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  • 1
    Publication Date: 2018-04-17
    Description: © The Author(s), 2018. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in International Journal of Environmental Research and Public Health 15 (2018): 723, doi:10.3390/ijerph15040723.
    Description: There has been a massive increase in recent years of the use of lead (Pb) isotopes in attempts to better understand sources and pathways of Pb in the environment and in man or experimental animals. Unfortunately, there have been many cases where the quality of the isotopic data, especially that obtained by quadrupole inductively coupled plasma mass spectrometry (Q-ICP-MS), are questionable, resulting in questionable identification of potential sources, which, in turn, impacts study interpretation and conclusions. We present several cases where the isotopic data have compromised interpretation because of the use of only the major isotopes 208Pb/206Pb and 207Pb/206Pb, or their graphing in other combinations. We also present some examples comparing high precision data from thermal ionization (TIMS) or multi-collector plasma mass spectrometry (MC-ICP-MS) to illustrate the deficiency in the Q-ICP-MS data. In addition, we present cases where Pb isotopic ratios measured on Q-ICP-MS are virtually impossible for terrestrial samples. We also evaluate the Pb isotopic data for rat studies, which had concluded that Pb isotopic fractionation occurs between different organs and suggest that this notion of biological fractionation of Pb as an explanation for isotopic differences is not valid. Overall, the brief review of these case studies shows that Q-ICP-MS as commonly practiced is not a suitable technique for precise and accurate Pb isotopic analysis in the environment and health fields
    Keywords: Lead isotopes ; ICP-MS ; TIMS ; MC-ICP-MS ; Environment ; Humans ; Rats ; Fractionation
    Repository Name: Woods Hole Open Access Server
    Type: Article
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  • 2
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-12
    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〉
    Keywords: Algorithms ; Amyotrophic Lateral Sclerosis/diagnosis ; *Awards and Prizes ; Biomedical Research/economics/*manpower/*methods ; Breast Neoplasms/diagnosis/pathology ; *Competitive Behavior ; Cooperative Behavior ; Crowdsourcing/economics/*methods ; Datasets as Topic ; Drug Industry/economics/methods ; Humans ; Information Dissemination ; *Interdisciplinary Communication ; Internet/utilization ; Male ; Models, Biological ; Monitoring, Physiologic/instrumentation ; Prognosis ; Reproducibility of Results ; Smartphone/utilization ; Statistics as Topic ; Systems Biology/manpower/methods ; Time Factors
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  • 3
    Publication Date: 2016-03-10
    Description: Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Thal, David M -- Sun, Bingfa -- Feng, Dan -- Nawaratne, Vindhya -- Leach, Katie -- Felder, Christian C -- Bures, Mark G -- Evans, David A -- Weis, William I -- Bachhawat, Priti -- Kobilka, Tong Sun -- Sexton, Patrick M -- Kobilka, Brian K -- Christopoulos, Arthur -- U19 GM106990/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):335-40. doi: 10.1038/nature17188. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, 3052, Victoria, Australia. ; ConfometRx, 3070 Kenneth Street, Santa Clara, California 95054, USA. ; Neuroscience, Eli Lilly, Indianapolis, Indiana 46285, USA. ; Computational Chemistry and Chemoinformatics, Eli Lilly, Indianapolis, Indiana 46285, USA. ; Computational Chemistry and Chemoinformatics, Eli Lilly, Sunninghill Road, Windlesham GU20 6PH, UK. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Structural Biology, 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/26958838" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcholine/metabolism ; Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Alzheimer Disease ; Crystallization ; Crystallography, X-Ray ; Drug Inverse Agonism ; Humans ; Models, Molecular ; Nicotinic Acids/metabolism/pharmacology ; Receptor, Muscarinic M1/*chemistry/metabolism ; Receptor, Muscarinic M4/*chemistry/metabolism ; Schizophrenia ; Static Electricity ; Substrate Specificity ; Surface Properties ; Thiophenes/metabolism/pharmacology ; Tiotropium Bromide/pharmacology
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  • 4
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bender, Eric -- England -- Nature. 2016 May 11;533(7602):S59. doi: 10.1038/533S59a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27167392" target="_blank"〉PubMed〈/a〉
    Keywords: Diffusion of Innovation ; Drug Discovery/*economics/*methods/organization & administration/trends ; Drug Industry/economics/*methods/organization & administration/*trends ; Humans ; Leadership ; Patient Advocacy
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  • 5
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gibney, Elizabeth -- England -- Nature. 2016 Mar 17;531(7594):284-5. doi: 10.1038/531284a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26983517" target="_blank"〉PubMed〈/a〉
    Keywords: Artificial Intelligence/*trends ; Child ; Diagnosis ; *Games, Recreational/psychology ; Humans ; Language ; Learning ; Male ; Smartphone/trends
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  • 6
    Publication Date: 2016-01-21
    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〉
    Keywords: Amino Acid Motifs ; Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; Human papillomavirus 16/chemistry/*metabolism/pathogenicity ; Humans ; Models, Biological ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Oncogene Proteins, Viral/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; *Proteolysis ; Repressor Proteins/*chemistry/genetics/*metabolism ; Tumor Suppressor Protein p53/*chemistry/genetics/*metabolism ; Ubiquitin-Protein Ligases/*chemistry
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  • 7
    Publication Date: 2016-01-26
    Description: Intracellular aggregation of the human amyloid protein alpha-synuclein is causally linked to Parkinson's disease. While the isolated protein is intrinsically disordered, its native structure in mammalian cells is not known. Here we use nuclear magnetic resonance (NMR) and electron paramagnetic resonance (EPR) spectroscopy to derive atomic-resolution insights into the structure and dynamics of alpha-synuclein in different mammalian cell types. We show that the disordered nature of monomeric alpha-synuclein is stably preserved in non-neuronal and neuronal cells. Under physiological cell conditions, alpha-synuclein is amino-terminally acetylated and adopts conformations that are more compact than when in buffer, with residues of the aggregation-prone non-amyloid-beta component (NAC) region shielded from exposure to the cytoplasm, which presumably counteracts spontaneous aggregation. These results establish that different types of crowded intracellular environments do not inherently promote alpha-synuclein oligomerization and, more generally, that intrinsic structural disorder is sustainable in mammalian cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Theillet, Francois-Xavier -- Binolfi, Andres -- Bekei, Beata -- Martorana, Andrea -- Rose, Honor May -- Stuiver, Marchel -- Verzini, Silvia -- Lorenz, Dorothea -- van Rossum, Marleen -- Goldfarb, Daniella -- Selenko, Philipp -- England -- Nature. 2016 Feb 4;530(7588):45-50. doi: 10.1038/nature16531. Epub 2016 Jan 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉In-Cell NMR Laboratory, Department of NMR-supported Structural Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Robert-Rossle Strasse 10, 13125 Berlin, Germany. ; Department of Chemical Physics, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Molecular Physiology and Cell Biology, Leibniz Institute of Molecular Pharmacology (FMP Berlin), Robert-Rossle Strasse 10, 13125 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26808899" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Cell Line ; Cytoplasm/chemistry/metabolism ; Electron Spin Resonance Spectroscopy ; HeLa Cells ; Humans ; Intracellular Space/*chemistry/*metabolism ; Neurons/cytology/metabolism ; Nuclear Magnetic Resonance, Biomolecular ; Protein Conformation ; alpha-Synuclein/*chemistry/*metabolism
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  • 8
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maxmen, Amy -- England -- Nature. 2016 Mar 17;531(7594):S58-9. doi: 10.1038/531S58a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26981730" target="_blank"〉PubMed〈/a〉
    Keywords: Asthma/epidemiology/psychology/therapy ; California ; Cities/*statistics & numerical data ; Crime/psychology ; *Health Behavior ; Humans ; *Parks, Recreational ; Poverty/psychology ; Social Class ; Stress, Psychological/prevention & control/*psychology/therapy ; Uncertainty
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  • 9
    Publication Date: 2016-01-21
    Description: RNA polymerase (Pol) II produces messenger RNA during transcription of protein-coding genes in all eukaryotic cells. The Pol II structure is known at high resolution from X-ray crystallography for two yeast species. Structural studies of mammalian Pol II, however, remain limited to low-resolution electron microscopy analysis of human Pol II and its complexes with various proteins. Here we report the 3.4 A resolution cryo-electron microscopy structure of mammalian Pol II in the form of a transcribing complex comprising DNA template and RNA transcript. We use bovine Pol II, which is identical to the human enzyme except for seven amino-acid residues. The obtained atomic model closely resembles its yeast counterpart, but also reveals unknown features. Binding of nucleic acids to the polymerase involves 'induced fit' of the mobile Pol II clamp and active centre region. DNA downstream of the transcription bubble contacts a conserved 'TPSA motif' in the jaw domain of the Pol II subunit RPB5, an interaction that is apparently already established during transcription initiation. Upstream DNA emanates from the active centre cleft at an angle of approximately 105 degrees with respect to downstream DNA. This position of upstream DNA allows for binding of the general transcription elongation factor DSIF (SPT4-SPT5) that we localize over the active centre cleft in a conserved position on the clamp domain of Pol II. Our results define the structure of mammalian Pol II in its functional state, indicate that previous crystallographic analysis of yeast Pol II is relevant for understanding gene transcription in all eukaryotes, and provide a starting point for a mechanistic analysis of human transcription.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bernecky, Carrie -- Herzog, Franz -- Baumeister, Wolfgang -- Plitzko, Jurgen M -- Cramer, Patrick -- England -- Nature. 2016 Jan 28;529(7587):551-4. doi: 10.1038/nature16482. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Biophysical Chemistry, Department of Molecular Biology, Am Fassberg 11, 37077 Gottingen, Germany. ; Gene Center Munich, Ludwig-Maximilians-Universitat Munchen, Feodor-Lynen-Strasse 25, 81377 Munich, Germany. ; Max Planck Institute for Biochemistry, Department of Molecular Structural Biology, Am Klopferspitz 18, 82152 Martinsried, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789250" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Motifs ; Animals ; Catalytic Domain ; Cattle ; *Cryoelectron Microscopy ; DNA/genetics/metabolism/ultrastructure ; Humans ; Models, Molecular ; Nucleic Acids/chemistry/metabolism ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; RNA Polymerase II/chemistry/*metabolism/*ultrastructure ; RNA, Messenger/biosynthesis/genetics/ultrastructure ; Saccharomyces cerevisiae/enzymology ; Templates, Genetic ; *Transcription Elongation, Genetic
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  • 10
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McKinlay, Roger -- England -- Nature. 2016 Mar 31;531(7596):573-5. doi: 10.1038/531573a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Royal Institute of Navigation, and a former head of engineering at Thales UK. He sits on the EPSRC Quantum Technology Strategic Advisory Board.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27029262" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cues ; Facility Design and Construction ; Geographic Information Systems/instrumentation/*utilization ; Hippocampus/anatomy & histology/physiology ; Humans ; Maps as Topic ; Orientation/physiology ; Satellite Communications/utilization ; Smartphone/utilization ; Spatial Learning/*physiology ; Spatial Memory/physiology ; Spatial Navigation/*physiology
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  • 11
    Publication Date: 2016-03-05
    Description: Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846772/" 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/PMC4846772/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beyaz, Semir -- Mana, Miyeko D -- Roper, Jatin -- Kedrin, Dmitriy -- Saadatpour, Assieh -- Hong, Sue-Jean -- Bauer-Rowe, Khristian E -- Xifaras, Michael E -- Akkad, Adam -- Arias, Erika -- Pinello, Luca -- Katz, Yarden -- Shinagare, Shweta -- Abu-Remaileh, Monther -- Mihaylova, Maria M -- Lamming, Dudley W -- Dogum, Rizkullah -- Guo, Guoji -- Bell, George W -- Selig, Martin -- Nielsen, G Petur -- Gupta, Nitin -- Ferrone, Cristina R -- Deshpande, Vikram -- Yuan, Guo-Cheng -- Orkin, Stuart H -- Sabatini, David M -- Yilmaz, Omer H -- AI47389/AI/NIAID NIH HHS/ -- DK043351/DK/NIDDK NIH HHS/ -- K08 CA198002/CA/NCI NIH HHS/ -- K99 AG041765/AG/NIA NIH HHS/ -- K99 AG045144/AG/NIA NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 AG041765/AG/NIA NIH HHS/ -- R00 AG045144/AG/NIA NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32DK007191/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 3;531(7592):53-8. doi: 10.1038/nature17173.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The David H. Koch Institute for Integrative Cancer Research at MIT, Department of Biology, MIT, Cambridge, Massachusetts 02139, USA. ; Division of Hematology/Oncology, Boston Children's Hospital and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Division of Gastroenterology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, Massachusetts 02111, USA. ; Departments of Pathology, Gastroenterology, and Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Whitehead Institute for Biomedical Research, Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, Massachusetts 02142, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin 53705, USA. ; Division of Digestive Diseases, University of Mississippi Medical Center, Jackson, Missisippi 39216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935695" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; Cell Self Renewal/drug effects ; Cell Transformation, Neoplastic/*drug effects ; Colonic Neoplasms/*pathology ; Diet, High-Fat/*adverse effects ; Female ; Genes, APC ; Humans ; Intestines/*pathology ; Male ; Mice ; Obesity/chemically induced/pathology ; Organoids/drug effects/metabolism/pathology ; PPAR delta/metabolism ; Signal Transduction/drug effects ; Stem Cell Niche/drug effects ; Stem Cells/*drug effects/metabolism/*pathology ; beta Catenin/metabolism
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  • 12
    Publication Date: 2016-04-07
    Description: As the last habitable continent colonized by humans, the site of multiple domestication hotspots, and the location of the largest Pleistocene megafaunal extinction, South America is central to human prehistory. Yet remarkably little is known about human population dynamics during colonization, subsequent expansions, and domestication. Here we reconstruct the spatiotemporal patterns of human population growth in South America using a newly aggregated database of 1,147 archaeological sites and 5,464 calibrated radiocarbon dates spanning fourteen thousand to two thousand years ago (ka). We demonstrate that, rather than a steady exponential expansion, the demographic history of South Americans is characterized by two distinct phases. First, humans spread rapidly throughout the continent, but remained at low population sizes for 8,000 years, including a 4,000-year period of 'boom-and-bust' oscillations with no net growth. Supplementation of hunting with domesticated crops and animals had a minimal impact on population carrying capacity. Only with widespread sedentism, beginning ~5 ka, did a second demographic phase begin, with evidence for exponential population growth in cultural hotspots, characteristic of the Neolithic transition worldwide. The unique extent of humanity's ability to modify its environment to markedly increase carrying capacity in South America is therefore an unexpectedly recent phenomenon.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goldberg, Amy -- Mychajliw, Alexis M -- Hadly, Elizabeth A -- England -- Nature. 2016 Apr 14;532(7598):232-5. doi: 10.1038/nature17176. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biology Department, Stanford University, Stanford, California 94305, USA. ; Woods Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049941" target="_blank"〉PubMed〈/a〉
    Keywords: Agriculture/history ; Archaeology ; Climate ; Geographic Mapping ; History, Ancient ; Human Migration/*history ; Humans ; Population Dynamics/*history ; Radiometric Dating ; Siberia/ethnology ; South America
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  • 13
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bruggeman, Jeroen -- England -- Nature. 2016 Apr 14;532(7598):177. doi: 10.1038/532177e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Amsterdam, the Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075089" target="_blank"〉PubMed〈/a〉
    Keywords: *Cooperative Behavior ; Female ; Humans ; *Interpersonal Relations ; Male ; *Morals ; Punishment/*psychology ; *Religion and Psychology
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  • 14
    Publication Date: 2016-03-10
    Description: The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayashi, Ryuhei -- Ishikawa, Yuki -- Sasamoto, Yuzuru -- Katori, Ryosuke -- Nomura, Naoki -- Ichikawa, Tatsuya -- Araki, Saori -- Soma, Takeshi -- Kawasaki, Satoshi -- Sekiguchi, Kiyotoshi -- Quantock, Andrew J -- Tsujikawa, Motokazu -- Nishida, Kohji -- England -- Nature. 2016 Mar 17;531(7594):376-80. doi: 10.1038/nature17000. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan. ; Structural Biophysics Group, School of Optometry and Vision Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF24 4HQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958835" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Cornea/*cytology/*growth & development/physiology ; Corneal Transplantation ; Ectoderm/cytology ; Epithelial Cells/cytology ; Epithelium, Corneal/cytology ; Female ; Humans ; Induced Pluripotent Stem Cells/*cytology ; Lens, Crystalline/cytology ; Mice ; Morphogenesis ; Phenotype ; Rabbits ; *Recovery of Function ; Retinal Pigment Epithelium/cytology
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  • 15
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Munoz-Sanjuan, Ignacio -- England -- Nature. 2016 Mar 10;531(7593):141. doi: 10.1038/531141a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961621" target="_blank"〉PubMed〈/a〉
    Keywords: *Biomedical Research/ethics ; Clinical Trials as Topic ; Family Planning Services ; Genetic Counseling ; Genetic Testing ; Health Services Accessibility/*ethics ; *Healthy Volunteers ; Heterozygote ; Humans ; *Huntington Disease/drug therapy/epidemiology/genetics ; Lobbying ; Quality of Life ; *Research Personnel ; *Residence Characteristics ; Venezuela/epidemiology
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  • 16
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wald, Chelsea -- England -- Nature. 2016 May 5;533(7601):S47. doi: 10.1038/533S47a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27144610" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Austria ; Entrepreneurship/economics/organization & administration ; Humans ; Inventions/economics ; Inventors/economics/education/psychology ; Research/*economics/*organization & administration ; Research Personnel/economics/education/psychology ; *Technology Transfer ; Uncertainty
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  • 17
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wald, Chelsea -- England -- Nature. 2016 Mar 3;531(7592):S14-5. doi: 10.1038/531S14a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934520" target="_blank"〉PubMed〈/a〉
    Keywords: Aged, 80 and over ; Animals ; Brain/*physiology ; Cognition/*physiology ; Cognition Disorders/prevention & control/psychology ; Communication ; Female ; Friends/psychology ; Humans ; Inflammation/pathology/prevention & control/therapy ; *Interpersonal Relations ; Longevity/physiology ; Male ; Memory/physiology ; Primates/anatomy & histology/physiology ; *Social Networking ; Thinking/physiology ; White Matter/pathology
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  • 18
    Publication Date: 2016-01-28
    Description: Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1beta and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Zeng, Melody Y -- Yang, Dahai -- Motro, Benny -- Nunez, Gabriel -- R01AI063331/AI/NIAID NIH HHS/ -- R01DK091191/DK/NIDDK NIH HHS/ -- T32 HL007517/HL/NHLBI NIH HHS/ -- T32DK094775/DK/NIDDK NIH HHS/ -- T32HL007517/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):354-7. doi: 10.1038/nature16959. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814970" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics/metabolism ; Biocatalysis ; Carrier Proteins/chemistry/genetics/*metabolism ; Caspase 1/metabolism ; Catalytic Domain ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes/genetics ; Enzyme Activation ; HEK293 Cells ; Humans ; Inflammasomes/*chemistry/*metabolism ; Interleukin-1beta/secretion ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Potassium/*metabolism ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/chemistry/deficiency/genetics/*metabolism
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  • 19
    Publication Date: 2016-03-17
    Description: Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Headley, Mark B -- Bins, Adriaan -- Nip, Alyssa -- Roberts, Edward W -- Looney, Mark R -- Gerard, Audrey -- Krummel, Matthew F -- P01 HL024136/HL/NHLBI NIH HHS/ -- R21 CA167601/CA/NCI NIH HHS/ -- R21CA167601/CA/NCI NIH HHS/ -- U54 CA163123/CA/NCI NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):513-7. doi: 10.1038/nature16985. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA. ; Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef, 91105AZ Amsterdam, The Netherlands. ; Departments of Medicine and Laboratory Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW512, California 94143-0511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capillaries/pathology ; Cell Line, Tumor ; Cell Lineage ; *Cell Movement ; Dendritic Cells/cytology/immunology ; Female ; Genes, Reporter/genetics ; Humans ; Lung/blood supply/cytology/*immunology/*pathology ; Lung Neoplasms/*immunology/pathology/*secondary ; Male ; Melanoma, Experimental/immunology/pathology ; Mice ; Microscopy, Confocal ; Myeloid Cells/cytology ; Neoplasm Metastasis/*immunology/*pathology ; Neoplastic Cells, Circulating/pathology
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  • 20
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nardone, Roland M -- MacLeod, Roderick A F -- Capes-Davis, Amanda -- England -- Nature. 2016 Apr 21;532(7599):313.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27127813" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; DNA Contamination ; Databases, Factual ; *Disease Models, Animal ; Guidelines as Topic ; Heterografts/*standards ; Humans ; National Cancer Institute (U.S.) ; Neoplasms/*pathology ; Quality Control ; Reproducibility of Results ; United States ; Xenograft Model Antitumor Assays/*standards
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  • 21
    Publication Date: 2016-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Butler, Declan -- England -- Nature. 2016 Feb 4;530(7588):13-4. doi: 10.1038/nature.2016.19259.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842033" target="_blank"〉PubMed〈/a〉
    Keywords: Brazil/epidemiology ; Diagnostic Errors/*statistics & numerical data ; Female ; Humans ; Infectious Disease Transmission, Vertical/statistics & numerical data ; Microcephaly/*diagnosis/*epidemiology/etiology/virology ; Pregnancy ; *Uncertainty ; Zika Virus/isolation & purification/*pathogenicity ; Zika Virus Infection/*epidemiology/transmission/virology
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  • 22
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    Nature Publishing Group (NPG)
    Publication Date: 2016-02-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heuckeroth, Robert O -- England -- Nature. 2016 Mar 3;531(7592):44-5. doi: 10.1038/nature16877. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Hospital of Philadelphia Research Institute and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863191" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage ; *Cell- and Tissue-Based Therapy ; Drug Discovery/*methods ; Enteric Nervous System/*pathology ; Female ; Hirschsprung Disease/*drug therapy/*pathology ; Humans ; Male ; Neurons/*pathology
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  • 23
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-24
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hollon, Nick G -- Phillips, Paul E M -- England -- Nature. 2016 Mar 31;531(7596):588-9. doi: 10.1038/nature17314. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Psychiatry &Behavioral Sciences and the Department of Pharmacology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007851" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Decision Making ; Humans ; Male ; Neurons/*metabolism ; Nucleus Accumbens/*cytology/*metabolism ; Receptors, Dopamine D2/*metabolism ; *Risk Management
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  • 24
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hood, Bruce -- England -- Nature. 2016 Mar 24;531(7595):438-40. doi: 10.1038/531438a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Bristol, UK, and founder of Speakezee.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27008953" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Child, Preschool ; *Consumer Behavior ; Efficiency, Organizational/trends ; Humans ; Object Attachment ; Ownership ; Recycling/*economics/*trends ; Self Concept ; Social Class
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  • 25
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2016 Apr 21;532(7599):289-90. doi: 10.1038/532289a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27111607" target="_blank"〉PubMed〈/a〉
    Keywords: CRISPR-Cas Systems/genetics ; China ; *Embryo Research/ethics/legislation & jurisprudence ; Female ; Genetic Engineering/ethics/legislation & jurisprudence/*trends ; *Genetic Research/ethics/legislation & jurisprudence ; Great Britain ; Humans ; Pregnancy ; Sweden
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  • 26
    Publication Date: 2016-03-24
    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〉
    Keywords: Animals ; Arrestins/chemistry/*metabolism ; Biosensing Techniques ; Cattle ; Cell Line ; Cell Membrane/metabolism ; Cell Survival ; Crystallography, X-Ray ; Fluorescence Resonance Energy Transfer ; Humans ; Kinetics ; Models, Molecular ; Protein Binding ; Protein Conformation ; Receptors, G-Protein-Coupled/chemistry/*metabolism ; Signal Transduction ; Substrate Specificity ; Time Factors
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  • 27
    Publication Date: 2016-05-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watson, Traci -- England -- Nature. 2016 May 5;533(7602):155. doi: 10.1038/nature.2016.19864.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27172024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Egypt ; Female ; *Flowers ; History, Ancient ; Humans ; Infrared Rays ; *Mummies/history ; Religion/history ; *Symbolism ; Tattooing/*history
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  • 28
    Publication Date: 2016-03-05
    Description: The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Jordan, Robert -- Lo, Michael K -- Ray, Adrian S -- Mackman, Richard L -- Soloveva, Veronica -- Siegel, Dustin -- Perron, Michel -- Bannister, Roy -- Hui, Hon C -- Larson, Nate -- Strickley, Robert -- Wells, Jay -- Stuthman, Kelly S -- Van Tongeren, Sean A -- Garza, Nicole L -- Donnelly, Ginger -- Shurtleff, Amy C -- Retterer, Cary J -- Gharaibeh, Dima -- Zamani, Rouzbeh -- Kenny, Tara -- Eaton, Brett P -- Grimes, Elizabeth -- Welch, Lisa S -- Gomba, Laura -- Wilhelmsen, Catherine L -- Nichols, Donald K -- Nuss, Jonathan E -- Nagle, Elyse R -- Kugelman, Jeffrey R -- Palacios, Gustavo -- Doerffler, Edward -- Neville, Sean -- Carra, Ernest -- Clarke, Michael O -- Zhang, Lijun -- Lew, Willard -- Ross, Bruce -- Wang, Queenie -- Chun, Kwon -- Wolfe, Lydia -- Babusis, Darius -- Park, Yeojin -- Stray, Kirsten M -- Trancheva, Iva -- Feng, Joy Y -- Barauskas, Ona -- Xu, Yili -- Wong, Pamela -- Braun, Molly R -- Flint, Mike -- McMullan, Laura K -- Chen, Shan-Shan -- Fearns, Rachel -- Swaminathan, Swami -- Mayers, Douglas L -- Spiropoulou, Christina F -- Lee, William A -- Nichol, Stuart T -- Cihlar, Tomas -- Bavari, Sina -- R01 AI113321/AI/NIAID NIH HHS/ -- R01AI113321/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA. ; United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ; Boston University School of Medicine, Boston, Massachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934220" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use ; Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacokinetics/pharmacology/*therapeutic use ; Cell Line, Tumor ; Ebolavirus/drug effects ; Female ; HeLa Cells ; Hemorrhagic Fever, Ebola/*drug therapy/prevention & control ; Humans ; Macaca mulatta/*virology ; Male ; Molecular Sequence Data ; Organ Specificity ; Prodrugs/pharmacokinetics/pharmacology/therapeutic use ; Ribonucleotides/pharmacokinetics/pharmacology/*therapeutic use
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  • 29
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearce, Warren -- Hartley, Sarah -- Nerlich, Brigitte -- England -- Nature. 2016 Mar 3;531(7592):35. doi: 10.1038/531035d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Nottingham, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935688" target="_blank"〉PubMed〈/a〉
    Keywords: Humans ; *Information Dissemination ; Research/*standards
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  • 30
    Publication Date: 2016-04-07
    Description: Cells receive growth and survival stimuli through their attachment to an extracellular matrix (ECM). Overcoming the addiction to ECM-induced signals is required for anchorage-independent growth, a property of most malignant cells. Detachment from ECM is associated with enhanced production of reactive oxygen species (ROS) owing to altered glucose metabolism. Here we identify an unconventional pathway that supports redox homeostasis and growth during adaptation to anchorage independence. We observed that detachment from monolayer culture and growth as anchorage-independent tumour spheroids was accompanied by changes in both glucose and glutamine metabolism. Specifically, oxidation of both nutrients was suppressed in spheroids, whereas reductive formation of citrate from glutamine was enhanced. Reductive glutamine metabolism was highly dependent on cytosolic isocitrate dehydrogenase-1 (IDH1), because the activity was suppressed in cells homozygous null for IDH1 or treated with an IDH1 inhibitor. This activity occurred in absence of hypoxia, a well-known inducer of reductive metabolism. Rather, IDH1 mitigated mitochondrial ROS in spheroids, and suppressing IDH1 reduced spheroid growth through a mechanism requiring mitochondrial ROS. Isotope tracing revealed that in spheroids, isocitrate/citrate produced reductively in the cytosol could enter the mitochondria and participate in oxidative metabolism, including oxidation by IDH2. This generates NADPH in the mitochondria, enabling cells to mitigate mitochondrial ROS and maximize growth. Neither IDH1 nor IDH2 was necessary for monolayer growth, but deleting either one enhanced mitochondrial ROS and reduced spheroid size, as did deletion of the mitochondrial citrate transporter protein. Together, the data indicate that adaptation to anchorage independence requires a fundamental change in citrate metabolism, initiated by IDH1-dependent reductive carboxylation and culminating in suppression of mitochondrial ROS.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860952/" 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/PMC4860952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Lei -- Shestov, Alexander A -- Swain, Pamela -- Yang, Chendong -- Parker, Seth J -- Wang, Qiong A -- Terada, Lance S -- Adams, Nicholas D -- McCabe, Michael T -- Pietrak, Beth -- Schmidt, Stan -- Metallo, Christian M -- Dranka, Brian P -- Schwartz, Benjamin -- DeBerardinis, Ralph J -- R01 CA157996/CA/NCI NIH HHS/ -- R01 CA188652/CA/NCI NIH HHS/ -- R01CA157996/CA/NCI NIH HHS/ -- R01CA188652/CA/NCI NIH HHS/ -- England -- Nature. 2016 Apr 14;532(7598):255-8. doi: 10.1038/nature17393. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, Texas 75390-8502, USA. ; Department of Radiology, University of Pennsylvania School of Medicine, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104, USA. ; Seahorse Bioscience, 16 Esquire Road, North Billerica, Massachusetts 01862, USA. ; Department of Bioengineering, University of California, San Diego, La Jolla, California 92093, USA. ; Touchstone Diabetes Center, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, USA. ; Department of Pediatrics, UT Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049945" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Adhesion ; Cell Hypoxia ; Cell Line, Tumor ; Cell Proliferation ; Citric Acid/*metabolism ; Contact Inhibition ; Cytosol/enzymology/metabolism ; Extracellular Matrix/metabolism ; Glucose/metabolism ; Glutamic Acid/metabolism ; Glutamine/metabolism ; *Homeostasis ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/deficiency/genetics/*metabolism ; Isocitrates/metabolism ; Mitochondria/*metabolism ; NADP/biosynthesis ; Neoplasms/enzymology/*metabolism/*pathology ; Oxidation-Reduction ; Oxidative Stress ; Reactive Oxygen Species/*metabolism ; Spheroids, Cellular/metabolism/pathology
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  • 31
    Publication Date: 2016-04-07
    Description: In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joesch, Maximilian -- Meister, Markus -- England -- Nature. 2016 Apr 14;532(7598):236-9. doi: 10.1038/nature17158. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049951" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Color ; Color Perception/*physiology/radiation effects ; Color Vision/*physiology/radiation effects ; Darkness ; Female ; Humans ; Male ; Mice ; Models, Neurological ; Neural Pathways/*physiology/radiation effects ; Retinal Cone Photoreceptor Cells/*metabolism/radiation effects ; Retinal Ganglion Cells/metabolism/radiation effects ; Retinal Rod Photoreceptor Cells/*metabolism/radiation effects ; Synapses/metabolism/radiation effects ; Territoriality ; Ultraviolet Rays
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  • 32
    Publication Date: 2016-04-15
    Description: Promoters are DNA sequences that have an essential role in controlling gene expression. While recent whole cancer genome analyses have identified numerous hotspots of somatic point mutations within promoters, many have not yet been shown to perturb gene expression or drive cancer development. As such, positive selection alone may not adequately explain the frequency of promoter point mutations in cancer genomes. Here we show that increased mutation density at gene promoters can be linked to promoter activity and differential nucleotide excision repair (NER). By analysing 1,161 human cancer genomes across 14 cancer types, we find evidence for increased local density of somatic point mutations within the centres of DNase I-hypersensitive sites (DHSs) in gene promoters. Mutated DHSs were strongly associated with transcription initiation activity, in which active promoters but not enhancers of equal DNase I hypersensitivity were most mutated relative to their flanking regions. Notably, analysis of genome-wide maps of NER shows that NER is impaired within the DHS centre of active gene promoters, while XPC-deficient skin cancers do not show increased promoter mutation density, pinpointing differential NER as the underlying cause of these mutation hotspots. Consistent with this finding, we observe that melanomas with an ultraviolet-induced DNA damage mutation signature show greatest enrichment of promoter mutations, whereas cancers that are not highly dependent on NER, such as colon cancer, show no sign of such enrichment. Taken together, our analysis has uncovered the presence of a previously unknown mechanism linking transcription initiation and NER as a major contributor of somatic point mutation hotspots at active gene promoters in cancer genomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perera, Dilmi -- Poulos, Rebecca C -- Shah, Anushi -- Beck, Dominik -- Pimanda, John E -- Wong, Jason W H -- England -- Nature. 2016 Apr 14;532(7598):259-63. doi: 10.1038/nature17437.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Prince of Wales Clinical School and Lowy Cancer Research Centre, UNSW Australia, Sydney 2052, Australia. ; Department of Haematology, Prince of Wales Hospital, Sydney 2031, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075100" target="_blank"〉PubMed〈/a〉
    Keywords: Colonic Neoplasms/genetics ; DNA Damage/genetics ; DNA Repair/*genetics/radiation effects ; Deoxyribonuclease I/metabolism ; Enhancer Elements, Genetic/genetics ; Gene Expression Regulation, Neoplastic/genetics ; Genome, Human/*genetics ; Humans ; Lung Neoplasms/genetics ; Melanoma/genetics ; Mutagenesis/*genetics ; *Mutation Rate ; Neoplasms/*genetics ; Point Mutation/genetics ; Promoter Regions, Genetic/*genetics ; *Transcription Initiation, Genetic ; Ultraviolet Rays
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  • 33
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pollock, Kevin -- England -- Nature. 2016 Mar 17;531(7594):S64-6. doi: 10.1038/531S64a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26981733" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cities ; *City Planning ; Feedback ; Humans ; *Physics ; Plague/epidemiology ; Rats ; *Urbanization ; Vietnam/epidemiology
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  • 34
    Publication Date: 2016-03-31
    Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
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  • 35
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉King, Anthony -- England -- Nature. 2016 Mar 3;531(7592):S18-9. doi: 10.1038/531S18a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934522" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; Brain/*physiology ; Bullying ; DNA Methylation ; Depression/complications/prevention & control/therapy ; Emotional Adjustment ; Epigenesis, Genetic/genetics ; Female ; Hippocampus/metabolism ; Humans ; Hydrocortisone/metabolism ; Maternal Behavior ; Memory/physiology ; Mice ; Models, Animal ; Oxytocin/metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects/genetics ; Psychological Trauma/complications/genetics/metabolism ; Rats ; *Resilience, Psychological ; Social Isolation/psychology ; Stress, Psychological/complications/genetics/metabolism/therapy
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  • 36
    Publication Date: 2016-02-04
    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〉
    Keywords: Aircraft ; Disease Outbreaks/statistics & numerical data ; Ebolavirus/classification/*genetics/pathogenicity ; *Epidemiological Monitoring ; Genome, Viral/*genetics ; Guinea/epidemiology ; Hemorrhagic Fever, Ebola/*epidemiology/*virology ; Humans ; Mutagenesis/genetics ; Mutation Rate ; Sequence Analysis, DNA/*instrumentation/*methods ; Time Factors
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  • 37
    Publication Date: 2016-03-31
    Description: Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/beta-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" 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/PMC4864035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Zinan -- Tang, Alan T -- Wong, Weng-Yew -- Bamezai, Sharika -- Goddard, Lauren M -- Shenkar, Robert -- Zhou, Su -- Yang, Jisheng -- Wright, Alexander C -- Foley, Matthew -- Arthur, J Simon C -- Whitehead, Kevin J -- Awad, Issam A -- Li, Dean Y -- Zheng, Xiangjian -- Kahn, Mark L -- P01 HL075215/HL/NHLBI NIH HHS/ -- P01 HL120846/HL/NHLBI NIH HHS/ -- P01 NS092521/NS/NINDS NIH HHS/ -- P01NS092521/NS/NINDS NIH HHS/ -- R01 HL094326/HL/NHLBI NIH HHS/ -- R01HL-084516/HL/NHLBI NIH HHS/ -- R01HL094326/HL/NHLBI NIH HHS/ -- R01NS075168/NS/NINDS NIH HHS/ -- T32HL07439/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. ; Laboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia. ; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois 60637, USA. ; Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA. ; Sydney Microscopy &Microanalysis, University of Sydney, Sydney, New South Wales 2050, Australia. ; Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, UK. ; Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA. ; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. ; Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027284" target="_blank"〉PubMed〈/a〉
    Keywords: ADAM Proteins/metabolism ; Animals ; Animals, Newborn ; Carrier Proteins/genetics/metabolism ; Disease Models, Animal ; Endothelial Cells/enzymology/*metabolism ; Female ; Hemangioma, Cavernous, Central Nervous System/etiology/*metabolism/pathology ; Humans ; Kruppel-Like Transcription Factors/deficiency/*metabolism ; MAP Kinase Kinase Kinase 3/deficiency/*metabolism ; *MAP Kinase Signaling System ; Male ; Mice ; Protein Binding ; rho GTP-Binding Proteins/metabolism
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  • 38
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    Nature Publishing Group (NPG)
    Publication Date: 2016-01-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Jan 7;529(7584):5. doi: 10.1038/529005a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738571" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bibliometrics ; *Cooperative Behavior ; Developed Countries ; Developing Countries ; *Group Processes ; Humans ; *International Cooperation ; Research/manpower/*organization & administration
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  • 39
    Publication Date: 2016-03-17
    Description: The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1beta resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" 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/PMC4854628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Loebbermann, Jens -- Nakaya, Helder I -- Khan, Nooruddin -- Ma, Hualing -- Gama, Leonardo -- Machiah, Deepa K -- Lawson, Benton -- Hakimpour, Paul -- Wang, Yi-chong -- Li, Shuzhao -- Sharma, Prachi -- Kaufman, Randal J -- Martinez, Jennifer -- Pulendran, Bali -- R01 DK088227/DK/NIDDK NIH HHS/ -- R01 DK103185/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK042394/DK/NIDDK NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- ZIA ES103286-01/Intramural NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):523-7. doi: 10.1038/nature17186. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508, Brazil. ; Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India. ; Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Virology Core, Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Degenerative Disease Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037 USA. ; National Institute of Environmental Health Sciences, Mail Drop D2-01 Research Triangle Park, North Carolina 27709, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982722" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/administration & dosage/deficiency/*metabolism/pharmacology ; Animals ; Antigen-Presenting Cells/immunology/metabolism ; Autophagy ; Colitis/etiology/*metabolism/pathology/prevention & control ; Disease Models, Animal ; Epithelial Cells/metabolism ; Female ; Humans ; Inflammasomes/*antagonists & inhibitors/metabolism ; Inflammation/etiology/*metabolism/pathology/prevention & control ; Interleukin-1beta/immunology ; Intestines/*metabolism/*pathology ; Male ; Mice ; Microtubule-Associated Proteins/deficiency/metabolism ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; Stress, Physiological ; Th17 Cells/immunology ; Ubiquitin-Activating Enzymes/deficiency/metabolism
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  • 40
    Publication Date: 2016-01-07
    Description: CRISPR-Cas9 nucleases are widely used for genome editing but can induce unwanted off-target mutations. Existing strategies for reducing genome-wide off-target effects of the widely used Streptococcus pyogenes Cas9 (SpCas9) are imperfect, possessing only partial or unproven efficacies and other limitations that constrain their use. Here we describe SpCas9-HF1, a high-fidelity variant harbouring alterations designed to reduce non-specific DNA contacts. SpCas9-HF1 retains on-target activities comparable to wild-type SpCas9 with 〉85% of single-guide RNAs (sgRNAs) tested in human cells. Notably, with sgRNAs targeted to standard non-repetitive sequences, SpCas9-HF1 rendered all or nearly all off-target events undetectable by genome-wide break capture and targeted sequencing methods. Even for atypical, repetitive target sites, the vast majority of off-target mutations induced by wild-type SpCas9 were not detected with SpCas9-HF1. With its exceptional precision, SpCas9-HF1 provides an alternative to wild-type SpCas9 for research and therapeutic applications. More broadly, our results suggest a general strategy for optimizing genome-wide specificities of other CRISPR-RNA-guided nucleases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinstiver, Benjamin P -- Pattanayak, Vikram -- Prew, Michelle S -- Tsai, Shengdar Q -- Nguyen, Nhu T -- Zheng, Zongli -- Joung, J Keith -- DP1 GM105378/DP/NCCDPHP CDC HHS/ -- R01 GM088040/GM/NIGMS NIH HHS/ -- R01 GM107427/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):490-5. doi: 10.1038/nature16526. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Pathology Unit, Center for Cancer Research, and Center for Computational and Integrative Biology, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735016" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; CRISPR-Associated Proteins/*genetics/*metabolism ; CRISPR-Cas Systems/*physiology ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; DNA/genetics/metabolism ; DNA-Binding Proteins/genetics/metabolism ; Endonucleases/genetics/*metabolism ; *Genetic Engineering ; Genome, Human/*genetics ; Humans ; Mutation ; Protein Binding ; RNA/genetics ; Reproducibility of Results ; Sequence Analysis, DNA ; Streptococcus pyogenes/enzymology/genetics ; Substrate Specificity
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  • 41
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-07
    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〉
    Keywords: Animals ; Developmental Biology/methods ; Embryo Research/*ethics ; Embryo, Mammalian/cytology/*embryology/metabolism ; Embryonic Development ; Fertilization in Vitro ; Humans ; *Laboratories ; Mice ; Time Factors
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  • 42
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-01
    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〉
    Keywords: Adolescent ; Adolescent Behavior/*drug effects/physiology/*psychology ; Child ; *Clinical Trials as Topic/economics ; Decision Making ; Gonadotropin-Releasing Hormone/agonists ; Humans ; National Institutes of Health (U.S.)/economics ; Puberty/*drug effects/*physiology/psychology ; Time Factors ; Transgender Persons/*psychology ; Treatment Outcome ; United States
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