nucleotide triphosphate turnover by intracellular Mg(2+) availability has potential to impact upon many of the cell's more than 600 MgATP-dependent enzymes and every cellular system where MgNTP hydrolysis becomes rate limiting. Indeed, we find that circadian control of translation by mTOR is regulated through [Mg(2+)]i oscillations. It will now be important to identify which additional biological processes are subject to this form of regulation in tissues of multicellular organisms such as plants and humans, in the context of health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feeney, Kevin A -- Hansen, Louise L -- Putker, Marrit -- Olivares-Yanez, Consuelo -- Day, Jason -- Eades, Lorna J -- Larrondo, Luis F -- Hoyle, Nathaniel P -- O'Neill, John S -- van Ooijen, Gerben -- 093734/Z/10/Z/Wellcome Trust/United Kingdom -- MC_UP_1201/4/Medical Research Council/United Kingdom -- England -- Nature. 2016 Apr 21;532(7599):375-9. doi: 10.1038/nature17407. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory for Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; School of Biological Sciences, University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, UK. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Earth Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EQ, UK. ; School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074515" target="_blank"〉PubMed〈/a〉

Description: Lymphoid tissue is a key reservoir established by HIV-1 during acute infection. It is a site associated with viral production, storage of viral particles in immune complexes, and viral persistence. Although combinations of antiretroviral drugs usually suppress viral replication and reduce viral RNA to undetectable levels in blood, it is unclear whether treatment fully suppresses viral replication in lymphoid tissue reservoirs. Here we show that virus evolution and trafficking between tissue compartments continues in patients with undetectable levels of virus in their bloodstream. We present a spatial and dynamic model of persistent viral replication and spread that indicates why the development of drug resistance is not a foregone conclusion under conditions in which drug concentrations are insufficient to completely block virus replication. These data provide new insights into the evolutionary and infection dynamics of the virus population within the host, revealing that HIV-1 can continue to replicate and replenish the viral reservoir despite potent antiretroviral therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lorenzo-Redondo, Ramon -- Fryer, Helen R -- Bedford, Trevor -- Kim, Eun-Young -- Archer, John -- Kosakovsky Pond, Sergei L -- Chung, Yoon-Seok -- Penugonda, Sudhir -- Chipman, Jeffrey G -- Fletcher, Courtney V -- Schacker, Timothy W -- Malim, Michael H -- Rambaut, Andrew -- Haase, Ashley T -- McLean, Angela R -- Wolinsky, Steven M -- AI1074340/AI/NIAID NIH HHS/ -- DA033773/DA/NIDA NIH HHS/ -- G1000196/Medical Research Council/United Kingdom -- GM110749/GM/NIGMS NIH HHS/ -- R01 DA033773/DA/NIDA NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2016 Feb 4;530(7588):51-6. doi: 10.1038/nature16933. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60011, USA. ; Institute for Emerging Infections, Department of Zoology, University of Oxford, Oxford, OX1 3PS, UK. ; Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Centro de Investigacao em Biodiversidade e Recursos Geneticos Universidade do Porto, 4485-661 Vairao, Portugal. ; Department of Medicine, University of California, San Diego, California 92093, USA. ; Division of AIDS, Center for Immunology and Pathology, Korea National Institutes of Health, Chungju-si, Chungcheongbuk-do, 28159, South Korea. ; Department of Surgery, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Antiviral Pharmacology Laboratory, University of Nebraska Medical Center, College of Pharmacy, Omaha, Nebraska 68198, USA. ; Division of Infectious Diseases, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Department of Infectious Diseases, King's College London, Guy's Hospital, London SE21 7DN, UK. ; Centre for Immunology, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3FL, UK. ; Department of Microbiology, University of Minnesota, Minneapolis, Minnesota 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814962" target="_blank"〉PubMed〈/a〉

Description: Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stanley, Sarah A -- Kelly, Leah -- Latcha, Kaamashri N -- Schmidt, Sarah F -- Yu, Xiaofei -- Nectow, Alexander R -- Sauer, Jeremy -- Dyke, Jonathan P -- Dordick, Jonathan S -- Friedman, Jeffrey M -- GM067545/GM/NIGMS NIH HHS/ -- GM095654/GM/NIGMS NIH HHS/ -- MH105941/MH/NIMH NIH HHS/ -- U01 MH105941/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 31;531(7596):647-50. doi: 10.1038/nature17183. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10065, USA. ; Department of Chemical &Biological Engineering, Center for Biotechnology &Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA. ; Department of Radiology, Weill Cornell Medical College, New York, New York 10065, USA. ; Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007848" target="_blank"〉PubMed〈/a〉

Description: Despite the success of potent anti-retroviral drugs in controlling human immunodeficiency virus type 1 (HIV-1) infection, little progress has been made in generating an effective HIV-1 vaccine. Although passive transfer of anti-HIV-1 broadly neutralizing antibodies can protect mice or macaques against a single high-dose challenge with HIV or simian/human (SIV/HIV) chimaeric viruses (SHIVs) respectively, the long-term efficacy of a passive antibody transfer approach for HIV-1 has not been examined. Here we show, on the basis of the relatively long-term protection conferred by hepatitis A immune globulin, the efficacy of a single injection (20 mg kg(-1)) of four anti-HIV-1-neutralizing monoclonal antibodies (VRC01, VRC01-LS, 3BNC117, and 10-1074 (refs 9 - 12)) in blocking repeated weekly low-dose virus challenges of the clade B SHIVAD8. Compared with control animals, which required two to six challenges (median = 3) for infection, a single broadly neutralizing antibody infusion prevented virus acquisition for up to 23 weekly challenges. This effect depended on antibody potency and half-life. The highest levels of plasma-neutralizing activity and, correspondingly, the longest protection were found in monkeys administered the more potent antibodies 3BNC117 and 10-1074 (median = 13 and 12.5 weeks, respectively). VRC01, which showed lower plasma-neutralizing activity, protected for a shorter time (median = 8 weeks). The introduction of a mutation that extends antibody half-life into the crystallizable fragment (Fc) domain of VRC01 increased median protection from 8 to 14.5 weeks. If administered to populations at high risk of HIV-1 transmission, such an immunoprophylaxis regimen could have a major impact on virus transmission.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gautam, Rajeev -- Nishimura, Yoshiaki -- Pegu, Amarendra -- Nason, Martha C -- Klein, Florian -- Gazumyan, Anna -- Golijanin, Jovana -- Buckler-White, Alicia -- Sadjadpour, Reza -- Wang, Keyun -- Mankoff, Zachary -- Schmidt, Stephen D -- Lifson, Jeffrey D -- Mascola, John R -- Nussenzweig, Michel C -- Martin, Malcolm A -- AI-100148/AI/NIAID NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- UM1 AI100663-01/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):105-9. doi: 10.1038/nature17677. Epub 2016 Apr 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Biostatistics Research Branch, Division of Clinical Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA. ; Laboratory of Experimental Immunology, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. ; AIDS and Cancer Virus Program, Leidos Biomedical Research, Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27120156" target="_blank"〉PubMed〈/a〉

Description: Homo floresiensis, a primitive hominin species discovered in Late Pleistocene sediments at Liang Bua (Flores, Indonesia), has generated wide interest and scientific debate. A major reason this taxon is controversial is because the H. floresiensis-bearing deposits, which include associated stone artefacts and remains of other extinct endemic fauna, were dated to between about 95 and 12 thousand calendar years (kyr) ago. These ages suggested that H. floresiensis survived until long after modern humans reached Australia by ~50 kyr ago. Here we report new stratigraphic and chronological evidence from Liang Bua that does not support the ages inferred previously for the H. floresiensis holotype (LB1), ~18 thousand calibrated radiocarbon years before present (kyr cal. BP), or the time of last appearance of this species (about 17 or 13-11 kyr cal. BP). Instead, the skeletal remains of H. floresiensis and the deposits containing them are dated to between about 100 and 60 kyr ago, whereas stone artefacts attributable to this species range from about 190 to 50 kyr in age. Whether H. floresiensis survived after 50 kyr ago--potentially encountering modern humans on Flores or other hominins dispersing through southeast Asia, such as Denisovans--is an open question.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sutikna, Thomas -- Tocheri, Matthew W -- Morwood, Michael J -- Saptomo, E Wahyu -- Jatmiko -- Awe, Rokus Due -- Wasisto, Sri -- Westaway, Kira E -- Aubert, Maxime -- Li, Bo -- Zhao, Jian-xin -- Storey, Michael -- Alloway, Brent V -- Morley, Mike W -- Meijer, Hanneke J M -- van den Bergh, Gerrit D -- Grun, Rainer -- Dosseto, Anthony -- Brumm, Adam -- Jungers, William L -- Roberts, Richard G -- England -- Nature. 2016 Apr 21;532(7599):366-9. doi: 10.1038/nature17179. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Archaeological Science, School of Earth and Environmental Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia. ; Pusat Penelitian Arkeologi Nasional, Jakarta 12510, Indonesia. ; Department of Anthropology, Lakehead University, Thunder Bay, Ontario P7B 5E1, Canada. ; Human Origins Program, Department of Anthropology, National Museum of Natural History, Smithsonian Institution, Washington DC 20013, USA. ; Traps MQ Luminescence Dating Facility, Department of Environmental Sciences, Macquarie University, Sydney, New South Wales 2109, Australia. ; Research Centre for Human Evolution, Place, Evolution and Rock Art Heritage Unit, Griffith University, Gold Coast, Queensland 4222, Australia. ; School of Earth and Environmental Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia. ; School of Earth Sciences, University of Queensland, Brisbane, Queensland 4072, Australia. ; QUADLAB, Section of Earth and Planetary System Science, Natural History Museum of Denmark, 1350 Copenhagen, Denmark. ; School of Geography, Environment and Earth Sciences, Victoria University of Wellington, Wellington 6012, New Zealand. ; Department of Natural History, University Museum of Bergen, University of Bergen, 5007 Bergen, Norway. ; Research Centre for Human Evolution, Environmental Futures Research Institute, Griffith University, Brisbane, Queensland 4111, Australia. ; Research School of Earth Sciences, Australian National University, Canberra, Australian Capital Territory 0200, Australia. ; GeoQuEST Research Centre, School of Earth and Environmental Sciences, University of Wollongong, Wollongong, New South Wales 2522, Australia. ; Department of Anatomical Sciences, Stony Brook University Medical Center, Stony Brook, New York 11794, USA. ; Association Vahatra, BP 3972, Antananarivo 101, Madagascar.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027286" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- Powell, Kendall -- England -- Nature. 2016 Feb 18;530(7590):265. doi: 10.1038/530265a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887471" target="_blank"〉PubMed〈/a〉

Description: Controlling dropwise condensation is fundamental to water-harvesting systems, desalination, thermal power generation, air conditioning, distillation towers, and numerous other applications. For any of these, it is essential to design surfaces that enable droplets to grow rapidly and to be shed as quickly as possible. However, approaches based on microscale, nanoscale or molecular-scale textures suffer from intrinsic trade-offs that make it difficult to optimize both growth and transport at once. Here we present a conceptually different design approach--based on principles derived from Namib desert beetles, cacti, and pitcher plants--that synergistically combines these aspects of condensation and substantially outperforms other synthetic surfaces. Inspired by an unconventional interpretation of the role of the beetle's bumpy surface geometry in promoting condensation, and using theoretical modelling, we show how to maximize vapour diffusion fluxat the apex of convex millimetric bumps by optimizing the radius of curvature and cross-sectional shape. Integrating this apex geometry with a widening slope, analogous to cactus spines, directly couples facilitated droplet growth with fast directional transport, by creating a free-energy profile that drives the droplet down the slope before its growth rate can decrease. This coupling is further enhanced by a slippery, pitcher-plant-inspired nanocoating that facilitates feedback between coalescence-driven growth and capillary-driven motion on the way down. Bumps that are rationally designed to integrate these mechanisms are able to grow and transport large droplets even against gravity and overcome the effect of an unfavourable temperature gradient. We further observe an unprecedented sixfold-higher exponent of growth rate, faster onset, higher steady-state turnover rate, and a greater volume of water collected compared to other surfaces. We envision that this fundamental understanding and rational design strategy can be applied to a wide range of water-harvesting and phase-change heat-transfer applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Kyoo-Chul -- Kim, Philseok -- Grinthal, Alison -- He, Neil -- Fox, David -- Weaver, James C -- Aizenberg, Joanna -- England -- Nature. 2016 Mar 3;531(7592):78-82. doi: 10.1038/nature16956. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, USA. ; Wyss Institute for Biologically Inspired Engineering, Harvard University, Cambridge, Massachusetts, USA. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909575" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2016 Mar 3;531(7592):15-6. doi: 10.1038/531015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935673" target="_blank"〉PubMed〈/a〉

Description: The cullin-RING ubiquitin E3 ligase (CRL) family comprises over 200 members in humans. The COP9 signalosome complex (CSN) regulates CRLs by removing their ubiquitin-like activator NEDD8. The CUL4A-RBX1-DDB1-DDB2 complex (CRL4A(DDB2)) monitors the genome for ultraviolet-light-induced DNA damage. CRL4A(DBB2) is inactive in the absence of damaged DNA and requires CSN to regulate the repair process. The structural basis of CSN binding to CRL4A(DDB2) and the principles of CSN activation are poorly understood. Here we present cryo-electron microscopy structures for CSN in complex with neddylated CRL4A ligases to 6.4 A resolution. The CSN conformers defined by cryo-electron microscopy and a novel apo-CSN crystal structure indicate an induced-fit mechanism that drives CSN activation by neddylated CRLs. We find that CSN and a substrate cannot bind simultaneously to CRL4A, favouring a deneddylated, inactive state for substrate-free CRL4 complexes. These architectural and regulatory principles appear conserved across CRL families, allowing global regulation by CSN.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cavadini, Simone -- Fischer, Eric S -- Bunker, Richard D -- Potenza, Alessandro -- Lingaraju, Gondichatnahalli M -- Goldie, Kenneth N -- Mohamed, Weaam I -- Faty, Mahamadou -- Petzold, Georg -- Beckwith, Rohan E J -- Tichkule, Ritesh B -- Hassiepen, Ulrich -- Abdulrahman, Wassim -- Pantelic, Radosav S -- Matsumoto, Syota -- Sugasawa, Kaoru -- Stahlberg, Henning -- Thoma, Nicolas H -- England -- Nature. 2016 Mar 31;531(7596):598-603. doi: 10.1038/nature17416.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, 4003 Basel, Switzerland. ; Department of Cancer Biology, Dana-Farber Cancer Institute, LC-4312, 360 Longwood Avenue, Boston, Massachusetts 02215, USA. ; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Center for Cellular Imaging and NanoAnalytics, Biozentrum, University of Basel, 4058 Basel, Switzerland. ; Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; Novartis Pharma AG, Institutes for Biomedical Research, Novartis Campus, 4056 Basel, Switzerland. ; Gatan R&D, 5974 W. Las Positas Boulevard, Pleasanton, California 94588, USA. ; Biosignal Research Center, Organization of Advanced Science and Technology, Kobe University, Kobe 657-8501, Japan. ; Graduate School of Science, Kobe University, Kobe, 657-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029275" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Check Hayden, Erika -- England -- Nature. 2016 Feb 11;530(7589):142-3. doi: 10.1038/530142a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863963" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Woolston, Chris -- England -- Nature. 2016 Mar 24;531(7595):539-41.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27014783" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karve, Shraddha Madhav -- Mangalam, Madhur -- England -- Nature. 2016 Mar 17;531(7594):305. doi: 10.1038/531305d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Indian Institute of Science Education and Research, Pune, India. ; University of Georgia, Athens, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26983529" target="_blank"〉PubMed〈/a〉

Description: The p53 pro-apoptotic tumour suppressor is mutated or functionally altered in most cancers. In epithelial tumours induced by 'high-risk' mucosal human papilloma viruses, including human cervical carcinoma and a growing number of head-and-neck cancers, p53 is degraded by the viral oncoprotein E6 (ref. 2). In this process, E6 binds to a short leucine (L)-rich LxxLL consensus sequence within the cellular ubiquitin ligase E6AP. Subsequently, the E6/E6AP heterodimer recruits and degrades p53 (ref. 4). Neither E6 nor E6AP are separately able to recruit p53 (refs 3, 5), and the precise mode of assembly of E6, E6AP and p53 is unknown. Here we solve the crystal structure of a ternary complex comprising full-length human papilloma virus type 16 (HPV-16) E6, the LxxLL motif of E6AP and the core domain of p53. The LxxLL motif of E6AP renders the conformation of E6 competent for interaction with p53 by structuring a p53-binding cleft on E6. Mutagenesis of critical positions at the E6-p53 interface disrupts p53 degradation. The E6-binding site of p53 is distal from previously described DNA- and protein-binding surfaces of the core domain. This suggests that, in principle, E6 may avoid competition with cellular factors by targeting both free and bound p53 molecules. The E6/E6AP/p53 complex represents a prototype of viral hijacking of both the ubiquitin-mediated protein degradation pathway and the p53 tumour suppressor pathway. The present structure provides a framework for the design of inhibitory therapeutic strategies against oncogenesis mediated by human papilloma virus.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez-Zapien, Denise -- Ruiz, Francesc Xavier -- Poirson, Juline -- Mitschler, Andre -- Ramirez, Juan -- Forster, Anne -- Cousido-Siah, Alexandra -- Masson, Murielle -- Vande Pol, Scott -- Podjarny, Alberto -- Trave, Gilles -- Zanier, Katia -- R01CA134737/CA/NCI NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):541-5. doi: 10.1038/nature16481. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Equipe labellisee Ligue, Biotechnologie et signalisation cellulaire UMR 7242, Ecole Superieure de Biotechnologie de Strasbourg, Boulevard Sebastien Brant, BP 10413, F-67412 Illkirch, France. ; Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC)/INSERM U964/CNRS UMR 7104/Universite de Strasbourg, 1 rue Laurent Fries, BP 10142, F-67404 Illkirch, France. ; Department of Pathology, University of Virginia, PO Box 800904, Charlottesville, Virginia 22908-0904, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789255" target="_blank"〉PubMed〈/a〉

Description: Land-use change occurs nowhere more rapidly than in the tropics, where the imbalance between deforestation and forest regrowth has large consequences for the global carbon cycle. However, considerable uncertainty remains about the rate of biomass recovery in secondary forests, and how these rates are influenced by climate, landscape, and prior land use. Here we analyse aboveground biomass recovery during secondary succession in 45 forest sites and about 1,500 forest plots covering the major environmental gradients in the Neotropics. The studied secondary forests are highly productive and resilient. Aboveground biomass recovery after 20 years was on average 122 megagrams per hectare (Mg ha(-1)), corresponding to a net carbon uptake of 3.05 Mg C ha(-1) yr(-1), 11 times the uptake rate of old-growth forests. Aboveground biomass stocks took a median time of 66 years to recover to 90% of old-growth values. Aboveground biomass recovery after 20 years varied 11.3-fold (from 20 to 225 Mg ha(-1)) across sites, and this recovery increased with water availability (higher local rainfall and lower climatic water deficit). We present a biomass recovery map of Latin America, which illustrates geographical and climatic variation in carbon sequestration potential during forest regrowth. The map will support policies to minimize forest loss in areas where biomass resilience is naturally low (such as seasonally dry forest regions) and promote forest regeneration and restoration in humid tropical lowland areas with high biomass resilience.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poorter, Lourens -- Bongers, Frans -- Aide, T Mitchell -- Almeyda Zambrano, Angelica M -- Balvanera, Patricia -- Becknell, Justin M -- Boukili, Vanessa -- Brancalion, Pedro H S -- Broadbent, Eben N -- Chazdon, Robin L -- Craven, Dylan -- de Almeida-Cortez, Jarcilene S -- Cabral, George A L -- de Jong, Ben H J -- Denslow, Julie S -- Dent, Daisy H -- DeWalt, Saara J -- Dupuy, Juan M -- Duran, Sandra M -- Espirito-Santo, Mario M -- Fandino, Maria C -- Cesar, Ricardo G -- Hall, Jefferson S -- Hernandez-Stefanoni, Jose Luis -- Jakovac, Catarina C -- Junqueira, Andre B -- Kennard, Deborah -- Letcher, Susan G -- Licona, Juan-Carlos -- Lohbeck, Madelon -- Marin-Spiotta, Erika -- Martinez-Ramos, Miguel -- Massoca, Paulo -- Meave, Jorge A -- Mesquita, Rita -- Mora, Francisco -- Munoz, Rodrigo -- Muscarella, Robert -- Nunes, Yule R F -- Ochoa-Gaona, Susana -- de Oliveira, Alexandre A -- Orihuela-Belmonte, Edith -- Pena-Claros, Marielos -- Perez-Garcia, Eduardo A -- Piotto, Daniel -- Powers, Jennifer S -- Rodriguez-Velazquez, Jorge -- Romero-Perez, I Eunice -- Ruiz, Jorge -- Saldarriaga, Juan G -- Sanchez-Azofeifa, Arturo -- Schwartz, Naomi B -- Steininger, Marc K -- Swenson, Nathan G -- Toledo, Marisol -- Uriarte, Maria -- van Breugel, Michiel -- van der Wal, Hans -- Veloso, Maria D M -- Vester, Hans F M -- Vicentini, Alberto -- Vieira, Ima C G -- Bentos, Tony Vizcarra -- Williamson, G Bruce -- Rozendaal, Danae M A -- England -- Nature. 2016 Feb 11;530(7589):211-4. doi: 10.1038/nature16512. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Forest Ecology and Forest Management Group, Wageningen University, PO Box 47, 6700 AA Wageningen, The Netherlands. ; PO Box 23360, Department of Biology, University of Puerto Rico, San Juan, PR 00931-3360, Puerto Rico. ; Spatial Ecology and Conservation Lab, Department of Geography, University of Alabama, Tuscaloosa, Alabama 35487, USA. ; Instituto de Investigaciones en Ecosistemas y Sustentabilidad, Universidad Nacional Autonoma de Mexico, CP58190, Morelia, Michoacan, Mexico. ; Department of Ecology and Evolutionary Biology, Brown University, Providence, Rhode Island 02912, USA. ; Department of Ecology and Evolutionary Biology, University of Connecticut, Storrs, Connecticut 06269, USA. ; Department of Forest Sciences, Luiz de Queiroz College of Agriculture, University of Sao Paulo, Avenida Padua Dias 11, 13418-900, Piracicaba, Sao Paulo, Brazil. ; SI ForestGEO, Smithsonian Tropical Research Institute, Roosevelt Avenue, Tupper Building - 401, Balboa, Ancon, Panama, Panama ; German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig, Deutscher Platz 5e, 04103 Leipzig, Germany. ; Institute for Biology, Leipzig University, Johannisallee 21, 04103 Leipzig, Germany. ; Departamento de Botanica, Universidade Federal de Pernambuco, Pernambuco, CEP 50670-901, Brazil. ; Department of Sustainability Science, El Colegio de la Frontera Sur, Unidad Campeche, Av. Rancho Poligono 2A, Parque Industrial Lerma, Campeche, Campeche, CP 24500, Mexico. ; Department of Ecology and Evolutionary Biology, Tulane University, New Orleans, Louisiana 70130, USA. ; Smithsonian Tropical Research Institute, Roosevelt Avenue, Tupper Building - 401, Balboa, Ancon, Panama, Panama ; Biological and Environmental Sciences, University of Stirling, Stirling FK9 4LA, UK. ; Department of Biological Sciences, Clemson University, 132 Long Hall, Clemson, South Carolina 29634, USA. ; Centro de Investigacion Cientifica de Yucatan, AC, Unidad de Recursos Naturales, Calle 43 No. 130, Colonia Chuburna de Hidalgo, CP 97200, Merida, Yucatan, Mexico. ; Earth and Atmospheric Sciences Department, University of Alberta, Edmonton, Alberta T6G 2E3, Canada. ; Departamento de Biologia Geral, Universidade Estadual de Montes Claros, Montes Claros, Minas Gerais, CEP 39401-089, Brazil. ; Fondo Patrimonio Natural para la Biodiversidad y Areas Protegidas, Calle 72 No. 12-65 piso 6, Bogota, Colombia. ; Biological Dynamics of Forest Fragments Project, Environmental Dynamics Research Coordination, Instituto Nacional de Pesquisas da Amazonia, Manaus, Amazonas, CEP 69067-375, Brazil. ; Centre for Crop Systems Analysis, Wageningen University, PO Box 430, 6700 AK Wageningen, The Netherlands. ; Knowledge, Technology and Innovation Group, Wageningen University, PO Box 8130, 6700 EW Wageningen, The Netherlands. ; Coordenacao de Tecnologia e Inovacao, Instituto Nacional de Pesquisas da Amazonia, Avenida Andre Araujo, 2936 - Aleixo, 69060-001 Manaus, Brazil. ; Department of Physical and Environmental Sciences, Colorado Mesa University, 1100 North Avenue, Grand Junction, Colorado 81501, USA. ; Department of Environmental Studies, Purchase College (State University of New York), Purchase, New York 10577, USA. ; Instituto Boliviano de Investigacion Forestal (IBIF), FCA-UAGRM, Casilla 6204, Santa Cruz de la Sierra, Bolivia. ; World Agroforestry Centre (ICRAF), PO Box 30677 - 00100, Nairobi, Kenya. ; Department of Geography, University of Wisconsin-Madison, 550 North Park Street, Madison, Wisconsin 53706, USA. ; Departamento de Ecologia y Recursos Naturales, Facultad de Ciencias, Universidad Nacional Autonoma de Mexico, Mexico 04510 DF, Mexico. ; Department of Ecology, Evolution and Environmental Biology, Columbia University, New York, New York 10027, USA. ; Section of Ecoinformatics and Biodiversity, Department of Bioscience, Aarhus University, Aarhus 8000, Denmark. ; Departamento de Ecologia, Instituto de Biociencias, Universidade de Sao Paulo, Rua do Matao, travessa 14, No. 321, Sao Paulo, CEP 05508-090, Brazil. ; Universidade Federal do Sul da Bahia, Centro de Formacao em Ciencias Agroflorestais, Itabuna-BA, 45613-204, Brazil. ; Department of Ecology, Evolution, &Behavior, University of Minnesota, Saint Paul, Minnesota 55108, USA. ; Department of Plant Biology, University of Minnesota, Saint Paul, Minnesota 55108, USA. ; School of Social Sciences, Geography Area, Universidad Pedagogica y Tecnologica de Colombia (UPTC), Tunja, Colombia. ; Department of Geography, 4841 Ellison Hall, University of California, Santa Barbara, California 93106, USA. ; Department of Biology, University of Maryland, College Park, Maryland 20742, USA. ; Yale-NUS College, 12 College Avenue West, Singapore 138610. ; Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore 11754. ; Departamento de Agricultura, Sociedad y Ambiente, El Colegio de la Frontera Sur - Unidad Villahermosa, 86280 Centro, Tabasco, Mexico. ; Institute for Biodiversity and Ecosystem Dynamics (IBED), University of Amsterdam, PO Box 94248, 1090 GE Amsterdam, The Netherlands. ; Bonhoeffer College, Bruggertstraat 60, 7545 AX Enschede, The Netherlands. ; Museu Paraense Emilio Goeldi, CP 399, CEP 66040-170, Belem, Brazil. ; Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana 70803-1705, USA. ; Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan S4S 0A2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840632" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Powell, Kendall -- England -- Nature. 2016 Feb 11;530(7589):148-51. doi: 10.1038/530148a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863966" target="_blank"〉PubMed〈/a〉

Description: Two-pore channels (TPCs) comprise a subfamily (TPC1-3) of eukaryotic voltage- and ligand-gated cation channels with two non-equivalent tandem pore-forming subunits that dimerize to form quasi-tetramers. Found in vacuolar or endolysosomal membranes, they regulate the conductance of sodium and calcium ions, intravesicular pH, trafficking and excitability. TPCs are activated by a decrease in transmembrane potential and an increase in cytosolic calcium concentrations, are inhibited by low luminal pH and calcium, and are regulated by phosphorylation. Here we report the crystal structure of TPC1 from Arabidopsis thaliana at 2.87 A resolution as a basis for understanding ion permeation, channel activation, the location of voltage-sensing domains and regulatory ion-binding sites. We determined sites of phosphorylation in the amino-terminal and carboxy-terminal domains that are positioned to allosterically modulate cytoplasmic Ca(2+) activation. One of the two voltage-sensing domains (VSD2) encodes voltage sensitivity and inhibition by luminal Ca(2+) and adopts a conformation distinct from the activated state observed in structures of other voltage-gated ion channels. The structure shows that potent pharmacophore trans-Ned-19 (ref. 17) acts allosterically by clamping the pore domains to VSD2. In animals, Ned-19 prevents infection by Ebola virus and other filoviruses, presumably by altering their fusion with the endolysosome and delivery of their contents into the cytoplasm.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863712/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863712/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kintzer, Alexander F -- Stroud, Robert M -- GM24485/GM/NIGMS NIH HHS/ -- P41-GM103311/GM/NIGMS NIH HHS/ -- P41-RR001614/RR/NCRR NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- R37 GM024485/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 10;531(7593):258-62. doi: 10.1038/nature17194.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961658" target="_blank"〉PubMed〈/a〉

Description: The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 x 10(-3) and 1.42 x 10(-3) mutations per site per year. This is equivalent to 16-27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15-60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quick, Joshua -- Loman, Nicholas J -- Duraffour, Sophie -- Simpson, Jared T -- Severi, Ettore -- Cowley, Lauren -- Bore, Joseph Akoi -- Koundouno, Raymond -- Dudas, Gytis -- Mikhail, Amy -- Ouedraogo, Nobila -- Afrough, Babak -- Bah, Amadou -- Baum, Jonathan H J -- Becker-Ziaja, Beate -- Boettcher, Jan Peter -- Cabeza-Cabrerizo, Mar -- Camino-Sanchez, Alvaro -- Carter, Lisa L -- Doerrbecker, Juliane -- Enkirch, Theresa -- Garcia-Dorival, Isabel -- Hetzelt, Nicole -- Hinzmann, Julia -- Holm, Tobias -- Kafetzopoulou, Liana Eleni -- Koropogui, Michel -- Kosgey, Abigael -- Kuisma, Eeva -- Logue, Christopher H -- Mazzarelli, Antonio -- Meisel, Sarah -- Mertens, Marc -- Michel, Janine -- Ngabo, Didier -- Nitzsche, Katja -- Pallasch, Elisa -- Patrono, Livia Victoria -- Portmann, Jasmine -- Repits, Johanna Gabriella -- Rickett, Natasha Y -- Sachse, Andreas -- Singethan, Katrin -- Vitoriano, Ines -- Yemanaberhan, Rahel L -- Zekeng, Elsa G -- Racine, Trina -- Bello, Alexander -- Sall, Amadou Alpha -- Faye, Ousmane -- Faye, Oumar -- Magassouba, N'Faly -- Williams, Cecelia V -- Amburgey, Victoria -- Winona, Linda -- Davis, Emily -- Gerlach, Jon -- Washington, Frank -- Monteil, Vanessa -- Jourdain, Marine -- Bererd, Marion -- Camara, Alimou -- Somlare, Hermann -- Camara, Abdoulaye -- Gerard, Marianne -- Bado, Guillaume -- Baillet, Bernard -- Delaune, Deborah -- Nebie, Koumpingnin Yacouba -- Diarra, Abdoulaye -- Savane, Yacouba -- Pallawo, Raymond Bernard -- Gutierrez, Giovanna Jaramillo -- Milhano, Natacha -- Roger, Isabelle -- Williams, Christopher J -- Yattara, Facinet -- Lewandowski, Kuiama -- Taylor, James -- Rachwal, Phillip -- Turner, Daniel J -- Pollakis, Georgios -- Hiscox, Julian A -- Matthews, David A -- O'Shea, Matthew K -- Johnston, Andrew McD -- Wilson, Duncan -- Hutley, Emma -- Smit, Erasmus -- Di Caro, Antonino -- Wolfel, Roman -- Stoecker, Kilian -- Fleischmann, Erna -- Gabriel, Martin -- Weller, Simon A -- Koivogui, Lamine -- Diallo, Boubacar -- Keita, Sakoba -- Rambaut, Andrew -- Formenty, Pierre -- Gunther, Stephan -- Carroll, Miles W -- Medical Research Council/United Kingdom -- England -- Nature. 2016 Feb 11;530(7589):228-32. doi: 10.1038/nature16996. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Microbiology and Infection, University of Birmingham, Birmingham B15 2TT, UK. ; The European Mobile Laboratory Consortium, Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany. ; Bernhard-Nocht-Institute for Tropical Medicine, D-20359 Hamburg, Germany. ; Ontario Institute for Cancer Research, Toronto M5G 0A3, Canada. ; Department of Computer Science, University of Toronto, Toronto M5S 3G4, Canada. ; European Centre for Disease Prevention and Control (ECDC), 171 65 Solna, Sweden. ; National Infection Service, Public Health England, London NW9 5EQ, UK. ; Institute of Evolutionary Biology, University of Edinburgh, Edinburgh EH9 2FL, UK. ; Postgraduate Training for Applied Epidemiology (PAE, German FETP), Robert Koch Institute, D-13302 Berlin, Germany. ; National Infection Service, Public Health England, Porton Down, Wiltshire SP4 0JG, UK. ; Swiss Tropical and Public Health Institute, 4002 Basel, Switzerland. ; Robert Koch Institute, D-13302 Berlin, Germany. ; University College London, London WC1E 6BT, UK. ; Paul-Ehrlich-Institut, Division of Veterinary Medicine, D-63225 Langen, Germany. ; Institute of Infection and Global Health, University of Liverpool, Liverpool L69 7BE, UK. ; Laboratory for Clinical and Epidemiological Virology, Department of Microbiology and Immunology, KU Leuven, Leuven B-3000, Belgium. ; Ministry of Health Guinea, Conakry BP 585, Guinea. ; Kenya Medical Research Institute, Nairobi P.O. BOX 54840 - 00200, Kenya. ; National Institute for Infectious Diseases L. Spallanzani, 00149 Rome, Italy. ; Friedrich-Loeffler-Institute, D-17493 Greifswald, Germany. ; Federal Office for Civil Protection, Spiez Laboratory, 3700 Spiez, Switzerland. ; Janssen-Cilag, Stockholm, Box 7073 - 19207, Sweden. ; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool L69 7BE, UK. ; Institute of Virology, Technische Universitat Munchen, D-81675 Munich, Germany. ; Public Health Agency of Canada, Winnipeg, Manitoba R3E 3R2, Canada. ; Institut Pasteur Dakar, Dakar, DP 220 Senegal. ; Laboratoire de Fievres Hemorragiques de Guinee, Conakry BP 5680, Guinea. ; Sandia National Laboratories, PO Box 5800 MS1363, Albuquerque, New Mexico 87185-1363, USA. ; Ratoma Ebola Diagnostic Center, Conakry, Guinea. ; MRIGlobal, Kansas City, Missouri 64110-2241, USA. ; Expertise France, Laboratoire K-plan de Forecariah en Guinee, 75006 Paris, France. ; Federation des Laboratoires - HIA Begin, 94163 Saint-Mande cedex, France. ; Laboratoire de Biologie - Centre de Traitement des Soignants, Conakry, Guinea. ; World Health Organization, Conakry BP 817, Guinea. ; London School of Hygiene and Tropical Medicine, London EC1E 7HT, UK. ; Norwegian Institute of Public Health, PO Box 4404 Nydalen, 0403 Oslo, Norway. ; Public Health Wales, Cardiff CF11 9LJ, UK. ; Defence Science and Technology Laboratory (Dstl) Porton Down, Salisbury SP4 0JQ, UK. ; Oxford Nanopore Technologies, Oxford OX4 4GA, UK. ; Department of Cellular and Molecular Medicine, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK. ; Academic Department of Military Medicine, Royal Centre for Defence Medicine, Birmingham B15 2TH, UK. ; Centre of Defence Pathology, Royal Centre for Defence Medicine, Birmingham B15 2TH, UK. ; Queen Elizabeth Hospital, Birmingham B12 2TH, UK. ; Bundeswehr Institute of Microbiology, D-80937 Munich, Germany. ; Institut National de Sante Publique, Conakry BP 1147, Guinea. ; Fogarty International Center, National Institutes of Health, Bethesda, MD 20892-2220, USA. ; Centre for Immunology, Infection and Evolution, University of Edinburgh, Edinburgh EH9 2FL, UK. ; University of Southampton, South General Hospital, Southampton SO16 6YD, UK. ; NIHR Health Protection Research Unit in Emerging and Zoonotic Infections, PHE Porton Down, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840485" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2016 May 5;533(7601):15-6. doi: 10.1038/533015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147010" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2016 Mar 31;531(7596):560. doi: 10.1038/531560a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029280" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullard, Asher -- England -- Nature. 2016 Feb 18;530(7590):367-9. doi: 10.1038/530367a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887498" target="_blank"〉PubMed〈/a〉

Description: The conserved Piwi family of proteins and piwi-interacting RNAs (piRNAs) have a central role in genomic stability, which is inextricably linked to germ-cell formation, by forming Piwi ribonucleoproteins (piRNPs) that silence transposable elements. In Drosophila melanogaster and other animals, primordial germ-cell specification in the developing embryo is driven by maternal messenger RNAs and proteins that assemble into specialized messenger ribonucleoproteins (mRNPs) localized in the germ (pole) plasm at the posterior of the oocyte. Maternal piRNPs, especially those loaded on the Piwi protein Aubergine (Aub), are transmitted to the germ plasm to initiate transposon silencing in the offspring germ line. The transport of mRNAs to the oocyte by midoogenesis is an active, microtubule-dependent process; mRNAs necessary for primordial germ-cell formation are enriched in the germ plasm at late oogenesis via a diffusion and entrapment mechanism, the molecular identity of which remains unknown. Aub is a central component of germ granule RNPs, which house mRNAs in the germ plasm, and interactions between Aub and Tudor are essential for the formation of germ granules. Here we show that Aub-loaded piRNAs use partial base-pairing characteristics of Argonaute RNPs to bind mRNAs randomly in Drosophila, acting as an adhesive trap that captures mRNAs in the germ plasm, in a Tudor-dependent manner. Notably, germ plasm mRNAs in drosophilids are generally longer and more abundant than other mRNAs, suggesting that they provide more target sites for piRNAs to promote their preferential tethering in germ granules. Thus, complexes containing Tudor, Aub piRNPs and mRNAs couple piRNA inheritance with germline specification. Our findings reveal an unexpected function for piRNP complexes in mRNA trapping that may be generally relevant to the function of animal germ granules.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795963/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795963/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vourekas, Anastassios -- Alexiou, Panagiotis -- Vrettos, Nicholas -- Maragkakis, Manolis -- Mourelatos, Zissimos -- GM072777/GM/NIGMS NIH HHS/ -- R01 GM072777/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):390-4. doi: 10.1038/nature17150. Epub 2016 Mar 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, Division of Neuropathology, Institute for Translational Medicine and Therapeutics, Perelman School of Medicine; PENN Genome Frontiers Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26950602" target="_blank"〉PubMed〈/a〉

Description: The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davies, Benjamin -- Hatton, Edouard -- Altemose, Nicolas -- Hussin, Julie G -- Pratto, Florencia -- Zhang, Gang -- Hinch, Anjali Gupta -- Moralli, Daniela -- Biggs, Daniel -- Diaz, Rebeca -- Preece, Chris -- Li, Ran -- Bitoun, Emmanuelle -- Brick, Kevin -- Green, Catherine M -- Camerini-Otero, R Daniel -- Myers, Simon R -- Donnelly, Peter -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095552/Z/11/Z/Wellcome Trust/United Kingdom -- 098387/Z/12/Z/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):171-6. doi: 10.1038/nature16931. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK. ; Department of Statistics, University of Oxford, 24-29 St. Giles', Oxford OX1 3LB, UK. ; Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840484" target="_blank"〉PubMed〈/a〉

Description: Observing marine mammal (MM) populations continuously in time and space over the immense ocean areas they inhabit is challenging but essential for gathering an unambiguous record of their distribution, as well as understanding their behaviour and interaction with prey species. Here we use passive ocean acoustic waveguide remote sensing (POAWRS) in an important North Atlantic feeding ground to instantaneously detect, localize and classify MM vocalizations from diverse species over an approximately 100,000 km(2) region. More than eight species of vocal MMs are found to spatially converge on fish spawning areas containing massive densely populated herring shoals at night-time and diffuse herring distributions during daytime. We find the vocal MMs divide the enormous fish prey field into species-specific foraging areas with varying degrees of spatial overlap, maintained for at least two weeks of the herring spawning period. The recorded vocalization rates are diel (24 h)-dependent for all MM species, with some significantly more vocal at night and others more vocal during the day. The four key baleen whale species of the region: fin, humpback, blue and minke have vocalization rate trends that are highly correlated to trends in fish shoaling density and to each other over the diel cycle. These results reveal the temporospatial dynamics of combined multi-species MM foraging activities in the vicinity of an extensive fish prey field that forms a massive ecological hotspot, and would be unattainable with conventional methodologies. Understanding MM behaviour and distributions is essential for management of marine ecosystems and for accessing anthropogenic impacts on these protected marine species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Delin -- Garcia, Heriberto -- Huang, Wei -- Tran, Duong D -- Jain, Ankita D -- Yi, Dong Hoon -- Gong, Zheng -- Jech, J Michael -- Godo, Olav Rune -- Makris, Nicholas C -- Ratilal, Purnima -- England -- Nature. 2016 Mar 17;531(7594):366-70. doi: 10.1038/nature16960. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Ocean Acoustics and Ecosystem Sensing, Northeastern University, 360 Huntington Avenue, Boston, Massachusetts 02115, USA. ; Laboratory for Undersea Remote Sensing, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA. ; Northeast Fisheries Science Center, 166 Water Street, Woods Hole, Massachusetts 02543, USA. ; Institute of Marine Research, Post Office Box 1870, Nordnes, N-5817 Bergen, Norway.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934221" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nowogrodzki, Anna -- England -- Nature. 2016 Mar 31;531(7596):561. doi: 10.1038/nature.2016.19599.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029258" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2016 Mar 10;531(7593):149. doi: 10.1038/531149a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961633" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Savage, Neil -- England -- Nature. 2016 May 11;533(7602):S56-8. doi: 10.1038/533S56a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27167391" target="_blank"〉PubMed〈/a〉

Description: The past rapid growth of Northern Hemisphere continental ice sheets, which terminated warm and stable climate periods, is generally attributed to reduced summer insolation in boreal latitudes. Yet such summer insolation is near to its minimum at present, and there are no signs of a new ice age. This challenges our understanding of the mechanisms driving glacial cycles and our ability to predict the next glacial inception. Here we propose a critical functional relationship between boreal summer insolation and global carbon dioxide (CO2) concentration, which explains the beginning of the past eight glacial cycles and might anticipate future periods of glacial inception. Using an ensemble of simulations generated by an Earth system model of intermediate complexity constrained by palaeoclimatic data, we suggest that glacial inception was narrowly missed before the beginning of the Industrial Revolution. The missed inception can be accounted for by the combined effect of relatively high late-Holocene CO2 concentrations and the low orbital eccentricity of the Earth. Additionally, our analysis suggests that even in the absence of human perturbations no substantial build-up of ice sheets would occur within the next several thousand years and that the current interglacial would probably last for another 50,000 years. However, moderate anthropogenic cumulative CO2 emissions of 1,000 to 1,500 gigatonnes of carbon will postpone the next glacial inception by at least 100,000 years. Our simulations demonstrate that under natural conditions alone the Earth system would be expected to remain in the present delicately balanced interglacial climate state, steering clear of both large-scale glaciation of the Northern Hemisphere and its complete deglaciation, for an unusually long time.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ganopolski, A -- Winkelmann, R -- Schellnhuber, H J -- England -- Nature. 2016 Jan 14;529(7585):200-3. doi: 10.1038/nature16494.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Potsdam Institute for Climate Impact Research, 14412 Potsdam, Germany. ; Physics Institute, Potsdam University, 14476 Potsdam, Germany. ; Santa Fe Institute, Santa Fe, New Mexico 87501, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762457" target="_blank"〉PubMed〈/a〉

Description: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Darren J -- Childs, Bennett G -- Durik, Matej -- Wijers, Melinde E -- Sieben, Cynthia J -- Zhong, Jian -- Saltness, Rachel A -- Jeganathan, Karthik B -- Verzosa, Grace Casaclang -- Pezeshki, Abdulmohammad -- Khazaie, Khashayarsha -- Miller, Jordan D -- van Deursen, Jan M -- AG041122/AG/NIA NIH HHS/ -- HL111121/HL/NHLBI NIH HHS/ -- P01 AG041122/AG/NIA NIH HHS/ -- R01 CA096985/CA/NCI NIH HHS/ -- R01CA96985/CA/NCI NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840489" target="_blank"〉PubMed〈/a〉

Description: The process of ageing makes death increasingly likely, involving a random aspect that produces a wide distribution of lifespan even in homogeneous populations. The study of this stochastic behaviour may link molecular mechanisms to the ageing process that determines lifespan. Here, by collecting high-precision mortality statistics from large populations, we observe that interventions as diverse as changes in diet, temperature, exposure to oxidative stress, and disruption of genes including the heat shock factor hsf-1, the hypoxia-inducible factor hif-1, and the insulin/IGF-1 pathway components daf-2, age-1, and daf-16 all alter lifespan distributions by an apparent stretching or shrinking of time. To produce such temporal scaling, each intervention must alter to the same extent throughout adult life all physiological determinants of the risk of death. Organismic ageing in Caenorhabditis elegans therefore appears to involve aspects of physiology that respond in concert to a diverse set of interventions. In this way, temporal scaling identifies a novel state variable, r(t), that governs the risk of death and whose average decay dynamics involves a single effective rate constant of ageing, kr. Interventions that produce temporal scaling influence lifespan exclusively by altering kr. Such interventions, when applied transiently even in early adulthood, temporarily alter kr with an attendant transient increase or decrease in the rate of change in r and a permanent effect on remaining lifespan. The existence of an organismal ageing dynamics that is invariant across genetic and environmental contexts provides the basis for a new, quantitative framework for evaluating the manner and extent to which specific molecular processes contribute to the aspect of ageing that determines lifespan.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stroustrup, Nicholas -- Anthony, Winston E -- Nash, Zachary M -- Gowda, Vivek -- Gomez, Adam -- Lopez-Moyado, Isaac F -- Apfeld, Javier -- Fontana, Walter -- P40 OD010440/OD/NIH HHS/ -- R01 AG034994/AG/NIA NIH HHS/ -- England -- Nature. 2016 Feb 4;530(7588):103-7. doi: 10.1038/nature16550. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814965" target="_blank"〉PubMed〈/a〉

Description: The current outbreak of Ebola virus in West Africa is unprecedented, causing more cases and fatalities than all previous outbreaks combined, and has yet to be controlled. Several post-exposure interventions have been employed under compassionate use to treat patients repatriated to Europe and the United States. However, the in vivo efficacy of these interventions against the new outbreak strain of Ebola virus is unknown. Here we show that lipid-nanoparticle-encapsulated short interfering RNAs (siRNAs) rapidly adapted to target the Makona outbreak strain of Ebola virus are able to protect 100% of rhesus monkeys against lethal challenge when treatment was initiated at 3 days after exposure while animals were viraemic and clinically ill. Although all infected animals showed evidence of advanced disease including abnormal haematology, blood chemistry and coagulopathy, siRNA-treated animals had milder clinical features and fully recovered, while the untreated control animals succumbed to the disease. These results represent the first, to our knowledge, successful demonstration of therapeutic anti-Ebola virus efficacy against the new outbreak strain in nonhuman primates and highlight the rapid development of lipid-nanoparticle-delivered siRNA as a countermeasure against this highly lethal human disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467030/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467030/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thi, Emily P -- Mire, Chad E -- Lee, Amy C H -- Geisbert, Joan B -- Zhou, Joy Z -- Agans, Krystle N -- Snead, Nicholas M -- Deer, Daniel J -- Barnard, Trisha R -- Fenton, Karla A -- MacLachlan, Ian -- Geisbert, Thomas W -- U19 AI109711/AI/NIAID NIH HHS/ -- U19AI109711/AI/NIAID NIH HHS/ -- England -- Nature. 2015 May 21;521(7552):362-5. doi: 10.1038/nature14442. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tekmira Pharmaceuticals, Burnaby, British Columbia V5J 5J8, Canada. ; 1] Galveston National Laboratory, University of Texas Medical Branch, Galveston, Texas 77550, USA [2] Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77550, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901685" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Geddes, Linda -- England -- Nature. 2015 Nov 5;527(7576):22-5. doi: 10.1038/527022a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536940" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 May 28;521(7553):394. doi: 10.1038/521394a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017406" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Oliveira, Joao Ricardo Mendes -- England -- Nature. 2015 Oct 22;526(7574):506. doi: 10.1038/526506e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Federal University of Pernambuco, Recife, Brazil.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26490608" target="_blank"〉PubMed〈/a〉

Description: Robots have transformed many industries, most notably manufacturing, and have the power to deliver tremendous benefits to society, such as in search and rescue, disaster response, health care and transportation. They are also invaluable tools for scientific exploration in environments inaccessible to humans, from distant planets to deep oceans. A major obstacle to their widespread adoption in more complex environments outside factories is their fragility. Whereas animals can quickly adapt to injuries, current robots cannot 'think outside the box' to find a compensatory behaviour when they are damaged: they are limited to their pre-specified self-sensing abilities, can diagnose only anticipated failure modes, and require a pre-programmed contingency plan for every type of potential damage, an impracticality for complex robots. A promising approach to reducing robot fragility involves having robots learn appropriate behaviours in response to damage, but current techniques are slow even with small, constrained search spaces. Here we introduce an intelligent trial-and-error algorithm that allows robots to adapt to damage in less than two minutes in large search spaces without requiring self-diagnosis or pre-specified contingency plans. Before the robot is deployed, it uses a novel technique to create a detailed map of the space of high-performing behaviours. This map represents the robot's prior knowledge about what behaviours it can perform and their value. When the robot is damaged, it uses this prior knowledge to guide a trial-and-error learning algorithm that conducts intelligent experiments to rapidly discover a behaviour that compensates for the damage. Experiments reveal successful adaptations for a legged robot injured in five different ways, including damaged, broken, and missing legs, and for a robotic arm with joints broken in 14 different ways. This new algorithm will enable more robust, effective, autonomous robots, and may shed light on the principles that animals use to adapt to injury.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cully, Antoine -- Clune, Jeff -- Tarapore, Danesh -- Mouret, Jean-Baptiste -- England -- Nature. 2015 May 28;521(7553):503-7. doi: 10.1038/nature14422.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Sorbonne Universites, Universite Pierre et Marie Curie (UPMC), Paris 06, UMR 7222, Institut des Systemes Intelligents et de Robotique (ISIR), F-75005, Paris, France [2] CNRS, UMR 7222, Institut des Systemes Intelligents et de Robotique (ISIR), F-75005, Paris, France. ; Department of Computer Science, University of Wyoming, Laramie, Wyoming 82071, USA. ; 1] Sorbonne Universites, Universite Pierre et Marie Curie (UPMC), Paris 06, UMR 7222, Institut des Systemes Intelligents et de Robotique (ISIR), F-75005, Paris, France [2] CNRS, UMR 7222, Institut des Systemes Intelligents et de Robotique (ISIR), F-75005, Paris, France [3] Inria, Team Larsen, Villers-les-Nancy, F-54600, France [4] CNRS, Loria, UMR 7503, Vandoeuvre-les-Nancy, F-54500, France [5] Universite de Lorraine, Loria, UMR 7503, Vandoeuvre-les-Nancy, F-54500, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26017452" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tollefson, Jeff -- England -- Nature. 2015 Sep 24;525(7570):434-5. doi: 10.1038/525434a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399805" target="_blank"〉PubMed〈/a〉

Description: Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells. Here we investigate the causal DNA variant at this locus and the mechanism by which it leads to neuroblastoma tumorigenesis. We first imputed all possible genotypes across the LMO1 locus and then mapped highly associated single nucleotide polymorphism (SNPs) to areas of chromatin accessibility, evolutionary conservation and transcription factor binding sites. We show that SNP rs2168101 G〉T is the most highly associated variant (combined P = 7.47 x 10(-29), odds ratio 0.65, 95% confidence interval 0.60-0.70), and resides in a super-enhancer defined by extensive acetylation of histone H3 lysine 27 within the first intron of LMO1. The ancestral G allele that is associated with tumour formation resides in a conserved GATA transcription factor binding motif. We show that the newly evolved protective TATA allele is associated with decreased total LMO1 expression (P = 0.028) in neuroblastoma primary tumours, and ablates GATA3 binding (P 〈 0.0001). We demonstrate allelic imbalance favouring the G-containing strand in tumours heterozygous for this SNP, as demonstrated both by RNA sequencing (P 〈 0.0001) and reporter assays (P = 0.002). These findings indicate that a recently evolved polymorphism within a super-enhancer element in the first intron of LMO1 influences neuroblastoma susceptibility through differential GATA transcription factor binding and direct modulation of LMO1 expression in cis, and this leads to an oncogenic dependency in tumour cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775078/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4775078/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oldridge, Derek A -- Wood, Andrew C -- Weichert-Leahey, Nina -- Crimmins, Ian -- Sussman, Robyn -- Winter, Cynthia -- McDaniel, Lee D -- Diamond, Maura -- Hart, Lori S -- Zhu, Shizhen -- Durbin, Adam D -- Abraham, Brian J -- Anders, Lars -- Tian, Lifeng -- Zhang, Shile -- Wei, Jun S -- Khan, Javed -- Bramlett, Kelli -- Rahman, Nazneen -- Capasso, Mario -- Iolascon, Achille -- Gerhard, Daniela S -- Guidry Auvil, Jaime M -- Young, Richard A -- Hakonarson, Hakon -- Diskin, Sharon J -- Look, A Thomas -- Maris, John M -- 100210/Wellcome Trust/United Kingdom -- 100210/Z/12/Z/Wellcome Trust/United Kingdom -- 1K99CA178189/CA/NCI NIH HHS/ -- R00-CA151869/CA/NCI NIH HHS/ -- R01 CA124709/CA/NCI NIH HHS/ -- R01 CA180692/CA/NCI NIH HHS/ -- R01-CA109901/CA/NCI NIH HHS/ -- R01-CA124709/CA/NCI NIH HHS/ -- R01-CA180692/CA/NCI NIH HHS/ -- RC1MD004418/MD/NIMHD NIH HHS/ -- T32 HG000046/HG/NHGRI NIH HHS/ -- T32-HG000046/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Dec 17;528(7582):418-21. doi: 10.1038/nature15540. Epub 2015 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; Medical Scientist Training Program, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Molecular Medicine and Pathology, University of Auckland, Auckland, Auckland Region 1142, New Zealand. ; Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota 55905, USA. ; Whitehead Institute for Biomedical Research and MIT, Boston, Massachusetts 02142, USA. ; Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA. ; Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Thermo Fisher Scientific, Austin, Texas 78744, USA. ; The Institute of Cancer Research, London SM2 5NG, UK. ; University of Naples Federico II, 80131 Naples, Italy. ; CEINGE Biotecnologie Avanzate, 80131 Naples, Italy. ; Office of Cancer Genomics, National Cancer Institute, Bethesda, Maryland 20892, USA. ; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26560027" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, Dan -- England -- Nature. 2015 Mar 12;519(7542):148-50. doi: 10.1038/519148a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762265" target="_blank"〉PubMed〈/a〉

Description: Rising temperatures and lessening fresh water supplies are threatening agricultural productivity and have motivated efforts to improve plant water use and drought tolerance. During water deficit, plants produce elevated levels of abscisic acid (ABA), which improves water consumption and stress tolerance by controlling guard cell aperture and other protective responses. One attractive strategy for controlling water use is to develop compounds that activate ABA receptors, but agonists approved for use have yet to be developed. In principle, an engineered ABA receptor that can be activated by an existing agrochemical could achieve this goal. Here we describe a variant of the ABA receptor PYRABACTIN RESISTANCE 1 (PYR1) that possesses nanomolar sensitivity to the agrochemical mandipropamid and demonstrate its efficacy for controlling ABA responses and drought tolerance in transgenic plants. Furthermore, crystallographic studies provide a mechanistic basis for its activity and demonstrate the relative ease with which the PYR1 ligand-binding pocket can be altered to accommodate new ligands. Thus, we have successfully repurposed an agrochemical for a new application using receptor engineering. We anticipate that this strategy will be applied to other plant receptors and represents a new avenue for crop improvement.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Youl -- Peterson, Francis C -- Mosquna, Assaf -- Yao, Jin -- Volkman, Brian F -- Cutler, Sean R -- England -- Nature. 2015 Apr 23;520(7548):545-8. doi: 10.1038/nature14123. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Plant Cell Biology and Department of Botany and Plant Sciences, University of California, Riverside, California 92521, USA [2] Institute for Integrative Genome Biology, Riverside, California 92521, USA. ; Department of Biochemistry, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652827" target="_blank"〉PubMed〈/a〉

Description: Continuing degradation of coral reef ecosystems has generated substantial interest in how management can support reef resilience. Fishing is the primary source of diminished reef function globally, leading to widespread calls for additional marine reserves to recover fish biomass and restore key ecosystem functions. Yet there are no established baselines for determining when these conservation objectives have been met or whether alternative management strategies provide similar ecosystem benefits. Here we establish empirical conservation benchmarks and fish biomass recovery timelines against which coral reefs can be assessed and managed by studying the recovery potential of more than 800 coral reefs along an exploitation gradient. We show that resident reef fish biomass in the absence of fishing (B0) averages approximately 1,000 kg ha(-1), and that the vast majority (83%) of fished reefs are missing more than half their expected biomass, with severe consequences for key ecosystem functions such as predation. Given protection from fishing, reef fish biomass has the potential to recover within 35 years on average and less than 60 years when heavily depleted. Notably, alternative fisheries restrictions are largely (64%) successful at maintaining biomass above 50% of B0, sustaining key functions such as herbivory. Our results demonstrate that crucial ecosystem functions can be maintained through a range of fisheries restrictions, allowing coral reef managers to develop recovery plans that meet conservation and livelihood objectives in areas where marine reserves are not socially or politically feasible solutions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉MacNeil, M Aaron -- Graham, Nicholas A J -- Cinner, Joshua E -- Wilson, Shaun K -- Williams, Ivor D -- Maina, Joseph -- Newman, Steven -- Friedlander, Alan M -- Jupiter, Stacy -- Polunin, Nicholas V C -- McClanahan, Tim R -- England -- Nature. 2015 Apr 16;520(7547):341-4. doi: 10.1038/nature14358. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Australian Institute of Marine Science, PMB 3 Townsville MC, Townsville, Queensland 4810, Australia [2] Department of Mathematics and Statistics, Dalhousie University, Halifax, Nova Scotia B3H 3J5, Canada [3] Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811, Australia. ; Australian Research Council Centre of Excellence for Coral Reef Studies, James Cook University, Townsville, Queensland 4811, Australia. ; 1] Department of Parks and Wildlife, Kensington, Perth, Western Australia 6151, Australia [2] Oceans Institute, University of Western Australia, Crawley, Western Australia 6009, Australia. ; Coral Reef Ecosystems Division, NOAA Pacific Islands Fisheries Science Center, Honolulu, Hawaii 96818, USA. ; 1] Australian Research Council Centre of Excellence for Environmental Decisions (CEED), University of Queensland, Brisbane, St Lucia, Queensland 4074, Australia [2] Wildlife Conservation Society, Marine Programs, Bronx, New York 10460, USA. ; School of Marine Science and Technology, Newcastle University, Newcastle upon Tyne NE1 7RU, UK. ; 1] Fisheries Ecology Research Lab, Department of Biology, University of Hawaii, Honolulu, Hawaii 96822, USA [2] Pristine Seas-National Geographic, Washington DC 20036, USA. ; Wildlife Conservation Society, Marine Programs, Bronx, New York 10460, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855298" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gong, Zhaohui -- England -- Nature. 2015 Jan 8;517(7533):145. doi: 10.1038/517145c.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ningbo University School of Medicine, Ningbo, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567273" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Hong -- Thompson, Julian R -- Flower, Roger J -- England -- Nature. 2015 Sep 24;525(7570):455. doi: 10.1038/525455e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Oslo, Norway. ; University College London, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26399818" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gould, Julie -- England -- Nature. 2015 Dec 3;528(7580):22-5. doi: 10.1038/528022a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26632571" target="_blank"〉PubMed〈/a〉

Description: Ribosomes are translational machineries that catalyse protein synthesis. Ribosome structures from various species are known at the atomic level, but obtaining the structure of the human ribosome has remained a challenge; efforts to address this would be highly relevant with regard to human diseases. Here we report the near-atomic structure of the human ribosome derived from high-resolution single-particle cryo-electron microscopy and atomic model building. The structure has an average resolution of 3.6 A, reaching 2.9 A resolution in the most stable regions. It provides unprecedented insights into ribosomal RNA entities and amino acid side chains, notably of the transfer RNA binding sites and specific molecular interactions with the exit site tRNA. It reveals atomic details of the subunit interface, which is seen to remodel strongly upon rotational movements of the ribosomal subunits. Furthermore, the structure paves the way for analysing antibiotic side effects and diseases associated with deregulated protein synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khatter, Heena -- Myasnikov, Alexander G -- Natchiar, S Kundhavai -- Klaholz, Bruno P -- England -- Nature. 2015 Apr 30;520(7549):640-5. doi: 10.1038/nature14427. Epub 2015 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Centre for Integrative Biology (CBI), Department of Integrated Structural Biology, IGBMC (Institute of Genetics and of Molecular and Cellular Biology), 1 rue Laurent Fries, 67404 Illkirch, France [2] Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France [3] Institut National de la Sante et de la Recherche Medicale (INSERM) U964, 67404 Illkirch, France [4] Universite de Strasbourg, 67081 Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25901680" target="_blank"〉PubMed〈/a〉

Description: In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 A resolution, and with a non-nucleotide antagonist BPTU at 2.2 A resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408927/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dandan -- Gao, Zhan-Guo -- Zhang, Kaihua -- Kiselev, Evgeny -- Crane, Steven -- Wang, Jiang -- Paoletta, Silvia -- Yi, Cuiying -- Ma, Limin -- Zhang, Wenru -- Han, Gye Won -- Liu, Hong -- Cherezov, Vadim -- Katritch, Vsevolod -- Jiang, Hualiang -- Stevens, Raymond C -- Jacobson, Kenneth A -- Zhao, Qiang -- Wu, Beili -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54GM094618/GM/NIGMS NIH HHS/ -- Z01 DK031116-21/Intramural NIH HHS/ -- Z01DK031116-26/DK/NIDDK NIH HHS/ -- ZIA DK031116-26/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):317-21. doi: 10.1038/nature14287. Epub 2015 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA. ; Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA. ; Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong, Shanghai 201203, China. ; 1] Bridge Institute, Department of Chemistry, University of Southern California, Los Angeles, California 90089, USA [2] Bridge Institute, Department of Biological Sciences, University of Southern California, Los Angeles, California 90089, USA [3] iHuman Institute, ShanghaiTech University, 99 Haike Road, Pudong, Shanghai 201203, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25822790" target="_blank"〉PubMed〈/a〉

Description: G-protein-coupled receptors (GPCRs) constitute the largest family of membrane receptors in eukaryotes. Crystal structures have provided insight into GPCR interactions with ligands and G proteins, but our understanding of the conformational dynamics of activation is incomplete. Metabotropic glutamate receptors (mGluRs) are dimeric class C GPCRs that modulate neuronal excitability, synaptic plasticity, and serve as drug targets for neurological disorders. A 'clamshell' ligand-binding domain (LBD), which contains the ligand-binding site, is coupled to the transmembrane domain via a cysteine-rich domain, and LBD closure seems to be the first step in activation. Crystal structures of isolated mGluR LBD dimers led to the suggestion that activation also involves a reorientation of the dimer interface from a 'relaxed' to an 'active' state, but the relationship between ligand binding, LBD closure and dimer interface rearrangement in activation remains unclear. Here we use single-molecule fluorescence resonance energy transfer to probe the activation mechanism of full-length mammalian group II mGluRs. We show that the LBDs interconvert between three conformations: resting, activated and a short-lived intermediate state. Orthosteric agonists induce transitions between these conformational states, with efficacy determined by occupancy of the active conformation. Unlike mGluR2, mGluR3 displays basal dynamics, which are Ca(2+)-dependent and lead to basal protein activation. Our results support a general mechanism for the activation of mGluRs in which agonist binding induces closure of the LBDs, followed by dimer interface reorientation. Our experimental strategy should be widely applicable to study conformational dynamics in GPCRs and other membrane proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597782/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vafabakhsh, Reza -- Levitz, Joshua -- Isacoff, Ehud Y -- 2PN2EY018241/EY/NEI NIH HHS/ -- PN2 EY018241/EY/NEI NIH HHS/ -- England -- Nature. 2015 Aug 27;524(7566):497-501. doi: 10.1038/nature14679. Epub 2015 Aug 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA. ; Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; Physical Bioscience Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26258295" target="_blank"〉PubMed〈/a〉

Description: The TRPA1 ion channel (also known as the wasabi receptor) is a detector of noxious chemical agents encountered in our environment or produced endogenously during tissue injury or drug metabolism. These include a broad class of electrophiles that activate the channel through covalent protein modification. TRPA1 antagonists hold potential for treating neurogenic inflammatory conditions provoked or exacerbated by irritant exposure. Despite compelling reasons to understand TRPA1 function, structural mechanisms underlying channel regulation remain obscure. Here we use single-particle electron cryo- microscopy to determine the structure of full-length human TRPA1 to approximately 4 A resolution in the presence of pharmacophores, including a potent antagonist. Several unexpected features are revealed, including an extensive coiled-coil assembly domain stabilized by polyphosphate co-factors and a highly integrated nexus that converges on an unpredicted transient receptor potential (TRP)-like allosteric domain. These findings provide new insights into the mechanisms of TRPA1 regulation, and establish a blueprint for structure-based design of analgesic and anti-inflammatory agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409540/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paulsen, Candice E -- Armache, Jean-Paul -- Gao, Yuan -- Cheng, Yifan -- Julius, David -- R01 GM098672/GM/NIGMS NIH HHS/ -- R01 NS055299/NS/NINDS NIH HHS/ -- R01GM098672/GM/NIGMS NIH HHS/ -- R01NS055299/NS/NINDS NIH HHS/ -- T32 GM008284/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 23;520(7548):511-7. doi: 10.1038/nature14367. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Physiology, University of California, San Francisco, California 94158-2517, USA. ; Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA. ; 1] Department of Physiology, University of California, San Francisco, California 94158-2517, USA [2] Keck Advanced Microscopy Laboratory, Department of Biochemistry and Biophysics, University of California, San Francisco, California 94158-2517, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855297" target="_blank"〉PubMed〈/a〉

Description: During eukaryotic translation initiation, 43S complexes, comprising a 40S ribosomal subunit, initiator transfer RNA and initiation factors (eIF) 2, 3, 1 and 1A, attach to the 5'-terminal region of messenger RNA and scan along it to the initiation codon. Scanning on structured mRNAs also requires the DExH-box protein DHX29. Mammalian eIF3 contains 13 subunits and participates in nearly all steps of translation initiation. Eight subunits having PCI (proteasome, COP9 signalosome, eIF3) or MPN (Mpr1, Pad1, amino-terminal) domains constitute the structural core of eIF3, to which five peripheral subunits are flexibly linked. Here we present a cryo-electron microscopy structure of eIF3 in the context of the DHX29-bound 43S complex, showing the PCI/MPN core at approximately 6 A resolution. It reveals the organization of the individual subunits and their interactions with components of the 43S complex. We were able to build near-complete polyalanine-level models of the eIF3 PCI/MPN core and of two peripheral subunits. The implications for understanding mRNA ribosomal attachment and scanning are discussed.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719162/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4719162/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉des Georges, Amedee -- Dhote, Vidya -- Kuhn, Lauriane -- Hellen, Christopher U T -- Pestova, Tatyana V -- Frank, Joachim -- Hashem, Yaser -- R01 GM029169/GM/NIGMS NIH HHS/ -- R01 GM059660/GM/NIGMS NIH HHS/ -- R01 GM29169/GM/NIGMS NIH HHS/ -- R01 GM59660/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Sep 24;525(7570):491-5. doi: 10.1038/nature14891. Epub 2015 Sep 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HHMI, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203, USA. ; CNRS, Proteomic Platform Strasbourg - Esplanade, Strasbourg 67084, France. ; Department of Biological Sciences, Columbia University, New York, New York 10032, USA. ; CNRS, Architecture et Reactivite de l'ARN, Universite de Strasbourg, Strasbourg 67084, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26344199" target="_blank"〉PubMed〈/a〉

Description: Growing evidence demonstrates that climatic conditions can have a profound impact on the functioning of modern human societies, but effects on economic activity appear inconsistent. Fundamental productive elements of modern economies, such as workers and crops, exhibit highly non-linear responses to local temperature even in wealthy countries. In contrast, aggregate macroeconomic productivity of entire wealthy countries is reported not to respond to temperature, while poor countries respond only linearly. Resolving this conflict between micro and macro observations is critical to understanding the role of wealth in coupled human-natural systems and to anticipating the global impact of climate change. Here we unify these seemingly contradictory results by accounting for non-linearity at the macro scale. We show that overall economic productivity is non-linear in temperature for all countries, with productivity peaking at an annual average temperature of 13 degrees C and declining strongly at higher temperatures. The relationship is globally generalizable, unchanged since 1960, and apparent for agricultural and non-agricultural activity in both rich and poor countries. These results provide the first evidence that economic activity in all regions is coupled to the global climate and establish a new empirical foundation for modelling economic loss in response to climate change, with important implications. If future adaptation mimics past adaptation, unmitigated warming is expected to reshape the global economy by reducing average global incomes roughly 23% by 2100 and widening global income inequality, relative to scenarios without climate change. In contrast to prior estimates, expected global losses are approximately linear in global mean temperature, with median losses many times larger than leading models indicate.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Burke, Marshall -- Hsiang, Solomon M -- Miguel, Edward -- England -- Nature. 2015 Nov 12;527(7577):235-9. doi: 10.1038/nature15725. Epub 2015 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth System Science, Stanford University, California 94305, USA. ; Center on Food Security and the Environment, Stanford University, California 94305, USA. ; Goldman School of Public Policy, University of California, Berkeley, California 94720, USA. ; National Bureau of Economic Research. ; Department of Economics, University of California, Berkeley, California, 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503051" target="_blank"〉PubMed〈/a〉

Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉

Description: The cave infills at Sterkfontein contain one of the richest assemblages of Australopithecus fossils in the world, including the nearly complete skeleton StW 573 ('Little Foot') in its lower section, as well as early stone tools in higher sections. However, the chronology of the site remains controversial owing to the complex history of cave infilling. Much of the existing chronology based on uranium-lead dating and palaeomagnetic stratigraphy has recently been called into question by the recognition that dated flowstones fill cavities formed within previously cemented breccias and therefore do not form a stratigraphic sequence. Earlier dating with cosmogenic nuclides suffered a high degree of uncertainty and has been questioned on grounds of sediment reworking. Here we use isochron burial dating with cosmogenic aluminium-26 and beryllium-10 to show that the breccia containing StW 573 did not undergo significant reworking, and that it was deposited 3.67 +/- 0.16 million years ago, far earlier than the 2.2 million year flowstones found within it. The skeleton is thus coeval with early Australopithecus afarensis in eastern Africa. We also date the earliest stone tools at Sterkfontein to 2.18 +/- 0.21 million years ago, placing them in the Oldowan at a time similar to that found elsewhere in South Africa at Swartkans and Wonderwerk.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Granger, Darryl E -- Gibbon, Ryan J -- Kuman, Kathleen -- Clarke, Ronald J -- Bruxelles, Laurent -- Caffee, Marc W -- England -- Nature. 2015 Jun 4;522(7554):85-8. doi: 10.1038/nature14268. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Earth, Atmospheric, and Planetary Sciences, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Anthropology, University of New Brunswick, Fredericton, New Brunswick E3B 5A3, Canada. ; 1] Evolutionary Studies Institute, University of the Witwatersrand, WITS 2050, Johannesburg, South Africa [2] School of Geography, Archaeology and Environmental Studies, University of the Witwatersrand, WITS 2050, Johannesburg, South Africa. ; Evolutionary Studies Institute, University of the Witwatersrand, WITS 2050, Johannesburg, South Africa. ; 1] School of Geography, Archaeology and Environmental Studies, University of the Witwatersrand, WITS 2050, Johannesburg, South Africa [2] French National Institute for Preventive Archaeological Research (Inrap), 561 rue Etienne Lenoir, km delta, 30900 Nimes, France [3] University of Toulouse Jean Jaures, UMR 5608 du CNRS (TRACES), Maison de la Recherche, 5 Allees Antonio Matchado, F-31058 Toulouse, France. ; 1] Department of Earth, Atmospheric, and Planetary Sciences, Purdue University, West Lafayette, Indiana 47907, USA [2] Department of Physics and Astronomy, Purdue University, West Lafayette, Indiana 47907, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830884" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2015 May 21;521(7552):269. doi: 10.1038/nature.2015.17560.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25993935" target="_blank"〉PubMed〈/a〉

Description: Most present-generation climate models simulate an increase in global-mean surface temperature (GMST) since 1998, whereas observations suggest a warming hiatus. It is unclear to what extent this mismatch is caused by incorrect model forcing, by incorrect model response to forcing or by random factors. Here we analyse simulations and observations of GMST from 1900 to 2012, and show that the distribution of simulated 15-year trends shows no systematic bias against the observations. Using a multiple regression approach that is physically motivated by surface energy balance, we isolate the impact of radiative forcing, climate feedback and ocean heat uptake on GMST--with the regression residual interpreted as internal variability--and assess all possible 15- and 62-year trends. The differences between simulated and observed trends are dominated by random internal variability over the shorter timescale and by variations in the radiative forcings used to drive models over the longer timescale. For either trend length, spread in simulated climate feedback leaves no traceable imprint on GMST trends or, consequently, on the difference between simulations and observations. The claim that climate models systematically overestimate the response to radiative forcing from increasing greenhouse gas concentrations therefore seems to be unfounded.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marotzke, Jochem -- Forster, Piers M -- England -- Nature. 2015 Jan 29;517(7536):565-70. doi: 10.1038/nature14117.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Meteorology, Bundesstrasse 53, 20146 Hamburg, Germany. ; School of Earth and Environment, University of Leeds, Leeds LS2 9JT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25631444" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2015 Jan 1;517(7532):5. doi: 10.1038/517005a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25557694" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Knight, Rob -- England -- Nature. 2015 Feb 26;518(7540):S5. doi: 10.1038/518S5a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California, San Diego.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715279" target="_blank"〉PubMed〈/a〉

Description: Appropriate responses to an imminent threat brace us for adversities. The ability to sense and predict threatening or stressful events is essential for such adaptive behaviour. In the mammalian brain, one putative stress sensor is the paraventricular nucleus of the thalamus (PVT), an area that is readily activated by both physical and psychological stressors. However, the role of the PVT in the establishment of adaptive behavioural responses remains unclear. Here we show in mice that the PVT regulates fear processing in the lateral division of the central amygdala (CeL), a structure that orchestrates fear learning and expression. Selective inactivation of CeL-projecting PVT neurons prevented fear conditioning, an effect that can be accounted for by an impairment in fear-conditioning-induced synaptic potentiation onto somatostatin-expressing (SOM(+)) CeL neurons, which has previously been shown to store fear memory. Consistently, we found that PVT neurons preferentially innervate SOM(+) neurons in the CeL, and stimulation of PVT afferents facilitated SOM(+) neuron activity and promoted intra-CeL inhibition, two processes that are critical for fear learning and expression. Notably, PVT modulation of SOM(+) CeL neurons was mediated by activation of the brain-derived neurotrophic factor (BDNF) receptor tropomysin-related kinase B (TrkB). As a result, selective deletion of either Bdnf in the PVT or Trkb in SOM(+) CeL neurons impaired fear conditioning, while infusion of BDNF into the CeL enhanced fear learning and elicited unconditioned fear responses. Our results demonstrate that the PVT-CeL pathway constitutes a novel circuit essential for both the establishment of fear memory and the expression of fear responses, and uncover mechanisms linking stress detection in PVT with the emergence of adaptive behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376633/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376633/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Penzo, Mario A -- Robert, Vincent -- Tucciarone, Jason -- De Bundel, Dimitri -- Wang, Minghui -- Van Aelst, Linda -- Darvas, Martin -- Parada, Luis F -- Palmiter, Richard D -- He, Miao -- Huang, Z Josh -- Li, Bo -- R01 MH082808/MH/NIMH NIH HHS/ -- R01 MH094705/MH/NIMH NIH HHS/ -- R01 MH101214/MH/NIMH NIH HHS/ -- R01 NS082266/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 26;519(7544):455-9. doi: 10.1038/nature13978. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Ecole Normale Superieure de Cachan, 94230 Cachan, France. ; 1] Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA [2] Medical Scientist Training Program &Program in Neuroscience, Stony Brook University, Stony Brook, New York 11790, USA. ; CNRS, UMR-5203, INSERM U661, Institut de Genomique Fonctionnelle, 34090 Montpellier, France. ; Department of Pathology, University of Washington, Seattle, Washington 98104, USA. ; Department of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute; Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600269" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marris, Emma -- England -- Nature. 2015 Apr 23;520(7548):415. doi: 10.1038/nature.2015.17263.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25903602" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yingying -- England -- Nature. 2015 Dec 17;528(7582):S170-3. doi: 10.1038/528S170a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26673023" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2015 Mar 19;519(7543):276-8. doi: 10.1038/519276a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25788077" target="_blank"〉PubMed〈/a〉

Description: Fear memories allow animals to avoid danger, thereby increasing their chances of survival. Fear memories can be retrieved long after learning, but little is known about how retrieval circuits change with time. Here we show that the dorsal midline thalamus of rats is required for the retrieval of auditory conditioned fear at late (24 hours, 7 days, 28 days), but not early (0.5 hours, 6 hours) time points after learning. Consistent with this, the paraventricular nucleus of the thalamus (PVT), a subregion of the dorsal midline thalamus, showed increased c-Fos expression only at late time points, indicating that the PVT is gradually recruited for fear retrieval. Accordingly, the conditioned tone responses of PVT neurons increased with time after training. The prelimbic (PL) prefrontal cortex, which is necessary for fear retrieval, sends dense projections to the PVT. Retrieval at late time points activated PL neurons projecting to the PVT, and optogenetic silencing of these projections impaired retrieval at late, but not early, time points. In contrast, silencing of PL inputs to the basolateral amygdala impaired retrieval at early, but not late, time points, indicating a time-dependent shift in retrieval circuits. Retrieval at late time points also activated PVT neurons projecting to the central nucleus of the amygdala, and silencing these projections at late, but not early, time points induced a persistent attenuation of fear. Thus, the PVT may act as a crucial thalamic node recruited into cortico-amygdalar networks for retrieval and maintenance of long-term fear memories.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376623/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Do-Monte, Fabricio H -- Quinones-Laracuente, Kelvin -- Quirk, Gregory J -- G12 MD007600/MD/NIMHD NIH HHS/ -- K99 MH105549/MH/NIMH NIH HHS/ -- P50 MH086400/MH/NIMH NIH HHS/ -- P50-MH086400/MH/NIMH NIH HHS/ -- R01-MH058883/MH/NIMH NIH HHS/ -- R25 GM061838/GM/NIGMS NIH HHS/ -- R25-GM061838/GM/NIGMS NIH HHS/ -- R37 MH058883/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Mar 26;519(7544):460-3. doi: 10.1038/nature14030. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Psychiatry, University of Puerto Rico School of Medicine, PO Box 365067, San Juan 00936, Puerto Rico [2] Department of Anatomy &Neurobiology, University of Puerto Rico School of Medicine, P.O. Box 365067, San Juan 00936, Puerto Rico.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600268" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Victor, David G -- England -- Nature. 2015 Apr 2;520(7545):27-9. doi: 10.1038/520027a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory on International Law and Regulation, University of California, San Diego, USA. He is also chairman of the Global Agenda Council on Governance for Sustainability at the World Economic Forum.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25832390" target="_blank"〉PubMed〈/a〉