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  • Articles  (475)
  • United States  (263)
  • Crystallography, X-Ray  (121)
  • Molecular Sequence Data  (115)
  • 2015-2019  (475)
  • Medicine  (475)
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  • 1
    Publication Date: 2016-01-20
    Description: Massive open online courses (MOOCs) are often characterized as remedies to educational disparities related to social class. Using data from 68 MOOCs offered by Harvard and MIT between 2012 and 2014, we found that course participants from the United States tended to live in more-affluent and better-educated neighborhoods than the average U.S. resident. Among those who did register for courses, students with greater socioeconomic resources were more likely to earn a certificate. Furthermore, these differences in MOOC access and completion were larger for adolescents and young adults, the traditional ages where people find on-ramps into science, technology, engineering, and mathematics (STEM) coursework and careers. Our findings raise concerns that MOOCs and similar approaches to online learning can exacerbate rather than reduce disparities in educational outcomes related to socioeconomic status.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hansen, John D -- Reich, Justin -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1245-8. doi: 10.1126/science.aab3782. Epub 2015 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard Graduate School of Education, Harvard University, Cambridge, MA 02138, USA. john_hansen@mail.harvard.edu. ; Office of Digital Learning, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785488" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Career Choice ; Certification/*methods ; Education, Distance/*methods ; Engineering/education ; Humans ; Internet ; Learning ; Mathematics/education ; *Online Systems ; Science/education ; *Social Class ; Students ; Technology/education ; United States ; Young Adult
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-04-16
    Description: RlmN is a dual-specificity RNA methylase that modifies C2 of adenosine 2503 (A2503) in 23S rRNA and C2 of adenosine 37 (A37) in several Escherichia coli transfer RNAs (tRNAs). A related methylase, Cfr, modifies C8 of A2503 via a similar mechanism, conferring resistance to multiple classes of antibiotics. Here, we report the x-ray structure of a key intermediate in the RlmN reaction, in which a Cys(118)--〉Ala variant of the protein is cross-linked to a tRNA(Glu)substrate through the terminal methylene carbon of a formerly methylcysteinyl residue and C2 of A37. RlmN contacts the entire length of tRNA(Glu), accessing A37 by using an induced-fit strategy that completely unfolds the tRNA anticodon stem-loop, which is likely critical for recognition of both tRNA and ribosomal RNA substrates.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwalm, Erica L -- Grove, Tyler L -- Booker, Squire J -- Boal, Amie K -- GM100011/GM/NIGMS NIH HHS/ -- GM101957/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):309-12. doi: 10.1126/science.aad5367.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA. ; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. Howard Hughes Medical Institute, Pennsylvania State University, University Park, PA 16802, USA. squire@psu.edu akb20@psu.edu. ; Department of Chemistry, Pennsylvania State University, University Park, PA 16802, USA. Department of Biochemistry and Molecular Biology, Pennsylvania State University, University Park, PA 16802, USA. squire@psu.edu akb20@psu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27081063" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/chemistry ; Alanine/chemistry/genetics ; Amino Acid Substitution ; Anticodon/chemistry ; Catalytic Domain ; Crystallography, X-Ray ; Cysteine/chemistry/genetics ; Escherichia coli Proteins/*chemistry/genetics/*ultrastructure ; Methylation ; Methyltransferases/*chemistry/genetics/*ultrastructure ; Nucleic Acid Conformation ; Protein Structure, Tertiary ; RNA, Bacterial/*chemistry ; RNA, Transfer, Glu/*chemistry/*ultrastructure ; S-Adenosylmethionine/chemistry
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  • 3
    Publication Date: 2016-01-23
    Description: Mono-ubiquitination of Fancd2 is essential for repairing DNA interstrand cross-links (ICLs), but the underlying mechanisms are unclear. The Fan1 nuclease, also required for ICL repair, is recruited to ICLs by ubiquitinated (Ub) Fancd2. This could in principle explain how Ub-Fancd2 promotes ICL repair, but we show that recruitment of Fan1 by Ub-Fancd2 is dispensable for ICL repair. Instead, Fan1 recruitment--and activity--restrains DNA replication fork progression and prevents chromosome abnormalities from occurring when DNA replication forks stall, even in the absence of ICLs. Accordingly, Fan1 nuclease-defective knockin mice are cancer-prone. Moreover, we show that a Fan1 variant in high-risk pancreatic cancers abolishes recruitment by Ub-Fancd2 and causes genetic instability without affecting ICL repair. Therefore, Fan1 recruitment enables processing of stalled forks that is essential for genome stability and health.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770513/" 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/PMC4770513/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lachaud, Christophe -- Moreno, Alberto -- Marchesi, Francesco -- Toth, Rachel -- Blow, J Julian -- Rouse, John -- WT096598MA/Wellcome Trust/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):846-9. doi: 10.1126/science.aad5634. Epub 2016 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK. ; Centre for Gene Regulation and Expression, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK. ; School of Veterinary Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Bearsden Road, Glasgow G61 1QH, UK. ; Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, Sir James Black Centre, University of Dundee, Dundee DD1 5EH, Scotland, UK. j.rouse@dundee.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26797144" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Chromosome Aberrations ; DNA Repair ; *DNA Replication ; Endodeoxyribonucleases/genetics/*metabolism ; Fanconi Anemia Complementation Group D2 Protein/genetics/*metabolism ; Female ; Gene Knock-In Techniques ; Genetic Predisposition to Disease ; Genomic Instability/*genetics ; Liver Neoplasms/genetics/pathology ; Lung Neoplasms/genetics/pathology ; Lymphoma/genetics/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Pancreatic Neoplasms/*genetics ; *Ubiquitination
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  • 4
    Publication Date: 2016-02-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Claiborne, Anne B -- English, Rebecca A -- Kahn, Jeffrey P -- 10002265/PHS HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):668-70. doi: 10.1126/science.aaf3091. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Medicine, U.S. National Academies of Sciences, Engineering, and Medicine, Washington, DC 20001, USA. aclaiborne@nas.edu. ; Institute of Medicine, U.S. National Academies of Sciences, Engineering, and Medicine, Washington, DC 20001, USA. ; Johns Hopkins Berman Institute of Bioethics, Johns Hopkins University, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842937" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Nucleus/genetics ; DNA, Mitochondrial/genetics ; Ethics, Medical ; *Government Regulation ; Humans ; Mitochondrial Diseases/genetics/*prevention & control ; Mitochondrial Replacement Therapy/*ethics/*standards ; *Oocytes ; United States ; United States Food and Drug Administration ; *Zygote
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jon -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):16-9. doi: 10.1126/science.351.6268.16.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26721985" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/*economics ; Communicable Disease Control/*economics ; Financial Management ; Humans ; National Institutes of Health (U.S.) ; United States ; Vaccines/*economics
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  • 6
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shanahan, Jesse -- New York, N.Y. -- Science. 2016 Jan 22;351(6271):418. doi: 10.1126/science.351.6271.418.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jesse Shanahan is a master's student in astronomy at Wesleyan University in Middletown, Connecticut. Send your story to SciCareerEditor@aaas.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26798017" target="_blank"〉PubMed〈/a〉
    Keywords: Astronomy/*education ; *Career Mobility ; Disabled Persons/*psychology/statistics & numerical data ; Fear ; *Hostility ; Humans ; Male ; United States
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  • 7
    Publication Date: 2016-04-02
    Description: The recent rapid spread of Zika virus and its unexpected linkage to birth defects and an autoimmune neurological syndrome have generated worldwide concern. Zika virus is a flavivirus like the dengue, yellow fever, and West Nile viruses. We present the 3.8 angstrom resolution structure of mature Zika virus, determined by cryo-electron microscopy (cryo-EM). The structure of Zika virus is similar to other known flavivirus structures, except for the ~10 amino acids that surround the Asn(154) glycosylation site in each of the 180 envelope glycoproteins that make up the icosahedral shell. The carbohydrate moiety associated with this residue, which is recognizable in the cryo-EM electron density, may function as an attachment site of the virus to host cells. This region varies not only among Zika virus strains but also in other flaviviruses, which suggests that differences in this region may influence virus transmission and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845755/" 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/PMC4845755/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sirohi, Devika -- Chen, Zhenguo -- Sun, Lei -- Klose, Thomas -- Pierson, Theodore C -- Rossmann, Michael G -- Kuhn, Richard J -- R01 AI073755/AI/NIAID NIH HHS/ -- R01 AI076331/AI/NIAID NIH HHS/ -- R01AI073755/AI/NIAID NIH HHS/ -- R01AI076331/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 22;352(6284):467-70. doi: 10.1126/science.aaf5316. Epub 2016 Mar 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Markey Center for Structural Biology and Purdue Institute for Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47907, USA. ; Viral Pathogenesis Section, Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27033547" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; Glycosylation ; Humans ; Molecular Sequence Data ; Protein Structure, Tertiary ; Viral Envelope Proteins/chemistry/ultrastructure ; Viral Matrix Proteins/chemistry/ultrastructure ; Zika Virus/*chemistry/*ultrastructure
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  • 8
    Publication Date: 2016-04-16
    Description: The nuclear pore complex (NPC) controls the transport of macromolecules between the nucleus and cytoplasm, but its molecular architecture has thus far remained poorly defined. We biochemically reconstituted NPC core protomers and elucidated the underlying protein-protein interaction network. Flexible linker sequences, rather than interactions between the structured core scaffold nucleoporins, mediate the assembly of the inner ring complex and its attachment to the NPC coat. X-ray crystallographic analysis of these scaffold nucleoporins revealed the molecular details of their interactions with the flexible linker sequences and enabled construction of full-length atomic structures. By docking these structures into the cryoelectron tomographic reconstruction of the intact human NPC and validating their placement with our nucleoporin interactome, we built a composite structure of the NPC symmetric core that contains ~320,000 residues and accounts for ~56 megadaltons of the NPC's structured mass. Our approach provides a paradigm for the structure determination of similarly complex macromolecular assemblies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Daniel H -- Stuwe, Tobias -- Schilbach, Sandra -- Rundlet, Emily J -- Perriches, Thibaud -- Mobbs, George -- Fan, Yanbin -- Thierbach, Karsten -- Huber, Ferdinand M -- Collins, Leslie N -- Davenport, Andrew M -- Jeon, Young E -- Hoelz, Andre -- 5 T32 GM07616/GM/NIGMS NIH HHS/ -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- R01 GM111461/GM/NIGMS NIH HHS/ -- R01-GM111461/GM/NIGMS NIH HHS/ -- T32 GM007616/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):aaf1015. doi: 10.1126/science.aaf1015. Epub 2016 Apr 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. ; Division of Chemistry and Chemical Engineering, California Institute of Technology, 1200 East California Boulevard, Pasadena, CA 91125, USA. hoelz@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27081075" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Amino Acid Sequence ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cytoplasm/metabolism ; Electron Microscope Tomography ; Fungal Proteins/chemistry/genetics/metabolism ; Humans ; Molecular Sequence Data ; Nuclear Pore/chemistry/*metabolism/*ultrastructure ; Nuclear Pore Complex Proteins/chemistry/genetics/*metabolism ; *Protein Interaction Maps ; Protein Structure, Tertiary ; Protein Subunits/chemistry/genetics/metabolism
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  • 9
    Publication Date: 2016-02-27
    Description: Ebola virus disease in humans is highly lethal, with case fatality rates ranging from 25 to 90%. There is no licensed treatment or vaccine against the virus, underscoring the need for efficacious countermeasures. We ascertained that a human survivor of the 1995 Kikwit Ebola virus disease outbreak maintained circulating antibodies against the Ebola virus surface glycoprotein for more than a decade after infection. From this survivor we isolated monoclonal antibodies (mAbs) that neutralize recent and previous outbreak variants of Ebola virus and mediate antibody-dependent cell-mediated cytotoxicity in vitro. Strikingly, monotherapy with mAb114 protected macaques when given as late as 5 days after challenge. Treatment with a single human mAb suggests that a simplified therapeutic strategy for human Ebola infection may be possible.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Corti, Davide -- Misasi, John -- Mulangu, Sabue -- Stanley, Daphne A -- Kanekiyo, Masaru -- Wollen, Suzanne -- Ploquin, Aurelie -- Doria-Rose, Nicole A -- Staupe, Ryan P -- Bailey, Michael -- Shi, Wei -- Choe, Misook -- Marcus, Hadar -- Thompson, Emily A -- Cagigi, Alberto -- Silacci, Chiara -- Fernandez-Rodriguez, Blanca -- Perez, Laurent -- Sallusto, Federica -- Vanzetta, Fabrizia -- Agatic, Gloria -- Cameroni, Elisabetta -- Kisalu, Neville -- Gordon, Ingelise -- Ledgerwood, Julie E -- Mascola, John R -- Graham, Barney S -- Muyembe-Tamfun, Jean-Jacques -- Trefry, John C -- Lanzavecchia, Antonio -- Sullivan, Nancy J -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1339-42. doi: 10.1126/science.aad5224. Epub 2016 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Research in Biomedicine, Universita della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. Humabs BioMed SA, 6500 Bellinzona, Switzerland. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. ; U.S. Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702, USA. ; Institute for Research in Biomedicine, Universita della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. ; Humabs BioMed SA, 6500 Bellinzona, Switzerland. ; National Institute for Biomedical Research, National Laboratory of Public Health, Kinshasa B.P. 1197, Democratic Republic of the Congo. ; Institute for Research in Biomedicine, Universita della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA. njsull@mail.nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26917593" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Animals ; Antibodies, Monoclonal/*administration & dosage/immunology/isolation & ; purification ; Antibodies, Neutralizing/*administration & dosage/immunology/isolation & ; purification ; Antibodies, Viral/*administration & dosage/immunology/isolation & purification ; Clinical Trials as Topic ; Disease Outbreaks ; Ebolavirus/*immunology ; Female ; Hemorrhagic Fever, Ebola/epidemiology/*prevention & control ; Humans ; Macaca ; Male ; Molecular Sequence Data ; Survivors
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  • 10
    Publication Date: 2016-04-02
    Description: Global climate change is a major threat to biodiversity. Large-scale analyses have generally focused on the impacts of climate change on the geographic ranges of species and on phenology, the timing of ecological phenomena. We used long-term monitoring of the abundance of breeding birds across Europe and the United States to produce, for both regions, composite population indices for two groups of species: those for which climate suitability has been either improving or declining since 1980. The ratio of these composite indices, the climate impact indicator (CII), reflects the divergent fates of species favored or disadvantaged by climate change. The trend in CII is positive and similar in the two regions. On both continents, interspecific and spatial variation in population abundance trends are well predicted by climate suitability trends.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stephens, Philip A -- Mason, Lucy R -- Green, Rhys E -- Gregory, Richard D -- Sauer, John R -- Alison, Jamie -- Aunins, Ainars -- Brotons, Lluis -- Butchart, Stuart H M -- Campedelli, Tommaso -- Chodkiewicz, Tomasz -- Chylarecki, Przemyslaw -- Crowe, Olivia -- Elts, Jaanus -- Escandell, Virginia -- Foppen, Ruud P B -- Heldbjerg, Henning -- Herrando, Sergi -- Husby, Magne -- Jiguet, Frederic -- Lehikoinen, Aleksi -- Lindstrom, Ake -- Noble, David G -- Paquet, Jean-Yves -- Reif, Jiri -- Sattler, Thomas -- Szep, Tibor -- Teufelbauer, Norbert -- Trautmann, Sven -- van Strien, Arco J -- van Turnhout, Chris A M -- Vorisek, Petr -- Willis, Stephen G -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):84-7. doi: 10.1126/science.aac4858.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Conservation Ecology Group, School of Biological and Biomedical Sciences, Durham University, South Road, Durham DH1 3LE, UK. ; Royal Society for the Protection of Birds, Centre for Conservation Science, The Lodge, Sandy, Bedfordshire SG19 2DL, UK. ; Royal Society for the Protection of Birds, Centre for Conservation Science, The Lodge, Sandy, Bedfordshire SG19 2DL, UK. Conservation Science Group, Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. ; United States Geological Survey, Patuxent Wildlife Research Center, 12100 Beech Forest Road, Laurel, MD 20708, USA. ; Institute of Integrative Biology, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. ; Faculty of Biology, University of Latvia, Jelgavas iela 1, Riga, LV-1004, Latvia. ; Center for Mediterranean Forest Research, Centre Tecnologic Forestal de Catalunya, InForest JRU, Solsona 25280, Spain. REAF, Cerdanyola del Valles 08193, Catalonia, Spain. CSIC, Cerdanyola del Valles 08193, Catalonia, Spain. ; Conservation Science Group, Department of Zoology, University of Cambridge, Downing Street, Cambridge CB2 3EJ, UK. BirdLife International, The David Attenborough Building, Pembroke Street, Cambridge CB2 3QZ, UK. ; MITO2000 National Committee; c/o Dream Italia, Via Garibaldi 3, 52015, Pratovecchio-Stia, Arezzo, Italy. ; Ogolnopolskie Towarzystwo Ochrony Ptakow, Odrowaza 24,05-270 Marki, Poland. ; Museum and Institute of Zoology, Polish Academy of Sciences, Wilcza 64, 00-679 Warszawa, Poland. ; BirdWatch Ireland, Unit 20 Block D Bullford Business Campus, Kilcoole, County Wicklow, Ireland. ; Institute of Ecology and Earth Sciences, University of Tartu, Vanemuise Street 46, 51014 Tartu, Estonia. Estonian Ornithological Society, Veski 4, 51005 Tartu, Estonia. ; Sociedad Espanola de Ornitologia/BirdLife Melquiades Biencinto, 34, 28053 Madrid. Spain. ; European Bird Census Council, Post Office Box 6521, 6503 GA Nijmegen, Netherlands. Sovon Dutch Centre for Field Ornithology, Post Office Box 6521, 6503 GA Nijmegen, Netherlands. Department of Animal Ecology and Ecophysiology, Institute for Water and Wetland Research, Radboud University, Post Office Box 9010, 6500 GL Nijmegen, Netherlands. ; Dansk Ornitologisk Forening-BirdLife Denmark and University of Aarhus, Vesterbrogade 140, 1620 Kobenhavn V, Denmark. ; European Bird Census Council-Catalan Ornithological Institute, Natural History Museum of Barcelona, Placa Leonardo da Vinci 4-5, 08019 Barcelona, Catalonia, Spain. ; Section for Science, Nord University, 7600 Levanger, Norway. ; UMR7204 Sorbonne Universites-MNHN-CNRS-UPMC, CESCO, CRBPO, CP 135, 43 Rue Buffon, 75005 Paris, France. ; The Helsinki Lab of Ornithology, Finnish Museum of Natural History, Post Office Box 17, 00014 University of Helsinki, Finland. ; Biodiversity Unit, Department of Biology, Lund University, Ecology Building, S-223 62 Lund, Sweden. ; The British Trust for Ornithology, The Nunnery, Thetford, Norfolk IP24 2PU, UK. ; Natagora, Departement Etudes, Rue Nanon 98, B-5000 Namur, Belgium. ; Institute for Environmental Studies, Faculty of Science, Charles University in Prague, Czech Republic. Department of Zoology and Laboratory of Ornithology, Faculty of Science, Palacky University Olomouc, 17 Listopadu 50, 771 43 Olomouc, Czech Republic. ; Swiss Ornithological Institute, Seerose 1, 6204 Sempach, Switzerland. ; Institute of Environmental Sciences, University of Nyiregyhaza, Sostoi ut 31/b, 4400 Nyiregyhaza, Hungary. ; BirdLife Austria, Museumsplatz 1/10/8, A-1070 Vienna, Austria. ; Dachverband Deutscher Avifaunisten e.V. (Federation of German Avifaunists), An den Speichern 6, D-48157 Munster, Germany. ; Statistics Netherlands, Post Office Box 24500, 2490 HA The Hague, Netherlands. ; Sovon Dutch Centre for Field Ornithology, Post Office Box 6521, 6503 GA Nijmegen, Netherlands. Department of Animal Ecology and Ecophysiology, Institute for Water and Wetland Research, Radboud University, Post Office Box 9010, 6500 GL Nijmegen, Netherlands. ; Department of Zoology and Laboratory of Ornithology, Faculty of Science, Palacky University Olomouc, 17 Listopadu 50, 771 43 Olomouc, Czech Republic. Pan-European Common Bird Monitoring Scheme, Czech Society for Ornithology, Na Belidle 252/34, CZ-15000 Prague 5, Czech Republic.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034371" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Migration ; Animals ; Biodiversity ; *Birds ; Breeding ; *Climate Change ; Ecological Parameter Monitoring ; Europe ; Population Dynamics ; United States
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  • 11
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-03-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stone, Richard -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1138-40. doi: 10.1126/science.351.6278.1138.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965605" target="_blank"〉PubMed〈/a〉
    Keywords: Computer Simulation ; *Explosions ; *Forensic Sciences ; Humans ; *Nuclear Weapons ; United States
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  • 12
    Publication Date: 2016-02-26
    Description: T cell-mediated destruction of insulin-producing beta cells in the pancreas causes type 1 diabetes (T1D). CD4 T cell responses play a central role in beta cell destruction, but the identity of the epitopes recognized by pathogenic CD4 T cells remains unknown. We found that diabetes-inducing CD4 T cell clones isolated from nonobese diabetic mice recognize epitopes formed by covalent cross-linking of proinsulin peptides to other peptides present in beta cell secretory granules. These hybrid insulin peptides (HIPs) are antigenic for CD4 T cells and can be detected by mass spectrometry in beta cells. CD4 T cells from the residual pancreatic islets of two organ donors who had T1D also recognize HIPs. Autoreactive T cells targeting hybrid peptides may explain how immune tolerance is broken in T1D.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delong, Thomas -- Wiles, Timothy A -- Baker, Rocky L -- Bradley, Brenda -- Barbour, Gene -- Reisdorph, Richard -- Armstrong, Michael -- Powell, Roger L -- Reisdorph, Nichole -- Kumar, Nitesh -- Elso, Colleen M -- DeNicola, Megan -- Bottino, Rita -- Powers, Alvin C -- Harlan, David M -- Kent, Sally C -- Mannering, Stuart I -- Haskins, Kathryn -- 1K01DK094941/DK/NIDDK NIH HHS/ -- 1R01DK081166/DK/NIDDK NIH HHS/ -- 5U01DK89572/DK/NIDDK NIH HHS/ -- DK104211/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):711-4. doi: 10.1126/science.aad2791.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. thomas.delong@ucdenver.edu katie.haskins@ucdenver.edu. ; Department of Immunology and Microbiology, University of Colorado School of Medicine, Denver, Anschutz Medical Campus, Aurora, CO 80045, USA. ; Pharmaceutical Sciences, University of Colorado School of Medicine, Aurora, CO 80045, USA. ; Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. ; Department of Medicine, Diabetes Division, Diabetes Center of Excellence, University of Massachusetts Medical School, Worcester, MA, USA. ; Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA. ; Division of Diabetes, Endocrinology, and Metabolism, Department of Medicine, and Department of Molecular Physiology and Biophysics, Vanderbilt University Medical Center, Nashville, TN, USA. VA Tennessee Valley Healthcare System, Nashville, TN, USA. ; Immunology and Diabetes Unit, St. Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria 3065, Australia. University of Melbourne, Department of Medicine, St. Vincent's Hospital, Fitzroy, Victoria 3065, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912858" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; C-Peptide/chemistry/*immunology ; CD4-Positive T-Lymphocytes/*immunology ; Clone Cells ; Diabetes Mellitus, Experimental/*immunology/pathology ; Diabetes Mellitus, Type 1/*immunology/pathology ; Epitopes/*immunology ; Immune Tolerance ; Insulin-Secreting Cells/*immunology/pathology ; Mice ; Mice, Inbred NOD ; Molecular Sequence Data ; Peptides/chemistry/immunology
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  • 13
    Publication Date: 2016-01-28
    Description: Mitochondria undergo fragmentation in response to electron transport chain (ETC) poisons and mitochondrial DNA-linked disease mutations, yet how these stimuli mechanistically connect to the mitochondrial fission and fusion machinery is poorly understood. We found that the energy-sensing adenosine monophosphate (AMP)-activated protein kinase (AMPK) is genetically required for cells to undergo rapid mitochondrial fragmentation after treatment with ETC inhibitors. Moreover, direct pharmacological activation of AMPK was sufficient to rapidly promote mitochondrial fragmentation even in the absence of mitochondrial stress. A screen for substrates of AMPK identified mitochondrial fission factor (MFF), a mitochondrial outer-membrane receptor for DRP1, the cytoplasmic guanosine triphosphatase that catalyzes mitochondrial fission. Nonphosphorylatable and phosphomimetic alleles of the AMPK sites in MFF revealed that it is a key effector of AMPK-mediated mitochondrial fission.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toyama, Erin Quan -- Herzig, Sebastien -- Courchet, Julien -- Lewis, Tommy L Jr -- Loson, Oliver C -- Hellberg, Kristina -- Young, Nathan P -- Chen, Hsiuchen -- Polleux, Franck -- Chan, David C -- Shaw, Reuben J -- K99 NS091526/NS/NINDS NIH HHS/ -- K99NS091526/NS/NINDS NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01CA172229/CA/NCI NIH HHS/ -- R01DK080425/DK/NIDDK NIH HHS/ -- R01GM062967/GM/NIGMS NIH HHS/ -- R01GM110039/GM/NIGMS NIH HHS/ -- R01NS089456/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 15;351(6270):275-81. doi: 10.1126/science.aab4138.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular and Cell Biology Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. ; Department of Neuroscience, Zuckerman Mind Brain Behavior Institute and Kavli Institute for Brain Science, Columbia University, New York, NY 10032, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. ; Molecular and Cell Biology Laboratory and Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037, USA. shaw@salk.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26816379" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/genetics/*metabolism ; Adenosine Monophosphate/metabolism ; Amino Acid Motifs ; Cell Line, Tumor ; Cytoplasm/enzymology ; Dactinomycin/analogs & derivatives/pharmacology ; *Energy Metabolism ; Enzyme Activation ; GTP Phosphohydrolases/genetics/metabolism ; Humans ; Microtubule-Associated Proteins/genetics/metabolism ; Mitochondria/drug effects/enzymology/*physiology ; *Mitochondrial Dynamics ; Mitochondrial Proteins/genetics/metabolism ; Molecular Sequence Data ; Rotenone/pharmacology ; *Stress, Physiological
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  • 14
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McNutt, Marcia -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):641. doi: 10.1126/science.aaf4014. Epub 2016 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Marcia McNutt Editor-in-Chief Science Journals.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912832" target="_blank"〉PubMed〈/a〉
    Keywords: Corrosion ; Federal Government ; Humans ; Michigan ; *Public Health ; Safety/*economics ; Trust ; United States ; United States Environmental Protection Agency ; Water Supply/*economics
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  • 15
    Publication Date: 2016-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fahlgren, Noah -- Bart, Rebecca -- Herrera-Estrella, Luis -- Rellan-Alvarez, Ruben -- Chitwood, Daniel H -- Dinneny, Jose R -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):824. doi: 10.1126/science.351.6275.824-a. Epub 2016 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Donald Danforth Plant Science Center, St. Louis, MO 63132, USA. ; Nacional de Genomica para la Biodiversidad, Irapuato, 36821, Mexico. ; Donald Danforth Plant Science Center, St. Louis, MO 63132, USA. jdinneny@carnegiescience.edu dchitwood@danforthcenter.org. ; Carnegie Institution for Science, Stanford, CA 94305, USA. jdinneny@carnegiescience.edu dchitwood@danforthcenter.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912883" target="_blank"〉PubMed〈/a〉
    Keywords: China ; Food, Genetically Modified/*adverse effects ; Genetic Engineering/*utilization ; Health ; Humans ; Plants, Genetically Modified/*adverse effects/genetics ; United States ; Zea mays/genetics
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  • 16
    Publication Date: 2016-03-26
    Description: Brazil has experienced an unprecedented epidemic of Zika virus (ZIKV), with ~30,000 cases reported to date. ZIKV was first detected in Brazil in May 2015, and cases of microcephaly potentially associated with ZIKV infection were identified in November 2015. We performed next-generation sequencing to generate seven Brazilian ZIKV genomes sampled from four self-limited cases, one blood donor, one fatal adult case, and one newborn with microcephaly and congenital malformations. Results of phylogenetic and molecular clock analyses show a single introduction of ZIKV into the Americas, which we estimated to have occurred between May and December 2013, more than 12 months before the detection of ZIKV in Brazil. The estimated date of origin coincides with an increase in air passengers to Brazil from ZIKV-endemic areas, as well as with reported outbreaks in the Pacific Islands. ZIKV genomes from Brazil are phylogenetically interspersed with those from other South American and Caribbean countries. Mapping mutations onto existing structural models revealed the context of viral amino acid changes present in the outbreak lineage; however, no shared amino acid changes were found among the three currently available virus genomes from microcephaly cases. Municipality-level incidence data indicate that reports of suspected microcephaly in Brazil best correlate with ZIKV incidence around week 17 of pregnancy, although this correlation does not demonstrate causation. Our genetic description and analysis of ZIKV isolates in Brazil provide a baseline for future studies of the evolution and molecular epidemiology of this emerging virus in the Americas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faria, Nuno Rodrigues -- Azevedo, Raimunda do Socorro da Silva -- Kraemer, Moritz U G -- Souza, Renato -- Cunha, Mariana Sequetin -- Hill, Sarah C -- Theze, Julien -- Bonsall, Michael B -- Bowden, Thomas A -- Rissanen, Ilona -- Rocco, Iray Maria -- Nogueira, Juliana Silva -- Maeda, Adriana Yurika -- Vasami, Fernanda Giseli da Silva -- Macedo, Fernando Luiz de Lima -- Suzuki, Akemi -- Rodrigues, Sueli Guerreiro -- Cruz, Ana Cecilia Ribeiro -- Nunes, Bruno Tardeli -- Medeiros, Daniele Barbosa de Almeida -- Rodrigues, Daniela Sueli Guerreiro -- Nunes Queiroz, Alice Louize -- da Silva, Eliana Vieira Pinto -- Henriques, Daniele Freitas -- Travassos da Rosa, Elisabeth Salbe -- de Oliveira, Consuelo Silva -- Martins, Livia Caricio -- Vasconcelos, Helena Baldez -- Casseb, Livia Medeiros Neves -- Simith, Darlene de Brito -- Messina, Jane P -- Abade, Leandro -- Lourenco, Jose -- Carlos Junior Alcantara, Luiz -- de Lima, Maricelia Maia -- Giovanetti, Marta -- Hay, Simon I -- de Oliveira, Rodrigo Santos -- Lemos, Poliana da Silva -- de Oliveira, Layanna Freitas -- de Lima, Clayton Pereira Silva -- da Silva, Sandro Patroca -- de Vasconcelos, Janaina Mota -- Franco, Luciano -- Cardoso, Jedson Ferreira -- Vianez-Junior, Joao Lidio da Silva Goncalves -- Mir, Daiana -- Bello, Gonzalo -- Delatorre, Edson -- Khan, Kamran -- Creatore, Marisa -- Coelho, Giovanini Evelim -- de Oliveira, Wanderson Kleber -- Tesh, Robert -- Pybus, Oliver G -- Nunes, Marcio R T -- Vasconcelos, Pedro F C -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095066/Wellcome Trust/United Kingdom -- 102427/Wellcome Trust/United Kingdom -- MR/L009528/1/Medical Research Council/United Kingdom -- R24 AT 120942/AT/NCCIH NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):345-9. doi: 10.1126/science.aaf5036. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. ; Instituto Adolfo Lutz, University of Sao Paulo, Sao Paulo, Brazil. ; Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. ; Oswaldo Cruz Foundation (FIOCRUZ), Salvador, Bahia, Brazil. ; Centre of Post Graduation in Collective Health, Department of Health, Universidade Estadual de Feira de Santana, Feira de Santana, Bahia, Brazil. ; Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA 98121, USA. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. ; Laboratorio de AIDS and Imunologia Molecular, Instituto Oswaldo Cruz, FIOCRUZ, Rio de Janeiro, Brazil. ; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Department of Medicine, Division of Infectious Diseases, University of Toronto, Toronto, Ontario, Canada. ; Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. ; Brazilian Ministry of Health, Brasilia, Brazil. ; Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. ; Department of Zoology, University of Oxford, South Parks Road, Oxford OX1 3PS, UK. Metabiota, San Francisco, CA 94104, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Center for Technological Innovation, Evandro Chagas Institute, Ministry of Health, Ananindeua, PA 67030-000, Brazil. Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br. ; Department of Arbovirology and Hemorrhagic Fevers, Evandro Chagas Institute, Ministry of Health, Ananindeua, Para State, Brazil. oliver.pybus@zoo.ox.ac.uk marcionunesbrasil@yahoo.com.br pedrovasconcelos@iec.pa.gov.br.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013429" target="_blank"〉PubMed〈/a〉
    Keywords: Aedes/virology ; Americas/epidemiology ; Animals ; *Disease Outbreaks ; Female ; Genome, Viral/genetics ; Humans ; Incidence ; Insect Vectors/virology ; Microcephaly/*epidemiology/virology ; Molecular Epidemiology ; Molecular Sequence Data ; Mutation ; Pacific Islands/epidemiology ; Phylogeny ; Pregnancy ; RNA, Viral/genetics ; Sequence Analysis, RNA ; Travel ; Zika Virus/classification/*genetics/isolation & purification ; Zika Virus Infection/*epidemiology/transmission/*virology
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  • 17
    Publication Date: 2016-01-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mervis, Jeffrey -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):115. doi: 10.1126/science.351.6269.115.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26744390" target="_blank"〉PubMed〈/a〉
    Keywords: Female ; Financing, Organized/*statistics & numerical data ; Humans ; Research Personnel ; Research Support as Topic/*statistics & numerical data ; *Sexism ; United States ; *Women, Working
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  • 18
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mervis, Jeffrey -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):10-1. doi: 10.1126/science.351.6268.10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉With reporting from Science's news staff.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26721980" target="_blank"〉PubMed〈/a〉
    Keywords: Biomedical Research/*economics ; Budgets ; Humans ; National Institutes of Health (U.S.)/*economics ; *Research Support as Topic ; United States ; United States National Aeronautics and Space Administration/economics
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  • 19
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-04-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Underwood, Emily -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):277-8. doi: 10.1126/science.352.6283.277.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27081045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Brain ; *Datasets as Topic ; European Union ; Humans ; International Cooperation ; Neurosciences/*trends ; United States
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  • 20
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-04-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Varmus, Harold -- New York, N.Y. -- Science. 2016 Apr 8;352(6282):123. doi: 10.1126/science.aaf7301.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harold Varmus is the Lewis Thomas University Professor at the Meyer Cancer Center, Weill Cornell Medicine, New York, NY; Senior Associate Member of the New York Genome Center, New York, NY; and former director of the U.S. National Cancer Institute. varmus@med.cornell.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27124426" target="_blank"〉PubMed〈/a〉
    Keywords: Federal Government ; Humans ; Information Dissemination ; *Leadership ; Medical Oncology/economics/*trends ; Neoplasms/diagnosis/drug therapy/prevention & control ; United States
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  • 21
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-04-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fu, He -- New York, N.Y. -- Science. 2016 Apr 22;352(6284):486. doi: 10.1126/science.352.6284.486.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉He Fu is a Ph.D. candidate in the Department of Microbiology at the University of Illinois, Urbana-Champaign. For more on life and careers, visit sciencecareers.org. Send your story to SciCareerEditor@aaas.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27102487" target="_blank"〉PubMed〈/a〉
    Keywords: *Career Choice ; China ; *International Educational Exchange ; Microbiology/*education ; United States
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  • 22
    Publication Date: 2016-02-27
    Description: Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Misasi, John -- Gilman, Morgan S A -- Kanekiyo, Masaru -- Gui, Miao -- Cagigi, Alberto -- Mulangu, Sabue -- Corti, Davide -- Ledgerwood, Julie E -- Lanzavecchia, Antonio -- Cunningham, James -- Muyembe-Tamfun, Jean Jacques -- Baxa, Ulrich -- Graham, Barney S -- Xiang, Ye -- Sullivan, Nancy J -- McLellan, Jason S -- 5K08AI079381/AI/NIAID NIH HHS/ -- HHSN261200800001E/PHS HHS/ -- T32GM008704/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1343-6. doi: 10.1126/science.aad6117. Epub 2016 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Division of Infectious Diseases, Boston Children's Hospital, Boston, MA 02215, USA. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ; Centre for Infectious Diseases Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084 China. ; Institute for Research in Biomedicine, Universita della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. ; Institute for Research in Biomedicine, Universita della Svizzera Italiana, CH-6500 Bellinzona, Switzerland. Institute of Microbiology, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. ; National Institute for Biomedical Research, National Laboratory of Public Health, Kinshasa B.P. 1197, Democratic Republic of the Congo. ; Electron Microscopy Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. ; Centre for Infectious Diseases Research, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing Advanced Innovation Center for Structural Biology, Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084 China. njsull@mail.nih.gov yxiang@mail.tsinghua.edu.cn. ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. njsull@mail.nih.gov yxiang@mail.tsinghua.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26917592" target="_blank"〉PubMed〈/a〉
    Keywords: Antibodies, Monoclonal/*chemistry/immunology ; Antibodies, Neutralizing/*chemistry/immunology ; Antibodies, Viral/*chemistry/immunology ; Cathepsins/chemistry ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Ebolavirus/*immunology ; Hemorrhagic Fever, Ebola/immunology/*prevention & control ; Humans ; Protein Conformation ; Proteolysis ; Viral Envelope Proteins/chemistry/*immunology
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  • 23
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-02
    Description: Secreted and integral membrane proteins compose up to one-third of the biological proteome. These proteins contain hydrophobic signals that direct their translocation across or insertion into the lipid bilayer by the Sec61 protein-conducting channel. The molecular basis of how hydrophobic signals within a nascent polypeptide trigger channel opening is not understood. Here, we used cryo-electron microscopy to determine the structure of an active Sec61 channel that has been opened by a signal sequence. The signal supplants helix 2 of Sec61alpha, which triggers a rotation that opens the central pore both axially across the membrane and laterally toward the lipid bilayer. Comparisons with structures of Sec61 in other states suggest a pathway for how hydrophobic signals engage the channel to gain access to the lipid bilayer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4700591/" 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/PMC4700591/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Voorhees, Rebecca M -- Hegde, Ramanujan S -- MC_UP_A022_1007/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):88-91. doi: 10.1126/science.aad4992.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Medical Research Council, Francis Crick Avenue, Cambridge CB2 0QH, UK. ; MRC Laboratory of Molecular Biology, Medical Research Council, Francis Crick Avenue, Cambridge CB2 0QH, UK. rhegde@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26721998" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Dogs ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry ; Membrane Proteins/*chemistry ; Protein Sorting Signals ; Protein Structure, Secondary ; Ribosomes/chemistry
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  • 24
    Publication Date: 2016-02-26
    Description: With functions that range from cell envelope structure to signal transduction and transport, lipoproteins constitute 2 to 3% of bacterial genomes and play critical roles in bacterial physiology, pathogenicity, and antibiotic resistance. Lipoproteins are synthesized with a signal peptide securing them to the cytoplasmic membrane with the lipoprotein domain in the periplasm or outside the cell. Posttranslational processing requires a signal peptidase II (LspA) that removes the signal peptide. Here, we report the crystal structure of LspA from Pseudomonas aeruginosa complexed with the antimicrobial globomycin at 2.8 angstrom resolution. Mutagenesis studies identify LspA as an aspartyl peptidase. In an example of molecular mimicry, globomycin appears to inhibit by acting as a noncleavable peptide that sterically blocks the active site. This structure should inform rational antibiotic drug discovery.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vogeley, Lutz -- El Arnaout, Toufic -- Bailey, Jonathan -- Stansfeld, Phillip J -- Boland, Coilin -- Caffrey, Martin -- BB/I019855/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):876-80. doi: 10.1126/science.aad3747.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. ; Department of Biochemistry, University of Oxford, South Parks Road, Oxford, UK. ; School of Medicine and School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland. martin.caffrey@tcd.ie.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912896" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Anti-Bacterial Agents/*chemistry/pharmacology ; Aspartic Acid Endopeptidases/*antagonists & inhibitors/*chemistry/genetics ; Bacterial Proteins/*antagonists & inhibitors/*chemistry/genetics ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Mutagenesis ; Peptides/*chemistry/pharmacology ; Protein Conformation ; Protein Processing, Post-Translational ; Pseudomonas aeruginosa/*enzymology ; Substrate Specificity
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  • 25
    Publication Date: 2016-02-26
    Description: Monoubiquitinated histone H2B plays multiple roles in transcription activation. H2B is deubiquitinated by the Spt-Ada-Gcn5 acetyltransferase (SAGA) coactivator, which contains a four-protein subcomplex known as the deubiquitinating (DUB) module. The crystal structure of the Ubp8/Sgf11/Sus1/Sgf73 DUB module bound to a ubiquitinated nucleosome reveals that the DUB module primarily contacts H2A/H2B, with an arginine cluster on the Sgf11 zinc finger domain docking on the conserved H2A/H2B acidic patch. The Ubp8 catalytic domain mediates additional contacts with H2B, as well as with the conjugated ubiquitin. We find that the DUB module deubiquitinates H2B both in the context of the nucleosome and in H2A/H2B dimers complexed with the histone chaperone, FACT, suggesting that SAGA could target H2B at multiple stages of nucleosome disassembly and reassembly during transcription.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morgan, Michael T -- Haj-Yahya, Mahmood -- Ringel, Alison E -- Bandi, Prasanthi -- Brik, Ashraf -- Wolberger, Cynthia -- GM-095822/GM/NIGMS NIH HHS/ -- Y1-CO-1020/CO/NCI NIH HHS/ -- Y1-GM-1104/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):725-8. doi: 10.1126/science.aac5681.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. ; Department of Chemistry, Ben-Gurion University of the Negev, Beer Sheva 8410501, Israel. ; Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa 3200008, Israel. ; Department of Biophysics and Biophysical Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. cwolberg@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912860" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Crystallography, X-Ray ; Endopeptidases/*chemistry ; Histone Acetyltransferases/*chemistry ; Histones/*chemistry ; Nuclear Proteins/*chemistry ; Nucleosomes/enzymology ; Protein Multimerization ; Protein Structure, Secondary ; RNA-Binding Proteins/*chemistry ; Saccharomyces cerevisiae Proteins/*chemistry ; Trans-Activators/*chemistry ; Transcription Factors/*chemistry ; Transcriptional Activation ; Ubiquitin/chemistry ; *Ubiquitination ; Xenopus laevis ; Zinc Fingers
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  • 26
    Publication Date: 2016-02-26
    Description: The U4/U6.U5 triple small nuclear ribonucleoprotein (tri-snRNP) is a major spliceosome building block. We obtained a three-dimensional structure of the 1.8-megadalton human tri-snRNP at a resolution of 7 angstroms using single-particle cryo-electron microscopy (cryo-EM). We fit all known high-resolution structures of tri-snRNP components into the EM density map and validated them by protein cross-linking. Our model reveals how the spatial organization of Brr2 RNA helicase prevents premature U4/U6 RNA unwinding in isolated human tri-snRNPs and how the ubiquitin C-terminal hydrolase-like protein Sad1 likely tethers the helicase Brr2 to its preactivation position. Comparison of our model with cryo-EM three-dimensional structures of the Saccharomyces cerevisiae tri-snRNP and Schizosaccharomyces pombe spliceosome indicates that Brr2 undergoes a marked conformational change during spliceosome activation, and that the scaffolding protein Prp8 is also rearranged to accommodate the spliceosome's catalytic RNA network.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Agafonov, Dmitry E -- Kastner, Berthold -- Dybkov, Olexandr -- Hofele, Romina V -- Liu, Wen-Ti -- Urlaub, Henning -- Luhrmann, Reinhard -- Stark, Holger -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1416-20. doi: 10.1126/science.aad2085. Epub 2016 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. ; Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center Gottingen, D-37075 Gottingen, Germany. ; Department of 3D Electron Cryomicroscopy, Georg-August Universitat Gottingen, D-37077 Gottingen, Germany. Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. ; Bioanalytical Mass Spectrometry, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. Bioanalytics Group, Institute for Clinical Chemistry, University Medical Center Gottingen, D-37075 Gottingen, Germany. reinhard.luehrmann@mpi-bpc.mpg.de hstark1@gwdg.de henning.urlaub@mpibpc.mpg.de. ; Department of Cellular Biochemistry, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. reinhard.luehrmann@mpi-bpc.mpg.de hstark1@gwdg.de henning.urlaub@mpibpc.mpg.de. ; Department of 3D Electron Cryomicroscopy, Georg-August Universitat Gottingen, D-37077 Gottingen, Germany. Department of Structural Dynamics, Max Planck Institute for Biophysical Chemistry, D-37077 Gottingen, Germany. reinhard.luehrmann@mpi-bpc.mpg.de hstark1@gwdg.de henning.urlaub@mpibpc.mpg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912367" target="_blank"〉PubMed〈/a〉
    Keywords: Cryoelectron Microscopy ; Crystallography, X-Ray ; DEAD-box RNA Helicases/chemistry ; Enzyme Activation ; HeLa Cells ; Humans ; Models, Molecular ; Peptide Elongation Factors/chemistry ; Protein Conformation ; RNA Helicases/chemistry ; RNA-Binding Proteins/chemistry ; Ribonucleoprotein, U4-U6 Small Nuclear/*chemistry ; Ribonucleoprotein, U5 Small Nuclear/*chemistry ; Ribonucleoproteins, Small Nuclear/chemistry ; Saccharomyces cerevisiae Proteins/chemistry ; Schizosaccharomyces/metabolism ; Ubiquitin Thiolesterase/chemistry
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  • 27
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alberts, Bruce -- New York, N.Y. -- Science. 2016 Jan 15;351(6270):207. doi: 10.1126/science.aaf2001.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Bruce Alberts is the Chancellor's Leadership Chair in Biochemistry and Biophysics for Science and Education at the University of California, San Francisco, CA, and emeritus editor-in-chief of Science. Bruce.Alberts@ucsf.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26816352" target="_blank"〉PubMed〈/a〉
    Keywords: *Career Choice ; *Faculty ; Humans ; Leadership ; Policy Making ; *Power (Psychology) ; Schools/*manpower/trends ; Teaching/*manpower/methods/trends ; United States
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  • 28
    Publication Date: 2016-03-12
    Description: Poly(ethylene terephthalate) (PET) is used extensively worldwide in plastic products, and its accumulation in the environment has become a global concern. Because the ability to enzymatically degrade PET has been thought to be limited to a few fungal species, biodegradation is not yet a viable remediation or recycling strategy. By screening natural microbial communities exposed to PET in the environment, we isolated a novel bacterium, Ideonella sakaiensis 201-F6, that is able to use PET as its major energy and carbon source. When grown on PET, this strain produces two enzymes capable of hydrolyzing PET and the reaction intermediate, mono(2-hydroxyethyl) terephthalic acid. Both enzymes are required to enzymatically convert PET efficiently into its two environmentally benign monomers, terephthalic acid and ethylene glycol.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshida, Shosuke -- Hiraga, Kazumi -- Takehana, Toshihiko -- Taniguchi, Ikuo -- Yamaji, Hironao -- Maeda, Yasuhito -- Toyohara, Kiyotsuna -- Miyamoto, Kenji -- Kimura, Yoshiharu -- Oda, Kohei -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1196-9. doi: 10.1126/science.aad6359.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Applied Biology, Faculty of Textile Science, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan. ; Department of Applied Biology, Faculty of Textile Science, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. ; Life Science Materials Laboratory, ADEKA, 7-2-34 Higashiogu, Arakawa-ku, Tokyo 116-8553, Japan. ; Department of Polymer Science, Faculty of Textile Science, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan. ; Ecology-Related Material Group Innovation Research Institute, Teijin, Hinode-cho 2-1, Iwakuni, Yamaguchi 740-8511, Japan. ; Department of Biosciences and Informatics, Keio University, 3-14-1 Hiyoshi, Kohoku-ku, Yokohama, Kanagawa 223-8522, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965627" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Betaproteobacteria/*enzymology ; Environmental Restoration and Remediation ; Enzymes/classification/genetics/metabolism ; Hydrolysis ; Microbial Consortia ; Molecular Sequence Data ; Phthalic Acids/metabolism ; Phylogeny ; Plastics/*metabolism ; Polyethylene Terephthalates/*metabolism ; Recycling
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  • 29
    Publication Date: 2016-01-09
    Description: beta-Barrel outer membrane proteins (OMPs) are found in the outer membranes of Gram-negative bacteria and are essential for nutrient import, signaling, and adhesion. A 200-kilodalton five-component complex called the beta-barrel assembly machinery (BAM) complex has been implicated in the biogenesis of OMPs. We report the structure of the BAM complex from Escherichia coli, revealing that binding of BamCDE modulates the conformation of BamA, the central component, which may serve to regulate the BAM complex. The periplasmic domain of BamA was in a closed state that prevents access to the barrel lumen, which indicates substrate OMPs may not be threaded through the barrel during biogenesis. Further, conformational shifts in the barrel domain lead to opening of the exit pore and rearrangement at the lateral gate.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bakelar, Jeremy -- Buchanan, Susan K -- Noinaj, Nicholas -- 1K22AI113078-01/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):180-6. doi: 10.1126/science.aad3460.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. ; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ; Markey Center for Structural Biology, Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, USA. nnoinaj@purdue.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26744406" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry ; Crystallography, X-Ray ; Escherichia coli/*metabolism ; Escherichia coli Proteins/*chemistry ; Multiprotein Complexes/*chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 30
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-04-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, Elizabeth -- New York, N.Y. -- Science. 2016 Apr 22;352(6284):394-5. doi: 10.1126/science.352.6284.394. Epub 2016 Apr 21.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27102455" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Evolution, Molecular ; Foundations ; Genes ; Genetic Research/*economics ; Great Britain ; Humans ; *Research Support as Topic ; *Selection, Genetic ; Sweden ; United States
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  • 31
    Publication Date: 2016-03-12
    Description: AMPA-type glutamate receptors (AMPARs), which are central mediators of rapid neurotransmission and synaptic plasticity, predominantly exist as heteromers of the subunits GluA1 to GluA4. Here we report the first AMPAR heteromer structures, which deviate substantially from existing GluA2 homomer structures. Crystal structures of the GluA2/3 and GluA2/4 N-terminal domains reveal a novel compact conformation with an alternating arrangement of the four subunits around a central axis. This organization is confirmed by cysteine cross-linking in full-length receptors, and it permitted us to determine the structure of an intact GluA2/3 receptor by cryogenic electron microscopy. Two models in the ligand-free state, at resolutions of 8.25 and 10.3 angstroms, exhibit substantial vertical compression and close associations between domain layers, reminiscent of N-methyl-D-aspartate receptors. Model 1 resembles a resting state and model 2 a desensitized state, thus providing snapshots of gating transitions in the nominal absence of ligand. Our data reveal organizational features of heteromeric AMPARs and provide a framework to decipher AMPAR architecture and signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4852135/" 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/PMC4852135/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herguedas, Beatriz -- Garcia-Nafria, Javier -- Cais, Ondrej -- Fernandez-Leiro, Rafael -- Krieger, James -- Ho, Hinze -- Greger, Ingo H -- MC_U105174197/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):aad3873. doi: 10.1126/science.aad3873. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neurobiology Division, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, UK. ; Structural Studies Division, MRC Laboratory of Molecular Biology, Cambridge, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26966189" target="_blank"〉PubMed〈/a〉
    Keywords: Brain/metabolism ; Cryoelectron Microscopy ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Ligands ; Models, Molecular ; *Protein Multimerization ; Protein Structure, Tertiary ; Receptors, AMPA/*chemistry/ultrastructure
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  • 32
    Publication Date: 2016-02-06
    Description: SH3 and multiple ankyrin repeat domains 3 (SHANK3) haploinsufficiency is causative for the neurological features of Phelan-McDermid syndrome (PMDS), including a high risk of autism spectrum disorder (ASD). We used unbiased, quantitative proteomics to identify changes in the phosphoproteome of Shank3-deficient neurons. Down-regulation of protein kinase B (PKB/Akt)-mammalian target of rapamycin complex 1 (mTORC1) signaling resulted from enhanced phosphorylation and activation of serine/threonine protein phosphatase 2A (PP2A) regulatory subunit, B56beta, due to increased steady-state levels of its kinase, Cdc2-like kinase 2 (CLK2). Pharmacological and genetic activation of Akt or inhibition of CLK2 relieved synaptic deficits in Shank3-deficient and PMDS patient-derived neurons. CLK2 inhibition also restored normal sociability in a Shank3-deficient mouse model. Our study thereby provides a novel mechanistic and potentially therapeutic understanding of deregulated signaling downstream of Shank3 deficiency.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bidinosti, Michael -- Botta, Paolo -- Kruttner, Sebastian -- Proenca, Catia C -- Stoehr, Natacha -- Bernhard, Mario -- Fruh, Isabelle -- Mueller, Matthias -- Bonenfant, Debora -- Voshol, Hans -- Carbone, Walter -- Neal, Sarah J -- McTighe, Stephanie M -- Roma, Guglielmo -- Dolmetsch, Ricardo E -- Porter, Jeffrey A -- Caroni, Pico -- Bouwmeester, Tewis -- Luthi, Andreas -- Galimberti, Ivan -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1199-203. doi: 10.1126/science.aad5487. Epub 2016 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Friedrich Miescher Institute, Basel, Switzerland. ; Analytical Sciences and Imaging, Novartis Institutes for Biomedical Research, Basel, Switzerland. ; Neuroscience, Novartis Institutes for Biomedical Research, Cambridge, USA. ; Developmental Molecular Pathways, Novartis Institutes for Biomedical Research, Basel, Switzerland. ivan.galimberti@novartis.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26847545" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Autism Spectrum Disorder/*drug therapy/enzymology/genetics ; Chromosome Deletion ; Chromosome Disorders/genetics ; Chromosomes, Human, Pair 22/genetics ; Disease Models, Animal ; Down-Regulation ; Gene Knockdown Techniques ; Humans ; Insulin-Like Growth Factor I/metabolism ; Mice ; Molecular Sequence Data ; Multiprotein Complexes/metabolism ; Nerve Tissue Proteins/*genetics ; Neurons/enzymology ; Phosphorylation ; Protein Phosphatase 2/metabolism ; Protein-Serine-Threonine Kinases/*antagonists & inhibitors/metabolism ; Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism ; Proteomics ; Proto-Oncogene Proteins c-akt/genetics/metabolism ; Rats ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
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  • 33
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-03-12
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blum, Arlene -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1117. doi: 10.1126/science.aaf5468. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Arlene Blum is founder and executive director of the Green Science Policy Institute, Berkeley, CA. arlene@GreenSciencePolicy.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965592" target="_blank"〉PubMed〈/a〉
    Keywords: Consumer Product Safety/*legislation & jurisprudence ; Health ; Household Products/*toxicity ; Humans ; Manufactured Materials/*toxicity ; United States
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  • 34
    Publication Date: 2016-02-04
    Description: Bacterial adaptive immunity and genome engineering involving the CRISPR (clustered regularly interspaced short palindromic repeats)-associated (Cas) protein Cas9 begin with RNA-guided DNA unwinding to form an RNA-DNA hybrid and a displaced DNA strand inside the protein. The role of this R-loop structure in positioning each DNA strand for cleavage by the two Cas9 nuclease domains is unknown. We determine molecular structures of the catalytically active Streptococcus pyogenes Cas9 R-loop that show the displaced DNA strand located near the RuvC nuclease domain active site. These protein-DNA interactions, in turn, position the HNH nuclease domain adjacent to the target DNA strand cleavage site in a conformation essential for concerted DNA cutting. Cas9 bends the DNA helix by 30 degrees , providing the structural distortion needed for R-loop formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Fuguo -- Taylor, David W -- Chen, Janice S -- Kornfeld, Jack E -- Zhou, Kaihong -- Thompson, Aubri J -- Nogales, Eva -- Doudna, Jennifer A -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):867-71. doi: 10.1126/science.aad8282. Epub 2016 Jan 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. ; Department of Chemistry, University of California, Berkeley, CA 94720, USA. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA. Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. doudna@berkeley.edu enogales@lbl.gov. ; Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720, USA. California Institute for Quantitative Biosciences, University of California, Berkeley, CA 94720, USA. Howard Hughes Medical Institute, University of California, Berkeley, CA 94720, USA. Department of Chemistry, University of California, Berkeley, CA 94720, USA. Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Physical Biosciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. doudna@berkeley.edu enogales@lbl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26841432" target="_blank"〉PubMed〈/a〉
    Keywords: *CRISPR-Cas Systems ; Catalytic Domain ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Crystallography, X-Ray ; DNA/*chemistry ; *DNA Cleavage ; Endonucleases/*chemistry/ultrastructure ; Genetic Engineering ; Genome ; Nucleic Acid Conformation ; Protein Conformation ; RNA/chemistry ; RNA, Guide ; Streptococcus pyogenes/*enzymology
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  • 35
    Publication Date: 2016-03-26
    Description: Induction of broadly neutralizing antibodies (bnAbs) is a major HIV vaccine goal. Germline-targeting immunogens aim to initiate bnAb induction by activating bnAb germline precursor B cells. Critical unmet challenges are to determine whether bnAb precursor naive B cells bind germline-targeting immunogens and occur at sufficient frequency in humans for reliable vaccine responses. Using deep mutational scanning and multitarget optimization, we developed a germline-targeting immunogen (eOD-GT8) for diverse VRC01-class bnAbs. We then used the immunogen to isolate VRC01-class precursor naive B cells from HIV-uninfected donors. Frequencies of true VRC01-class precursors, their structures, and their eOD-GT8 affinities support this immunogen as a candidate human vaccine prime. These methods could be applied to germline targeting for other classes of HIV bnAbs and for Abs to other pathogens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872700/" 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/PMC4872700/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jardine, Joseph G -- Kulp, Daniel W -- Havenar-Daughton, Colin -- Sarkar, Anita -- Briney, Bryan -- Sok, Devin -- Sesterhenn, Fabian -- Ereno-Orbea, June -- Kalyuzhniy, Oleksandr -- Deresa, Isaiah -- Hu, Xiaozhen -- Spencer, Skye -- Jones, Meaghan -- Georgeson, Erik -- Adachi, Yumiko -- Kubitz, Michael -- deCamp, Allan C -- Julien, Jean-Philippe -- Wilson, Ian A -- Burton, Dennis R -- Crotty, Shane -- Schief, William R -- P01 AI094419/AI/NIAID NIH HHS/ -- P01 AI110657/AI/NIAID NIH HHS/ -- P41GM103393/GM/NIGMS NIH HHS/ -- R01 AI084817/AI/NIAID NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1458-63. doi: 10.1126/science.aad9195.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. ; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Program in Molecular Structure and Function, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada. ; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Vaccine and Infectious Disease Division, Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. ; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Program in Molecular Structure and Function, Hospital for Sick Children Research Institute, Toronto, Ontario M5G 0A4, Canada. Departments of Biochemistry and Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. ; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02129, USA. ; Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. Division of Infectious Diseases, Department of Medicine, University of California San Diego School of Medicine, La Jolla, CA, USA. schief@scripps.edu shane@lji.org. ; Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla, CA 92037, USA. IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA. Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, The Scripps Research Institute, La Jolla, CA 92037, USA. Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02129, USA. schief@scripps.edu shane@lji.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013733" target="_blank"〉PubMed〈/a〉
    Keywords: AIDS Vaccines/*immunology ; Amino Acid Sequence ; Antibodies, Monoclonal/chemistry/*immunology/isolation & purification ; Antibodies, Neutralizing/chemistry/*immunology/isolation & purification ; Antibody Affinity ; B-Lymphocytes/immunology ; Cell Separation ; Combinatorial Chemistry Techniques ; Epitopes, B-Lymphocyte/chemistry/genetics/*immunology ; Germ Cells/*immunology ; HIV Antibodies/chemistry/*immunology/isolation & purification ; HIV-1/*immunology ; Humans ; Molecular Sequence Data ; Mutation ; Peptide Library ; Precursor Cells, B-Lymphoid/*immunology ; Protein Conformation
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 36
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaiser, Jocelyn -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):14. doi: 10.1126/science.351.6268.14.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26721983" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Databases, Genetic/*economics ; Financial Support ; Human Genome Project/*economics ; Humans ; Models, Animal ; National Human Genome Research Institute (U.S.)/*economics ; United States
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 37
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Richmond, Geraldine -- New York, N.Y. -- Science. 2016 Jan 29;351(6272):427. doi: 10.1126/science.aaf2869. Epub 2016 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Geraldine Richmond is president of AAAS and Presidential Chair in Science and professor in the Department of Chemistry and Biochemistry at the University of Oregon, Eugene, OR. richmond@oregon.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26823402" target="_blank"〉PubMed〈/a〉
    Keywords: Africa ; Asia ; *Food Supply ; Humans ; *Internationality ; United States ; *Water Supply
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 38
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-04-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaiser, Jocelyn -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):20. doi: 10.1126/science.352.6281.20.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034352" target="_blank"〉PubMed〈/a〉
    Keywords: Awards and Prizes ; Biomedical Research/*economics ; *Financing, Government ; National Institute of General Medical Sciences (U.S.) ; United States
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 39
    Publication Date: 2016-01-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaiser, Jocelyn -- Couzin-Frankel, Jennifer -- New York, N.Y. -- Science. 2016 Jan 22;351(6271):325-6. doi: 10.1126/science.351.6271.325.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26797992" target="_blank"〉PubMed〈/a〉
    Keywords: Biomedical Research/*organization & administration ; Federal Government ; Humans ; Neoplasms/*therapy ; Policy ; United States
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  • 40
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-03-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roman, Joe -- Kraska, James -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1258-60. doi: 10.1126/science.aad4247.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gund Institute for Ecological Economics, University of Vermont, Burlington, VT 05405, USA. jroman@uvm.edu. ; Stockton Center for the Study of International Law, U.S. Naval War College, Newport, RI 02841, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989232" target="_blank"〉PubMed〈/a〉
    Keywords: *Bays ; *Conservation of Natural Resources ; Cuba ; Diplomacy ; United States
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  • 41
    Publication Date: 2016-04-02
    Description: Recent studies have implicated long noncoding RNAs (lncRNAs) as regulators of many important biological processes. Here we report on the identification and characterization of a lncRNA, lnc13, that harbors a celiac disease-associated haplotype block and represses expression of certain inflammatory genes under homeostatic conditions. Lnc13 regulates gene expression by binding to hnRNPD, a member of a family of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). Upon stimulation, lnc13 levels are reduced, thereby allowing increased expression of the repressed genes. Lnc13 levels are significantly decreased in small intestinal biopsy samples from patients with celiac disease, which suggests that down-regulation of lnc13 may contribute to the inflammation seen in this disease. Furthermore, the lnc13 disease-associated variant binds hnRNPD less efficiently than its wild-type counterpart, thus helping to explain how these single-nucleotide polymorphisms contribute to celiac disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Castellanos-Rubio, Ainara -- Fernandez-Jimenez, Nora -- Kratchmarov, Radomir -- Luo, Xiaobing -- Bhagat, Govind -- Green, Peter H R -- Schneider, Robert -- Kiledjian, Megerditch -- Bilbao, Jose Ramon -- Ghosh, Sankar -- R01-AI093985/AI/NIAID NIH HHS/ -- R01-DK102180/DK/NIDDK NIH HHS/ -- R01-GM067005/GM/NIGMS NIH HHS/ -- R37-AI33443/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 1;352(6281):91-5. doi: 10.1126/science.aad0467.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. ; Department of Genetics, Physical Anthropology, and Animal Physiology, University of the Basque Country (UPV-EHU), BioCruces Research Institute, Leioa 48940, Basque Country, Spain. ; Department of Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. ; Center for Celiac Disease, Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Alexandria Center for Life Sciences, New York University School of Medicine, New York, NY 10016, USA. ; Alexandria Center for Life Sciences, New York University School of Medicine, New York, NY 10016, USA. ; Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA. ; Department of Microbiology and Immunology, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. sg2715@columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27034373" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Celiac Disease/*genetics/pathology ; Down-Regulation ; Gene Expression Regulation ; *Genetic Predisposition to Disease ; Haplotypes ; Heterogeneous-Nuclear Ribonucleoproteins/genetics ; Humans ; Inflammation/*genetics ; Mice ; Molecular Sequence Data ; Polymorphism, Single Nucleotide ; RNA, Long Noncoding/*genetics
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  • 42
    Publication Date: 2016-02-26
    Description: The oxidation of methane with sulfate is an important microbial metabolism in the global carbon cycle. In marine methane seeps, this process is mediated by consortia of anaerobic methanotrophic archaea (ANME) that live in syntrophy with sulfate-reducing bacteria (SRB). The underlying interdependencies within this uncultured symbiotic partnership are poorly understood. We used a combination of rate measurements and single-cell stable isotope probing to demonstrate that ANME in deep-sea sediments can be catabolically and anabolically decoupled from their syntrophic SRB partners using soluble artificial oxidants. The ANME still sustain high rates of methane oxidation in the absence of sulfate as the terminal oxidant, lending support to the hypothesis that interspecies extracellular electron transfer is the syntrophic mechanism for the anaerobic oxidation of methane.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scheller, Silvan -- Yu, Hang -- Chadwick, Grayson L -- McGlynn, Shawn E -- Orphan, Victoria J -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):703-7. doi: 10.1126/science.aad7154.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Geological and Planetary Sciences, California Institute of Technology, Pasadena, CA 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912857" target="_blank"〉PubMed〈/a〉
    Keywords: Anaerobiosis ; *Carbon Cycle ; Electron Transport ; Geologic Sediments/microbiology ; Methane/*metabolism ; Methanosarcinales/classification/genetics/*metabolism ; Molecular Sequence Data ; Oxidation-Reduction ; Phylogeny ; RNA, Archaeal/classification/genetics ; Seawater/microbiology ; Sulfates/*metabolism ; Sulfur-Reducing Bacteria/metabolism
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  • 43
    Publication Date: 2016-01-28
    Description: Seagrasses colonized the sea on at least three independent occasions to form the basis of one of the most productive and widespread coastal ecosystems on the planet. Here we report the genome of Zostera marina (L.), the first, to our knowledge, marine angiosperm to be fully sequenced. This reveals unique insights into the genomic losses and gains involved in achieving the structural and physiological adaptations required for its marine lifestyle, arguably the most severe habitat shift ever accomplished by flowering plants. Key angiosperm innovations that were lost include the entire repertoire of stomatal genes, genes involved in the synthesis of terpenoids and ethylene signalling, and genes for ultraviolet protection and phytochromes for far-red sensing. Seagrasses have also regained functions enabling them to adjust to full salinity. Their cell walls contain all of the polysaccharides typical of land plants, but also contain polyanionic, low-methylated pectins and sulfated galactans, a feature shared with the cell walls of all macroalgae and that is important for ion homoeostasis, nutrient uptake and O2/CO2 exchange through leaf epidermal cells. The Z. marina genome resource will markedly advance a wide range of functional ecological studies from adaptation of marine ecosystems under climate warming, to unravelling the mechanisms of osmoregulation under high salinities that may further inform our understanding of the evolution of salt tolerance in crop plants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olsen, Jeanine L -- Rouze, Pierre -- Verhelst, Bram -- Lin, Yao-Cheng -- Bayer, Till -- Collen, Jonas -- Dattolo, Emanuela -- De Paoli, Emanuele -- Dittami, Simon -- Maumus, Florian -- Michel, Gurvan -- Kersting, Anna -- Lauritano, Chiara -- Lohaus, Rolf -- Topel, Mats -- Tonon, Thierry -- Vanneste, Kevin -- Amirebrahimi, Mojgan -- Brakel, Janina -- Bostrom, Christoffer -- Chovatia, Mansi -- Grimwood, Jane -- Jenkins, Jerry W -- Jueterbock, Alexander -- Mraz, Amy -- Stam, Wytze T -- Tice, Hope -- Bornberg-Bauer, Erich -- Green, Pamela J -- Pearson, Gareth A -- Procaccini, Gabriele -- Duarte, Carlos M -- Schmutz, Jeremy -- Reusch, Thorsten B H -- Van de Peer, Yves -- England -- Nature. 2016 Feb 18;530(7590):331-5. doi: 10.1038/nature16548. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Groningen Institute of Evolutionary Life Sciences (GELIFES), University of Groningen, PO Box 11103, 9700 CC Groningen, The Netherlands. ; Department of Plant Systems Biology, VIB and Department of Plant Biotechnology and Bioinformatics, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. ; GEOMAR Helmholtz Centre for Ocean Research-Kiel, Evolutionary Ecology, Dusternbrooker Weg 20, D-24105 Kiel, Germany. ; Sorbonne Universite, UPMC Univ Paris 06, CNRS, UMR 8227, Integrative Biology of Marine Models, Station Biologique de Roscoff, CS 90074, F-29688, Roscoff cedex, France. ; Stazione Zoologica Anton Dohrn, Villa Comunale, 80121 Naples, Italy. ; Dipartimento di Scienze Agrarie e Ambientali, University of Udine, Via delle Scienze 206, 33100 Udine, Italy. ; INRA, UR1164 URGI-Research Unit in Genomics-Info, INRA de Versailles-Grignon, Route de Saint-Cyr, Versailles 78026, France. ; Institute for Evolution and Biodiversity, Westfalische Wilhelms-University of Munster, Hufferstrasse 1, D-48149 Munster, Germany. ; Institute for Computer Science, Heinrich Heine University, D-40255 Duesseldorf, Germany. ; Department of Biological and Environmental Sciences, Bioinformatics Infrastructure for Life Sciences (BILS), University of Gothenburg, Medicinaregatan 18A, 40530 Gothenburg, Sweden. ; Department of Energy Joint Genome Institute, 2800 Mitchell Dr., #100, Walnut Creek, California 94598, USA. ; Environmental and Marine Biology, Faculty of Science and Engineering, Abo Akademi University, Artillerigatan 6, FI-20520 Turku/Abo, Finland. ; HudsonAlpha Institute for Biotechnology, 601 Genome Way NW, Huntsville, Alabama 35806, USA. ; Marine Ecology Group, Nord University, Postbox 1490, 8049 Bodo, Norway. ; Amplicon Express, 2345 NE Hopkins Ct., Pullman, Washington 99163, USA. ; School of Marine Science and Policy, Department of Plant and Soil Sciences, Delaware Biotechnology Institute, University of Delaware, 15-Innovation Way, Newark, Delaware 19711, USA. ; Marine Ecology and Evolution, Centre for Marine Sciences (CCMAR), University of Algarve, 8005-139 Faro, Portugal. ; King Abdullah University of Science and Technology (KAUST), Red Sea Research Center (RSRC), Thuwal 23955-6900, Saudi Arabia. ; University of Kiel, Faculty of Mathematics and Natural Sciences, Christian-Albrechts-Platz 4, 24118 Kiel, Germany. ; Genomics Research Institute, University of Pretoria, Hatfield Campus, Pretoria 0028, South Africa. ; Bioinformatics Institute Ghent, Ghent University, Ghent B-9000, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814964" target="_blank"〉PubMed〈/a〉
    Keywords: Acclimatization/genetics ; Adaptation, Physiological/*genetics ; Cell Wall/chemistry ; Ethylenes/biosynthesis ; *Evolution, Molecular ; Gene Duplication ; Genes, Plant/genetics ; Genome, Plant/*genetics ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Oceans and Seas ; Osmoregulation/genetics ; Phylogeny ; Plant Leaves/metabolism ; Plant Stomata/genetics ; Pollen/metabolism ; Salinity ; Salt-Tolerance/genetics ; *Seawater ; Seaweed/genetics ; Terpenes/metabolism ; Zosteraceae/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 44
    Publication Date: 2016-02-24
    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〉
    Keywords: Amino Acid Motifs ; Binding Sites ; Biocatalysis ; Cross-Linking Reagents/chemistry ; Crystallography, X-Ray ; Eukaryotic Initiation Factor-2B/*chemistry/metabolism ; Guanosine Diphosphate/metabolism ; Guanosine Triphosphate/metabolism ; Models, Molecular ; Phosphorylation ; Protein Binding ; Protein Biosynthesis ; Protein Structure, Quaternary ; Protein Subunits/chemistry/metabolism ; Schizosaccharomyces/*chemistry
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  • 45
    Publication Date: 2016-04-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Check Hayden, Erika -- England -- Nature. 2016 Apr 28;532(7600):424-5. doi: 10.1038/532424a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27121817" target="_blank"〉PubMed〈/a〉
    Keywords: Biomedical Research/*economics/legislation & jurisprudence/*trends ; *Federal Government ; Financing, Government/economics/legislation & jurisprudence ; Humans ; Immunotherapy/economics ; Information Dissemination ; Leadership ; Neoplasms/economics/genetics/immunology/*therapy ; *Private Sector/economics ; *Public-Private Sector Partnerships/economics ; United States
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  • 46
    Publication Date: 2016-01-07
    Description: Catalysis in biology is restricted to RNA (ribozymes) and protein enzymes, but synthetic biomolecular catalysts can also be made of DNA (deoxyribozymes) or synthetic genetic polymers. In vitro selection from synthetic random DNA libraries identified DNA catalysts for various chemical reactions beyond RNA backbone cleavage. DNA-catalysed reactions include RNA and DNA ligation in various topologies, hydrolytic cleavage and photorepair of DNA, as well as reactions of peptides and small molecules. In spite of comprehensive biochemical studies of DNA catalysts for two decades, fundamental mechanistic understanding of their function is lacking in the absence of three-dimensional models at atomic resolution. Early attempts to solve the crystal structure of an RNA-cleaving deoxyribozyme resulted in a catalytically irrelevant nucleic acid fold. Here we report the crystal structure of the RNA-ligating deoxyribozyme 9DB1 (ref. 14) at 2.8 A resolution. The structure captures the ligation reaction in the post-catalytic state, revealing a compact folding unit stabilized by numerous tertiary interactions, and an unanticipated organization of the catalytic centre. Structure-guided mutagenesis provided insights into the basis for regioselectivity of the ligation reaction and allowed remarkable manipulation of substrate recognition and reaction rate. Moreover, the structure highlights how the specific properties of deoxyribose are reflected in the backbone conformation of the DNA catalyst, in support of its intricate three-dimensional organization. The structural principles underlying the catalytic ability of DNA elucidate differences and similarities in DNA versus RNA catalysts, which is relevant for comprehending the privileged position of folded RNA in the prebiotic world and in current organisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ponce-Salvatierra, Almudena -- Wawrzyniak-Turek, Katarzyna -- Steuerwald, Ulrich -- Hobartner, Claudia -- Pena, Vladimir -- England -- Nature. 2016 Jan 14;529(7585):231-4. doi: 10.1038/nature16471. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Research Group Nucleic Acid Chemistry, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; Research Group Macromolecular Crystallography, Max Planck Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Gottingen, Germany. ; Institute for Organic and Biomolecular Chemistry, Georg-August-University Gottingen, Tammannstr. 2, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735012" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; DNA, Catalytic/chemical synthesis/*chemistry/metabolism ; Deoxyribose/chemistry/metabolism ; Kinetics ; Models, Molecular ; Molecular Sequence Data ; *Nucleic Acid Conformation ; Nucleotides/chemistry/metabolism ; Polynucleotide Ligases/chemistry/metabolism ; RNA/chemistry/metabolism ; RNA Folding ; Substrate Specificity
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  • 47
    Publication Date: 2016-01-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Frank -- England -- Nature. 2016 Jan 14;529(7585):156. doi: 10.1038/529156e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Calgary, Alberta, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762447" target="_blank"〉PubMed〈/a〉
    Keywords: Chemical Hazard Release/*prevention & control ; Equipment Safety ; *Materials Testing ; Oil and Gas Industry/*instrumentation/methods ; United States
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  • 48
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    Publication Date: 2016-01-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Jan 28;529(7587):437-8. doi: 10.1038/529437b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26819007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; China ; Cities ; Congo ; Conservation of Natural Resources/*legislation & jurisprudence ; Ecosystem ; Great Britain ; *Parks, Recreational/legislation & jurisprudence ; Pleasure ; Uganda ; United States ; *Wilderness
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  • 49
    Publication Date: 2016-02-24
    Description: All Gram-negative bacteria, mitochondria and chloroplasts have outer membrane proteins (OMPs) that perform many fundamental biological processes. The OMPs in Gram-negative bacteria are inserted and folded into the outer membrane by the beta-barrel assembly machinery (BAM). The mechanism involved is poorly understood, owing to the absence of a structure of the entire BAM complex. Here we report two crystal structures of the Escherichia coli BAM complex in two distinct states: an inward-open state and a lateral-open state. Our structures reveal that the five polypeptide transport-associated domains of BamA form a ring architecture with four associated lipoproteins, BamB-BamE, in the periplasm. Our structural, functional studies and molecular dynamics simulations indicate that these subunits rotate with respect to the integral membrane beta-barrel of BamA to induce movement of the beta-strands of the barrel and promote insertion of the nascent OMP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gu, Yinghong -- Li, Huanyu -- Dong, Haohao -- Zeng, Yi -- Zhang, Zhengyu -- Paterson, Neil G -- Stansfeld, Phillip J -- Wang, Zhongshan -- Zhang, Yizheng -- Wang, Wenjian -- Dong, Changjiang -- G1100110/1/Medical Research Council/United Kingdom -- WT106121MA/Wellcome Trust/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):64-9. doi: 10.1038/nature17199. Epub 2016 Feb 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedical Research Centre, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK. ; Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Oxfordshire OX11 0DE, UK. ; Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK. ; Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical College, Xuzhou 221004, China. ; Key Laboratory of Bio-resources and Eco-environment, Ministry of Education, Sichuan Key Laboratory of Molecular Biology and Biotechnology, College of Life Sciences, Sichuan University, Chengdu 610064, China. ; Laboratory of Department of Surgery, the First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong 510080, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26901871" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Outer Membrane Proteins/*chemistry/*metabolism ; Crystallography, X-Ray ; Escherichia coli/*chemistry ; Escherichia coli Proteins/*chemistry/*metabolism ; Lipoproteins/chemistry/metabolism ; Models, Molecular ; Molecular Dynamics Simulation ; Movement ; Multiprotein Complexes/*chemistry/*metabolism ; Periplasm/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Protein Subunits/chemistry/metabolism ; Rotation
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  • 50
    Publication Date: 2016-03-10
    Description: Many biopolymers, including polysaccharides, must be translocated across at least one membrane to reach their site of biological function. Cellulose is a linear glucose polymer synthesized and secreted by a membrane-integrated cellulose synthase. Here, in crystallo enzymology with the catalytically active bacterial cellulose synthase BcsA-BcsB complex reveals structural snapshots of a complete cellulose biosynthesis cycle, from substrate binding to polymer translocation. Substrate- and product-bound structures of BcsA provide the basis for substrate recognition and demonstrate the stepwise elongation of cellulose. Furthermore, the structural snapshots show that BcsA translocates cellulose via a ratcheting mechanism involving a 'finger helix' that contacts the polymer's terminal glucose. Cooperating with BcsA's gating loop, the finger helix moves 'up' and 'down' in response to substrate binding and polymer elongation, respectively, thereby pushing the elongated polymer into BcsA's transmembrane channel. This mechanism is validated experimentally by tethering BcsA's finger helix, which inhibits polymer translocation but not elongation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843519/" 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/PMC4843519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morgan, Jacob L W -- McNamara, Joshua T -- Fischer, Michael -- Rich, Jamie -- Chen, Hong-Ming -- Withers, Stephen G -- Zimmer, Jochen -- 1R01GM101001/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 GM101001/GM/NIGMS NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):329-34. doi: 10.1038/nature16966. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Virginia School of Medicine, Center for Membrane Biology, Molecular Physiology and Biological Physics, 480 Ray C. Hunt Drive, Charlottesville, Virginia 22908, USA. ; Department of Chemistry, University of British Columbia, 2036 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958837" target="_blank"〉PubMed〈/a〉
    Keywords: Cellulose/*biosynthesis/chemistry/*metabolism ; Crystallography, X-Ray ; Glucose/metabolism ; Glucosyltransferases/*chemistry/*metabolism ; Intracellular Membranes/chemistry/*metabolism ; Models, Molecular ; Movement ; Protein Structure, Secondary ; Proteolipids/chemistry/metabolism ; Rhodobacter sphaeroides/enzymology ; Substrate Specificity
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  • 51
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    Nature Publishing Group (NPG)
    Publication Date: 2016-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 18;530(7590):253-4. doi: 10.1038/530253b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887453" target="_blank"〉PubMed〈/a〉
    Keywords: Biomedical Research/*economics/*trends ; Child ; *Federal Government ; *Goals ; Humans ; Immunotherapy ; Information Dissemination ; Neoplasms/*therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; United States
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  • 52
    Publication Date: 2016-01-15
    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〉
    Keywords: Amino Acid Isomerases/chemistry/metabolism ; Anti-Bacterial Agents/biosynthesis ; Binding Sites ; *Biocatalysis ; Brevibacillus/*enzymology ; Carbohydrate Metabolism ; Carrier Proteins/chemistry/metabolism ; Catalytic Domain ; Coenzymes/metabolism ; Crystallography, X-Ray ; Gramicidin/*biosynthesis ; Hydroxymethyl and Formyl Transferases/chemistry/metabolism ; Models, Molecular ; Multienzyme Complexes/chemistry/metabolism ; Pantetheine/analogs & derivatives/metabolism ; Peptide Synthases/*chemistry/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; RNA, Transfer/chemistry/metabolism
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  • 53
    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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  • 54
    Publication Date: 2016-02-09
    Description: The tremendous pandemic potential of coronaviruses was demonstrated twice in the past few decades by two global outbreaks of deadly pneumonia. Entry of coronaviruses into cells is mediated by the transmembrane spike glycoprotein S, which forms a trimer carrying receptor-binding and membrane fusion functions. S also contains the principal antigenic determinants and is the target of neutralizing antibodies. Here we present the structure of a mouse coronavirus S trimer ectodomain determined at 4.0 A resolution by single particle cryo-electron microscopy. It reveals the metastable pre-fusion architecture of S and highlights key interactions stabilizing it. The structure shares a common core with paramyxovirus F proteins, implicating mechanistic similarities and an evolutionary connection between these viral fusion proteins. The accessibility of the highly conserved fusion peptide at the periphery of the trimer indicates potential vaccinology strategies to elicit broadly neutralizing antibodies against coronaviruses. Finally, comparison with crystal structures of human coronavirus S domains allows rationalization of the molecular basis for species specificity based on the use of spatially contiguous but distinct domains.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Walls, Alexandra C -- Tortorici, M Alejandra -- Bosch, Berend-Jan -- Frenz, Brandon -- Rottier, Peter J M -- DiMaio, Frank -- Rey, Felix A -- Veesler, David -- GM103310/GM/NIGMS NIH HHS/ -- T32GM008268/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Mar 3;531(7592):114-7. doi: 10.1038/nature16988. Epub 2016 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, Washington 98195, USA. ; Institut Pasteur, Unite de Virologie Structurale, 75015 Paris, France. ; CNRS UMR 3569 Virologie, 75015 Paris, France. ; Virology Division, Department of Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, 3584 CL Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26855426" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Antibodies, Neutralizing/immunology ; Cell Line ; Coronavirus Infections/immunology/virology ; *Cryoelectron Microscopy ; Drosophila melanogaster ; Mice ; Models, Molecular ; Molecular Sequence Data ; Murine hepatitis virus/*chemistry/immunology/*ultrastructure ; Protein Multimerization ; Protein Structure, Tertiary ; Spike Glycoprotein, Coronavirus/*chemistry/immunology/*ultrastructure ; Viral Vaccines/chemistry/immunology ; Virus Internalization
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  • 55
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    Publication Date: 2016-05-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 May 11;533(7602):146. doi: 10.1038/533146a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27172009" target="_blank"〉PubMed〈/a〉
    Keywords: Device Approval/legislation & jurisprudence ; Drug Approval/legislation & jurisprudence ; Electronic Cigarettes/*adverse effects/utilization ; Humans ; Industry/legislation & jurisprudence ; Nicotine/administration & dosage/adverse effects/analysis ; Research Personnel ; Smoking/epidemiology/mortality/*prevention & control ; Tobacco Products/adverse effects/utilization ; United States ; United States Food and Drug Administration/*legislation & jurisprudence
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  • 56
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roth, Alvin E -- England -- Nature. 2016 Apr 14;532(7598):178. doi: 10.1038/532178a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stanford University, California, USA. He shared the 2012 Nobel Memorial Prize in Economic Sciences with Lloyd Shapley.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075091" target="_blank"〉PubMed〈/a〉
    Keywords: Algorithms ; Economics/*history ; Female ; *Game Theory ; History, 20th Century ; History, 21st Century ; Humans ; Male ; Marketing/history ; Marriage/psychology ; Mathematics/*history ; Nobel Prize ; United States
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  • 57
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    Publication Date: 2016-05-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 May 11;533(7602):145. doi: 10.1038/533145a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27172008" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anxiety ; Biomedical Research/*trends ; Breast Feeding/*adverse effects ; Clinical Trials as Topic/ethics/methods ; Female ; Humans ; Infant ; Infant, Newborn ; Milk, Human/*chemistry/*metabolism ; Mothers/psychology ; Pharmaceutical Preparations/*administration & dosage/*metabolism ; Risk Assessment ; Safety ; *Uncertainty ; United States ; United States Food and Drug Administration
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  • 58
    Publication Date: 2016-03-05
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauer, Michael -- Valantine, Hannah -- Collins, Francis S -- England -- Nature. 2016 Mar 3;531(7592):35. doi: 10.1038/531035b.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institutes of Health, Bethesda, Maryland, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935689" target="_blank"〉PubMed〈/a〉
    Keywords: Congresses as Topic ; *National Institutes of Health (U.S.)/economics/organization & administration ; *Organizational Policy ; Sexual Harassment/*prevention & control/statistics & numerical data ; United States ; Workplace
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  • 59
    Publication Date: 2016-01-21
    Description: Ubiquitination is a central process affecting all facets of cellular signalling and function. A critical step in ubiquitination is the transfer of ubiquitin from an E2 ubiquitin-conjugating enzyme to a substrate or a growing ubiquitin chain, which is mediated by E3 ubiquitin ligases. RING-type E3 ligases typically facilitate the transfer of ubiquitin from the E2 directly to the substrate. The RING-between-RING (RBR) family of RING-type E3 ligases, however, breaks this paradigm by forming a covalent intermediate with ubiquitin similarly to HECT-type E3 ligases. The RBR family includes Parkin and HOIP, the central catalytic factor of the LUBAC (linear ubiquitin chain assembly complex). While structural insights into the RBR E3 ligases Parkin and HHARI in their overall auto-inhibited forms are available, no structures exist of intact fully active RBR E3 ligases or any of their complexes. Thus, the RBR mechanism of action has remained largely unknown. Here we present the first structure, to our knowledge, of the fully active human HOIP RBR in its transfer complex with an E2~ubiquitin conjugate, which elucidates the intricate nature of RBR E3 ligases. The active HOIP RBR adopts a conformation markedly different from that of auto-inhibited RBRs. HOIP RBR binds the E2~ubiquitin conjugate in an elongated fashion, with the E2 and E3 catalytic centres ideally aligned for ubiquitin transfer, which structurally both requires and enables a HECT-like mechanism. In addition, three distinct helix-IBR-fold motifs inherent to RBRs form ubiquitin-binding regions that engage the activated ubiquitin of the E2~ubiquitin conjugate and, surprisingly, an additional regulatory ubiquitin molecule. The features uncovered reveal critical states of the HOIP RBR E3 ligase cycle, and comparison with Parkin and HHARI suggests a general mechanism for RBR E3 ligases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lechtenberg, Bernhard C -- Rajput, Akhil -- Sanishvili, Ruslan -- Dobaczewska, Malgorzata K -- Ware, Carl F -- Mace, Peter D -- Riedl, Stefan J -- P30 CA030199/CA/NCI NIH HHS/ -- P30CA030199/CA/NCI NIH HHS/ -- R01AA017238/AA/NIAAA NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):546-50. doi: 10.1038/nature16511. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉NCI-Designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA. ; X-ray Science Division, Advanced Photon Source, Argonne National Laboratory, 9700 South Cass Avenue, Argonne, Illinois 60439, USA. ; Biochemistry Department, University of Otago, 710 Cumberland Street, Dunedin 9054, New Zealand.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789245" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Motifs ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Models, Molecular ; Multiprotein Complexes/*chemistry/*metabolism ; *RING Finger Domains ; Ubiquitin/*chemistry/metabolism ; Ubiquitin-Conjugating Enzymes/*chemistry/metabolism ; Ubiquitin-Protein Ligases/*chemistry/*metabolism
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  • 60
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 May 5;533(7601):7. doi: 10.1038/533007a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27146996" target="_blank"〉PubMed〈/a〉
    Keywords: Americas ; *Bone and Bones/metabolism ; Burial/ethics/*legislation & jurisprudence ; Dissent and Disputes/*legislation & jurisprudence ; *Federal Government ; Genome, Human/genetics ; Genomics ; History, Ancient ; Human Migration/history ; Humans ; Indians, North American/classification/genetics/*legislation & jurisprudence ; Indians, South American/classification/genetics/legislation & jurisprudence ; *Phylogeny ; Research Personnel/*legislation & jurisprudence ; United States ; Washington
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  • 61
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    Nature Publishing Group (NPG)
    Publication Date: 2016-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2016 Feb 4;530(7588):17. doi: 10.1038/530017a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842036" target="_blank"〉PubMed〈/a〉
    Keywords: Attention/drug effects ; Cognition Disorders/*complications/*drug therapy/psychology ; Depression/*complications/drug therapy/*psychology ; *Drug Discovery ; *Drug Industry/legislation & jurisprudence ; Humans ; Memory/drug effects ; Schizophrenia/drug therapy ; United States ; United States Food and Drug Administration/legislation & jurisprudence
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  • 62
    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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  • 63
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Callaway, Ewen -- England -- Nature. 2016 Apr 14;532(7598):159-60. doi: 10.1038/nature.2016.19714.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075075" target="_blank"〉PubMed〈/a〉
    Keywords: Financing, Organized/economics/*legislation & jurisprudence/*organization & ; administration ; Great Britain ; Laboratories/*economics ; National Institutes of Health (U.S.)/legislation & jurisprudence ; Research Personnel/*economics ; United States
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  • 64
    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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  • 65
    Publication Date: 2016-01-15
    Description: Many important natural products are produced by multidomain non-ribosomal peptide synthetases (NRPSs). During synthesis, intermediates are covalently bound to integrated carrier domains and transported to neighbouring catalytic domains in an assembly line fashion. Understanding the structural basis for catalysis with non-ribosomal peptide synthetases will facilitate bioengineering to create novel products. Here we describe the structures of two different holo-non-ribosomal peptide synthetase modules, each revealing a distinct step in the catalytic cycle. One structure depicts the carrier domain cofactor bound to the peptide bond-forming condensation domain, whereas a second structure captures the installation of the amino acid onto the cofactor within the adenylation domain. These structures demonstrate that a conformational change within the adenylation domain guides transfer of intermediates between domains. Furthermore, one structure shows that the condensation and adenylation domains simultaneously adopt their catalytic conformations, increasing the overall efficiency in a revised structural cycle. These structures and the single-particle electron microscopy analysis demonstrate a highly dynamic domain architecture and provide the foundation for understanding the structural mechanisms that could enable engineering of novel non-ribosomal peptide synthetases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Drake, Eric J -- Miller, Bradley R -- Shi, Ce -- Tarrasch, Jeffrey T -- Sundlov, Jesse A -- Allen, C Leigh -- Skiniotis, Georgios -- Aldrich, Courtney C -- Gulick, Andrew M -- GM-068440/GM/NIGMS NIH HHS/ -- GM-115601/GM/NIGMS NIH HHS/ -- R01 GM068440/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):235-8. doi: 10.1038/nature16163.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hauptman-Woodward Medical Research Institute, 700 Ellicott Street, Buffalo, New York 14203, USA. ; Department of Structural Biology, University at Buffalo, Buffalo, New York 14203, USA. ; Center for Drug Design and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762461" target="_blank"〉PubMed〈/a〉
    Keywords: Acinetobacter baumannii/*enzymology ; Biocatalysis ; Carrier Proteins/metabolism ; Coenzymes/metabolism ; Crystallography, X-Ray ; Escherichia coli/*enzymology ; Holoenzymes/*chemistry/metabolism ; Models, Molecular ; Pantetheine/analogs & derivatives/metabolism ; Peptide Synthases/*chemistry/metabolism ; Protein Structure, Tertiary
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  • 66
    Publication Date: 2016-04-21
    Description: The CRISPR-Cas systems, as exemplified by CRISPR-Cas9, are RNA-guided adaptive immune systems used by bacteria and archaea to defend against viral infection. The CRISPR-Cpf1 system, a new class 2 CRISPR-Cas system, mediates robust DNA interference in human cells. Although functionally conserved, Cpf1 and Cas9 differ in many aspects including their guide RNAs and substrate specificity. Here we report the 2.38 A crystal structure of the CRISPR RNA (crRNA)-bound Lachnospiraceae bacterium ND2006 Cpf1 (LbCpf1). LbCpf1 has a triangle-shaped architecture with a large positively charged channel at the centre. Recognized by the oligonucleotide-binding domain of LbCpf1, the crRNA adopts a highly distorted conformation stabilized by extensive intramolecular interactions and the (Mg(H2O)6)(2+) ion. The oligonucleotide-binding domain also harbours a looped-out helical domain that is important for LbCpf1 substrate binding. Binding of crRNA or crRNA lacking the guide sequence induces marked conformational changes but no oligomerization of LbCpf1. Our study reveals the crRNA recognition mechanism and provides insight into crRNA-guided substrate binding of LbCpf1, establishing a framework for engineering LbCpf1 to improve its efficiency and specificity for genome editing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, De -- Ren, Kuan -- Qiu, Xiaolin -- Zheng, Jianlin -- Guo, Minghui -- Guan, Xiaoyu -- Liu, Hongnan -- Li, Ningning -- Zhang, Bailing -- Yang, Daijun -- Ma, Chuang -- Wang, Shuo -- Wu, Dan -- Ma, Yunfeng -- Fan, Shilong -- Wang, Jiawei -- Gao, Ning -- Huang, Zhiwei -- England -- Nature. 2016 Apr 28;532(7600):522-6. doi: 10.1038/nature17944. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China. ; Ministry of Education Key Laboratory of Protein Sciences, Center for Structural Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096363" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Proteins/*chemistry/*metabolism ; CRISPR-Associated Proteins/*chemistry/*metabolism ; CRISPR-Cas Systems ; Clustered Regularly Interspaced Short Palindromic Repeats/*genetics ; Crystallography, X-Ray ; Firmicutes/*enzymology ; Genetic Engineering ; Models, Molecular ; Nucleic Acid Conformation ; Protein Binding ; Protein Structure, Tertiary ; RNA Stability ; RNA, Bacterial/*chemistry/genetics/*metabolism ; RNA, Guide/chemistry/genetics/metabolism ; Substrate Specificity
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  • 67
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    Nature Publishing Group (NPG)
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Apr 14;532(7598):147-8. doi: 10.1038/532147b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075057" target="_blank"〉PubMed〈/a〉
    Keywords: Financing, Organized/*legislation & jurisprudence/*organization & administration ; National Institute of Allergy and Infectious Diseases (U.S.) ; *Research Personnel/economics/psychology ; Surveys and Questionnaires ; United States
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  • 68
    Publication Date: 2016-04-30
    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〉
    Keywords: Climate Change/*statistics & numerical data ; *Forecasting ; Global Warming/statistics & numerical data ; Greenhouse Effect/statistics & numerical data ; Humidity ; Motivation ; *Public Opinion ; Rain ; Seasons ; Temperature ; Time Factors ; United States ; *Weather
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  • 69
    Publication Date: 2016-04-05
    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〉
    Keywords: Benzamides/chemistry/metabolism ; Binding Sites ; Crystallography, X-Ray ; Endoplasmic Reticulum/metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Intracellular Membranes/metabolism ; Isoxazoles/chemistry/metabolism ; Ligands ; Models, Molecular ; Piperidines/chemistry/metabolism ; Protein Structure, Tertiary ; Pyridines/chemistry/metabolism ; Receptors, sigma/*chemistry/metabolism ; Substrate Specificity
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  • 70
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    Nature Publishing Group (NPG)
    Publication Date: 2016-05-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eisenstein, Michael -- England -- Nature. 2016 May 5;533(7601):S20-1. doi: 10.1038/533S20a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27144604" target="_blank"〉PubMed〈/a〉
    Keywords: Federal Government ; Financing, Government/economics/statistics & numerical data ; Great Britain ; Humans ; Inventions/economics ; Investments/*economics/statistics & numerical data ; National Institutes of Health (U.S.)/economics ; Patents as Topic ; Research/*economics/statistics & numerical data ; Research Support as Topic/economics/statistics & numerical data ; United States
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  • 71
    Publication Date: 2016-04-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lewis, Simon L -- England -- Nature. 2016 Apr 21;532(7599):283. doi: 10.1038/532283a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27111605" target="_blank"〉PubMed〈/a〉
    Keywords: China ; Environmental Policy/*legislation & jurisprudence ; Global Warming/*legislation & jurisprudence/*prevention & control ; Human Activities/legislation & jurisprudence ; *International Cooperation ; Islands ; Paris ; *Politics ; *Temperature ; United States
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  • 72
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Mar 10;531(7593):140. doi: 10.1038/531140a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961620" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CRISPR-Cas Systems/*genetics ; Directed Molecular Evolution/methods ; Dual Use Research/ethics/legislation & jurisprudence ; Embryo Research/ethics ; *Genetic Engineering/ethics/legislation & jurisprudence/trends ; Genome, Human/genetics ; Genomics/ethics/trends ; Germ-Line Mutation/ethics/genetics ; Government Regulation ; Humans ; Public Opinion ; Risk Assessment ; *Security Measures/legislation & jurisprudence ; United States
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  • 73
    Publication Date: 2016-03-08
    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〉
    Keywords: Adenosine Triphosphatases/*chemistry/*metabolism ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Hydrophobic and Hydrophilic Interactions ; Lipid Bilayers/chemistry/metabolism ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Protein Sorting Signals ; Protein Structure, Tertiary
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  • 74
    Publication Date: 2016-04-15
    Description: Accurate modelling and prediction of the local to continental-scale hydroclimate response to global warming is essential given the strong impact of hydroclimate on ecosystem functioning, crop yields, water resources, and economic security. However, uncertainty in hydroclimate projections remains large, in part due to the short length of instrumental measurements available with which to assess climate models. Here we present a spatial reconstruction of hydroclimate variability over the past twelve centuries across the Northern Hemisphere derived from a network of 196 at least millennium-long proxy records. We use this reconstruction to place recent hydrological changes and future precipitation scenarios in a long-term context of spatially resolved and temporally persistent hydroclimate patterns. We find a larger percentage of land area with relatively wetter conditions in the ninth to eleventh and the twentieth centuries, whereas drier conditions are more widespread between the twelfth and nineteenth centuries. Our reconstruction reveals that prominent seesaw patterns of alternating moisture regimes observed in instrumental data across the Mediterranean, western USA, and China have operated consistently over the past twelve centuries. Using an updated compilation of 128 temperature proxy records, we assess the relationship between the reconstructed centennial-scale Northern Hemisphere hydroclimate and temperature variability. Even though dry and wet conditions occurred over extensive areas under both warm and cold climate regimes, a statistically significant co-variability of hydroclimate and temperature is evident for particular regions. We compare the reconstructed hydroclimate anomalies with coupled atmosphere-ocean general circulation model simulations and find reasonable agreement during pre-industrial times. However, the intensification of the twentieth-century-mean hydroclimate anomalies in the simulations, as compared to previous centuries, is not supported by our new multi-proxy reconstruction. This finding suggests that much work remains before we can model hydroclimate variability accurately, and highlights the importance of using palaeoclimate data to place recent and predicted hydroclimate changes in a millennium-long context.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ljungqvist, Fredrik Charpentier -- Krusic, Paul J -- Sundqvist, Hanna S -- Zorita, Eduardo -- Brattstrom, Gudrun -- Frank, David -- England -- Nature. 2016 Apr 7;532(7597):94-8. doi: 10.1038/nature17418.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of History, Stockholm University, SE-10691 Stockholm, Sweden. ; Centre for Medieval Studies, Stockholm University, SE-10691 Stockholm, Sweden. ; Bolin Centre for Climate Research, Stockholm University, SE-10691 Stockholm, Sweden. ; Navarino Environmental Observatory, GR-24001 Messinia, Greece. ; Department of Physical Geography, Stockholm University, SE-10691 Stockholm, Sweden. ; Helmholtz-Zentrum Geesthacht, Institute for Coastal Research, DE-21502 Geesthacht, Germany. ; Department of Mathematics, Stockholm University, SE-10691 Stockholm, Sweden. ; Swiss Federal Research Institute WSL, CH-8903 Birmensdorf, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078569" target="_blank"〉PubMed〈/a〉
    Keywords: Atmosphere ; China ; *Climate ; Climate Change/*statistics & numerical data ; Ecosystem ; Geographic Mapping ; Geologic Sediments/chemistry ; History, 15th Century ; History, 16th Century ; History, 17th Century ; History, 18th Century ; History, 19th Century ; History, 20th Century ; History, 21st Century ; History, Medieval ; Hydrology ; Ice/analysis ; Mediterranean Region ; Models, Theoretical ; *Rain ; Soil/chemistry ; Spatio-Temporal Analysis ; Temperature ; Trees/anatomy & histology/growth & development ; Uncertainty ; United States
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  • 75
    Publication Date: 2016-01-28
    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〉
    Keywords: Anti-HIV Agents/administration & dosage/pharmacology/therapeutic use ; Carrier State/blood/*drug therapy/*virology ; Drug Resistance, Viral/drug effects ; HIV Infections/blood/*drug therapy/*virology ; HIV-1/drug effects/genetics/*growth & development/isolation & purification ; Haplotypes/drug effects ; Humans ; Lymph Nodes/drug effects/virology ; Models, Biological ; Molecular Sequence Data ; Phylogeny ; Selection, Genetic/drug effects ; Sequence Analysis, DNA ; Spatio-Temporal Analysis ; Time Factors ; *Viral Load/drug effects ; *Virus Replication/drug effects
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  • 76
    Publication Date: 2016-04-28
    Description: The Bacillus thuringiensis delta-endotoxins (Bt toxins) are widely used insecticidal proteins in engineered crops that provide agricultural, economic, and environmental benefits. The development of insect resistance to Bt toxins endangers their long-term effectiveness. Here we have developed a phage-assisted continuous evolution selection that rapidly evolves high-affinity protein-protein interactions, and applied this system to evolve variants of the Bt toxin Cry1Ac that bind a cadherin-like receptor from the insect pest Trichoplusia ni (TnCAD) that is not natively bound by wild-type Cry1Ac. The resulting evolved Cry1Ac variants bind TnCAD with high affinity (dissociation constant Kd = 11-41 nM), kill TnCAD-expressing insect cells that are not susceptible to wild-type Cry1Ac, and kill Cry1Ac-resistant T. ni insects up to 335-fold more potently than wild-type Cry1Ac. Our findings establish that the evolution of Bt toxins with novel insect cell receptor affinity can overcome insect Bt toxin resistance and confer lethality approaching that of the wild-type Bt toxin against non-resistant insects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4865400/" 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/PMC4865400/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Badran, Ahmed H -- Guzov, Victor M -- Huai, Qing -- Kemp, Melissa M -- Vishwanath, Prashanth -- Kain, Wendy -- Nance, Autumn M -- Evdokimov, Artem -- Moshiri, Farhad -- Turner, Keith H -- Wang, Ping -- Malvar, Thomas -- Liu, David R -- R01 EB022376/EB/NIBIB NIH HHS/ -- R01EB022376/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 May 5;533(7601):58-63. doi: 10.1038/nature17938. Epub 2016 Apr 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA. ; Monsanto Company, 245 First Street, Suite 200, Cambridge, Massachusetts 02142, USA. ; Department of Entomology, Cornell University, Geneva, New York 14456, USA. ; Monsanto Company, 700 Chesterfield Parkway West, Chesterfield, Missouri 63017, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27120167" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Bacillus thuringiensis/*genetics ; Bacterial Proteins/*genetics/*metabolism ; Bacteriophages/genetics ; Biotechnology ; Cadherins/metabolism ; Cell Death ; Consensus Sequence ; Crops, Agricultural/genetics/metabolism ; Directed Molecular Evolution/*methods ; Endotoxins/*genetics/*metabolism ; Genetic Variation/*genetics ; Hemolysin Proteins/*genetics/*metabolism ; *Insecticide Resistance ; Insecticides/metabolism ; Molecular Sequence Data ; Moths/cytology/*physiology ; Mutagenesis/genetics ; Pest Control, Biological/*methods ; Plants, Genetically Modified ; Protein Binding/genetics ; Protein Stability ; Selection, Genetic
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  • 77
    Publication Date: 2016-02-19
    Description: Retroviral integrase catalyses the integration of viral DNA into host target DNA, which is an essential step in the life cycle of all retroviruses. Previous structural characterization of integrase-viral DNA complexes, or intasomes, from the spumavirus prototype foamy virus revealed a functional integrase tetramer, and it is generally believed that intasomes derived from other retroviral genera use tetrameric integrase. However, the intasomes of orthoretroviruses, which include all known pathogenic species, have not been characterized structurally. Here, using single-particle cryo-electron microscopy and X-ray crystallography, we determine an unexpected octameric integrase architecture for the intasome of the betaretrovirus mouse mammary tumour virus. The structure is composed of two core integrase dimers, which interact with the viral DNA ends and structurally mimic the integrase tetramer of prototype foamy virus, and two flanking integrase dimers that engage the core structure via their integrase carboxy-terminal domains. Contrary to the belief that tetrameric integrase components are sufficient to catalyse integration, the flanking integrase dimers were necessary for mouse mammary tumour virus integrase activity. The integrase octamer solves a conundrum for betaretroviruses as well as alpharetroviruses by providing critical carboxy-terminal domains to the intasome core that cannot be provided in cis because of evolutionarily restrictive catalytic core domain-carboxy-terminal domain linker regions. The octameric architecture of the intasome of mouse mammary tumour virus provides new insight into the structural basis of retroviral DNA integration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ballandras-Colas, Allison -- Brown, Monica -- Cook, Nicola J -- Dewdney, Tamaria G -- Demeler, Borries -- Cherepanov, Peter -- Lyumkis, Dmitry -- Engelman, Alan N -- 9 P41 GM103310/GM/NIGMS NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- P41 GM103331/GM/NIGMS NIH HHS/ -- P50 GM082251/GM/NIGMS NIH HHS/ -- P50 GM103368/GM/NIGMS NIH HHS/ -- R01 AI070042/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):358-61. doi: 10.1038/nature16955.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Department of Medicine, Harvard Medical School, 450 Brookline Avenue, Boston, Massachusetts 02215, USA. ; Laboratory of Genetics and Helmsley Center for Genomic Medicine, The Salk Institute for Biological Studies, 10010 N Torrey Pines Road, La Jolla, California 92037, USA. ; Clare Hall Laboratories, The Francis Crick Institute, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK. ; Department of Biochemistry, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78229, USA. ; Division of Medicine, Imperial College London, St. Mary's Campus, Norfolk Place, London W2 1PG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887496" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; *Cryoelectron Microscopy ; Crystallography, X-Ray ; DNA, Viral/chemistry/*metabolism/*ultrastructure ; Integrases/*chemistry/metabolism/*ultrastructure ; Mammary Tumor Virus, Mouse/chemistry/*enzymology/genetics/ultrastructure ; Models, Molecular ; *Protein Multimerization ; Protein Structure, Quaternary ; Spumavirus/chemistry/enzymology ; Virus Integration
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  • 78
    Publication Date: 2016-01-21
    Description: Cellular immunity against viral infection and tumour cells depends on antigen presentation by major histocompatibility complex class I (MHC I) molecules. Intracellular antigenic peptides are transported into the endoplasmic reticulum by the transporter associated with antigen processing (TAP) and then loaded onto the nascent MHC I molecules, which are exported to the cell surface and present peptides to the immune system. Cytotoxic T lymphocytes recognize non-self peptides and program the infected or malignant cells for apoptosis. Defects in TAP account for immunodeficiency and tumour development. To escape immune surveillance, some viruses have evolved strategies either to downregulate TAP expression or directly inhibit TAP activity. So far, neither the architecture of TAP nor the mechanism of viral inhibition has been elucidated at the structural level. Here we describe the cryo-electron microscopy structure of human TAP in complex with its inhibitor ICP47, a small protein produced by the herpes simplex virus I. Here we show that the 12 transmembrane helices and 2 cytosolic nucleotide-binding domains of the transporter adopt an inward-facing conformation with the two nucleotide-binding domains separated. The viral inhibitor ICP47 forms a long helical hairpin, which plugs the translocation pathway of TAP from the cytoplasmic side. Association of ICP47 precludes substrate binding and prevents nucleotide-binding domain closure necessary for ATP hydrolysis. This work illustrates a striking example of immune evasion by persistent viruses. By blocking viral antigens from entering the endoplasmic reticulum, herpes simplex virus is hidden from cytotoxic T lymphocytes, which may contribute to establishing a lifelong infection in the host.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oldham, Michael L -- Hite, Richard K -- Steffen, Alanna M -- Damko, Ermelinda -- Li, Zongli -- Walz, Thomas -- Chen, Jue -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Jan 28;529(7587):537-40. doi: 10.1038/nature16506. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. ; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, Maryland 20815, USA. ; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789246" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/antagonists & ; inhibitors/chemistry/*metabolism/*ultrastructure ; Amino Acid Sequence ; Antigens, Viral/immunology/metabolism ; *Cryoelectron Microscopy ; Endoplasmic Reticulum/metabolism ; Herpesvirus 1, Human/chemistry/*immunology/metabolism/ultrastructure ; Immediate-Early Proteins/chemistry/*metabolism/*ultrastructure ; *Immune Evasion ; Models, Molecular ; Molecular Sequence Data ; Protein Binding ; Protein Conformation
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  • 79
    Publication Date: 2016-02-04
    Description: G protein-coupled receptors (GPCRs) are physiologically important transmembrane signalling proteins that trigger intracellular responses upon binding of extracellular ligands. Despite recent breakthroughs in GPCR crystallography, the details of ligand-induced signal transduction are not well understood owing to missing dynamical information. In principle, such information can be provided by NMR, but so far only limited data of functional relevance on few side-chain sites of eukaryotic GPCRs have been obtained. Here we show that receptor motions can be followed at virtually any backbone site in a thermostabilized mutant of the turkey beta1-adrenergic receptor (beta1AR). Labelling with [(15)N]valine in a eukaryotic expression system provides over twenty resolved resonances that report on structure and dynamics in six ligand complexes and the apo form. The response to the various ligands is heterogeneous in the vicinity of the binding pocket, but gets transformed into a homogeneous readout at the intracellular side of helix 5 (TM5), which correlates linearly with ligand efficacy for the G protein pathway. The effect of several pertinent, thermostabilizing point mutations was assessed by reverting them to the native sequence. Whereas the response to ligands remains largely unchanged, binding of the G protein mimetic nanobody NB80 and G protein activation are only observed when two conserved tyrosines (Y227 and Y343) are restored. Binding of NB80 leads to very strong spectral changes throughout the receptor, including the extracellular ligand entrance pocket. This indicates that even the fully thermostabilized receptor undergoes activating motions in TM5, but that the fully active state is only reached in presence of Y227 and Y343 by stabilization with a G protein-like partner. The combined analysis of chemical shift changes from the point mutations and ligand responses identifies crucial connections in the allosteric activation pathway, and presents a general experimental method to delineate signal transmission networks at high resolution in GPCRs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Isogai, Shin -- Deupi, Xavier -- Opitz, Christian -- Heydenreich, Franziska M -- Tsai, Ching-Ju -- Brueckner, Florian -- Schertler, Gebhard F X -- Veprintsev, Dmitry B -- Grzesiek, Stephan -- England -- Nature. 2016 Feb 11;530(7589):237-41. doi: 10.1038/nature16577. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Focal Area Structural Biology and Biophysics, Biozentrum, University of Basel, CH-4056 Basel, Switzerland. ; Paul Scherrer Institute, CH-5232 Villigen PSI, Switzerland. ; Department of Biology, ETH Zurich, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840483" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-1 Receptor Agonists/chemistry/pharmacology ; Adrenergic beta-1 Receptor Antagonists/pharmacology ; Allosteric Regulation/drug effects/genetics ; Animals ; Apoproteins/chemistry/genetics/metabolism ; Binding Sites/drug effects ; Crystallography, X-Ray ; Drug Partial Agonism ; Heterotrimeric GTP-Binding Proteins/metabolism ; Ligands ; Models, Molecular ; Movement ; *Nuclear Magnetic Resonance, Biomolecular ; Point Mutation/genetics ; Protein Stability ; Protein Structure, Secondary/drug effects ; Receptors, Adrenergic, beta-1/*chemistry/genetics/*metabolism ; *Signal Transduction/drug effects/genetics ; Turkeys
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  • 80
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2016-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winston, Patrick Henry -- England -- Nature. 2016 Feb 18;530(7590):282. doi: 10.1038/530282a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. He was a graduate student of Marvin Minsky's in the 1960s, and thereafter an admiring friend and colleague.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887486" target="_blank"〉PubMed〈/a〉
    Keywords: Artificial Intelligence/*history ; Child ; History, 20th Century ; History, 21st Century ; Humans ; Microscopy, Confocal/history ; Neural Networks (Computer) ; Robotics/history ; Software/history ; United States
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  • 81
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Witze, Alexandra -- England -- Nature. 2016 Apr 7;532(7597):17. doi: 10.1038/532017a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27078544" target="_blank"〉PubMed〈/a〉
    Keywords: Aircraft ; Arctic Regions ; Climate Change/statistics & numerical data ; Ecosystem ; Environmental Monitoring/*instrumentation/*methods ; Geographic Mapping ; Ice Cover ; Satellite Communications ; *Snow ; United States ; United States National Aeronautics and Space Administration ; Water Supply/*statistics & numerical data
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  • 82
    Publication Date: 2016-04-01
    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〉
    Keywords: Allosteric Regulation ; Apoproteins/chemistry/metabolism/ultrastructure ; Binding Sites ; *Biocatalysis ; Carrier Proteins/chemistry/metabolism/ultrastructure ; Cryoelectron Microscopy ; Crystallography, X-Ray ; Cullin Proteins/chemistry/metabolism/ultrastructure ; DNA Damage ; DNA-Binding Proteins/chemistry/metabolism/ultrastructure ; Humans ; Kinetics ; Models, Molecular ; Multiprotein Complexes/chemistry/*metabolism/*ultrastructure ; Peptide Hydrolases/chemistry/*metabolism/*ultrastructure ; Protein Binding ; Ubiquitination ; Ubiquitins/metabolism
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  • 83
    Publication Date: 2016-02-26
    Description: Thalidomide and its derivatives, lenalidomide and pomalidomide, are immune modulatory drugs (IMiDs) used in the treatment of haematologic malignancies. IMiDs bind CRBN, the substrate receptor of the CUL4-RBX1-DDB1-CRBN (also known as CRL4(CRBN)) E3 ubiquitin ligase, and inhibit ubiquitination of endogenous CRL4(CRBN) substrates. Unexpectedly, IMiDs also repurpose the ligase to target new proteins for degradation. Lenalidomide induces degradation of the lymphoid transcription factors Ikaros and Aiolos (also known as IKZF1 and IKZF3), and casein kinase 1alpha (CK1alpha), which contributes to its clinical efficacy in the treatment of multiple myeloma and 5q-deletion associated myelodysplastic syndrome (del(5q) MDS), respectively. How lenalidomide alters the specificity of the ligase to degrade these proteins remains elusive. Here we present the 2.45 A crystal structure of DDB1-CRBN bound to lenalidomide and CK1alpha. CRBN and lenalidomide jointly provide the binding interface for a CK1alpha beta-hairpin-loop located in the kinase N-lobe. We show that CK1alpha binding to CRL4(CRBN) is strictly dependent on the presence of an IMiD. Binding of IKZF1 to CRBN similarly requires the compound and both, IKZF1 and CK1alpha, use a related binding mode. Our study provides a mechanistic explanation for the selective efficacy of lenalidomide in del(5q) MDS therapy. We anticipate that high-affinity protein-protein interactions induced by small molecules will provide opportunities for drug development, particularly for targeted protein degradation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petzold, Georg -- Fischer, Eric S -- Thoma, Nicolas H -- England -- Nature. 2016 Apr 7;532(7597):127-30. doi: 10.1038/nature16979. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland. ; University of Basel, Petersplatz 10, CH-4003 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909574" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites/drug effects ; Casein Kinase Ialpha/chemistry/*metabolism ; Catalytic Domain ; Crystallography, X-Ray ; Humans ; Ikaros Transcription Factor/chemistry/metabolism ; Models, Molecular ; Protein Binding/drug effects ; Proteolysis/drug effects ; Structure-Activity Relationship ; Substrate Specificity/drug effects ; Thalidomide/*analogs & derivatives/chemistry/metabolism/pharmacology ; Ubiquitin-Protein Ligases/chemistry/*metabolism ; Ubiquitination/drug effects
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  • 84
    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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  • 85
    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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  • 86
    Publication Date: 2016-02-19
    Description: Integration of the reverse-transcribed viral DNA into the host genome is an essential step in the life cycle of retroviruses. Retrovirus integrase catalyses insertions of both ends of the linear viral DNA into a host chromosome. Integrase from HIV-1 and closely related retroviruses share the three-domain organization, consisting of a catalytic core domain flanked by amino- and carboxy-terminal domains essential for the concerted integration reaction. Although structures of the tetrameric integrase-DNA complexes have been reported for integrase from prototype foamy virus featuring an additional DNA-binding domain and longer interdomain linkers, the architecture of a canonical three-domain integrase bound to DNA remained elusive. Here we report a crystal structure of the three-domain integrase from Rous sarcoma virus in complex with viral and target DNAs. The structure shows an octameric assembly of integrase, in which a pair of integrase dimers engage viral DNA ends for catalysis while another pair of non-catalytic integrase dimers bridge between the two viral DNA molecules and help capture target DNA. The individual domains of the eight integrase molecules play varying roles to hold the complex together, making an extensive network of protein-DNA and protein-protein contacts that show both conserved and distinct features compared with those observed for prototype foamy virus integrase. Our work highlights the diversity of retrovirus intasome assembly and provides insights into the mechanisms of integration by HIV-1 and related retroviruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yin, Zhiqi -- Shi, Ke -- Banerjee, Surajit -- Pandey, Krishan K -- Bera, Sibes -- Grandgenett, Duane P -- Aihara, Hideki -- AI087098/AI/NIAID NIH HHS/ -- AI100682/AI/NIAID NIH HHS/ -- GM109770/GM/NIGMS NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):362-6. doi: 10.1038/nature16950.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Institute for Molecular Virology, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. ; Northeastern Collaborative Access Team, Cornell University, Advanced Photon Source, Lemont, Illinois 60439, USA. ; Institute for Molecular Virology, St. Louis University Health Sciences Center, St. Louis, Missouri 63104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887497" target="_blank"〉PubMed〈/a〉
    Keywords: Catalytic Domain ; Crystallography, X-Ray ; DNA, Viral/*chemistry/metabolism ; HIV-1/enzymology/metabolism ; Integrases/*chemistry/metabolism ; Models, Molecular ; Protein Binding ; Protein Multimerization ; Rous sarcoma virus/*chemistry/*enzymology/genetics/metabolism ; Spumavirus/enzymology ; Virus Integration
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  • 87
    Publication Date: 2016-04-07
    Description: The serotonin transporter (SERT) terminates serotonergic signalling through the sodium- and chloride-dependent reuptake of neurotransmitter into presynaptic neurons. SERT is a target for antidepressant and psychostimulant drugs, which block reuptake and prolong neurotransmitter signalling. Here we report X-ray crystallographic structures of human SERT at 3.15 A resolution bound to the antidepressants (S)-citalopram or paroxetine. Antidepressants lock SERT in an outward-open conformation by lodging in the central binding site, located between transmembrane helices 1, 3, 6, 8 and 10, directly blocking serotonin binding. We further identify the location of an allosteric site in the complex as residing at the periphery of the extracellular vestibule, interposed between extracellular loops 4 and 6 and transmembrane helices 1, 6, 10 and 11. Occupancy of the allosteric site sterically hinders ligand unbinding from the central site, providing an explanation for the action of (S)-citalopram as an allosteric ligand. These structures define the mechanism of antidepressant action in SERT, and provide blueprints for future drug design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Coleman, Jonathan A -- Green, Evan M -- Gouaux, Eric -- 5R37MH070039/MH/NIMH NIH HHS/ -- R37 MH070039/MH/NIMH NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 21;532(7599):334-9. doi: 10.1038/nature17629. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Howard Hughes Medical Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049939" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Antidepressive Agents/chemistry/metabolism/pharmacology ; Citalopram/chemistry/metabolism/pharmacology ; Crystallography, X-Ray ; Dopamine Plasma Membrane Transport Proteins/chemistry ; Drug Design ; Extracellular Space/metabolism ; Humans ; Immunoglobulin Fab Fragments/immunology ; Intracellular Space/metabolism ; Ions/chemistry/metabolism ; Ligands ; Models, Molecular ; Paroxetine/chemistry/metabolism/pharmacology ; Protein Binding/drug effects ; Protein Conformation/drug effects ; Protein Stability ; Serotonin/metabolism ; Serotonin Plasma Membrane Transport Proteins/*chemistry/immunology/*metabolism ; Structure-Activity Relationship
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  • 88
    Publication Date: 2016-04-07
    Description: Signalling by ubiquitination regulates virtually every cellular process in eukaryotes. Covalent attachment of ubiquitin to a substrate is catalysed by the E1, E2 and E3 three-enzyme cascade, which links the carboxy terminus of ubiquitin to the epsilon-amino group of, in most cases, a lysine of the substrate via an isopeptide bond. Given the essential roles of ubiquitination in the regulation of the immune system, it is not surprising that the ubiquitination network is a common target for diverse infectious agents. For example, many bacterial pathogens exploit ubiquitin signalling using virulence factors that function as E3 ligases, deubiquitinases or as enzymes that directly attack ubiquitin. The bacterial pathogen Legionella pneumophila utilizes approximately 300 effectors that modulate diverse host processes to create a permissive niche for its replication in phagocytes. Here we demonstrate that members of the SidE effector family of L. pneumophila ubiquitinate multiple Rab small GTPases associated with the endoplasmic reticulum. Moreover, we show that these proteins are capable of catalysing ubiquitination without the need for the E1 and E2 enzymes. A putative mono-ADP-ribosyltransferase motif critical for the ubiquitination activity is also essential for the role of the SidE family in intracellular bacterial replication in a protozoan host. The E1/E2-independent ubiquitination catalysed by these enzymes is energized by nicotinamide adenine dinucleotide, which activates ubiquitin by the formation of ADP-ribosylated ubiquitin. These results establish that ubiquitination can be catalysed by a single enzyme, the activity of which does not require ATP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qiu, Jiazhang -- Sheedlo, Michael J -- Yu, Kaiwen -- Tan, Yunhao -- Nakayasu, Ernesto S -- Das, Chittaranjan -- Liu, Xiaoyun -- Luo, Zhao-Qing -- 2R01GM103401/GM/NIGMS NIH HHS/ -- K02AI085403/AI/NIAID NIH HHS/ -- R21AI105714/AI/NIAID NIH HHS/ -- R56AI103168/AI/NIAID NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):120-4. doi: 10.1038/nature17657. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Purdue Institute for Inflammation, Immunology and Infectious Disease and Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA. ; Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, Indiana 47907, USA. ; Institute of Analytical Chemistry and Synthetic and Functional Biomolecules Center, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China. ; Biological Science Division, Pacific Northwest National Laboratory, Richland, Washington 99352, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049943" target="_blank"〉PubMed〈/a〉
    Keywords: ADP Ribose Transferases/chemistry/metabolism ; Adenosine Diphosphate Ribose/metabolism ; Adenosine Triphosphate ; Amino Acid Motifs ; Amino Acid Sequence ; Bacterial Load ; Bacterial Proteins/*metabolism ; Biocatalysis ; Endoplasmic Reticulum/enzymology/metabolism ; Legionella pneumophila/*chemistry/cytology/enzymology/pathogenicity ; Membrane Proteins/metabolism ; Molecular Sequence Data ; NAD/metabolism ; Ubiquitin/chemistry/metabolism ; Ubiquitin-Activating Enzymes ; Ubiquitin-Conjugating Enzymes ; *Ubiquitination ; Virulence Factors/metabolism ; rab GTP-Binding Proteins/chemistry/metabolism
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  • 89
    Publication Date: 2016-03-11
    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〉
    Keywords: Allosteric Regulation/drug effects ; Arabidopsis/*chemistry ; Arabidopsis Proteins/*antagonists & inhibitors/*chemistry/metabolism ; Binding Sites ; Calcium/metabolism/pharmacology ; Calcium Channels/*chemistry/metabolism ; Carbolines/metabolism/pharmacology ; Crystallography, X-Ray ; Ebolavirus/drug effects ; Endosomes/drug effects/metabolism/virology ; *Ion Channel Gating/drug effects ; Ion Transport/drug effects ; Models, Molecular ; Phosphorylation ; Piperazines/metabolism/pharmacology ; Protein Structure, Tertiary/drug effects
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  • 90
    Publication Date: 2016-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cressey, Daniel -- England -- Nature. 2016 Mar 10;531(7593):152. doi: 10.1038/531152a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961636" target="_blank"〉PubMed〈/a〉
    Keywords: *Biological Evolution ; *Climate Change ; Conservation of Natural Resources/*methods ; Ecology/*methods ; *Plants ; Research ; *Seed Bank ; Seeds/*growth & development ; United States
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  • 91
    Publication Date: 2016-02-26
    Description: Contractile tails are composed of an inner tube wrapped by an outer sheath assembled in an extended, metastable conformation that stores mechanical energy necessary for its contraction. Contraction is used to propel the rigid inner tube towards target cells for DNA or toxin delivery. Although recent studies have revealed the structure of the contractile sheath of the type VI secretion system, the mechanisms by which its polymerization is controlled and coordinated with the assembly of the inner tube remain unknown. Here we show that the starfish-like TssA dodecameric complex interacts with tube and sheath components. Fluorescence microscopy experiments in enteroaggregative Escherichia coli reveal that TssA binds first to the type VI secretion system membrane core complex and then initiates tail polymerization. TssA remains at the tip of the growing structure and incorporates new tube and sheath blocks. On the basis of these results, we propose that TssA primes and coordinates tail tube and sheath biogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zoued, Abdelrahim -- Durand, Eric -- Brunet, Yannick R -- Spinelli, Silvia -- Douzi, Badreddine -- Guzzo, Mathilde -- Flaugnatti, Nicolas -- Legrand, Pierre -- Journet, Laure -- Fronzes, Remi -- Mignot, Tam -- Cambillau, Christian -- Cascales, Eric -- England -- Nature. 2016 Mar 3;531(7592):59-63. doi: 10.1038/nature17182. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratoire d'Ingenierie des Systemes Macromoleculaires, Institut de Microbiologie de la Mediterranee, CNRS UMR7255, Aix-Marseille Universite, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France. ; Architecture et Fonction des Macromolecules Biologiques, Centre National de la Recherche Scientifique, UMR 7257, Campus de Luminy, Case 932, 13288 Marseille Cedex 09, France. ; Architecture et Fonction des Macromolecules Biologiques, Aix-Marseille Universite, UMR 7257, Campus de Luminy, Case 932, 13288 Marseille Cedex 09, France. ; G5 Biologie structurale de la secretion bacterienne, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France. ; UMR 3528, CNRS, Institut Pasteur, 25-28 rue du Docteur Roux, 75015 Paris, France. ; Laboratoire de Chimie Bacterienne, Institut de Microbiologie de la Mediterranee, CNRS UMR7283, Aix-Marseille Universite, 31 Chemin Joseph Aiguier, 13402 Marseille Cedex 20, France. ; Synchrotron Soleil, L'Orme des merisiers, Saint-Aubin BP48, 91192 Gif-sur-Yvette Cedex, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909579" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Escherichia coli/*chemistry/ultrastructure ; Escherichia coli Proteins/*chemistry/*metabolism/ultrastructure ; Microscopy, Electron ; Microscopy, Fluorescence ; Models, Molecular ; *Polymerization ; Protein Structure, Tertiary ; Type VI Secretion Systems/chemistry/metabolism/ultrastructure
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  • 92
    Publication Date: 2016-02-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2016 Feb 11;530(7589):142. doi: 10.1038/nature.2016.19290.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863962" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Embryo Research/*legislation & jurisprudence ; Extrachromosomal Inheritance/genetics ; Female ; Follow-Up Studies ; Genetic Therapy/*legislation & jurisprudence/*methods ; Great Britain ; Haplorhini/genetics ; Heredity/genetics/physiology ; Humans ; Male ; Mitochondrial Diseases/genetics/*prevention & control ; Mitochondrial Replacement Therapy/adverse effects/*legislation & ; jurisprudence/*methods ; Mutation/genetics ; *Patient Safety ; Sex Factors ; United States ; United States Food and Drug Administration/legislation & jurisprudence
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 93
    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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  • 94
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    Nature Publishing Group (NPG)
    Publication Date: 2016-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kogleck, Larissa -- England -- Nature. 2016 Mar 17;531(7594):S102-3. doi: 10.1038/531S102a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982019" target="_blank"〉PubMed〈/a〉
    Keywords: China ; Cooperative Behavior ; Great Britain ; Italy ; Japan ; Journal Impact Factor ; Research/economics/*organization & administration/standards/*statistics & ; numerical data ; Switzerland ; United States
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 95
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2016-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 18;530(7590):253. doi: 10.1038/530253a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887454" target="_blank"〉PubMed〈/a〉
    Keywords: Aircraft/*instrumentation/*legislation & jurisprudence/standards ; Global Warming/*legislation & jurisprudence/*prevention & control ; Internationality ; United States ; United States Environmental Protection Agency/*legislation & jurisprudence
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 96
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2016-02-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 4;530(7588):6. doi: 10.1038/530006a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842020" target="_blank"〉PubMed〈/a〉
    Keywords: Ecology/*economics/*legislation & jurisprudence ; Environmental Policy/*legislation & jurisprudence ; Politics ; Research Support as Topic/*economics/*legislation & jurisprudence ; United States
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  • 97
    Publication Date: 2016-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kuzma, Jennifer -- England -- Nature. 2016 Mar 10;531(7593):165-7. doi: 10.1038/531165a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetic Engineering and Society Center at North Carolina State University, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26961641" target="_blank"〉PubMed〈/a〉
    Keywords: CRISPR-Cas Systems/genetics ; Crops, Agricultural/genetics ; *Dissent and Disputes ; Genetic Engineering/*legislation & jurisprudence ; *Government Regulation ; *Policy Making ; United States ; United States Department of Agriculture/legislation & jurisprudence ; United States Environmental Protection Agency/legislation & jurisprudence ; United States Food and Drug Administration/legislation & jurisprudence
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  • 98
    Publication Date: 2016-03-16
    Description: Polyketide synthases (PKSs) are biosynthetic factories that produce natural products with important biological and pharmacological activities. Their exceptional product diversity is encoded in a modular architecture. Modular PKSs (modPKSs) catalyse reactions colinear to the order of modules in an assembly line, whereas iterative PKSs (iPKSs) use a single module iteratively as exemplified by fungal iPKSs (fiPKSs). However, in some cases non-colinear iterative action is also observed for modPKSs modules and is controlled by the assembly line environment. PKSs feature a structural and functional separation into a condensing and a modifying region as observed for fatty acid synthases. Despite the outstanding relevance of PKSs, the detailed organization of PKSs with complete fully reducing modifying regions remains elusive. Here we report a hybrid crystal structure of Mycobacterium smegmatis mycocerosic acid synthase based on structures of its condensing and modifying regions. Mycocerosic acid synthase is a fully reducing iPKS, closely related to modPKSs, and the prototype of mycobacterial mycocerosic acid synthase-like PKSs. It is involved in the biosynthesis of C20-C28 branched-chain fatty acids, which are important virulence factors of mycobacteria. Our structural data reveal a dimeric linker-based organization of the modifying region and visualize dynamics and conformational coupling in PKSs. On the basis of comparative small-angle X-ray scattering, the observed modifying region architecture may be common also in modPKSs. The linker-based organization provides a rationale for the characteristic variability of PKS modules as a main contributor to product diversity. The comprehensive architectural model enables functional dissection and re-engineering of PKSs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herbst, Dominik A -- Jakob, Roman P -- Zahringer, Franziska -- Maier, Timm -- England -- Nature. 2016 Mar 24;531(7595):533-7. doi: 10.1038/nature16993. Epub 2016 Mar 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department Biozentrum, University of Basel, Klingelbergstrasse 50/70, 4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26976449" target="_blank"〉PubMed〈/a〉
    Keywords: Acyltransferases/*chemistry/*metabolism ; Crystallography, X-Ray ; Fatty Acid Synthases/metabolism ; Models, Molecular ; Mycobacterium smegmatis/enzymology ; Oxidation-Reduction ; Polyketide Synthases/*chemistry/*metabolism ; Protein Structure, Tertiary ; Virulence Factors
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  • 99
    Publication Date: 2016-04-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Waltz, Emily -- England -- Nature. 2016 Apr 21;532(7599):293. doi: 10.1038/nature.2016.19754.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27111611" target="_blank"〉PubMed〈/a〉
    Keywords: Agaricus/enzymology/*genetics ; CRISPR-Cas Systems/*genetics ; Catechol Oxidase/genetics/metabolism ; Crops, Agricultural/economics/enzymology/genetics ; Food, Genetically Modified ; Gene Deletion ; Genetic Engineering/economics/*legislation & jurisprudence ; Patents as Topic ; United States ; United States Department of Agriculture/*legislation & jurisprudence
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  • 100
    Publication Date: 2016-04-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ward, Alyssa -- Baldwin, Thomas O -- Antin, Parker B -- England -- Nature. 2016 Apr 14;532(7598):177. doi: 10.1038/532177d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ; University of California, Riverside, USA. ; University of Arizona, Tucson, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075087" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Confounding Factors (Epidemiology) ; *Learning ; Mice ; Mice, Transgenic/genetics ; National Institutes of Health (U.S.)/economics ; Reproducibility of Results ; Research/*standards ; United States
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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