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  • Amino Acid Sequence  (2,910)
  • Mutation  (2,852)
  • American Association for the Advancement of Science (AAAS)  (5,247)
  • American Association of Petroleum Geologists (AAPG)
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  • 1
    Publication Date: 2016-01-20
    Description: The final identity and functional properties of a neuron are specified by terminal differentiation genes, which are controlled by specific motifs in compact regulatory regions. To determine how these sequences integrate inputs from transcription factors that specify cell types, we compared the regulatory mechanism of Drosophila Rhodopsin genes that are expressed in subsets of photoreceptors to that of phototransduction genes that are expressed broadly, in all photoreceptors. Both sets of genes share an 11-base pair (bp) activator motif. Broadly expressed genes contain a palindromic version that mediates expression in all photoreceptors. In contrast, each Rhodopsin exhibits characteristic single-bp substitutions that break the symmetry of the palindrome and generate activator or repressor motifs critical for restricting expression to photoreceptor subsets. Sensory neuron subtypes can therefore evolve through single-bp changes in short regulatory motifs, allowing the discrimination of a wide spectrum of stimuli.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rister, Jens -- Razzaq, Ansa -- Boodram, Pamela -- Desai, Nisha -- Tsanis, Cleopatra -- Chen, Hongtao -- Jukam, David -- Desplan, Claude -- K99EY023995/EY/NEI NIH HHS/ -- R01 EY13010/EY/NEI NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1258-61. doi: 10.1126/science.aab3417.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Developmental Genetics, Department of Biology, New York University, 100 Washington Square East, New York, NY 10003-6688, USA. ; Center for Developmental Genetics, Department of Biology, New York University, 100 Washington Square East, New York, NY 10003-6688, USA. cd38@nyu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785491" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Pairing ; Drosophila Proteins/*genetics ; Drosophila melanogaster/genetics/growth & development ; *Gene Expression Regulation, Developmental ; Mutation ; Photoreceptor Cells, Invertebrate/*physiology ; Promoter Regions, Genetic/*genetics ; Rhodopsin/*genetics ; Transcription Factors/metabolism ; Vision, Ocular/*genetics
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2016-01-20
    Description: Congenital heart disease (CHD) patients have an increased prevalence of extracardiac congenital anomalies (CAs) and risk of neurodevelopmental disabilities (NDDs). Exome sequencing of 1213 CHD parent-offspring trios identified an excess of protein-damaging de novo mutations, especially in genes highly expressed in the developing heart and brain. These mutations accounted for 20% of patients with CHD, NDD, and CA but only 2% of patients with isolated CHD. Mutations altered genes involved in morphogenesis, chromatin modification, and transcriptional regulation, including multiple mutations in RBFOX2, a regulator of mRNA splicing. Genes mutated in other cohorts examined for NDD were enriched in CHD cases, particularly those with coexisting NDD. These findings reveal shared genetic contributions to CHD, NDD, and CA and provide opportunities for improved prognostic assessment and early therapeutic intervention in CHD patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Homsy, Jason -- Zaidi, Samir -- Shen, Yufeng -- Ware, James S -- Samocha, Kaitlin E -- Karczewski, Konrad J -- DePalma, Steven R -- McKean, David -- Wakimoto, Hiroko -- Gorham, Josh -- Jin, Sheng Chih -- Deanfield, John -- Giardini, Alessandro -- Porter, George A Jr -- Kim, Richard -- Bilguvar, Kaya -- Lopez-Giraldez, Francesc -- Tikhonova, Irina -- Mane, Shrikant -- Romano-Adesman, Angela -- Qi, Hongjian -- Vardarajan, Badri -- Ma, Lijiang -- Daly, Mark -- Roberts, Amy E -- Russell, Mark W -- Mital, Seema -- Newburger, Jane W -- Gaynor, J William -- Breitbart, Roger E -- Iossifov, Ivan -- Ronemus, Michael -- Sanders, Stephan J -- Kaltman, Jonathan R -- Seidman, Jonathan G -- Brueckner, Martina -- Gelb, Bruce D -- Goldmuntz, Elizabeth -- Lifton, Richard P -- Seidman, Christine E -- Chung, Wendy K -- T32 HL007208/HL/NHLBI NIH HHS/ -- Arthritis Research UK/United Kingdom -- British Heart Foundation/United Kingdom -- Department of Health/United Kingdom -- Howard Hughes Medical Institute/ -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1262-6. doi: 10.1126/science.aac9396.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Boston, MA, USA. Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA. ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. ; Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. NIHR Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation and Trust and Imperial College London, London, UK. National Heart & Lung Institute, Imperial College London, London, UK. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston MA, USA. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. ; Department of Cardiology, University College London and Great Ormond Street Hospital, London, UK. ; Department of Pediatrics, University of Rochester Medical Center, The School of Medicine and Dentistry, Rochester, NY, USA. ; Section of Cardiothoracic Surgery, University of Southern California Keck School of Medicine, Los Angeles, CA, USA. ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. ; Yale Center for Genome Analysis, Yale University, New Haven, CT, USA. ; Steven and Alexandra Cohen Children's Medical Center of New York, New Hyde Park, NY, USA. ; Departments of Systems Biology and Biomedical Informatics, Columbia University Medical Center, New York, NY, USA. Department of Applied Physics and Applied Mathematics, Columbia University, New York, NY, USA. ; Department of Neurology, Columbia University Medical Center, New York, NY, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, NY, USA. ; Department of Cardiology, Children's Hospital Boston, Boston, MA, USA. ; Division of Pediatric Cardiology, University of Michigan, Ann Arbor, MI, USA. ; Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. ; Department of Cardiology, Boston Children's Hospital, Boston, MA, USA. ; Department of Pediatric Cardiac Surgery, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, USA. ; Department of Psychiatry, University of California San Francisco, San Francisco, CA, USA. ; Heart Development and Structural Diseases Branch, Division of Cardiovascular Sciences, NHLBI/NIH, Bethesda, MD, USA. ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu. ; Mindich Child Health and Development Institute and Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu. ; Department of Pediatrics, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Division of Cardiology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu. ; Department of Genetics, Yale University School of Medicine, New Haven, CT, USA. Howard Hughes Medical Institute, Yale University, New Haven, CT, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu. ; Department of Genetics, Harvard Medical School, Boston, MA, USA. Howard Hughes Medical Institute, Harvard University, Boston, MA, USA. Cardiovascular Division, Brigham & Women's Hospital, Harvard University, Boston, MA, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu. ; Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, NY, USA. bruce.gelb@mssm.edu goldmuntz@email.chop.edu martina.brueckner@yale.edu richard.lifton@yale.edu cseidman@genetics.med.harvard.edu wkc15@cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785492" target="_blank"〉PubMed〈/a〉
    Keywords: Brain/abnormalities/metabolism ; Child ; Congenital Abnormalities/genetics ; Exome/genetics ; Heart Defects, Congenital/*diagnosis/*genetics ; Humans ; Mutation ; Nervous System Malformations/*genetics ; Neurogenesis/*genetics ; Prognosis ; RNA Splicing/genetics ; RNA, Messenger/genetics ; RNA-Binding Proteins/genetics ; Repressor Proteins/genetics ; Transcription, Genetic
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    Electronic ISSN: 1095-9203
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  • 3
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alexandrov, Ludmil B -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1175. doi: 10.1126/science.aad7363.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, NM 87545, USA. lba@lanl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785464" target="_blank"〉PubMed〈/a〉
    Keywords: *Computer Simulation ; DNA Mutational Analysis ; Genomics/*methods ; Humans ; *Models, Genetic ; *Mutagenesis ; Mutation ; Neoplasms/classification/*genetics/pathology
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  • 4
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jon -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1186-7. doi: 10.1126/science.350.6265.1186.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785474" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caenorhabditis elegans/genetics/physiology ; Caenorhabditis elegans Proteins/genetics/physiology ; Caloric Restriction ; Death ; Humans ; Hydra/genetics/physiology ; Longevity/genetics/*physiology ; Mice ; Mutation ; Phosphatidylinositol 3-Kinases/genetics/physiology
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  • 5
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2016-01-20
    Description: Research into stem cells and aging aims to understand how stem cells maintain tissue health, what mechanisms ultimately lead to decline in stem cell function with age, and how the regenerative capacity of somatic stem cells can be enhanced to promote healthy aging. Here, we explore the effects of aging on stem cells in different tissues. Recent research has focused on the ways that genetic mutations, epigenetic changes, and the extrinsic environmental milieu influence stem cell functionality over time. We describe each of these three factors, the ways in which they interact, and how these interactions decrease stem cell health over time. We are optimistic that a better understanding of these changes will uncover potential strategies to enhance stem cell function and increase tissue resiliency into old age.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goodell, Margaret A -- Rando, Thomas A -- P01 AG036695/AG/NIA NIH HHS/ -- R01 AG047820/AG/NIA NIH HHS/ -- R01 AR062185/AR/NIAMS NIH HHS/ -- R37 AG023806/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 4;350(6265):1199-204. doi: 10.1126/science.aab3388.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cells and Regenerative Medicine Center, Center for Cell and Gene Therapy, and Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. goodell@bcm.edu rando@stanford.edu. ; Glenn Center for the Biology of Aging and Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA, and Center for Regenerative Rehabilitation, Veterans Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA. goodell@bcm.edu rando@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26785478" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/*physiology ; Aging/*physiology ; Animals ; Cell Aging ; Epigenesis, Genetic ; Genetic Drift ; *Health ; Humans ; Mice ; Mutation ; Organ Specificity ; Selection, Genetic
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  • 6
    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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  • 7
    Publication Date: 2016-02-26
    Description: Hundreds of pathways for degradation converge at ubiquitin recognition by a proteasome. Here, we found that the five known proteasomal ubiquitin receptors in yeast are collectively nonessential for ubiquitin recognition and identified a sixth receptor, Rpn1. A site ( T1: ) in the Rpn1 toroid recognized ubiquitin and ubiquitin-like ( UBL: ) domains of substrate shuttling factors. T1 structures with monoubiquitin or lysine 48 diubiquitin show three neighboring outer helices engaging two ubiquitins. T1 contributes a distinct substrate-binding pathway with preference for lysine 48-linked chains. Proximal to T1 within the Rpn1 toroid is a second UBL-binding site ( T2: ) that assists in ubiquitin chain disassembly, by binding the UBL of deubiquitinating enzyme Ubp6. Thus, a two-site recognition domain intrinsic to the proteasome uses distinct ubiquitin-fold ligands to assemble substrates, shuttling factors, and a deubiquitinating enzyme.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shi, Yuan -- Chen, Xiang -- Elsasser, Suzanne -- Stocks, Bradley B -- Tian, Geng -- Lee, Byung-Hoon -- Shi, Yanhong -- Zhang, Naixia -- de Poot, Stefanie A H -- Tuebing, Fabian -- Sun, Shuangwu -- Vannoy, Jacob -- Tarasov, Sergey G -- Engen, John R -- Finley, Daniel -- Walters, Kylie J -- New York, N.Y. -- Science. 2016 Feb 19;351(6275). pii: aad9421. doi: 10.1126/science.aad9421.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. ; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. ; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. ; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China. ; Department of Analytical Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P. R. China. ; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. Linganore High School, Frederick, MD 21701, USA. ; Biophysics Resource, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. ; Department of Chemistry and Chemical Biology, Northeastern University, Boston, MA 02115, USA. j.engen@neu.edu kylie.walters@nih.gov daniel_finley@hms.harvard.edu. ; Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. j.engen@neu.edu kylie.walters@nih.gov daniel_finley@hms.harvard.edu. ; Protein Processing Section, Structural Biophysics Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. j.engen@neu.edu kylie.walters@nih.gov daniel_finley@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912900" target="_blank"〉PubMed〈/a〉
    Keywords: DNA-Binding Proteins/metabolism ; Endopeptidases/metabolism ; Metabolic Networks and Pathways ; Models, Molecular ; Mutation ; Proteasome Endopeptidase Complex/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae/*metabolism ; Saccharomyces cerevisiae Proteins/*chemistry/genetics/*metabolism ; Ubiquitin-Specific Proteases/metabolism ; Ubiquitination
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  • 8
    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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  • 9
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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〉Couzin-Frankel, Jennifer -- New York, N.Y. -- Science. 2016 Jan 29;351(6272):440-3. doi: 10.1126/science.351.6272.440.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26823410" target="_blank"〉PubMed〈/a〉
    Keywords: Child ; Child, Preschool ; DNA Mutational Analysis ; DNA Repair/genetics ; Female ; *Genes, Neoplasm ; *Genetic Predisposition to Disease ; Humans ; Male ; Mutation ; Neoplasms/*genetics/mortality ; Pedigree ; Tumor Suppressor Protein p53/genetics
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  • 10
    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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  • 11
    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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  • 12
    Publication Date: 2016-03-05
    Description: As tumors grow, they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGranahan, Nicholas -- Furness, Andrew J S -- Rosenthal, Rachel -- Ramskov, Sofie -- Lyngaa, Rikke -- Saini, Sunil Kumar -- Jamal-Hanjani, Mariam -- Wilson, Gareth A -- Birkbak, Nicolai J -- Hiley, Crispin T -- Watkins, Thomas B K -- Shafi, Seema -- Murugaesu, Nirupa -- Mitter, Richard -- Akarca, Ayse U -- Linares, Joseph -- Marafioti, Teresa -- Henry, Jake Y -- Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Schadendorf, Dirk -- Garraway, Levi A -- Makarov, Vladimir -- Rizvi, Naiyer A -- Snyder, Alexandra -- Hellmann, Matthew D -- Merghoub, Taha -- Wolchok, Jedd D -- Shukla, Sachet A -- Wu, Catherine J -- Peggs, Karl S -- Chan, Timothy A -- Hadrup, Sine R -- Quezada, Sergio A -- Swanton, Charles -- 12100/Cancer Research UK/United Kingdom -- 1R01CA155010-02/CA/NCI NIH HHS/ -- 1R01CA182461-01/CA/NCI NIH HHS/ -- 1R01CA184922-01/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1463-9. doi: 10.1126/science.aaf1490. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Francis Crick Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London (UCL), London WC1E 6BT, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, Denmark. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; The Francis Crick Institute, London WC2A 3LY, UK. ; Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. Department of Cellular Pathology, UCL, London WC1E 6BT, UK. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium (DKTK), 69121 Heidelberg, Germany. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Hematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, NY 10032, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Department of Internal Medicine, Brigham and Woman's Hospital, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940869" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/*immunology ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/genetics/*immunology ; Antineoplastic Agents/therapeutic use ; CD4-Positive T-Lymphocytes/*immunology ; CTLA-4 Antigen/immunology ; Carcinoma, Non-Small-Cell Lung/genetics/immunology ; Cell Cycle Checkpoints/immunology ; Female ; Humans ; *Immunologic Surveillance ; Lung Neoplasms/drug therapy/genetics/*immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Melanoma/immunology ; Middle Aged ; Mutation ; Programmed Cell Death 1 Receptor/immunology ; Skin Neoplasms/immunology
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  • 13
    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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  • 14
    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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  • 15
    Publication Date: 2016-04-16
    Description: Drug resistance compromises control of malaria. Here, we show that resistance to a commonly used antimalarial medication, atovaquone, is apparently unable to spread. Atovaquone pressure selects parasites with mutations in cytochrome b, a respiratory protein with low but essential activity in the mammalian blood phase of the parasite life cycle. Resistance mutations rescue parasites from the drug but later prove lethal in the mosquito phase, where parasites require full respiration. Unable to respire efficiently, resistant parasites fail to complete mosquito development, arresting their life cycle. Because cytochrome b is encoded by the maternally inherited parasite mitochondrion, even outcrossing with wild-type strains cannot facilitate spread of resistance. Lack of transmission suggests that resistance will be unable to spread in the field, greatly enhancing the utility of atovaquone in malaria control.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goodman, Christopher D -- Siregar, Josephine E -- Mollard, Vanessa -- Vega-Rodriguez, Joel -- Syafruddin, Din -- Matsuoka, Hiroyuki -- Matsuzaki, Motomichi -- Toyama, Tomoko -- Sturm, Angelika -- Cozijnsen, Anton -- Jacobs-Lorena, Marcelo -- Kita, Kiyoshi -- Marzuki, Sangkot -- McFadden, Geoffrey I -- AI031478/AI/NIAID NIH HHS/ -- RR00052/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 15;352(6283):349-53. doi: 10.1126/science.aad9279.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. gim@unimelb.edu.au deang@unimelb.edu.au. ; School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; School of BioSciences, University of Melbourne, Melbourne, VIC 3010, Australia. ; Johns Hopkins University Bloomberg School of Public Health, Department of Molecular Microbiology and Immunology, Malaria Research Institute, Baltimore, MD 21205, USA. ; Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia. Department of Parasitology, Faculty of Medicine, Hasanuddin University, Jalan Perintis Kemerdekaan Km10, Makassar 90245, Indonesia. ; Division of Medical Zoology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi 329-0498, Japan. ; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. ; Department of Biomedical Chemistry, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. School of Tropical Medicine and Global Health, Nagasaki University, Sakamoto, Nagasaki 852-8523, Japan. ; Eijkman Institute for Molecular Biology, JI Diponegoro no. 69, Jakarta, 10430, Indonesia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27081071" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/*parasitology ; Antimalarials/*pharmacology/therapeutic use ; Atovaquone/*pharmacology/therapeutic use ; Cell Line ; Cytochromes b/*genetics ; Drug Resistance/*genetics ; Genes, Mitochondrial/genetics ; Humans ; Life Cycle Stages/drug effects/genetics ; Malaria/drug therapy/*parasitology/transmission ; Male ; Mice ; Mitochondria/*genetics ; Mutation ; Plasmodium berghei/*drug effects/genetics/growth & development ; Selection, Genetic
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  • 16
    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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  • 17
    Publication Date: 2016-03-05
    Description: Oncogenes are activated through well-known chromosomal alterations such as gene fusion, translocation, and focal amplification. In light of recent evidence that the control of key genes depends on chromosome structures called insulated neighborhoods, we investigated whether proto-oncogenes occur within these structures and whether oncogene activation can occur via disruption of insulated neighborhood boundaries in cancer cells. We mapped insulated neighborhoods in T cell acute lymphoblastic leukemia (T-ALL) and found that tumor cell genomes contain recurrent microdeletions that eliminate the boundary sites of insulated neighborhoods containing prominent T-ALL proto-oncogenes. Perturbation of such boundaries in nonmalignant cells was sufficient to activate proto-oncogenes. Mutations affecting chromosome neighborhood boundaries were found in many types of cancer. Thus, oncogene activation can occur via genetic alterations that disrupt insulated neighborhoods in malignant cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hnisz, Denes -- Weintraub, Abraham S -- Day, Daniel S -- Valton, Anne-Laure -- Bak, Rasmus O -- Li, Charles H -- Goldmann, Johanna -- Lajoie, Bryan R -- Fan, Zi Peng -- Sigova, Alla A -- Reddy, Jessica -- Borges-Rivera, Diego -- Lee, Tong Ihn -- Jaenisch, Rudolf -- Porteus, Matthew H -- Dekker, Job -- Young, Richard A -- AI120766/AI/NIAID NIH HHS/ -- CA109901/CA/NCI NIH HHS/ -- HG002668/HG/NHGRI NIH HHS/ -- MH104610/MH/NIMH NIH HHS/ -- NS088538/NS/NINDS NIH HHS/ -- R01 GM 112720/GM/NIGMS NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG003143/HG/NHGRI NIH HHS/ -- R01 MH104610/MH/NIMH NIH HHS/ -- U01 DA 040588/DA/NIDA NIH HHS/ -- U01 HG007910/HG/NHGRI NIH HHS/ -- U01 R01 AI 117839/AI/NIAID NIH HHS/ -- U54 CA193419/CA/NCI NIH HHS/ -- U54 DK107980/DK/NIDDK NIH HHS/ -- U54 HG007010/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1454-8. doi: 10.1126/science.aad9024. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. ; Department of Pediatrics, Stanford University, Stanford, CA, USA. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Program in Systems Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA. Howard Hughes Medical Institute. ; Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. young@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940867" target="_blank"〉PubMed〈/a〉
    Keywords: *Chromosome Aberrations ; Chromosome Mapping ; *Gene Expression Regulation, Leukemic ; HEK293 Cells ; Humans ; Mutation ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*genetics ; Proto-Oncogenes/*genetics ; *Sequence Deletion ; Transcriptional Activation ; *Translocation, Genetic
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  • 18
    Publication Date: 2016-03-26
    Description: Sequencing of exomes and genomes has revealed abundant genetic variation affecting the coding sequences of human transcription factors (TFs), but the consequences of such variation remain largely unexplored. We developed a computational, structure-based approach to evaluate TF variants for their impact on DNA binding activity and used universal protein-binding microarrays to assay sequence-specific DNA binding activity across 41 reference and 117 variant alleles found in individuals of diverse ancestries and families with Mendelian diseases. We found 77 variants in 28 genes that affect DNA binding affinity or specificity and identified thousands of rare alleles likely to alter the DNA binding activity of human sequence-specific TFs. Our results suggest that most individuals have unique repertoires of TF DNA binding activities, which may contribute to phenotypic variation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Barrera, Luis A -- Vedenko, Anastasia -- Kurland, Jesse V -- Rogers, Julia M -- Gisselbrecht, Stephen S -- Rossin, Elizabeth J -- Woodard, Jaie -- Mariani, Luca -- Kock, Kian Hong -- Inukai, Sachi -- Siggers, Trevor -- Shokri, Leila -- Gordan, Raluca -- Sahni, Nidhi -- Cotsapas, Chris -- Hao, Tong -- Yi, Song -- Kellis, Manolis -- Daly, Mark J -- Vidal, Marc -- Hill, David E -- Bulyk, Martha L -- P50 HG004233/HG/NHGRI NIH HHS/ -- R01 HG003985/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1450-4. doi: 10.1126/science.aad2257. Epub 2016 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. ; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. ; Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Center for Human Genetics Research and Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA. ; Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Committee on Higher Degrees in Biophysics, Harvard University, Cambridge, MA 02138, USA. Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02139, USA. Program in Biological and Biomedical Sciences, Harvard University, Cambridge, MA 02138, USA. Center for Cancer Systems Biology (CCSB), Dana-Farber Cancer Institute, Boston, MA 02215, USA. Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27013732" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Binding Sites ; Computer Simulation ; DNA/*metabolism ; DNA-Binding Proteins/*genetics/metabolism ; Exome/genetics ; *Gene Expression Regulation ; Genetic Diseases, Inborn/*genetics ; Genetic Variation ; Genome, Human ; Humans ; Mutation ; Polymorphism, Single Nucleotide ; Protein Array Analysis ; Protein Binding ; Sequence Analysis, DNA ; Transcription Factors/*genetics/metabolism
    Print ISSN: 0036-8075
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  • 19
    Publication Date: 2016-01-02
    Description: Antibiotic treatment has two conflicting effects: the desired, immediate effect of inhibiting bacterial growth and the undesired, long-term effect of promoting the evolution of resistance. Although these contrasting outcomes seem inextricably linked, recent work has revealed several ways by which antibiotics can be combined to inhibit bacterial growth while, counterintuitively, selecting against resistant mutants. Decoupling treatment efficacy from the risk of resistance can be achieved by exploiting specific interactions between drugs, and the ways in which resistance mutations to a given drug can modulate these interactions or increase the sensitivity of the bacteria to other compounds. Although their practical application requires much further development and validation, and relies on advances in genomic diagnostics, these discoveries suggest novel paradigms that may restrict or even reverse the evolution of resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baym, Michael -- Stone, Laura K -- Kishony, Roy -- R01-GM081617/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):aad3292. doi: 10.1126/science.aad3292.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, MA, USA. ; Department of Systems Biology, Harvard Medical School, Boston, MA, USA. Department of Biology and Department of Computer Science, Technion - Israel Institute of Technology, Haifa, Israel. rkishony@technion.ac.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26722002" target="_blank"〉PubMed〈/a〉
    Keywords: Anti-Bacterial Agents/*pharmacology ; Bacteria/*drug effects/*genetics ; Drug Resistance, Bacterial/*genetics ; *Evolution, Molecular ; Humans ; Mutation ; Selection, Genetic
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  • 20
    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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  • 21
    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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  • 22
    Publication Date: 2016-01-09
    Description: The lung is constantly exposed to environmental atmospheric cues. How it senses and responds to these cues is poorly defined. Here, we show that Roundabout receptor (Robo) genes are expressed in pulmonary neuroendocrine cells (PNECs), a rare, innervated epithelial population. Robo inactivation in mouse lung results in an inability of PNECs to cluster into sensory organoids and triggers increased neuropeptide production upon exposure to air. Excess neuropeptides lead to an increase in immune infiltrates, which in turn remodel the matrix and irreversibly simplify the alveoli. We demonstrate in vivo that PNECs act as precise airway sensors that elicit immune responses via neuropeptides. These findings suggest that the PNEC and neuropeptide abnormalities documented in a wide array of pulmonary diseases may profoundly affect symptoms and progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Branchfield, Kelsey -- Nantie, Leah -- Verheyden, Jamie M -- Sui, Pengfei -- Wienhold, Mark D -- Sun, Xin -- 5T32AI007635/AI/NIAID NIH HHS/ -- HL097134/HL/NHLBI NIH HHS/ -- HL122406/HL/NHLBI NIH HHS/ -- R01 HL113870/HL/NHLBI NIH HHS/ -- T32 GM007133/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):707-10. doi: 10.1126/science.aad7969. Epub 2016 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genetics, Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA. ; Department of Pediatrics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53706, USA. ; Laboratory of Genetics, Department of Medical Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA. xsun@wisc.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26743624" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Clodronic Acid/pharmacology ; Lung/cytology/*immunology ; Lung Diseases/genetics/immunology ; Macrophages/drug effects/immunology ; Mice ; Mice, Mutant Strains ; Mutation ; Nerve Tissue Proteins/genetics/*physiology ; Neuroendocrine Cells/*immunology/metabolism ; Neuropeptides/*biosynthesis ; Receptors, Immunologic/genetics/*physiology
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  • 23
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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〉Roberts, Leslie -- New York, N.Y. -- Science. 2016 Apr 22;352(6284):403. doi: 10.1126/science.352.6284.403. Epub 2016 Apr 21.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27102460" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antimalarials/pharmacology/*therapeutic use ; Artemisinins/pharmacology/*therapeutic use ; Drug Resistance/*genetics ; Humans ; Malaria, Falciparum/*drug therapy/epidemiology/*parasitology ; Mutation ; Myanmar/epidemiology ; Plasmodium falciparum/*drug effects/genetics
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  • 24
    Publication Date: 2016-01-30
    Description: The "cancerized field" concept posits that cancer-prone cells in a given tissue share an oncogenic mutation, but only discreet clones within the field initiate tumors. Most benign nevi carry oncogenic BRAF(V600E) mutations but rarely become melanoma. The zebrafish crestin gene is expressed embryonically in neural crest progenitors (NCPs) and specifically reexpressed in melanoma. Live imaging of transgenic zebrafish crestin reporters shows that within a cancerized field (BRAF(V600E)-mutant; p53-deficient), a single melanocyte reactivates the NCP state, revealing a fate change at melanoma initiation in this model. NCP transcription factors, including sox10, regulate crestin expression. Forced sox10 overexpression in melanocytes accelerated melanoma formation, which is consistent with activation of NCP genes and super-enhancers leading to melanoma. Our work highlights NCP state reemergence as a key event in melanoma initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaufman, Charles K -- Mosimann, Christian -- Fan, Zi Peng -- Yang, Song -- Thomas, Andrew J -- Ablain, Julien -- Tan, Justin L -- Fogley, Rachel D -- van Rooijen, Ellen -- Hagedorn, Elliott J -- Ciarlo, Christie -- White, Richard M -- Matos, Dominick A -- Puller, Ann-Christin -- Santoriello, Cristina -- Liao, Eric C -- Young, Richard A -- Zon, Leonard I -- HG002668/HG/NHGRI NIH HHS/ -- K08 AR061071/AR/NIAMS NIH HHS/ -- R01 CA103846/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 29;351(6272):aad2197. doi: 10.1126/science.aad2197. Epub 2016 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA. ; Institute of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. ; Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY 10075, USA. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129, USA. ; Research Institute Children's Cancer Center Hamburg and Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. ; Harvard Stem Cell Institute, Boston, MA 02115, USA. Harvard Medical School, Boston, MA 02115, USA. Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. ; Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. ; Stem Cell Program and Division of Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Boston, MA 02115, USA. Harvard Stem Cell Institute, Boston, MA 02115, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Harvard Medical School, Boston, MA 02115, USA. Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. zon@enders.tch.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26823433" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Carcinogenesis/*genetics ; Embryonic Stem Cells/metabolism ; Enhancer Elements, Genetic ; *Gene Expression Regulation, Developmental ; *Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Green Fluorescent Proteins/genetics ; Melanocytes/metabolism ; Melanoma/*genetics ; Melanoma, Experimental/*genetics ; Mutation ; Nerve Tissue Proteins/genetics ; Neural Crest/*metabolism ; Proto-Oncogene Proteins B-raf/genetics ; SOXE Transcription Factors/genetics ; Skin Neoplasms/*genetics ; Tumor Suppressor Protein p53/genetics ; *Zebrafish ; Zebrafish Proteins/genetics
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  • 25
    Publication Date: 2016-03-12
    Description: Type IVa pili are filamentous cell surface structures observed in many bacteria. They pull cells forward by extending, adhering to surfaces, and then retracting. We used cryo-electron tomography of intact Myxococcus xanthus cells to visualize type IVa pili and the protein machine that assembles and retracts them (the type IVa pilus machine, or T4PM) in situ, in both the piliated and nonpiliated states, at a resolution of 3 to 4 nanometers. We found that T4PM comprises an outer membrane pore, four interconnected ring structures in the periplasm and cytoplasm, a cytoplasmic disc and dome, and a periplasmic stem. By systematically imaging mutants lacking defined T4PM proteins or with individual proteins fused to tags, we mapped the locations of all 10 T4PM core components and the minor pilins, thereby providing insights into pilus assembly, structure, and function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chang, Yi-Wei -- Rettberg, Lee A -- Treuner-Lange, Anke -- Iwasa, Janet -- Sogaard-Andersen, Lotte -- Jensen, Grant J -- R01 GM094800B/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):aad2001. doi: 10.1126/science.aad2001. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Institute of Technology, Pasadena, CA 91125, USA. Howard Hughes Medical Institute, Pasadena, CA 91125, USA. ; Howard Hughes Medical Institute, Pasadena, CA 91125, USA. ; Max Planck Institute for Terrestrial Microbiology, 35043 Marburg, Germany. ; University of Utah, Salt Lake City, UT 84112, USA. ; California Institute of Technology, Pasadena, CA 91125, USA. Howard Hughes Medical Institute, Pasadena, CA 91125, USA. jensen@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965631" target="_blank"〉PubMed〈/a〉
    Keywords: Bacterial Adhesion ; Cryoelectron Microscopy ; Fimbriae, Bacterial/genetics/*ultrastructure ; Microscopy, Electron, Transmission ; Models, Molecular ; Mutation ; Myxococcus xanthus/genetics/physiology/*ultrastructure
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  • 26
    Publication Date: 2015-04-04
    Description: Plant immunity against foreign gene invasion takes advantage of posttranscriptional gene silencing (PTGS). How plants elaborately avert inappropriate PTGS of endogenous coding genes remains unclear. We demonstrate in Arabidopsis that both 5'-3' and 3'-5' cytoplasmic RNA decay pathways act as repressors of transgene and endogenous PTGS. Disruption of bidirectional cytoplasmic RNA decay leads to pleiotropic developmental defects and drastic transcriptomic alterations, which are substantially rescued by PTGS mutants. Upon dysfunction of bidirectional RNA decay, a large number of 21- to 22-nucleotide endogenous small interfering RNAs are produced from coding transcripts, including multiple microRNA targets, which could interfere with their cognate gene expression and functions. This study highlights the risk of unwanted PTGS and identifies cytoplasmic RNA decay pathways as safeguards of plant transcriptome and development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Xinyan -- Zhu, Ying -- Liu, Xiaodan -- Hong, Xinyu -- Xu, Yang -- Zhu, Ping -- Shen, Yang -- Wu, Huihui -- Ji, Yusi -- Wen, Xing -- Zhang, Chen -- Zhao, Qiong -- Wang, Yichuan -- Lu, Jian -- Guo, Hongwei -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):120-3. doi: 10.1126/science.aaa2618.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. ; Biodynamic Optical Imaging Center, School of Life Sciences, Peking University, Beijing 100871, China. ; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. ; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. ; State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. hongweig@pku.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838384" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*genetics/growth & development/metabolism ; Arabidopsis Proteins/genetics/physiology ; Cytoplasm/*metabolism ; *Gene Expression Regulation, Plant ; Metabolic Networks and Pathways ; MicroRNAs/genetics/metabolism ; Mutation ; Plant Immunity/*genetics ; *RNA Interference ; RNA Replicase/genetics/physiology ; *RNA Stability ; RNA, Plant/*genetics/metabolism ; RNA, Small Interfering/genetics/metabolism ; *Suppression, Genetic ; Transcriptome ; Transgenes
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  • 27
    Publication Date: 2015-10-17
    Description: Although the genes essential for life have been identified in less complex model organisms, their elucidation in human cells has been hindered by technical barriers. We used extensive mutagenesis in haploid human cells to identify approximately 2000 genes required for optimal fitness under culture conditions. To study the principles of genetic interactions in human cells, we created a synthetic lethality network focused on the secretory pathway based exclusively on mutations. This revealed a genetic cross-talk governing Golgi homeostasis, an additional subunit of the human oligosaccharyltransferase complex, and a phosphatidylinositol 4-kinase beta adaptor hijacked by viruses. The synthetic lethality map parallels observations made in yeast and projects a route forward to reveal genetic networks in diverse aspects of human cell biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blomen, Vincent A -- Majek, Peter -- Jae, Lucas T -- Bigenzahn, Johannes W -- Nieuwenhuis, Joppe -- Staring, Jacqueline -- Sacco, Roberto -- van Diemen, Ferdy R -- Olk, Nadine -- Stukalov, Alexey -- Marceau, Caleb -- Janssen, Hans -- Carette, Jan E -- Bennett, Keiryn L -- Colinge, Jacques -- Superti-Furga, Giulio -- Brummelkamp, Thijn R -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1092-6. doi: 10.1126/science.aac7557. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. ; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. ; Department of Microbiology and Immunology, Stanford University School of Medicine, 299 Campus Drive, Stanford, CA 94305, USA. ; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. University of Montpellier, Institut de Recherche en Cancerologie de Montpellier Inserm U1194, Institut regional du Cancer Montpellier, 34000 Montpellier, France. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl. ; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, 1090 Vienna, Austria. Cancer Genomics Center (CGC.nl), Plesmanlaan 121, 1066CX, Amsterdam, Netherlands. jacques.colinge@inserm.fr gsuperti@cemm.at t.brummelkamp@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472760" target="_blank"〉PubMed〈/a〉
    Keywords: *Gene Regulatory Networks ; *Genes, Essential ; *Genes, Lethal ; Genetic Fitness/*genetics ; Golgi Apparatus/genetics ; *Haploidy ; Hexosyltransferases/genetics ; Humans ; Membrane Proteins/genetics ; Mutagenesis, Insertional ; Mutation ; Saccharomyces cerevisiae/genetics
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  • 28
    Publication Date: 2015-03-15
    Description: Immune checkpoint inhibitors, which unleash a patient's own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non-small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors was associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shapes response to anti-PD-1 therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rizvi, Naiyer A -- Hellmann, Matthew D -- Snyder, Alexandra -- Kvistborg, Pia -- Makarov, Vladimir -- Havel, Jonathan J -- Lee, William -- Yuan, Jianda -- Wong, Phillip -- Ho, Teresa S -- Miller, Martin L -- Rekhtman, Natasha -- Moreira, Andre L -- Ibrahim, Fawzia -- Bruggeman, Cameron -- Gasmi, Billel -- Zappasodi, Roberta -- Maeda, Yuka -- Sander, Chris -- Garon, Edward B -- Merghoub, Taha -- Wolchok, Jedd D -- Schumacher, Ton N -- Chan, Timothy A -- K23 CA149079/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):124-8. doi: 10.1126/science.aaa1348. Epub 2015 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. chant@mskcc.org. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Immune Monitoring Core, Ludwig Center for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Computation Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Mathematics, Columbia University, New York, NY, 10027, USA. ; Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; David Geffen School of Medicine at UCLA, 2825 Santa Monica Boulevard, Suite 200, Santa Monica, CA 90404, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY, 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Weill Cornell Medical College, New York, NY, 10065, USA. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. chant@mskcc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25765070" target="_blank"〉PubMed〈/a〉
    Keywords: Antibodies, Monoclonal, Humanized/*therapeutic use ; Antineoplastic Agents/*therapeutic use ; CD8-Positive T-Lymphocytes/immunology ; Carcinoma, Non-Small-Cell Lung/*drug therapy/*genetics/immunology ; Cohort Studies ; DNA Repair/genetics ; Disease-Free Survival ; Drug Resistance, Neoplasm/*genetics ; Humans ; Lung Neoplasms/*drug therapy/*genetics/immunology ; Mutation ; Programmed Cell Death 1 Receptor/*antagonists & inhibitors ; Smoking/genetics
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  • 29
    Publication Date: 2015-09-12
    Description: The function of neural circuits depends on the generation of specific classes of neurons. Neural identity is typically established near the time when neurons exit the cell cycle to become postmitotic cells, and it is generally accepted that, once the identity of a neuron has been established, its fate is maintained throughout life. Here, we show that network activity dynamically modulates the properties of fast-spiking (FS) interneurons through the postmitotic expression of the transcriptional regulator Er81. In the adult cortex, Er81 protein levels define a spectrum of FS basket cells with different properties, whose relative proportions are, however, continuously adjusted in response to neuronal activity. Our findings therefore suggest that interneuron properties are malleable in the adult cortex, at least to a certain extent.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702376/" 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/PMC4702376/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dehorter, Nathalie -- Ciceri, Gabriele -- Bartolini, Giorgia -- Lim, Lynette -- del Pino, Isabel -- Marin, Oscar -- 103714MA/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Sep 11;349(6253):1216-20. doi: 10.1126/science.aab3415.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Centre for Developmental Neurobiology, Medical Research Council, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK. Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, 03550 Sant Joan d'Alacant, Spain. ; Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, 03550 Sant Joan d'Alacant, Spain. ; MRC Centre for Developmental Neurobiology, Medical Research Council, New Hunt's House, Guy's Campus, King's College London, London SE1 1UL, UK. Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, 03550 Sant Joan d'Alacant, Spain. oscar.marin@kcl.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359400" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cerebral Cortex/cytology/metabolism/*physiology ; DNA-Binding Proteins/genetics/*metabolism ; Interneurons/cytology/metabolism/*physiology ; Mice ; Mice, Mutant Strains ; Mitosis ; Mutation ; Nerve Net/cytology/metabolism/*physiology ; Transcription Factors/genetics/*metabolism ; *Transcription, Genetic
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  • 30
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-03-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bohannon, John -- New York, N.Y. -- Science. 2015 Mar 20;347(6228):1300. doi: 10.1126/science.347.6228.1300.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25792310" target="_blank"〉PubMed〈/a〉
    Keywords: Albinism/genetics ; Animals ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Culicidae/genetics ; Drosophila melanogaster/*genetics ; Gene Targeting/*methods ; *Gene Transfer Techniques ; Gene Transfer, Horizontal ; *Genes, Recessive ; *Genes, X-Linked ; Humans ; Malaria/prevention & control ; Mutagenesis ; Mutation ; Pigmentation/genetics
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  • 31
    Publication Date: 2015-05-23
    Description: Extremophiles, microorganisms thriving in extreme environmental conditions, must have proteins and nucleic acids that are stable at extremes of temperature and pH. The nonenveloped, rod-shaped virus SIRV2 (Sulfolobus islandicus rod-shaped virus 2) infects the hyperthermophilic acidophile Sulfolobus islandicus, which lives at 80 degrees C and pH 3. We have used cryo-electron microscopy to generate a three-dimensional reconstruction of the SIRV2 virion at ~4 angstrom resolution, which revealed a previously unknown form of virion organization. Although almost half of the capsid protein is unstructured in solution, this unstructured region folds in the virion into a single extended alpha helix that wraps around the DNA. The DNA is entirely in the A-form, which suggests a common mechanism with bacterial spores for protecting DNA in the most adverse environments.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DiMaio, Frank -- Yu, Xiong -- Rensen, Elena -- Krupovic, Mart -- Prangishvili, David -- Egelman, Edward H -- GM035269/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 May 22;348(6237):914-7. doi: 10.1126/science.aaa4181.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. ; Institut Pasteur, Department of Microbiology, 25 rue du Dr. Roux, Paris 75015, France. ; Institut Pasteur, Department of Microbiology, 25 rue du Dr. Roux, Paris 75015, France. egelman@virginia.edu david.prangishvili@pasteur.fr. ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA. egelman@virginia.edu david.prangishvili@pasteur.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25999507" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; DNA, A-Form/*metabolism ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; Rudiviridae/*metabolism/ultrastructure ; Spores, Bacterial/genetics/virology ; Sulfolobus/*genetics/*virology ; Virion/*ultrastructure
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  • 32
    Publication Date: 2015-10-10
    Description: Strigolactones are naturally occurring signaling molecules that affect plant development, fungi-plant interactions, and parasitic plant infestations. We characterized the function of 11 strigolactone receptors from the parasitic plant Striga hermonthica using chemical and structural biology. We found a clade of polyspecific receptors, including one that is sensitive to picomolar concentrations of strigolactone. A crystal structure of a highly sensitive strigolactone receptor from Striga revealed a larger binding pocket than that of the Arabidopsis receptor, which could explain the increased range of strigolactone sensitivity. Thus, the sensitivity of Striga to strigolactones from host plants is driven by receptor sensitivity. By expressing strigolactone receptors in Arabidopsis, we developed a bioassay that can be used to identify chemicals and crops with altered strigolactone levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toh, Shigeo -- Holbrook-Smith, Duncan -- Stogios, Peter J -- Onopriyenko, Olena -- Lumba, Shelley -- Tsuchiya, Yuichiro -- Savchenko, Alexei -- McCourt, Peter -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):203-7. doi: 10.1126/science.aac9476.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto M5S 3B2, Canada. ; Department of Chemical Engineering and Applied Chemistry, Banting and Best Department of Medical Research, University of Toronto, 200 College Street, Toronto M5S 3E5, Canada. Center for Structural Genomics of Infectious Diseases, contracted by National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. ; Department of Chemical Engineering and Applied Chemistry, Banting and Best Department of Medical Research, University of Toronto, 200 College Street, Toronto M5S 3E5, Canada. ; Institute of Transformative Bio-Molecules, Nagoya University, Japan, Furo-cho, Chikusa-ku, Nagoya, Aichi 464-8602, Japan. ; Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto M5S 3B2, Canada. peter.mccourt@utoronto.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26450211" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/genetics/metabolism ; Catalytic Domain ; Germination/drug effects ; Heterocyclic Compounds, 3-Ring/*metabolism/pharmacology ; Lactones/*metabolism/pharmacology ; Molecular Sequence Data ; Phylogeny ; Plant Growth Regulators/*metabolism/pharmacology ; Plant Proteins/*chemistry/classification/genetics ; Protein Structure, Secondary ; Receptors, Cell Surface/*chemistry/classification/genetics ; Seeds/genetics/growth & development/metabolism ; Striga/genetics/growth & development/*metabolism ; Structure-Activity Relationship
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  • 33
    Publication Date: 2015-04-04
    Description: Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosenberg, Steven A -- Restifo, Nicholas P -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):62-8. doi: 10.1126/science.aaa4967.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Surgery Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, 9000 Rockville Pike, CRC Building, Room 3W-3940, Bethesda, MD 20892, USA. sar@nih.gov restifo@nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838374" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Neoplasm/immunology ; Genetic Engineering ; Humans ; Immunotherapy, Adoptive/*methods ; Lymphocyte Depletion ; Melanoma/genetics/secondary/therapy ; Mutation ; Neoplasms/genetics/immunology/*therapy ; Precision Medicine/*methods ; Skin Neoplasms/genetics/pathology/therapy ; T-Lymphocytes/transplantation
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  • 34
    Publication Date: 2015-01-03
    Description: Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4446723/" 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/PMC4446723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tomasetti, Cristian -- Vogelstein, Bert -- P30 CA006973/CA/NCI NIH HHS/ -- P30-CA006973/CA/NCI NIH HHS/ -- P50-CA62924/CA/NCI NIH HHS/ -- R01-CA57345/CA/NCI NIH HHS/ -- R37 CA043460/CA/NCI NIH HHS/ -- R37-CA43460/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):78-81. doi: 10.1126/science.1260825.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biostatistics and Bioinformatics, Department of Oncology, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine and Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, 550 North Broadway, Baltimore, MD 21205, USA. ctomasetti@jhu.edu vogelbe@jhmi.edu. ; Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute, Johns Hopkins Kimmel Cancer Center, 1650 Orleans Street, Baltimore, MD 21205, USA. ctomasetti@jhu.edu vogelbe@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554788" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Division/*genetics ; Gene-Environment Interaction ; Genetic Variation ; Humans ; Mutation ; Neoplasms/classification/*epidemiology/*genetics ; Risk ; Stem Cells/*physiology
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  • 35
    Publication Date: 2015-03-15
    Description: TREK-2 (KCNK10/K2P10), a two-pore domain potassium (K2P) channel, is gated by multiple stimuli such as stretch, fatty acids, and pH and by several drugs. However, the mechanisms that control channel gating are unclear. Here we present crystal structures of the human TREK-2 channel (up to 3.4 angstrom resolution) in two conformations and in complex with norfluoxetine, the active metabolite of fluoxetine (Prozac) and a state-dependent blocker of TREK channels. Norfluoxetine binds within intramembrane fenestrations found in only one of these two conformations. Channel activation by arachidonic acid and mechanical stretch involves conversion between these states through movement of the pore-lining helices. These results provide an explanation for TREK channel mechanosensitivity, regulation by diverse stimuli, and possible off-target effects of the serotonin reuptake inhibitor Prozac.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dong, Yin Yao -- Pike, Ashley C W -- Mackenzie, Alexandra -- McClenaghan, Conor -- Aryal, Prafulla -- Dong, Liang -- Quigley, Andrew -- Grieben, Mariana -- Goubin, Solenne -- Mukhopadhyay, Shubhashish -- Ruda, Gian Filippo -- Clausen, Michael V -- Cao, Lishuang -- Brennan, Paul E -- Burgess-Brown, Nicola A -- Sansom, Mark S P -- Tucker, Stephen J -- Carpenter, Elisabeth P -- 084655/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):1256-9. doi: 10.1126/science.1261512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. ; Pfizer Neusentis, Granta Park, Cambridge CB21 6GS, UK. ; OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. Department of Biochemistry, University of Oxford, Oxford OX1 3QU, UK. ; Clarendon Laboratory, Department of Physics, University of Oxford, Oxford OX1 3PU, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk. ; Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. OXION Initiative in Ion Channels and Disease, University of Oxford, Oxford OX1 3PN, UK. liz.carpenter@sgc.ox.ac.uk stephen.tucker@physics.ox.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25766236" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arachidonic Acid/pharmacology ; Binding Sites ; Crystallography, X-Ray ; Fluoxetine/analogs & derivatives/chemistry/metabolism/pharmacology ; Humans ; *Ion Channel Gating ; Models, Molecular ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Potassium/metabolism ; Potassium Channels, Tandem Pore Domain/antagonists & ; inhibitors/*chemistry/metabolism ; Protein Conformation ; Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 36
    Publication Date: 2015-11-01
    Description: It is unknown whether the human immune system frequently mounts a T cell response against mutations expressed by common epithelial cancers. Using a next-generation sequencing approach combined with high-throughput immunologic screening, we demonstrated that tumor-infiltrating lymphocytes (TILs) from 9 out of 10 patients with metastatic gastrointestinal cancers contained CD4(+) and/or CD8(+) T cells that recognized one to three neo-epitopes derived from somatic mutations expressed by the patient's own tumor. There were no immunogenic epitopes shared between these patients. However, we identified in one patient a human leukocyte antigen-C*08:02-restricted T cell receptor from CD8(+) TILs that targeted the KRAS(G12D) hotspot driver mutation found in many human cancers. Thus, a high frequency of patients with common gastrointestinal cancers harbor immunogenic mutations that can potentially be exploited for the development of highly personalized immunotherapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, Eric -- Ahmadzadeh, Mojgan -- Lu, Yong-Chen -- Gros, Alena -- Turcotte, Simon -- Robbins, Paul F -- Gartner, Jared J -- Zheng, Zhili -- Li, Yong F -- Ray, Satyajit -- Wunderlich, John R -- Somerville, Robert P -- Rosenberg, Steven A -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1387-90. doi: 10.1126/science.aad1253. Epub 2015 Oct 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. ; Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. sar@mail.nih.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26516200" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; CD8-Positive T-Lymphocytes/immunology ; Cell Line, Tumor ; Female ; Gastrointestinal Neoplasms/*genetics/*immunology/therapy ; HLA-C Antigens/genetics/immunology ; Humans ; Immunodominant Epitopes/genetics/immunology ; Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Middle Aged ; Mutation ; Precision Medicine/methods ; Proto-Oncogene Proteins/genetics/immunology ; Receptors, Antigen, T-Cell/immunology ; ras Proteins/genetics/immunology
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  • 37
    Publication Date: 2015-11-07
    Description: Understanding the evolution of sex determination in plants requires identifying the mechanisms underlying the transition from monoecious plants, where male and female flowers coexist, to unisexual individuals found in dioecious species. We show that in melon and cucumber, the androecy gene controls female flower development and encodes a limiting enzyme of ethylene biosynthesis, ACS11. ACS11 is expressed in phloem cells connected to flowers programmed to become female, and ACS11 loss-of-function mutants lead to male plants (androecy). CmACS11 represses the expression of the male promoting gene CmWIP1 to control the development and the coexistence of male and female flowers in monoecious species. Because monoecy can lead to dioecy, we show how a combination of alleles of CmACS11 and CmWIP1 can create artificial dioecy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Boualem, Adnane -- Troadec, Christelle -- Camps, Celine -- Lemhemdi, Afef -- Morin, Halima -- Sari, Marie-Agnes -- Fraenkel-Zagouri, Rina -- Kovalski, Irina -- Dogimont, Catherine -- Perl-Treves, Rafael -- Bendahmane, Abdelhafid -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):688-91. doi: 10.1126/science.aac8370.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut National de la Recherche Agronomique (INRA), Institute of Plant Sciences Paris-Saclay, CNRS, Universite Paris-Sud, Universite d'Evry, Universite Paris-Diderot, Batiment 630, 91405, Orsay, France. ; Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS, UMR 8601, Universite Rene Descartes, Paris, France. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, Israel. ; INRA, UR 1052, Unite de Genetique et d'Amelioration des Fruits et Legumes, BP 94, F-84143 Montfavet, France. ; Institut National de la Recherche Agronomique (INRA), Institute of Plant Sciences Paris-Saclay, CNRS, Universite Paris-Sud, Universite d'Evry, Universite Paris-Diderot, Batiment 630, 91405, Orsay, France. bendahm@evry.inra.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542573" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; *Biological Evolution ; Cucumis sativus/enzymology/genetics/growth & development ; Cucurbitaceae/enzymology/genetics/*growth & development ; Ethylenes/biosynthesis ; Flowers/enzymology/genetics/*growth & development ; Genes, Plant/genetics/physiology ; Lyases/genetics/*physiology ; Molecular Sequence Data ; Phloem/enzymology/genetics/growth & development ; Plant Proteins/genetics/*physiology ; Sex Determination Processes/*genetics
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  • 38
    Publication Date: 2015-10-17
    Description: Research in the genetics of neurodevelopmental disorders such as autism suggests that several hundred genes are likely risk factors for these disorders. This heterogeneity presents a challenge and an opportunity at the same time. Although the exact identity of many of the genes remains to be discovered, genes identified to date encode proteins that play roles in certain conserved pathways: protein synthesis, transcriptional and epigenetic regulation, and synaptic signaling. The next generation of research in neurodevelopmental disorders must address the neural circuitry underlying the behavioral symptoms and comorbidities, the cell types playing critical roles in these circuits, and common intercellular signaling pathways that link diverse genes. Results from clinical trials have been mixed so far. Only when we can leverage the heterogeneity of neurodevelopmental disorders into precision medicine will the mechanism-based therapeutics for these disorders start to unlock success.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4739545/" 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/PMC4739545/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahin, Mustafa -- Sur, Mriganka -- EF1451125/PHS HHS/ -- EY007023/EY/NEI NIH HHS/ -- MH085802/MH/NIMH NIH HHS/ -- NS090473/NS/NINDS NIH HHS/ -- P20 NS080199/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- U01 NS082320/NS/NINDS NIH HHS/ -- U54 NS092090/NS/NINDS NIH HHS/ -- U54NS092090/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 20;350(6263). pii: aab3897. doi: 10.1126/science.aab3897. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉F. M. Kirby Center for Neurobiology, Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA. mustafa.sahin@childrens.harvard.edu msur@mit.edu. ; Simons Center for the Social Brain, Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. mustafa.sahin@childrens.harvard.edu msur@mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472761" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/drug therapy/genetics ; Behavior ; Brain/growth & development/metabolism ; Chromatin Assembly and Disassembly ; Clinical Trials as Topic ; Epigenesis, Genetic ; Genes ; *Genetic Predisposition to Disease ; Humans ; Metabolic Networks and Pathways/genetics ; Mice ; Mutation ; Neural Pathways/metabolism ; Neurodevelopmental Disorders/*drug therapy/*genetics ; Precision Medicine/*methods ; Protein Biosynthesis/genetics ; Transcription, Genetic ; Translational Medical Research
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  • 39
    Publication Date: 2015-09-26
    Description: Cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) detects intracellular DNA and signals through the adapter protein STING to initiate the antiviral response to DNA viruses. Whether DNA viruses can prevent activation of the cGAS-STING pathway remains largely unknown. Here, we identify the oncogenes of the DNA tumor viruses, including E7 from human papillomavirus (HPV) and E1A from adenovirus, as potent and specific inhibitors of the cGAS-STING pathway. We show that the LXCXE motif of these oncoproteins, which is essential for blockade of the retinoblastoma tumor suppressor, is also important for antagonizing DNA sensing. E1A and E7 bind to STING, and silencing of these oncogenes in human tumor cells restores the cGAS-STING pathway. Our findings reveal a host-virus conflict that may have shaped the evolution of viral oncogenes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lau, Laura -- Gray, Elizabeth E -- Brunette, Rebecca L -- Stetson, Daniel B -- New York, N.Y. -- Science. 2015 Oct 30;350(6260):568-71. doi: 10.1126/science.aab3291. Epub 2015 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. ; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. stetson@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26405230" target="_blank"〉PubMed〈/a〉
    Keywords: Adenovirus E1A Proteins/chemistry/genetics/*metabolism ; Amino Acid Motifs ; Amino Acid Sequence ; DNA Tumor Viruses/*immunology ; DNA, Neoplasm/immunology ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Evolution, Molecular ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Membrane Proteins/*antagonists & inhibitors ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Nucleotides, Cyclic/*antagonists & inhibitors ; Oncogene Proteins, Viral/chemistry/genetics/*metabolism ; Retinoblastoma Protein/antagonists & inhibitors ; *Tumor Escape
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  • 40
    Publication Date: 2015-09-12
    Description: Podophyllotoxin is the natural product precursor of the chemotherapeutic etoposide, yet only part of its biosynthetic pathway is known. We used transcriptome mining in Podophyllum hexandrum (mayapple) to identify biosynthetic genes in the podophyllotoxin pathway. We selected 29 candidate genes to combinatorially express in Nicotiana benthamiana (tobacco) and identified six pathway enzymes, including an oxoglutarate-dependent dioxygenase that closes the core cyclohexane ring of the aryltetralin scaffold. By coexpressing 10 genes in tobacco-these 6 plus 4 previously discovered-we reconstitute the pathway to (-)-4'-desmethylepipodophyllotoxin (the etoposide aglycone), a naturally occurring lignan that is the immediate precursor of etoposide and, unlike podophyllotoxin, a potent topoisomerase inhibitor. Our results enable production of the etoposide aglycone in tobacco and circumvent the need for cultivation of mayapple and semisynthetic epimerization and demethylation of podophyllotoxin.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lau, Warren -- Sattely, Elizabeth S -- DP2 AT008321/AT/NCCIH NIH HHS/ -- R00 GM089985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 11;349(6253):1224-8. doi: 10.1126/science.aac7202.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. ; Department of Chemical Engineering, Stanford University, Stanford, CA 94305, USA. sattely@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359402" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biosynthetic Pathways/genetics ; Etoposide/*metabolism ; Gene Expression Regulation, Enzymologic ; Gene Expression Regulation, Plant ; *Genetic Engineering ; Methylation ; Mixed Function Oxygenases/genetics/*metabolism ; Molecular Sequence Data ; Podophyllotoxin/*analogs & derivatives/biosynthesis/*metabolism ; Podophyllum peltatum/*enzymology/genetics ; Tobacco/genetics/*metabolism ; Topoisomerase Inhibitors/*metabolism ; Transcriptome
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  • 41
    Publication Date: 2015-09-12
    Description: Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Shukla, Sachet A -- Blank, Christian -- Zimmer, Lisa -- Sucker, Antje -- Hillen, Uwe -- Foppen, Marnix H Geukes -- Goldinger, Simone M -- Utikal, Jochen -- Hassel, Jessica C -- Weide, Benjamin -- Kaehler, Katharina C -- Loquai, Carmen -- Mohr, Peter -- Gutzmer, Ralf -- Dummer, Reinhard -- Gabriel, Stacey -- Wu, Catherine J -- Schadendorf, Dirk -- Garraway, Levi A -- U54 HG003067/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):207-11. doi: 10.1126/science.aad0095. Epub 2015 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. ; Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany. Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany. Department of Dermatology, Venerology, and Allergology, University Medical Center, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany. ; Department of Dermatology, University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany. ; Department of Dermatology, University Hospital Tubingen, 72076 Tubingen, Germany. ; Department of Dermatology, University Hospital Kiel, 24105 Kiel, Germany. ; Department of Dermatology, University Medical Center, 55131 Mainz, Germany. ; Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany. ; Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359337" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/*pharmacology/therapeutic use ; Antigens, Neoplasm/*genetics ; *Biomarkers, Pharmacological ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/genetics/immunology ; Cohort Studies ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Exome ; Female ; Genomics ; HLA Antigens/genetics ; Humans ; Male ; Melanoma/*drug therapy/*genetics/secondary ; Middle Aged ; Mutation ; Skin Neoplasms/*drug therapy/*genetics/pathology ; Tumor Microenvironment/drug effects/immunology ; Young Adult
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  • 42
    Publication Date: 2015-09-01
    Description: DNA strand exchange plays a central role in genetic recombination across all kingdoms of life, but the physical basis for these reactions remains poorly defined. Using single-molecule imaging, we found that bacterial RecA and eukaryotic Rad51 and Dmc1 all stabilize strand exchange intermediates in precise three-nucleotide steps. Each step coincides with an energetic signature (0.3 kBT) that is conserved from bacteria to humans. Triplet recognition is strictly dependent on correct Watson-Crick pairing. Rad51, RecA, and Dmc1 can all step over mismatches, but only Dmc1 can stabilize mismatched triplets. This finding provides insight into why eukaryotes have evolved a meiosis-specific recombinase. We propose that canonical Watson-Crick base triplets serve as the fundamental unit of pairing interactions during DNA recombination.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4580133/" 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/PMC4580133/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Ja Yil -- Terakawa, Tsuyoshi -- Qi, Zhi -- Steinfeld, Justin B -- Redding, Sy -- Kwon, YoungHo -- Gaines, William A -- Zhao, Weixing -- Sung, Patrick -- Greene, Eric C -- CA146940/CA/NCI NIH HHS/ -- GM074739/GM/NIGMS NIH HHS/ -- R01 CA146940/CA/NCI NIH HHS/ -- R01 ES015252/ES/NIEHS NIH HHS/ -- R01 GM074739/GM/NIGMS NIH HHS/ -- R01ES015252/ES/NIEHS NIH HHS/ -- T32 GM007367/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):977-81. doi: 10.1126/science.aab2666.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. Department of Biophysics, Kyoto University, Sakyo, Kyoto, Japan. ; Department of Chemistry, Columbia University, New York, NY, USA. ; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA. Howard Hughes Medical Institute, Columbia University, New York, NY, USA. ecg2108@cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315438" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Base Pairing ; Base Sequence ; Cell Cycle Proteins/chemistry/metabolism ; DNA/*chemistry/*metabolism ; DNA, Single-Stranded/metabolism ; DNA-Binding Proteins/chemistry/metabolism ; Escherichia coli Proteins/chemistry/metabolism ; Evolution, Molecular ; *Homologous Recombination ; Humans ; Meiosis ; Molecular Dynamics Simulation ; Molecular Sequence Data ; Rad51 Recombinase/chemistry/*metabolism ; Rec A Recombinases/chemistry/*metabolism ; Recombinases/chemistry/*metabolism ; Saccharomyces cerevisiae Proteins/chemistry/*metabolism ; Thermodynamics
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  • 43
    Publication Date: 2015-04-04
    Description: T cell immunity directed against tumor-encoded amino acid substitutions occurs in some melanoma patients. This implicates missense mutations as a source of patient-specific neoantigens. However, a systematic evaluation of these putative neoantigens as targets of antitumor immunity is lacking. Moreover, it remains unknown whether vaccination can augment such responses. We found that a dendritic cell vaccine led to an increase in naturally occurring neoantigen-specific immunity and revealed previously undetected human leukocyte antigen (HLA) class I-restricted neoantigens in patients with advanced melanoma. The presentation of neoantigens by HLA-A*02:01 in human melanoma was confirmed by mass spectrometry. Vaccination promoted a diverse neoantigen-specific T cell receptor (TCR) repertoire in terms of both TCR-beta usage and clonal composition. Our results demonstrate that vaccination directed at tumor-encoded amino acid substitutions broadens the antigenic breadth and clonal diversity of antitumor immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4549796/" 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/PMC4549796/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carreno, Beatriz M -- Magrini, Vincent -- Becker-Hapak, Michelle -- Kaabinejadian, Saghar -- Hundal, Jasreet -- Petti, Allegra A -- Ly, Amy -- Lie, Wen-Rong -- Hildebrand, William H -- Mardis, Elaine R -- Linette, Gerald P -- 5U54HG00307/HG/NHGRI NIH HHS/ -- P30 CA091842/CA/NCI NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R21 CA179695/CA/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 May 15;348(6236):803-8. doi: 10.1126/science.aaa3828. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA. bcarreno@dom.wustl.edu. ; Genome Institute, Washington University School of Medicine, St. Louis, MO, USA. ; Department of Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA. ; Department of Microbiology and Immunology, University of Oklahoma Health Science Center, Oklahoma City, OK, USA. ; EMD Millipore Corporation, Billerica, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25837513" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution/immunology ; Antigen Presentation ; Antigens, Neoplasm/genetics/*immunology ; Cancer Vaccines/immunology/*therapeutic use ; Dendritic Cells/immunology/*transplantation ; HLA-A2 Antigen/genetics/*immunology ; Humans ; Immunotherapy, Active/*methods ; Melanoma/genetics/immunology/*therapy ; Monitoring, Immunologic ; Mutation ; Receptors, Antigen, T-Cell, alpha-beta/immunology ; Skin Neoplasms/genetics/immunology/*therapy ; T-Lymphocytes/*immunology
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  • 44
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-04-04
    Description: The clinical relevance of T cells in the control of a diverse set of human cancers is now beyond doubt. However, the nature of the antigens that allow the immune system to distinguish cancer cells from noncancer cells has long remained obscure. Recent technological innovations have made it possible to dissect the immune response to patient-specific neoantigens that arise as a consequence of tumor-specific mutations, and emerging data suggest that recognition of such neoantigens is a major factor in the activity of clinical immunotherapies. These observations indicate that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schumacher, Ton N -- Schreiber, Robert D -- R01CA04305926/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):69-74. doi: 10.1126/science.aaa4971.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. t.schumacher@nki.nl schreiber@immunology.wustl.edu. ; Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA. t.schumacher@nki.nl schreiber@immunology.wustl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838375" target="_blank"〉PubMed〈/a〉
    Keywords: Antigens, Neoplasm/genetics/*immunology ; Biomarkers, Tumor/genetics/*immunology ; DNA Mutational Analysis ; Exome ; Female ; Genes, Neoplasm ; Humans ; Immunotherapy/*methods ; Mutation ; Neoplasms/genetics/immunology/*therapy ; T-Lymphocytes/*immunology
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  • 45
    Publication Date: 2015-01-13
    Description: NADPH/NADP(+) (the reduced form of NADP(+)/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 A crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 A crystal structure of the entire enzyme (holo-TH). The membrane domain crystallized as a symmetric dimer, with each protomer containing a putative proton channel. The holo-TH is a highly asymmetric dimer with the NADP(H)-binding domain (dIII) in two different orientations. This unusual arrangement suggests a catalytic mechanism in which the two copies of dIII alternatively function in proton translocation and hydride transfer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479213/" 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/PMC4479213/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leung, Josephine H -- Schurig-Briccio, Lici A -- Yamaguchi, Mutsuo -- Moeller, Arne -- Speir, Jeffrey A -- Gennis, Robert B -- Stout, Charles D -- 1R01GM103838-01A1/GM/NIGMS NIH HHS/ -- 5R01GM061545/GM/NIGMS NIH HHS/ -- GM073197/GM/NIGMS NIH HHS/ -- GM095600/GM/NIGMS NIH HHS/ -- P41 GM103310/GM/NIGMS NIH HHS/ -- P41GM103310/GM/NIGMS NIH HHS/ -- R01 GM061545/GM/NIGMS NIH HHS/ -- R01 GM095600/GM/NIGMS NIH HHS/ -- R01 GM103838/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):178-81. doi: 10.1126/science.1260451.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA. ; Department of Biochemistry, University of Illinois, Urbana, IL 61801, USA. ; National Resource for Automated Molecular Microscopy, 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. dave@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25574024" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Crystallography, X-Ray ; Molecular Sequence Data ; NADP Transhydrogenases/*chemistry ; Protein Multimerization ; Protein Structure, Tertiary ; *Protons ; Thermus thermophilus/enzymology
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  • 46
    Publication Date: 2015-03-21
    Description: Base-pairing interactions between nucleic acids mediate target recognition in many biological processes. We developed a super-resolution imaging and modeling platform that enabled the in vivo determination of base pairing-mediated target recognition kinetics. We examined a stress-induced bacterial small RNA, SgrS, which induces the degradation of target messenger RNAs (mRNAs). SgrS binds to a primary target mRNA in a reversible and dynamic fashion, and formation of SgrS-mRNA complexes is rate-limiting, dictating the overall regulation efficiency in vivo. Examination of a secondary target indicated that differences in the target search kinetics contribute to setting the regulation priority among different target mRNAs. This super-resolution imaging and analysis approach provides a conceptual framework that can be generalized to other small RNA systems and other target search processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4410144/" 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/PMC4410144/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fei, Jingyi -- Singh, Digvijay -- Zhang, Qiucen -- Park, Seongjin -- Balasubramanian, Divya -- Golding, Ido -- Vanderpool, Carin K -- Ha, Taekjip -- GM 112659/GM/NIGMS NIH HHS/ -- GM065367/GM/NIGMS NIH HHS/ -- GM082837/GM/NIGMS NIH HHS/ -- GM092830/GM/NIGMS NIH HHS/ -- R01 GM065367/GM/NIGMS NIH HHS/ -- R01 GM082837/GM/NIGMS NIH HHS/ -- R01 GM092830/GM/NIGMS NIH HHS/ -- R01 GM112659/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 20;347(6228):1371-4. doi: 10.1126/science.1258849.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for the Physics of Living Cells, Department of Physics, University of Illinois, Urbana, IL, USA. ; Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA. ; Department of Microbiology, University of Illinois, Urbana, IL, USA. ; Center for the Physics of Living Cells, Department of Physics, University of Illinois, Urbana, IL, USA. Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, TX, USA. ; Department of Microbiology, University of Illinois, Urbana, IL, USA. tjha@illinois.edu cvanderp@life.uiuc.edu. ; Center for the Physics of Living Cells, Department of Physics, University of Illinois, Urbana, IL, USA. Center for Biophysics and Computational Biology, University of Illinois, Urbana, IL, USA. Carl R. Woese Institute for Genomic Biology, Howard Hughes Medical Institute, Urbana, IL, USA. Howard Hughes Medical Institute, Urbana, IL, USA. tjha@illinois.edu cvanderp@life.uiuc.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25792329" target="_blank"〉PubMed〈/a〉
    Keywords: *Base Pairing ; Endoribonucleases/chemistry/genetics ; Escherichia coli/genetics/metabolism ; Kinetics ; Molecular Imaging/*methods ; Mutation ; Phosphoenolpyruvate Sugar Phosphotransferase System/genetics ; *RNA Stability ; RNA, Messenger/*chemistry ; RNA, Small Untranslated/*chemistry
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  • 47
    Publication Date: 2015-01-31
    Description: The 18-kilodalton translocator protein (TSPO), proposed to be a key player in cholesterol transport into mitochondria, is highly expressed in steroidogenic tissues, metastatic cancer, and inflammatory and neurological diseases such as Alzheimer's and Parkinson's. TSPO ligands, including benzodiazepine drugs, are implicated in regulating apoptosis and are extensively used in diagnostic imaging. We report crystal structures (at 1.8, 2.4, and 2.5 angstrom resolution) of TSPO from Rhodobacter sphaeroides and a mutant that mimics the human Ala(147)--〉Thr(147) polymorphism associated with psychiatric disorders and reduced pregnenolone production. Crystals obtained in the lipidic cubic phase reveal the binding site of an endogenous porphyrin ligand and conformational effects of the mutation. The three crystal structures show the same tightly interacting dimer and provide insights into the controversial physiological role of TSPO and how the mutation affects cholesterol binding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Fei -- Liu, Jian -- Zheng, Yi -- Garavito, R Michael -- Ferguson-Miller, Shelagh -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- GM094625/GM/NIGMS NIH HHS/ -- GM26916/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):555-8. doi: 10.1126/science.1260590.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, MI 48824, USA. fergus20@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635101" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Cholesterol/metabolism ; Crystallography, X-Ray ; Humans ; Hydrogen Bonding ; Isoquinolines/metabolism ; Ligands ; Membrane Transport Proteins/*chemistry/*metabolism ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry ; Polymorphism, Single Nucleotide ; Porphyrins/metabolism ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protoporphyrins/metabolism ; Receptors, GABA/chemistry/genetics ; Rhodobacter sphaeroides/*chemistry
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  • 48
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-03-31
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vogel, Gretchen -- New York, N.Y. -- Science. 2015 Mar 27;347(6229):1407. doi: 10.1126/science.347.6229.1407.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25814564" target="_blank"〉PubMed〈/a〉
    Keywords: Ebola Vaccines/*genetics ; Ebolavirus/*genetics ; *Evolution, Molecular ; Hemorrhagic Fever, Ebola/*prevention & control/*virology ; Humans ; Mali/epidemiology ; Mutation ; Sequence Analysis, RNA
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  • 49
    Publication Date: 2015-08-15
    Description: Adenosine-to-inosine (A-to-I) editing is a highly prevalent posttranscriptional modification of RNA, mediated by ADAR (adenosine deaminase acting on RNA) enzymes. In addition to RNA editing, additional functions have been proposed for ADAR1. To determine the specific role of RNA editing by ADAR1, we generated mice with an editing-deficient knock-in mutation (Adar1(E861A), where E861A denotes Glu(861)--〉Ala(861)). Adar1(E861A/E861A) embryos died at ~E13.5 (embryonic day 13.5), with activated interferon and double-stranded RNA (dsRNA)-sensing pathways. Genome-wide analysis of the in vivo substrates of ADAR1 identified clustered hyperediting within long dsRNA stem loops within 3' untranslated regions of endogenous transcripts. Finally, embryonic death and phenotypes of Adar1(E861A/E861A) were rescued by concurrent deletion of the cytosolic sensor of dsRNA, MDA5. A-to-I editing of endogenous dsRNA is the essential function of ADAR1, preventing the activation of the cytosolic dsRNA response by endogenous transcripts.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liddicoat, Brian J -- Piskol, Robert -- Chalk, Alistair M -- Ramaswami, Gokul -- Higuchi, Miyoko -- Hartner, Jochen C -- Li, Jin Billy -- Seeburg, Peter H -- Walkley, Carl R -- R01GM102484/GM/NIGMS NIH HHS/ -- T32 HG000044/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1115-20. doi: 10.1126/science.aac7049. Epub 2015 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia. ; Department of Genetics, Stanford University, Stanford, CA 94305, USA. ; Department of Molecular Neurobiology, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany. ; Taconic Biosciences, 51063 Cologne, Germany. ; St. Vincent's Institute of Medical Research, Fitzroy, Victoria 3065, Australia. Department of Medicine, St. Vincent's Hospital, University of Melbourne, Fitzroy, Victoria 3065, Australia. cwalkley@svi.edu.au.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26275108" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Adenosine/genetics ; Adenosine Deaminase/genetics/*metabolism ; Animals ; DEAD-box RNA Helicases/genetics/*metabolism ; Embryo Loss/*genetics ; Gene Deletion ; Gene Knock-In Techniques ; Inosine/genetics ; Mice ; Mice, Mutant Strains ; Mutation ; Nucleic Acid Conformation ; *RNA Editing ; RNA, Double-Stranded/chemistry/*metabolism ; Transcription, Genetic
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  • 50
    Publication Date: 2015-06-06
    Description: Retroviruses depend on self-assembly of their capsid proteins (core particle) to yield infectious mature virions. Despite the essential role of the retroviral core, its high polymorphism has hindered high-resolution structural analyses. Here, we report the x-ray structure of the native capsid (CA) protein from bovine leukemia virus. CA is organized as hexamers that deviate substantially from sixfold symmetry, yet adjust to make two-dimensional pseudohexagonal arrays that mimic mature retroviral cores. Intra- and interhexameric quasi-equivalent contacts are uncovered, with flexible trimeric lateral contacts among hexamers, yet preserving very similar dimeric interfaces making the lattice. The conformation of each capsid subunit in the hexamer is therefore dictated by long-range interactions, revealing how the hexamers can also assemble into closed core particles, a relevant feature of retrovirus biology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Obal, G -- Trajtenberg, F -- Carrion, F -- Tome, L -- Larrieux, N -- Zhang, X -- Pritsch, O -- Buschiazzo, A -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):95-8. doi: 10.1126/science.aaa5182. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. ; Institut Pasteur, Unite de Virologie Structurale, Departement de Virologie and CNRS Unite Mixte de Recherche 3569, 28, Rue du Docteur Roux, 75015, Paris, France. ; Institut Pasteur de Montevideo, Unit of Protein Biophysics, Mataojo 2020, 11400, Montevideo, Uruguay. Departamento de Inmunobiologia, Facultad de Medicina, Universidad de la Republica, Avenida General Flores 2125, 11800, Montevideo, Uruguay. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy. ; Institut Pasteur de Montevideo, Unit of Protein Crystallography, Mataojo 2020, 11400, Montevideo, Uruguay. Institut Pasteur, Department of Structural Biology and Chemistry, 25, Rue du Dr Roux, 75015, Paris, France. pritsch@pasteur.edu.uy alebus@pasteur.edu.uy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044299" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Capsid/*chemistry ; Capsid Proteins/*chemistry/genetics ; Cattle ; Crystallography, X-Ray ; Leukemia Virus, Bovine/*chemistry/genetics ; Molecular Sequence Data ; Mutation ; Protein Multimerization ; Protein Structure, Secondary
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  • 51
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-06-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fredrickson, James K -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1425-7. doi: 10.1126/science.aab0946.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Pacific Northwest National Laboratory (PNNL), Richland, WA 99352, USA. jim.fredrickson@pnnl.gov.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113703" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/genetics/physiology ; Bacteria/genetics ; Genetic Fitness ; Microbial Consortia/genetics/*physiology ; Microbial Interactions/genetics/*physiology ; Mutation ; Synthetic Biology ; Yeasts/genetics/physiology
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  • 52
    Publication Date: 2015-07-15
    Description: Human inborn errors of immunity mediated by the cytokines interleukin-17A and interleukin-17F (IL-17A/F) underlie mucocutaneous candidiasis, whereas inborn errors of interferon-gamma (IFN-gamma) immunity underlie mycobacterial disease. We report the discovery of bi-allelic RORC loss-of-function mutations in seven individuals from three kindreds of different ethnic origins with both candidiasis and mycobacteriosis. The lack of functional RORgamma and RORgammaT isoforms resulted in the absence of IL-17A/F-producing T cells in these individuals, probably accounting for their chronic candidiasis. Unexpectedly, leukocytes from RORgamma- and RORgammaT-deficient individuals also displayed an impaired IFN-gamma response to Mycobacterium. This principally reflected profoundly defective IFN-gamma production by circulating gammadelta T cells and CD4(+)CCR6(+)CXCR3(+) alphabeta T cells. In humans, both mucocutaneous immunity to Candida and systemic immunity to Mycobacterium require RORgamma, RORgammaT, or both.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668938/" 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/PMC4668938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okada, Satoshi -- Markle, Janet G -- Deenick, Elissa K -- Mele, Federico -- Averbuch, Dina -- Lagos, Macarena -- Alzahrani, Mohammed -- Al-Muhsen, Saleh -- Halwani, Rabih -- Ma, Cindy S -- Wong, Natalie -- Soudais, Claire -- Henderson, Lauren A -- Marzouqa, Hiyam -- Shamma, Jamal -- Gonzalez, Marcela -- Martinez-Barricarte, Ruben -- Okada, Chizuru -- Avery, Danielle T -- Latorre, Daniela -- Deswarte, Caroline -- Jabot-Hanin, Fabienne -- Torrado, Egidio -- Fountain, Jeffrey -- Belkadi, Aziz -- Itan, Yuval -- Boisson, Bertrand -- Migaud, Melanie -- Arlehamn, Cecilia S Lindestam -- Sette, Alessandro -- Breton, Sylvain -- McCluskey, James -- Rossjohn, Jamie -- de Villartay, Jean-Pierre -- Moshous, Despina -- Hambleton, Sophie -- Latour, Sylvain -- Arkwright, Peter D -- Picard, Capucine -- Lantz, Olivier -- Engelhard, Dan -- Kobayashi, Masao -- Abel, Laurent -- Cooper, Andrea M -- Notarangelo, Luigi D -- Boisson-Dupuis, Stephanie -- Puel, Anne -- Sallusto, Federica -- Bustamante, Jacinta -- Tangye, Stuart G -- Casanova, Jean-Laurent -- 8UL1TR000043/TR/NCATS NIH HHS/ -- HHSN272200900044C/AI/NIAID NIH HHS/ -- HHSN272200900044C/PHS HHS/ -- R37 AI095983/AI/NIAID NIH HHS/ -- R37AI095983/AI/NIAID NIH HHS/ -- T32 AI007512/AI/NIAID NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):606-13. doi: 10.1126/science.aaa4282. Epub 2015 Jul 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu. ; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia. ; Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. ; Department of Pediatrics, Hadassah University Hospital, Jerusalem, Israel. ; Department of Immunology, School of Medicine, Universidad de Valparaiso, Santiago, Chile. Department of Pediatrics, Padre Hurtado Hospital and Clinica Alemana, Santiago, Chile. ; Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. ; Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia. ; Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University, Riyadh, Saudi Arabia. ; Immunology Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia. ; Institut Curie, INSERM U932, Paris, France. ; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA. ; Caritas Baby Hospital, Post Office Box 11535, Jerusalem, Israel. ; Department of Immunology, School of Medicine, Universidad de Valparaiso, Santiago, Chile. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. ; Trudeau Institute, Saranac Lake, NY 12983, USA. ; La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037, USA. ; Department of Radiology, Assistance Publique-Hopitaux de Paris (AP-HP), Necker Hospital for Sick Children, Paris, France. ; Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria, Australia. ; Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria, Australia. Australian Research Council Centre of Excellence for Advanced Molecular Imaging, Monash University, Clayton, Victoria, Australia. Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK. ; Laboratoire Dynamique du Genome et Systeme Immunitaire, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. ; Laboratoire Dynamique du Genome et Systeme Immunitaire, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. ; Institute of Cellular Medicine, Newcastle University and Great North Children's Hospital, Newcastle upon Tyne NE4 6BE, UK. ; Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Universite Paris Descartes-Sorbonne Paris Cite, Imagine Institute, Paris, France. ; Department of Paediatric Allergy Immunology, University of Manchester, Royal Manchester Children's Hospital, Manchester, UK. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. ; Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. ; Division of Immunology, Boston Children's Hospital, Boston, MA 02115, USA. Manton Center for Orphan Disease Research, Children's Hospital, Boston, MA 02115, USA. ; Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. Center of Medical Immunology, Institute for Research in Biomedicine, University of Italian Switzerland, Bellinzona, Switzerland. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Center for the Study of Primary Immunodeficiencies, AP-HP, Necker Hospital for Sick Children, Paris, France. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR 1163, Paris, France. Paris Descartes University, Imagine Institute, Paris, France. Pediatric Hematology-Immunology Unit, AP-HP, Necker Hospital for Sick Children, Paris, France. Howard Hughes Medical Institute, New York, NY 10065, USA. jmarkle@rockefeller.edu jean-laurent.casanova@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160376" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Candida albicans/*immunology ; Candidiasis, Chronic Mucocutaneous/complications/*genetics/immunology ; Cattle ; Child ; Child, Preschool ; DNA Mutational Analysis ; Exome/genetics ; Female ; Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor ; Humans ; Immunity/*genetics ; Interferon-gamma/immunology ; Interleukin-17/immunology ; Mice ; Mutation ; Mycobacterium bovis/immunology/isolation & purification ; Mycobacterium tuberculosis/immunology/isolation & purification ; Nuclear Receptor Subfamily 1, Group F, Member 3/*genetics ; Pedigree ; Receptors, Antigen, T-Cell, alpha-beta/genetics/immunology ; Receptors, Antigen, T-Cell, gamma-delta/genetics/immunology ; Severe Combined Immunodeficiency/*genetics ; T-Lymphocytes/immunology ; Thymus Gland/abnormalities/immunology ; Tuberculosis, Bovine/*genetics/immunology ; Tuberculosis, Pulmonary/*genetics/immunology
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  • 53
    Publication Date: 2015-06-27
    Description: Cardiac progenitor cells are multipotent and give rise to cardiac endothelium, smooth muscle, and cardiomyocytes. Here, we define and characterize the cardiomyoblast intermediate that is committed to the cardiomyocyte fate, and we characterize the niche signals that regulate commitment. Cardiomyoblasts express Hopx, which functions to coordinate local Bmp signals to inhibit the Wnt pathway, thus promoting cardiomyogenesis. Hopx integrates Bmp and Wnt signaling by physically interacting with activated Smads and repressing Wnt genes. The identification of the committed cardiomyoblast that retains proliferative potential will inform cardiac regenerative therapeutics. In addition, Bmp signals characterize adult stem cell niches in other tissues where Hopx-mediated inhibition of Wnt is likely to contribute to stem cell quiescence and to explain the role of Hopx as a tumor suppressor.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jain, Rajan -- Li, Deqiang -- Gupta, Mudit -- Manderfield, Lauren J -- Ifkovits, Jamie L -- Wang, Qiaohong -- Liu, Feiyan -- Liu, Ying -- Poleshko, Andrey -- Padmanabhan, Arun -- Raum, Jeffrey C -- Li, Li -- Morrisey, Edward E -- Lu, Min Min -- Won, Kyoung-Jae -- Epstein, Jonathan A -- 5-T32-GM-007170/GM/NIGMS NIH HHS/ -- K08 HL119553/HL/NHLBI NIH HHS/ -- K08 HL119553-02/HL/NHLBI NIH HHS/ -- R01 HL071546/HL/NHLBI NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):aaa6071. doi: 10.1126/science.aaa6071.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. ; Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. epsteinj@upenn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113728" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Bone Morphogenetic Proteins/genetics/*metabolism ; Cell Lineage/genetics ; Gene Expression ; *Gene Expression Regulation, Developmental ; Heart/*embryology ; Homeodomain Proteins/genetics/*metabolism ; Mice ; Mice, Mutant Strains ; Molecular Sequence Data ; Muscle, Smooth/cytology/metabolism ; Myoblasts, Cardiac/cytology/*metabolism ; Organogenesis/*genetics ; Stem Cell Niche/genetics/physiology ; Tumor Suppressor Proteins/genetics/*metabolism ; Wnt Signaling Pathway/*genetics
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  • 54
    Publication Date: 2015-01-09
    Description: The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295826/" 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/PMC4295826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Shuyu -- Tsun, Zhi-Yang -- Wolfson, Rachel L -- Shen, Kuang -- Wyant, Gregory A -- Plovanich, Molly E -- Yuan, Elizabeth D -- Jones, Tony D -- Chantranupong, Lynne -- Comb, William -- Wang, Tim -- Bar-Peled, Liron -- Zoncu, Roberto -- Straub, Christoph -- Kim, Choah -- Park, Jiwon -- Sabatini, Bernardo L -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA180754/CA/NCI NIH HHS/ -- F31 AG044064/AG/NIA NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jan 9;347(6218):188-94. doi: 10.1126/science.1257132. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Harvard Medical School, 260 Longwood Avenue, Boston, MA 02115, USA. ; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, 220 Longwood Avenue, Boston, MA 02115, USA. ; Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Department of Biology, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25567906" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Amino Acid Transport Systems/chemistry/genetics/*metabolism ; Arginine/deficiency/*metabolism ; HEK293 Cells ; Humans ; Lysosomes/*enzymology ; Molecular Sequence Data ; Monomeric GTP-Binding Proteins/*metabolism ; Multiprotein Complexes/*metabolism ; Protein Structure, Tertiary ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism
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  • 55
    Publication Date: 2015-02-01
    Description: During virus infection, the adaptor proteins MAVS and STING transduce signals from the cytosolic nucleic acid sensors RIG-I and cGAS, respectively, to induce type I interferons (IFNs) and other antiviral molecules. Here we show that MAVS and STING harbor two conserved serine and threonine clusters that are phosphorylated by the kinases IKK and/or TBK1 in response to stimulation. Phosphorylated MAVS and STING then bind to a positively charged surface of interferon regulatory factor 3 (IRF3) and thereby recruit IRF3 for its phosphorylation and activation by TBK1. We further show that TRIF, an adaptor protein in Toll-like receptor signaling, activates IRF3 through a similar phosphorylation-dependent mechanism. These results reveal that phosphorylation of innate adaptor proteins is an essential and conserved mechanism that selectively recruits IRF3 to activate the type I IFN pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Siqi -- Cai, Xin -- Wu, Jiaxi -- Cong, Qian -- Chen, Xiang -- Li, Tuo -- Du, Fenghe -- Ren, Junyao -- Wu, You-Tong -- Grishin, Nick V -- Chen, Zhijian J -- AI-93967/AI/NIAID NIH HHS/ -- GM-094575/GM/NIGMS NIH HHS/ -- GM-63692/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):aaa2630. doi: 10.1126/science.aaa2630. Epub 2015 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Departments of Biophysics and Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. ; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. Howard Hughes Medical Institute (HHMI), University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA. zhijian.chen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25636800" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/*metabolism ; Adaptor Proteins, Vesicular Transport/chemistry/*metabolism ; Amino Acid Sequence ; Animals ; Cell Line ; Humans ; I-kappa B Kinase/metabolism ; Interferon Regulatory Factor-3/chemistry/*metabolism ; Interferon-alpha/biosynthesis ; Interferon-beta/biosynthesis ; Membrane Proteins/chemistry/*metabolism ; Mice ; Molecular Sequence Data ; Phosphorylation ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/metabolism ; Recombinant Proteins/metabolism ; Sendai virus/physiology ; Serine/metabolism ; Signal Transduction ; Ubiquitination ; Vesiculovirus/physiology
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  • 56
    Publication Date: 2015-04-25
    Description: An organism with a single recessive loss-of-function allele will typically have a wild-type phenotype, whereas individuals homozygous for two copies of the allele will display a mutant phenotype. We have developed a method called the mutagenic chain reaction (MCR), which is based on the CRISPR/Cas9 genome-editing system for generating autocatalytic mutations, to produce homozygous loss-of-function mutations. In Drosophila, we found that MCR mutations efficiently spread from their chromosome of origin to the homologous chromosome, thereby converting heterozygous mutations to homozygosity in the vast majority of somatic and germline cells. MCR technology should have broad applications in diverse organisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687737/" 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/PMC4687737/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gantz, Valentino M -- Bier, Ethan -- R01 AI070654/AI/NIAID NIH HHS/ -- R01 AI110713/AI/NIAID NIH HHS/ -- R01 GM067247/GM/NIGMS NIH HHS/ -- R56 NS029870/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):442-4. doi: 10.1126/science.aaa5945. Epub 2015 Mar 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, CA 92095, USA. vgantz@ucsd.edu ebier@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908821" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Caspase 9 ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Drosophila melanogaster/genetics ; Female ; Genetic Engineering/*methods ; Genome, Insect ; Germ Cells ; *Heterozygote ; *Homozygote ; Male ; *Mutagenesis ; Mutation ; Phenotype
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  • 57
    Publication Date: 2015-12-19
    Description: Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahuja, Shivani -- Mukund, Susmith -- Deng, Lunbin -- Khakh, Kuldip -- Chang, Elaine -- Ho, Hoangdung -- Shriver, Stephanie -- Young, Clint -- Lin, Sophia -- Johnson, J P Jr -- Wu, Ping -- Li, Jun -- Coons, Mary -- Tam, Christine -- Brillantes, Bobby -- Sampang, Honorio -- Mortara, Kyle -- Bowman, Krista K -- Clark, Kevin R -- Estevez, Alberto -- Xie, Zhiwei -- Verschoof, Henry -- Grimwood, Michael -- Dehnhardt, Christoph -- Andrez, Jean-Christophe -- Focken, Thilo -- Sutherlin, Daniel P -- Safina, Brian S -- Starovasnik, Melissa A -- Ortwine, Daniel F -- Franke, Yvonne -- Cohen, Charles J -- Hackos, David H -- Koth, Christopher M -- Payandeh, Jian -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com. ; Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680203" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Membrane/chemistry ; Crystallization/methods ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Models, Molecular ; Molecular Sequence Data ; NAV1.7 Voltage-Gated Sodium Channel/*chemistry/genetics ; Pain Perception/drug effects ; Protein Engineering ; Protein Isoforms/antagonists & inhibitors/chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sodium Channel Blockers/*chemistry/*pharmacology ; Sulfonamides/*chemistry/*pharmacology ; Thiadiazoles/*chemistry/*pharmacology
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  • 58
    Publication Date: 2015-06-13
    Description: The spindle checkpoint of the cell division cycle senses kinetochores that are not attached to microtubules and prevents precocious onset of anaphase, which can lead to aneuploidy. The nuclear division cycle 80 complex (Ndc80C) is a major microtubule receptor at the kinetochore. Ndc80C also mediates the kinetochore recruitment of checkpoint proteins. We found that the checkpoint protein kinase monopolar spindle 1 (Mps1) directly bound to Ndc80C through two independent interactions. Both interactions involved the microtubule-binding surfaces of Ndc80C and were directly inhibited in the presence of microtubules. Elimination of one such interaction in human cells caused checkpoint defects expected from a failure to detect unattached kinetochores. Competition between Mps1 and microtubules for Ndc80C binding thus constitutes a direct mechanism for the detection of unattached kinetochores.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ji, Zhejian -- Gao, Haishan -- Yu, Hongtao -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1260-4. doi: 10.1126/science.aaa4029.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. ; Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 74390, USA. hongtao.yu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068854" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding, Competitive ; *Cell Cycle ; Cell Cycle Proteins/genetics/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microtubules/*metabolism ; Molecular Sequence Data ; Nuclear Proteins/*metabolism ; Protein Binding ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/*metabolism
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  • 59
    Publication Date: 2015-07-25
    Description: Lipid transfer between cell membrane bilayers at contacts between the endoplasmic reticulum (ER) and other membranes help to maintain membrane lipid homeostasis. We found that two similar ER integral membrane proteins, oxysterol-binding protein (OSBP)-related protein 5 (ORP5) and ORP8, tethered the ER to the plasma membrane (PM) via the interaction of their pleckstrin homology domains with phosphatidylinositol 4-phosphate (PI4P) in this membrane. Their OSBP-related domains (ORDs) harbored either PI4P or phosphatidylserine (PS) and exchanged these lipids between bilayers. Gain- and loss-of-function experiments showed that ORP5 and ORP8 could mediate PI4P/PS countertransport between the ER and the PM, thus delivering PI4P to the ER-localized PI4P phosphatase Sac1 for degradation and PS from the ER to the PM. This exchange helps to control plasma membrane PI4P levels and selectively enrich PS in the PM.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4638224/" 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/PMC4638224/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chung, Jeeyun -- Torta, Federico -- Masai, Kaori -- Lucast, Louise -- Czapla, Heather -- Tanner, Lukas B -- Narayanaswamy, Pradeep -- Wenk, Markus R -- Nakatsu, Fubito -- De Camilli, Pietro -- DA018343/DA/NIDA NIH HHS/ -- DK082700/DK/NIDDK NIH HHS/ -- DK45735/DK/NIDDK NIH HHS/ -- P30 DA018343/DA/NIDA NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- R01 DK082700/DK/NIDDK NIH HHS/ -- R37 NS036251/NS/NINDS NIH HHS/ -- R37NS036251/NS/NINDS NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):428-32. doi: 10.1126/science.aab1370.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, and Program for Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06520, USA. ; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 117456 Singapore. ; Department of Cell Biology, Howard Hughes Medical Institute, Kavli Institute for Neuroscience, and Program for Cellular Neuroscience, Neurodegeneration, and Repair, Yale School of Medicine, New Haven, CT 06520, USA. pietro.decamilli@yale.edu nakatsu@med.niigata-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206935" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Biological Transport ; Cell Membrane/*metabolism ; Endoplasmic Reticulum/*metabolism ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Molecular Sequence Data ; Phosphatidylinositol Phosphates/*metabolism ; Phosphatidylserines/*metabolism ; Protein Structure, Tertiary ; Receptors, Steroid/chemistry/genetics/*metabolism
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  • 60
    Publication Date: 2015-03-31
    Description: Severe influenza disease strikes otherwise healthy children and remains unexplained. We report compound heterozygous null mutations in IRF7, which encodes the transcription factor interferon regulatory factor 7, in an otherwise healthy child who suffered life-threatening influenza during primary infection. In response to influenza virus, the patient's leukocytes and plasmacytoid dendritic cells produced very little type I and III interferons (IFNs). Moreover, the patient's dermal fibroblasts and induced pluripotent stem cell (iPSC)-derived pulmonary epithelial cells produced reduced amounts of type I IFN and displayed increased influenza virus replication. These findings suggest that IRF7-dependent amplification of type I and III IFNs is required for protection against primary infection by influenza virus in humans. They also show that severe influenza may result from single-gene inborn errors of immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4431581/" 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/PMC4431581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ciancanelli, Michael J -- Huang, Sarah X L -- Luthra, Priya -- Garner, Hannah -- Itan, Yuval -- Volpi, Stefano -- Lafaille, Fabien G -- Trouillet, Celine -- Schmolke, Mirco -- Albrecht, Randy A -- Israelsson, Elisabeth -- Lim, Hye Kyung -- Casadio, Melina -- Hermesh, Tamar -- Lorenzo, Lazaro -- Leung, Lawrence W -- Pedergnana, Vincent -- Boisson, Bertrand -- Okada, Satoshi -- Picard, Capucine -- Ringuier, Benedicte -- Troussier, Francoise -- Chaussabel, Damien -- Abel, Laurent -- Pellier, Isabelle -- Notarangelo, Luigi D -- Garcia-Sastre, Adolfo -- Basler, Christopher F -- Geissmann, Frederic -- Zhang, Shen-Ying -- Snoeck, Hans-Willem -- Casanova, Jean-Laurent -- 1U19AI109945/AI/NIAID NIH HHS/ -- 5R01AI100887/AI/NIAID NIH HHS/ -- 5R01NS072381/NS/NINDS NIH HHS/ -- 8UL1TR000043/TR/NCATS NIH HHS/ -- HHSN272201400008C/PHS HHS/ -- R01 AI100887/AI/NIAID NIH HHS/ -- R01 NS072381/NS/NINDS NIH HHS/ -- U19 AI109945/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):448-53. doi: 10.1126/science.aaa1578. Epub 2015 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. ; Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY, USA. Department of Medicine, Columbia University Medical Center, New York, NY, USA. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ; Centre for Molecular and Cellular Biology of Inflammation (CMCBI), King's College London, London SE1 1UL, UK. ; Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA, USA. Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132 Genoa, Italy. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ; Department of Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA. ; Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France. University Paris Descartes, Imagine Institute, Paris, France. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France. University Paris Descartes, Imagine Institute, Paris, France. Study Centre for Primary Immunodeficiencies, AP-HP, Necker Hospital, Paris, France. ; Pediatric Intensive Care Unit, University Hospital, Angers, France. ; General Pediatrics Unit, University Hospital, Angers, France. ; Department of Systems Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA. Department of Systems Biology, Sidra Medical and Research Center, Doha, Qatar. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France. University Paris Descartes, Imagine Institute, Paris, France. ; Pediatric Immunology, Hematology and Oncology Unit, University Hospital Centre of Angers, Angers, France. INSERM U892, CNRS U6299, Angers, France. ; Division of Immunology and Manton Center for Orphan Disease Research, Children's Hospital, Harvard Medical School, Boston, MA, USA. ; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. ; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM UMR1163, Paris, France. University Paris Descartes, Imagine Institute, Paris, France. Pediatric Immuno-Hematology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France. Howard Hughes Medical Institute, New York, NY, USA. jean-laurent.casanova@rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25814066" target="_blank"〉PubMed〈/a〉
    Keywords: Child ; Dendritic Cells/immunology ; Female ; Fibroblasts/immunology ; Genes, Recessive ; *Heterozygote ; Humans ; Induced Pluripotent Stem Cells/immunology ; *Influenza A Virus, H1N1 Subtype ; Influenza, Human/complications/genetics/*immunology ; Interferon Regulatory Factor-7/*genetics ; Interferon Type I/*biosynthesis/genetics ; Leukocytes/immunology ; Lung/immunology ; Mutation ; Respiratory Distress Syndrome, Adult/genetics/*immunology/virology ; Respiratory Mucosa/immunology
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  • 61
    Publication Date: 2015-03-15
    Description: Rgs2, a regulator of G proteins, lowers blood pressure by decreasing signaling through Galphaq. Human patients expressing Met-Leu-Rgs2 (ML-Rgs2) or Met-Arg-Rgs2 (MR-Rgs2) are hypertensive relative to people expressing wild-type Met-Gln-Rgs2 (MQ-Rgs2). We found that wild-type MQ-Rgs2 and its mutant, MR-Rgs2, were destroyed by the Ac/N-end rule pathway, which recognizes N(alpha)-terminally acetylated (Nt-acetylated) proteins. The shortest-lived mutant, ML-Rgs2, was targeted by both the Ac/N-end rule and Arg/N-end rule pathways. The latter pathway recognizes unacetylated N-terminal residues. Thus, the Nt-acetylated Ac-MX-Rgs2 (X = Arg, Gln, Leu) proteins are specific substrates of the mammalian Ac/N-end rule pathway. Furthermore, the Ac/N-degron of Ac-MQ-Rgs2 was conditional, and Teb4, an endoplasmic reticulum (ER) membrane-embedded ubiquitin ligase, was able to regulate G protein signaling by targeting Ac-MX-Rgs2 proteins for degradation through their N(alpha)-terminal acetyl group.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4748709/" 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/PMC4748709/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Sang-Eun -- Kim, Jeong-Mok -- Seok, Ok-Hee -- Cho, Hanna -- Wadas, Brandon -- Kim, Seon-Young -- Varshavsky, Alexander -- Hwang, Cheol-Sang -- DK039520/DK/NIDDK NIH HHS/ -- GM031530/GM/NIGMS NIH HHS/ -- R01 DK039520/DK/NIDDK NIH HHS/ -- R01 GM031530/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 13;347(6227):1249-52. doi: 10.1126/science.aaa3844.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. ; Medical Genomics Research Center, KRIBB, Daejeon, South Korea. Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA. cshwang@postech.ac.kr avarsh@caltech.edu. ; Department of Life Sciences, Pohang University of Science and Technology, Pohang, Gyeongbuk 790-784, South Korea. cshwang@postech.ac.kr avarsh@caltech.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25766235" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Amino Acid Sequence ; GTP-Binding Protein alpha Subunits, Gq-G11/metabolism ; HEK293 Cells ; HeLa Cells ; Humans ; Membrane Proteins/genetics/metabolism ; Mutant Proteins/chemistry/metabolism ; Protein Processing, Post-Translational ; Protein Stability ; Proteolysis ; RGS Proteins/chemistry/genetics/*metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Signal Transduction ; Ubiquitin-Protein Ligases/genetics/metabolism ; Ubiquitination
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  • 62
    Publication Date: 2015-10-17
    Description: Polycomb repressive complex 2 (PRC2) catalyzes histone H3K27 trimethylation (H3K27me3), a hallmark of gene silencing. Here we report the crystal structures of an active PRC2 complex of 170 kilodaltons from the yeast Chaetomium thermophilum in both basal and stimulated states, which contain Ezh2, Eed, and the VEFS domain of Suz12 and are bound to a cancer-associated inhibiting H3K27M peptide and a S-adenosyl-l-homocysteine cofactor. The stimulated complex also contains an additional stimulating H3K27me3 peptide. Eed is engulfed by a belt-like structure of Ezh2, and Suz12(VEFS) contacts both of these two subunits to confer an unusual split active SET domain for catalysis. Comparison of PRC2 in the basal and stimulated states reveals a mobile Ezh2 motif that responds to stimulation to allosterically regulate the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiao, Lianying -- Liu, Xin -- GM114576/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):aac4383. doi: 10.1126/science.aac4383. Epub 2015 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; Cecil H. and Ida Green Center for Reproductive Biology Sciences and Division of Basic Research, Department of Obstetrics and Gynecology and Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. xin.liu@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472914" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalysis ; Catalytic Domain ; Chaetomium/genetics/*metabolism ; Crystallography, X-Ray ; Fungal Proteins/antagonists & inhibitors/*chemistry/metabolism ; *Gene Silencing ; Histones/*metabolism ; Humans ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Methylation ; Molecular Sequence Data ; Mutation ; Neoplasms/genetics ; Polycomb Repressive Complex 2/antagonists & inhibitors/*chemistry/metabolism ; Protein Structure, Tertiary ; S-Adenosylhomocysteine/chemistry/metabolism ; Transcription, Genetic
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  • 63
    Publication Date: 2015-06-27
    Description: Algal blooms produce large amounts of dimethyl sulfide (DMS), a volatile with a diverse signaling role in marine food webs that is emitted to the atmosphere, where it can affect cloud formation. The algal enzymes responsible for forming DMS from dimethylsulfoniopropionate (DMSP) remain unidentified despite their critical role in the global sulfur cycle. We identified and characterized Alma1, a DMSP lyase from the bloom-forming algae Emiliania huxleyi. Alma1 is a tetrameric, redox-sensitive enzyme of the aspartate racemase superfamily. Recombinant Alma1 exhibits biochemical features identical to the DMSP lyase in E. huxleyi, and DMS released by various E. huxleyi isolates correlates with their Alma1 levels. Sequence homology searches suggest that Alma1 represents a gene family present in major, globally distributed phytoplankton taxa and in other marine organisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Alcolombri, Uria -- Ben-Dor, Shifra -- Feldmesser, Ester -- Levin, Yishai -- Tawfik, Dan S -- Vardi, Assaf -- New York, N.Y. -- Science. 2015 Jun 26;348(6242):1466-9. doi: 10.1126/science.aab1586.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. ; Bioinformatics and Biological Computing Unit, Biological Services, Weizmann Institute of Science, Rehovot 76100, Israel. ; Nancy and Stephen Grand Israel National Center for Personalized Medicine, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel. assaf.vardi@weizmann.ac.il dan.tawfik@weizmann.ac.il. ; Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 76100, Israel. assaf.vardi@weizmann.ac.il dan.tawfik@weizmann.ac.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113722" target="_blank"〉PubMed〈/a〉
    Keywords: Algal Proteins/*chemistry/classification/genetics ; Amino Acid Sequence ; Bacteria/enzymology/genetics ; Carbon-Sulfur Lyases/*chemistry/classification/genetics ; Haptophyta/*enzymology/genetics ; Molecular Sequence Data ; Phylogeny ; Phytoplankton/enzymology ; RNA, Messenger/biosynthesis ; Recombinant Proteins/chemistry ; Sulfides/*metabolism
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  • 64
    Publication Date: 2015-09-26
    Description: Mitochondria fulfill central functions in cellular energetics, metabolism, and signaling. The outer membrane translocator complex (the TOM complex) imports most mitochondrial proteins, but its architecture is unknown. Using a cross-linking approach, we mapped the active translocator down to single amino acid residues, revealing different transport paths for preproteins through the Tom40 channel. An N-terminal segment of Tom40 passes from the cytosol through the channel to recruit chaperones from the intermembrane space that guide the transfer of hydrophobic preproteins. The translocator contains three Tom40 beta-barrel channels sandwiched between a central alpha-helical Tom22 receptor cluster and external regulatory Tom proteins. The preprotein-translocating trimeric complex exchanges with a dimeric isoform to assemble new TOM complexes. Dynamic coupling of alpha-helical receptors, beta-barrel channels, and chaperones generates a versatile machinery that transports about 1000 different proteins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shiota, Takuya -- Imai, Kenichiro -- Qiu, Jian -- Hewitt, Victoria L -- Tan, Khershing -- Shen, Hsin-Hui -- Sakiyama, Noriyuki -- Fukasawa, Yoshinori -- Hayat, Sikander -- Kamiya, Megumi -- Elofsson, Arne -- Tomii, Kentaro -- Horton, Paul -- Wiedemann, Nils -- Pfanner, Nikolaus -- Lithgow, Trevor -- Endo, Toshiya -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):1544-8. doi: 10.1126/science.aac6428.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, 2-4-7 Aomi, Koto-ku, Tokyo 135-0064, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. ; Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Victoria 3800, Australia. ; Department of Biochemistry and Biophysics and Science for Life Laboratory, Stockholm University, Box 1031, 17121 Solna, Sweden. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. ; Institut fur Biochemie und Molekularbiologie, Universitat Freiburg, 79104 Freiburg, Germany. Centre for Biological Signalling Studies, Universitat Freiburg, 79104 Freiburg, Germany. ; Department of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan. Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo-motoyama, Kita-ku, Kyoto 603-8555, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404837" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cytosol/metabolism ; Mitochondrial Membrane Transport Proteins/*chemistry/metabolism ; Molecular Chaperones ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; Protein Transport ; Saccharomyces cerevisiae Proteins/*chemistry/metabolism
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  • 65
    Publication Date: 2015-09-05
    Description: In a short hairpin RNA screen for genes that affect AKT phosphorylation, we identified the RAB35 small guanosine triphosphatase (GTPase)-a protein previously implicated in endomembrane trafficking-as a regulator of the phosphatidylinositol 3'-OH kinase (PI3K) pathway. Depletion of RAB35 suppresses AKT phosphorylation in response to growth factors, whereas expression of a dominant active GTPase-deficient mutant of RAB35 constitutively activates the PI3K/AKT pathway. RAB35 functions downstream of growth factor receptors and upstream of PDK1 and mTORC2 and copurifies with PI3K in immunoprecipitation assays. Two somatic RAB35 mutations found in human tumors generate alleles that constitutively activate PI3K/AKT signaling, suppress apoptosis, and transform cells in a PI3K-dependent manner. Furthermore, oncogenic RAB35 is sufficient to drive platelet-derived growth factor receptor alpha to LAMP2-positive endomembranes in the absence of ligand, suggesting that there may be latent oncogenic potential in dysregulated endomembrane trafficking.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600465/" 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/PMC4600465/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Douglas B -- Zoncu, Roberto -- Root, David E -- Sabatini, David M -- Sawyers, Charles L -- 1DP2CA195761-01/CA/NCI NIH HHS/ -- AI47389/AI/NIAID NIH HHS/ -- CA092629/CA/NCI NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA155169/CA/NCI NIH HHS/ -- GM07739/GM/NIGMS NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA155169/CA/NCI NIH HHS/ -- R01 CA193837/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):211-7. doi: 10.1126/science.aaa4903. Epub 2015 Sep 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Weill Cornell/Rockefeller University/Sloan Kettering Tri-Institutional MD-PhD Program, New York, NY 10021, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, CA 94720, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA. Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02142, USA. David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. sawyersc@mskcc.org sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26338797" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Cell Line, Tumor ; Gene Deletion ; Humans ; Immunoprecipitation ; Lysosomal-Associated Membrane Protein 2/metabolism ; Multiprotein Complexes/metabolism ; Mutation ; Neoplasms/genetics/*metabolism/pathology ; Oncogene Proteins/genetics/*metabolism ; Phosphatidylinositol 3-Kinases/*metabolism ; Phosphorylation/genetics ; Protein Transport ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA Interference ; RNA, Small Interfering/genetics ; Receptor, Platelet-Derived Growth Factor alpha/metabolism ; TOR Serine-Threonine Kinases/metabolism ; rab GTP-Binding Proteins/genetics/*metabolism
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  • 66
    Publication Date: 2015-08-15
    Description: The evolution of sexual reproduction is often explained by Red Queen dynamics: Organisms must continually evolve to maintain fitness relative to interacting organisms, such as parasites. Recombination accompanies sexual reproduction and helps diversify an organism's offspring, so that parasites cannot exploit static host genotypes. Here we show that Drosophila melanogaster plastically increases the production of recombinant offspring after infection. The response is consistent across genetic backgrounds, developmental stages, and parasite types but is not induced after sterile wounding. Furthermore, the response appears to be driven by transmission distortion rather than increased recombination. Our study extends the Red Queen model to include the increased production of recombinant offspring and uncovers a remarkable ability of hosts to actively distort their recombination fraction in rapid response to environmental cues.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Singh, Nadia D -- Criscoe, Dallas R -- Skolfield, Shelly -- Kohl, Kathryn P -- Keebaugh, Erin S -- Schlenke, Todd A -- New York, N.Y. -- Science. 2015 Aug 14;349(6249):747-50. doi: 10.1126/science.aab1768.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences and Bioinformatics Research Center, North Carolina State University, Raleigh, NC, USA. ndsingh@ncsu.edu schlenkt@reed.edu. ; Translational Biology and Molecular Medicine Program, Baylor College of Medicine, Houston, TX, USA. ; Department of Biology, Reed College, Portland, OR, USA. ; Department of Biology, Winthrop University, Rock Hill, SC, USA. ; Department of Biology, Emory University, Atlanta, GA, USA. ; Department of Biology, Reed College, Portland, OR, USA. ndsingh@ncsu.edu schlenkt@reed.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26273057" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Drosophila melanogaster/*genetics/growth & development/*parasitology ; Female ; *Genetic Fitness ; Genetic Variation ; Larva ; Male ; Mutation ; Parasitic Diseases/genetics ; *Recombination, Genetic ; Reproduction/genetics
    Print ISSN: 0036-8075
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  • 67
    facet.materialart.
    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-11-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, Elizabeth -- New York, N.Y. -- Science. 2015 Nov 27;350(6264):1014. doi: 10.1126/science.350.6264.1014.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26612928" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anopheles/*genetics/growth & development/*immunology ; Antibodies/*genetics ; Clustered Regularly Interspaced Short Palindromic Repeats ; Genetic Engineering/*methods ; Humans ; Life Cycle Stages/immunology ; Malaria/parasitology/*prevention & control ; Mice ; Mosquito Control/*methods ; Mutation
    Print ISSN: 0036-8075
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  • 68
    Publication Date: 2015-02-24
    Description: Notch receptors guide mammalian cell fate decisions by engaging the proteins Jagged and Delta-like (DLL). The 2.3 angstrom resolution crystal structure of the interacting regions of the Notch1-DLL4 complex reveals a two-site, antiparallel binding orientation assisted by Notch1 O-linked glycosylation. Notch1 epidermal growth factor-like repeats 11 and 12 interact with the DLL4 Delta/Serrate/Lag-2 (DSL) domain and module at the N-terminus of Notch ligands (MNNL) domains, respectively. Threonine and serine residues on Notch1 are functionalized with O-fucose and O-glucose, which act as surrogate amino acids by making specific, and essential, contacts to residues on DLL4. The elucidation of a direct chemical role for O-glycans in Notch1 ligand engagement demonstrates how, by relying on posttranslational modifications of their ligand binding sites, Notch proteins have linked their functional capacity to developmentally regulated biosynthetic pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445638/" 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/PMC4445638/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luca, Vincent C -- Jude, Kevin M -- Pierce, Nathan W -- Nachury, Maxence V -- Fischer, Suzanne -- Garcia, K Christopher -- 1R01-GM097015/GM/NIGMS NIH HHS/ -- R01 GM097015/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):847-53. doi: 10.1126/science.1261093.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA. kcgarcia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700513" target="_blank"〉PubMed〈/a〉
    Keywords: Alagille Syndrome/genetics ; Amino Acid Sequence ; Amino Acid Substitution ; Animals ; Cell Line ; Conserved Sequence ; Crystallography, X-Ray ; Fucose/chemistry ; Glucose/chemistry ; Glycosylation ; Intracellular Signaling Peptides and Proteins/*chemistry/genetics ; Ligands ; Membrane Proteins/*chemistry/genetics/ultrastructure ; Molecular Sequence Data ; Molecular Targeted Therapy ; Polysaccharides/chemistry ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics ; Protein Binding ; Protein Structure, Tertiary ; Rats ; Receptor, Notch1/*chemistry/genetics/ultrastructure ; Serine/chemistry/genetics ; Threonine/chemistry/genetics
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  • 69
    Publication Date: 2015-02-24
    Description: Macromolecular function is rooted in energy landscapes, where sequence determines not a single structure but an ensemble of conformations. Hence, evolution modifies a protein's function by altering its energy landscape. Here, we recreate the evolutionary pathway between two modern human oncogenes, Src and Abl, by reconstructing their common ancestors. Our evolutionary reconstruction combined with x-ray structures of the common ancestor and pre-steady-state kinetics reveals a detailed atomistic mechanism for selectivity of the successful cancer drug Gleevec. Gleevec affinity is gained during the evolutionary trajectory toward Abl and lost toward Src, primarily by shifting an induced-fit equilibrium that is also disrupted in the clinical T315I resistance mutation. This work reveals the mechanism of Gleevec specificity while offering insights into how energy landscapes evolve.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4405104/" 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/PMC4405104/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilson, C -- Agafonov, R V -- Hoemberger, M -- Kutter, S -- Zorba, A -- Halpin, J -- Buosi, V -- Otten, R -- Waterman, D -- Theobald, D L -- Kern, D -- GM094468/GM/NIGMS NIH HHS/ -- GM096053/GM/NIGMS NIH HHS/ -- GM100966-01/GM/NIGMS NIH HHS/ -- R01 GM094468/GM/NIGMS NIH HHS/ -- R01 GM096053/GM/NIGMS NIH HHS/ -- R01 GM100966/GM/NIGMS NIH HHS/ -- T32 EB009419/EB/NIBIB NIH HHS/ -- T32 GM007596/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):882-6. doi: 10.1126/science.aaa1823.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. ; Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. ; Howard Hughes Medical Institute and Department of Biochemistry, Brandeis University, Waltham, MA 02452, USA. dkern@brandeis.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700521" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/chemistry/*pharmacology ; Benzamides/chemistry/*pharmacology ; Drug Resistance, Neoplasm/*genetics ; Entropy ; *Evolution, Molecular ; Humans ; Imatinib Mesylate ; Mutation ; Oncogene Proteins v-abl/chemistry/genetics ; Phylogeny ; Piperazines/chemistry/*pharmacology ; Protein Binding ; Protein Kinase Inhibitors/chemistry/*pharmacology ; Protein Structure, Secondary ; Pyrimidines/chemistry/*pharmacology ; src-Family Kinases/*chemistry/classification/genetics
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  • 70
    Publication Date: 2015-06-27
    Description: Morphinan alkaloids from the opium poppy are used for pain relief. The direction of metabolites to morphinan biosynthesis requires isomerization of (S)- to (R)-reticuline. Characterization of high-reticuline poppy mutants revealed a genetic locus, designated STORR [(S)- to (R)-reticuline] that encodes both cytochrome P450 and oxidoreductase modules, the latter belonging to the aldo-keto reductase family. Metabolite analysis of mutant alleles and heterologous expression demonstrate that the P450 module is responsible for the conversion of (S)-reticuline to 1,2-dehydroreticuline, whereas the oxidoreductase module converts 1,2-dehydroreticuline to (R)-reticuline rather than functioning as a P450 redox partner. Proteomic analysis confirmed that these two modules are contained on a single polypeptide in vivo. This modular assembly implies a selection pressure favoring substrate channeling. The fusion protein STORR may enable microbial-based morphinan production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winzer, Thilo -- Kern, Marcelo -- King, Andrew J -- Larson, Tony R -- Teodor, Roxana I -- Donninger, Samantha L -- Li, Yi -- Dowle, Adam A -- Cartwright, Jared -- Bates, Rachel -- Ashford, David -- Thomas, Jerry -- Walker, Carol -- Bowser, Tim A -- Graham, Ian A -- BB/K018809/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):309-12. doi: 10.1126/science.aab1852. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Novel Agricultural Products, Department of Biology, University of York, York YO10 5DD, UK. ; Bioscience Technology Facility, Department of Biology, University of York, York YO10 5DD, UK. ; GlaxoSmithKline, 1061 Mountain Highway, Post Office Box 168, Boronia, Victoria 3155, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113639" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Benzylisoquinolines/chemistry/*metabolism ; Cytochrome P-450 Enzyme System/genetics/*metabolism ; Genetic Loci ; Isoquinolines/chemistry/*metabolism ; Molecular Sequence Data ; Morphinans/chemistry/*metabolism ; Mutation ; Oxidation-Reduction ; Papaver/*enzymology/genetics ; Plant Proteins/genetics/*metabolism ; Quaternary Ammonium Compounds/chemistry/*metabolism
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  • 71
    facet.materialart.
    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-11-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaiser, Jocelyn -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):619. doi: 10.1126/science.350.6261.619.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542550" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ascorbic Acid/pharmacology/*therapeutic use ; Biological Transport ; Free Radicals/metabolism ; Glucose/metabolism ; Glucose Transporter Type 1/genetics/metabolism ; Mice ; Mutation ; Neoplasms/*drug therapy/genetics/metabolism ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins B-raf/genetics ; Vitamins/pharmacology/*therapeutic use ; ras Proteins/genetics
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  • 72
    Publication Date: 2015-02-14
    Description: Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A beta loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Appleby, Todd C -- Perry, Jason K -- Murakami, Eisuke -- Barauskas, Ona -- Feng, Joy -- Cho, Aesop -- Fox, David 3rd -- Wetmore, Diana R -- McGrath, Mary E -- Ray, Adrian S -- Sofia, Michael J -- Swaminathan, S -- Edwards, Thomas E -- New York, N.Y. -- Science. 2015 Feb 13;347(6223):771-5. doi: 10.1126/science.1259210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. todd.appleby@gilead.com tedwards@be4.com. ; Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. todd.appleby@gilead.com tedwards@be4.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678663" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Hepacivirus/enzymology/genetics/*physiology ; Molecular Sequence Data ; Protein Structure, Secondary ; RNA Replicase/*chemistry ; RNA, Viral/*biosynthesis ; Ribonucleotides/*chemistry ; Sofosbuvir ; Uridine Monophosphate/analogs & derivatives/chemistry ; Viral Nonstructural Proteins/*chemistry ; *Virus Replication
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  • 73
    Publication Date: 2015-11-07
    Description: Anion exchanger 1 (AE1), also known as band 3 or SLC4A1, plays a key role in the removal of carbon dioxide from tissues by facilitating the exchange of chloride and bicarbonate across the plasma membrane of erythrocytes. An isoform of AE1 is also present in the kidney. Specific mutations in human AE1 cause several types of hereditary hemolytic anemias and/or distal renal tubular acidosis. Here we report the crystal structure of the band 3 anion exchanger domain (AE1(CTD)) at 3.5 angstroms. The structure is locked in an outward-facing open conformation by an inhibitor. Comparing this structure with a substrate-bound structure of the uracil transporter UraA in an inward-facing conformation allowed us to identify the anion-binding position in the AE1(CTD), and to propose a possible transport mechanism that could explain why selected mutations lead to disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arakawa, Takatoshi -- Kobayashi-Yurugi, Takami -- Alguel, Yilmaz -- Iwanari, Hiroko -- Hatae, Hinako -- Iwata, Momi -- Abe, Yoshito -- Hino, Tomoya -- Ikeda-Suno, Chiyo -- Kuma, Hiroyuki -- Kang, Dongchon -- Murata, Takeshi -- Hamakubo, Takao -- Cameron, Alexander D -- Kobayashi, Takuya -- Hamasaki, Naotaka -- Iwata, So -- BB/D019516/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- WT089809/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Nov 6;350(6261):680-4. doi: 10.1126/science.aaa4335.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. ; Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan. ; Faculty of Pharmaceutical Sciences, Nagasaki International University, 2825-7 Huis Ten Bosch-cho, Sasebo, Nagasaki 859-3298, Japan. ; Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. ; Department of Protein Structure, Function and Design, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. ; Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Chemistry, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage, Chiba 263-8522, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. School of Life Sciences, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. ; Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Human Receptor Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. JST, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Department of Cell Biology, Kyoto University Faculty of Medicine, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan. Division of Molecular Biosciences, Membrane Protein Crystallography group, Imperial College London, London SW7 2AZ, UK. Membrane Protein Laboratory, Diamond Light Source, Harwell Science and Innovation Campus, Didcot, Chilton, Oxfordshire OX11 0DE, UK. Research Complex at Harwell Rutherford, Appleton Laboratory, Harwell Oxford, Didcot, Oxfordshire OX11 0FA, UK. Platform for Drug Discovery, Informatics, and Structural Life Science, Konoe-cho, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26542571" target="_blank"〉PubMed〈/a〉
    Keywords: Anion Exchange Protein 1, Erythrocyte/*chemistry/genetics ; Crystallography, X-Ray ; Disease/genetics ; Escherichia coli Proteins/chemistry ; Humans ; Membrane Transport Proteins/chemistry ; Mutation ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 74
    Publication Date: 2015-08-08
    Description: The pathological assembly of Abeta, tau, and alpha-synuclein is at the heart of Alzheimer's and Parkinson's diseases. Extracellular deposits of Abeta and intraneuronal tau inclusions define Alzheimer's disease, whereas intracellular inclusions of alpha-synuclein make up the Lewy pathology of Parkinson's disease. Most cases of disease are sporadic, but some are inherited in a dominant manner. Mutations frequently occur in the genes encoding Abeta, tau, and alpha-synuclein. Overexpression of these mutant proteins can give rise to disease-associated phenotypes. Protein assembly begins in specific regions of the brain during the process of Alzheimer's and Parkinson's diseases, from where it spreads to other areas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goedert, Michel -- U105184291/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):1255555. doi: 10.1126/science.1255555.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, Medical Research Council, Francis Crick Avenue, Cambridge CB2 0QH, UK. mg@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26250687" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/genetics/*metabolism/pathology ; Amyloid beta-Protein Precursor/genetics/*metabolism ; Brain/metabolism/pathology ; Humans ; Lewy Bodies/metabolism ; Mutation ; Parkinson Disease/genetics/*metabolism/pathology ; Prion Diseases/*metabolism ; Prions/genetics/*metabolism ; alpha-Synuclein/genetics/*metabolism ; tau Proteins/genetics/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 75
    Publication Date: 2015-12-19
    Description: The voltage-gated calcium channel Ca(v)1.1 is engaged in the excitation-contraction coupling of skeletal muscles. The Ca(v)1.1 complex consists of the pore-forming subunit alpha1 and auxiliary subunits alpha2delta, beta, and gamma. We report the structure of the rabbit Ca(v)1.1 complex determined by single-particle cryo-electron microscopy. The four homologous repeats of the alpha1 subunit are arranged clockwise in the extracellular view. The gamma subunit, whose structure resembles claudins, interacts with the voltage-sensing domain of repeat IV (VSD(IV)), whereas the cytosolic beta subunit is located adjacent to VSD(II) of alpha1. The alpha2 subunit interacts with the extracellular loops of repeats I to III through its VWA and Cache1 domains. The structure reveals the architecture of a prototypical eukaryotic Ca(v) channel and provides a framework for understanding the function and disease mechanisms of Ca(v) and Na(v) channels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Jianping -- Yan, Zhen -- Li, Zhangqiang -- Yan, Chuangye -- Lu, Shan -- Dong, Mengqiu -- Yan, Nieng -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aad2395. doi: 10.1126/science.aad2395.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. ; National Institute of Biological Sciences, Beijing 102206, China. ; State Key Laboratory of Membrane Biology, Tsinghua University, Beijing 100084, China. Tsinghua-Peking Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China. Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China. nyan@tsinghua.edu.cn.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680202" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Calcium Channels, L-Type/*chemistry/genetics/isolation & purification ; Cell Membrane/chemistry ; Cryoelectron Microscopy ; Molecular Sequence Data ; Muscle, Skeletal/chemistry ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Protein Subunits/isolation & purification ; Rabbits
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  • 76
    Publication Date: 2015-10-24
    Description: The relationship between microRNA (miRNA) regulation and the specification of behavior is only beginning to be explored. We found that mutation of a single miRNA locus (miR-iab4/iab8) in Drosophila larvae affects the animal's capacity to correct its orientation if turned upside down (self-righting). One of the miRNA targets involved in this behavior is the Hox gene Ultrabithorax, whose derepression in two metameric neurons leads to self-righting defects. In vivo neural activity analysis reveals that these neurons, the self-righting node (SRN), have different activity patterns in wild type and miRNA mutants, whereas thermogenetic manipulation of SRN activity results in changes in self-righting behavior. Our work thus reveals a miRNA-encoded behavior and suggests that other miRNAs might also be involved in behavioral control in Drosophila and other species.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Picao-Osorio, Joao -- Johnston, Jamie -- Landgraf, Matthias -- Berni, Jimena -- Alonso, Claudio R -- 092986/Z/Wellcome Trust/United Kingdom -- 098410/Z/12/Z/Wellcome Trust/United Kingdom -- 105568/Z/14/Z/Wellcome Trust/United Kingdom -- BB/I022414/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):815-20. doi: 10.1126/science.aad0217. Epub 2015 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sussex Neuroscience, School of Life Science, University of Sussex, Brighton BN1 9QG, UK. ; Department of Zoology, University of Cambridge, Cambridge CB2 3EJ, UK. ; Sussex Neuroscience, School of Life Science, University of Sussex, Brighton BN1 9QG, UK. c.alonso@sussex.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26494171" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/*physiology ; Drosophila Proteins/genetics ; Drosophila melanogaster/genetics/*physiology ; Gene Expression Regulation ; Genetic Loci ; Homeodomain Proteins/genetics ; Larva/genetics/physiology ; MicroRNAs/genetics/*physiology ; Mutation ; Neurons/physiology ; Orientation/*physiology ; Transcription Factors/genetics
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  • 77
    Publication Date: 2015-04-04
    Description: Posttranslational histone modifications are believed to allow the epigenetic transmission of distinct chromatin states, independently of associated DNA sequences. Histone H3 lysine 9 (H3K9) methylation is essential for heterochromatin formation; however, a demonstration of its epigenetic heritability is lacking. Fission yeast has a single H3K9 methyltransferase, Clr4, that directs all H3K9 methylation and heterochromatin. Using releasable tethered Clr4 reveals that an active process rapidly erases H3K9 methylation from tethering sites in wild-type cells. However, inactivation of the putative histone demethylase Epe1 allows H3K9 methylation and silent chromatin maintenance at the tethering site through many mitotic divisions, and transgenerationally through meiosis, after release of tethered Clr4. Thus, H3K9 methylation is a heritable epigenetic mark whose transmission is usually countered by its active removal, which prevents the unauthorized inheritance of heterochromatin.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397586/" 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/PMC4397586/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Audergon, Pauline N C B -- Catania, Sandra -- Kagansky, Alexander -- Tong, Pin -- Shukla, Manu -- Pidoux, Alison L -- Allshire, Robin C -- 092076/Wellcome Trust/United Kingdom -- 093852/Wellcome Trust/United Kingdom -- 095021/Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 3;348(6230):132-5. doi: 10.1126/science.1260638.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Centre for Cell Biology and Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, Scotland, UK. ; Wellcome Trust Centre for Cell Biology and Institute of Cell Biology, School of Biological Sciences, The University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, Scotland, UK. robin.allshire@ed.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25838386" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Cycle Proteins/*metabolism ; *Epigenesis, Genetic ; Heterochromatin/metabolism ; Histones/*metabolism ; Lysine/*metabolism ; Methylation ; Methyltransferases/*metabolism ; Mutation ; Nuclear Proteins/genetics ; Protein Processing, Post-Translational/*genetics ; Schizosaccharomyces/*enzymology/*genetics ; Schizosaccharomyces pombe Proteins/genetics/*metabolism
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  • 78
    Publication Date: 2015-04-11
    Description: Mountain gorillas are an endangered great ape subspecies and a prominent focus for conservation, yet we know little about their genomic diversity and evolutionary past. We sequenced whole genomes from multiple wild individuals and compared the genomes of all four Gorilla subspecies. We found that the two eastern subspecies have experienced a prolonged population decline over the past 100,000 years, resulting in very low genetic diversity and an increased overall burden of deleterious variation. A further recent decline in the mountain gorilla population has led to extensive inbreeding, such that individuals are typically homozygous at 34% of their sequence, leading to the purging of severely deleterious recessive mutations from the population. We discuss the causes of their decline and the consequences for their future survival.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668944/" 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/PMC4668944/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Yali -- Prado-Martinez, Javier -- Sudmant, Peter H -- Narasimhan, Vagheesh -- Ayub, Qasim -- Szpak, Michal -- Frandsen, Peter -- Chen, Yuan -- Yngvadottir, Bryndis -- Cooper, David N -- de Manuel, Marc -- Hernandez-Rodriguez, Jessica -- Lobon, Irene -- Siegismund, Hans R -- Pagani, Luca -- Quail, Michael A -- Hvilsom, Christina -- Mudakikwa, Antoine -- Eichler, Evan E -- Cranfield, Michael R -- Marques-Bonet, Tomas -- Tyler-Smith, Chris -- Scally, Aylwyn -- 098051/Wellcome Trust/United Kingdom -- 099769/Z/12/Z/Wellcome Trust/United Kingdom -- 260372/European Research Council/International -- HG002385/HG/NHGRI NIH HHS/ -- R01 HG002385/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):242-5. doi: 10.1126/science.aaa3952. Epub 2015 Apr 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. ; Institut de Biologia Evolutiva (CSIC/UPF), Parque de Investigacion Biomedica de Barcelona (PRBB), Barcelona, Catalonia 08003, Spain. ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge CB3 0WA, UK. ; Department of Biology, University of Copenhagen, DK-2200 Copenhagen N, Denmark. ; Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. Department of Biological, Geological and Environmental Sciences, University of Bologna, 40134 Bologna, Italy. ; Research and Conservation, Copenhagen Zoo, DK-2000 Frederiksberg, Denmark. ; Rwanda Development Board, KG 9 Avenue, Kigali, Rwanda. ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA. Howard Hughes Medical Institute, Seattle, WA 91895, USA. ; Gorilla Doctors, Karen C. Drayer Wildlife Health Center, University of California, Davis, CA 95616, USA. ; Institut de Biologia Evolutiva (CSIC/UPF), Parque de Investigacion Biomedica de Barcelona (PRBB), Barcelona, Catalonia 08003, Spain. Centro Nacional de Analisis Genomico (Parc Cientific de Barcelona), Baldiri Reixac 4, 08028 Barcelona, Spain. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK. cts@sanger.ac.uk aos21@cam.ac.uk. ; Department of Genetics, University of Cambridge, Cambridge CB2 3EH, UK. cts@sanger.ac.uk aos21@cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859046" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological ; Animals ; Biological Evolution ; DNA Copy Number Variations ; Democratic Republic of the Congo ; Endangered Species ; Female ; *Genetic Variation ; *Genome ; Gorilla gorilla/classification/*genetics/physiology ; Homozygote ; *Inbreeding ; Linkage Disequilibrium ; Male ; Mutation ; Population Dynamics ; Rwanda ; Selection, Genetic ; Sequence Analysis, DNA ; Species Specificity ; Time Factors
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  • 79
    Publication Date: 2015-06-27
    Description: Light-gated rhodopsin cation channels from chlorophyte algae have transformed neuroscience research through their use as membrane-depolarizing optogenetic tools for targeted photoactivation of neuron firing. Photosuppression of neuronal action potentials has been limited by the lack of equally efficient tools for membrane hyperpolarization. We describe anion channel rhodopsins (ACRs), a family of light-gated anion channels from cryptophyte algae that provide highly sensitive and efficient membrane hyperpolarization and neuronal silencing through light-gated chloride conduction. ACRs strictly conducted anions, completely excluding protons and larger cations, and hyperpolarized the membrane of cultured animal cells with much faster kinetics at less than one-thousandth of the light intensity required by the most efficient currently available optogenetic proteins. Natural ACRs provide optogenetic inhibition tools with unprecedented light sensitivity and temporal precision.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4764398/" 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/PMC4764398/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Govorunova, Elena G -- Sineshchekov, Oleg A -- Janz, Roger -- Liu, Xiaoqin -- Spudich, John L -- R01 GM027750/GM/NIGMS NIH HHS/ -- R01GM027750/GM/NIGMS NIH HHS/ -- R21MH098288/MH/NIMH NIH HHS/ -- S10RR022531/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):647-50. doi: 10.1126/science.aaa7484. Epub 2015 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Membrane Biology, Department of Biochemistry and Molecular Biology, University of Texas Medical School, Houston, TX 77030, USA. ; Department of Neurobiology and Anatomy, University of Texas Medical School, Houston, TX 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26113638" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chloride Channels/classification/genetics/*physiology ; Cryptophyta/genetics/*metabolism ; HEK293 Cells ; Humans ; Ion Channel Gating ; Light ; Membrane Potentials/physiology/*radiation effects ; Molecular Sequence Data ; Neural Inhibition ; Neurons/physiology/*radiation effects ; Optogenetics/*methods ; Photic Stimulation ; Phylogeny ; Rhodopsins, Microbial/classification/genetics/*physiology ; Transfection
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  • 80
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-10-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stokstad, Erik -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):266. doi: 10.1126/science.350.6258.266.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26472889" target="_blank"〉PubMed〈/a〉
    Keywords: Chemistry/*trends ; DNA/*chemistry/genetics ; *DNA Repair ; DNA Repair Enzymes/*chemistry ; Mutagenesis ; Mutation ; *Nobel Prize
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  • 81
    Publication Date: 2015-02-24
    Description: Mutations in sunlight-induced melanoma arise from cyclobutane pyrimidine dimers (CPDs), DNA photoproducts that are typically created picoseconds after an ultraviolet (UV) photon is absorbed at thymine or cytosine. We found that in melanocytes, CPDs are generated for 〉3 hours after exposure to UVA, a major component of the radiation in sunlight and in tanning beds. These "dark CPDs" constitute the majority of CPDs and include the cytosine-containing CPDs that initiate UV-signature C--〉T mutations. Dark CPDs arise when UV-induced reactive oxygen and nitrogen species combine to excite an electron in fragments of the pigment melanin. This creates a quantum triplet state that has the energy of a UV photon but induces CPDs by energy transfer to DNA in a radiation-independent manner. Melanin may thus be carcinogenic as well as protective against cancer. These findings also validate the long-standing suggestion that chemically generated excited electronic states are relevant to mammalian biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432913/" 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/PMC4432913/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Premi, Sanjay -- Wallisch, Silvia -- Mano, Camila M -- Weiner, Adam B -- Bacchiocchi, Antonella -- Wakamatsu, Kazumasa -- Bechara, Etelvino J H -- Halaban, Ruth -- Douki, Thierry -- Brash, Douglas E -- 2 P50 CA121974/CA/NCI NIH HHS/ -- P30 DK034989/DK/NIDDK NIH HHS/ -- P30 DK34989/DK/NIDDK NIH HHS/ -- P50 CA121974/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):842-7. doi: 10.1126/science.1256022.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. ; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo 05513-970 SP, Brazil. ; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA. ; Department of Chemistry, Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan. ; Departamento de Bioquimica, Instituto de Quimica, Universidade de Sao Paulo, Sao Paulo 05513-970 SP, Brazil. Departamento de Ciencias Exatas e da Terra, Universidade Federal de Sao Paulo, Diadema, Sao Paulo 09972-270 SP, Brazil. ; Department of Dermatology, Yale University School of Medicine, New Haven, CT 06520, USA. Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA. ; INAC/LCIB UMR-E3 CEA-UJF/Commissariat a l'Energie Atomique (CEA), 38054 Grenoble Cedex 9, France. ; Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520, USA. Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA. douglas.brash@yale.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700512" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cytosine/metabolism ; DNA/chemistry/genetics/*radiation effects ; DNA Damage/*genetics ; Energy Transfer ; Humans ; Melanins/chemistry/*metabolism ; Melanocytes/metabolism/*radiation effects ; Melanoma/*genetics ; Mice ; Mice, Inbred C57BL ; Mutagenesis ; Mutation ; Neoplasms, Radiation-Induced/*genetics ; Photons ; Pyrimidine Dimers/*metabolism ; Receptor, Melanocortin, Type 1/genetics ; Skin Neoplasms/*genetics ; Sunlight/adverse effects ; Thymine/metabolism ; Ultraviolet Rays
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  • 82
    Publication Date: 2015-04-04
    Description: Mammalian mitochondrial ribosomes (mitoribosomes) synthesize mitochondrially encoded membrane proteins that are critical for mitochondrial function. Here we present the complete atomic structure of the porcine 55S mitoribosome at 3.8 angstrom resolution by cryo-electron microscopy and chemical cross-linking/mass spectrometry. The structure of the 28S subunit in the complex was resolved at 3.6 angstrom resolution by focused alignment, which allowed building of a detailed atomic structure including all of its 15 mitoribosomal-specific proteins. The structure reveals the intersubunit contacts in the 55S mitoribosome, the molecular architecture of the mitoribosomal messenger RNA (mRNA) binding channel and its interaction with transfer RNAs, and provides insight into the highly specialized mechanism of mRNA recruitment to the 28S subunit. Furthermore, the structure contributes to a mechanistic understanding of aminoglycoside ototoxicity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greber, Basil J -- Bieri, Philipp -- Leibundgut, Marc -- Leitner, Alexander -- Aebersold, Ruedi -- Boehringer, Daniel -- Ban, Nenad -- New York, N.Y. -- Science. 2015 Apr 17;348(6232):303-8. doi: 10.1126/science.aaa3872. Epub 2015 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Biology, Institute of Molecular Systems Biology, Auguste-Piccard-Hof 1, ETH Zurich, CH-8093 Zurich, Switzerland. ; Department of Biology, Institute of Molecular Systems Biology, Auguste-Piccard-Hof 1, ETH Zurich, CH-8093 Zurich, Switzerland. Faculty of Science, University of Zurich, CH-8057 Zurich, Switzerland. ; Department of Biology, Institute of Molecular Biology and Biophysics, Otto-Stern-Weg 5, ETH Zurich, CH-8093 Zurich, Switzerland. ban@mol.biol.ethz.ch.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25837512" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoglycosides/chemistry ; Animals ; Anti-Bacterial Agents/chemistry ; Binding Sites ; GTP-Binding Proteins/chemistry ; Humans ; Mitochondria/*ultrastructure ; Mitochondrial Membranes/ultrastructure ; Mitochondrial Proteins/*biosynthesis/genetics ; Mutation ; Nucleic Acid Conformation ; Protein Structure, Secondary ; RNA, Messenger/chemistry ; RNA, Ribosomal, 16S/chemistry ; RNA, Transfer/chemistry ; Ribosomal Proteins/chemistry ; Ribosome Subunits, Large/chemistry/physiology/*ultrastructure ; Swine
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  • 83
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2015-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stokstad, Erik -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):170. doi: 10.1126/science.348.6231.170.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859025" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Bivalvia/genetics ; Cell Lineage ; *Leukemia/genetics ; Mutation ; *Retroelements
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  • 84
    Publication Date: 2015-07-25
    Description: Development of the cerebral cortex is influenced by sensory experience during distinct phases of postnatal development known as critical periods. Disruption of experience during a critical period produces neurons that lack specificity for particular stimulus features, such as location in the somatosensory system. Synaptic plasticity is the agent by which sensory experience affects cortical development. Here, we describe, in mice, a developmental critical period that affects plasticity itself. Transient neonatal disruption of signaling via the C-terminal domain of "disrupted in schizophrenia 1" (DISC1)-a molecule implicated in psychiatric disorders-resulted in a lack of long-term potentiation (LTP) (persistent strengthening of synapses) and experience-dependent potentiation in adulthood. Long-term depression (LTD) (selective weakening of specific sets of synapses) and reversal of LTD were present, although impaired, in adolescence and absent in adulthood. These changes may form the basis for the cognitive deficits associated with mutations in DISC1 and the delayed onset of a range of psychiatric symptoms in late adolescence.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Greenhill, Stuart D -- Juczewski, Konrad -- de Haan, Annelies M -- Seaton, Gillian -- Fox, Kevin -- Hardingham, Neil R -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 24;349(6246):424-7. doi: 10.1126/science.aaa8481.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biosciences, Cardiff University, Cardiff, CF23 3AX, UK. ; National Institute on Alcohol Abuse and Alcoholism, NIH, Rockville, MD 20852, USA. ; School of Biosciences, Cardiff University, Cardiff, CF23 3AX, UK. sbinrh@cardiff.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26206934" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Animals ; Cerebral Cortex/*growth & development/physiopathology ; Cognition Disorders/genetics/physiopathology ; Long-Term Potentiation/drug effects/*genetics ; Mental Disorders/*genetics/physiopathology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins/*genetics ; Neuronal Plasticity/drug effects/*genetics ; Synapses/drug effects/physiology ; Tamoxifen/pharmacology
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  • 85
    Publication Date: 2015-06-06
    Description: The detailed molecular interactions between native HIV-1 capsid protein (CA) hexamers that shield the viral genome and proteins have been elusive. We report crystal structures describing interactions between CA monomers related by sixfold symmetry within hexamers (intrahexamer) and threefold and twofold symmetry between neighboring hexamers (interhexamer). The structures describe how CA builds hexagonal lattices, the foundation of mature capsids. Lattice structure depends on an adaptable hydration layer modulating interactions among CA molecules. Disruption of this layer alters interhexamer interfaces, highlighting an inherent structural variability. A CA-targeting antiviral affects capsid stability by binding across CA molecules and subtly altering interhexamer interfaces remote to the ligand-binding site. Inherent structural plasticity, hydration layer rearrangement, and effector binding affect capsid stability and have functional implications for the retroviral life cycle.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4584149/" 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/PMC4584149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gres, Anna T -- Kirby, Karen A -- KewalRamani, Vineet N -- Tanner, John J -- Pornillos, Owen -- Sarafianos, Stefan G -- AI076119/AI/NIAID NIH HHS/ -- AI099284/AI/NIAID NIH HHS/ -- AI100890/AI/NIAID NIH HHS/ -- AI112417/AI/NIAID NIH HHS/ -- AI120860/AI/NIAID NIH HHS/ -- GM066087/GM/NIGMS NIH HHS/ -- GM103368/GM/NIGMS NIH HHS/ -- P50 GM103368/GM/NIGMS NIH HHS/ -- R01 AI076119/AI/NIAID NIH HHS/ -- R01 AI099284/AI/NIAID NIH HHS/ -- R01 AI100890/AI/NIAID NIH HHS/ -- R01 AI120860/AI/NIAID NIH HHS/ -- R01 GM066087/GM/NIGMS NIH HHS/ -- R21 AI112417/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 3;349(6243):99-103. doi: 10.1126/science.aaa5936. Epub 2015 Jun 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. ; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA. ; Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA. ; Department of Chemistry, University of Missouri, Columbia, MO 65211, USA. Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA. ; Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA 22908, USA. ; Christopher S. Bond Life Sciences Center, University of Missouri, Columbia, MO 65211, USA. Department of Molecular Microbiology and Immunology, University of Missouri School of Medicine, Columbia, MO 65211, USA. Department of Biochemistry, University of Missouri, Columbia, MO 65211, USA. sarafianoss@missouri.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26044298" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Capsid/*chemistry ; Crystallography, X-Ray ; HIV-1/*chemistry/genetics ; Molecular Sequence Data ; Protein Multimerization ; Protein Structure, Secondary ; gag Gene Products, Human Immunodeficiency Virus/*chemistry/genetics
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  • 86
    Publication Date: 2015-04-25
    Description: In cells, biosynthetic machinery coordinates protein synthesis and folding to optimize efficiency and minimize off-pathway outcomes. However, it has been difficult to delineate experimentally the mechanisms responsible. Using fluorescence resonance energy transfer, we studied cotranslational folding of the first nucleotide-binding domain from the cystic fibrosis transmembrane conductance regulator. During synthesis, folding occurred discretely via sequential compaction of N-terminal, alpha-helical, and alpha/beta-core subdomains. Moreover, the timing of these events was critical; premature alpha-subdomain folding prevented subsequent core formation. This process was facilitated by modulating intrinsic folding propensity in three distinct ways: delaying alpha-subdomain compaction, facilitating beta-strand intercalation, and optimizing translation kinetics via codon usage. Thus, de novo folding is translationally tuned by an integrated cellular response that shapes the cotranslational folding landscape at critical stages of synthesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Soo Jung -- Yoon, Jae Seok -- Shishido, Hideki -- Yang, Zhongying -- Rooney, LeeAnn A -- Barral, Jose M -- Skach, William R -- P30CA069533/CA/NCI NIH HHS/ -- P30EYE010572/PHS HHS/ -- R01DK51818/DK/NIDDK NIH HHS/ -- R01GM53457/GM/NIGMS NIH HHS/ -- S10OD012246/OD/NIH HHS/ -- S10RR025571/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Apr 24;348(6233):444-8. doi: 10.1126/science.aaa3974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biology, Oregon Health and Science University (OHSU), Portland, OR 97239, USA. ; Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77550-0620, USA. Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77550-0620, USA. ; Department of Biochemistry and Molecular Biology, Oregon Health and Science University (OHSU), Portland, OR 97239, USA. Cystic Fibrosis Foundation Therapeutics, Bethesda, MD 20814, USA. skachw@ohsu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25908822" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Codon/chemistry/*metabolism ; Cystic Fibrosis Transmembrane Conductance ; Regulator/*biosynthesis/*chemistry/genetics ; Fluorescence Resonance Energy Transfer ; Humans ; Kinetics ; Molecular Sequence Data ; *Peptide Chain Elongation, Translational ; *Protein Folding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Ribosomes/chemistry/metabolism
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  • 87
    Publication Date: 2015-01-24
    Description: Chemokines and their receptors control cell migration during development, immune system responses, and in numerous diseases, including inflammation and cancer. The structural basis of receptor:chemokine recognition has been a long-standing unanswered question due to the challenges of structure determination for membrane protein complexes. Here, we report the crystal structure of the chemokine receptor CXCR4 in complex with the viral chemokine antagonist vMIP-II at 3.1 angstrom resolution. The structure revealed a 1:1 stoichiometry and a more extensive binding interface than anticipated from the paradigmatic two-site model. The structure helped rationalize a large body of mutagenesis data and together with modeling provided insights into CXCR4 interactions with its endogenous ligand CXCL12, its ability to recognize diverse ligands, and the specificity of CC and CXC receptors for their respective chemokines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4362693/" 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/PMC4362693/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Qin, Ling -- Kufareva, Irina -- Holden, Lauren G -- Wang, Chong -- Zheng, Yi -- Zhao, Chunxia -- Fenalti, Gustavo -- Wu, Huixian -- Han, Gye Won -- Cherezov, Vadim -- Abagyan, Ruben -- Stevens, Raymond C -- Handel, Tracy M -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- R01 GM071872/GM/NIGMS NIH HHS/ -- R01 GM081763/GM/NIGMS NIH HHS/ -- R21 AI101687/AI/NIAID NIH HHS/ -- U01 GM094612/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Mar 6;347(6226):1117-22. doi: 10.1126/science.1261064. Epub 2015 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. ; University of California, San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA 92093, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu. ; Department of Integrative Structural and Computational Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. ; Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. ; Department of Chemistry, Bridge Institute. ; Department of Chemistry, Bridge Institute. Department of Biological Sciences, Bridge Institute, University of Southern California, Los Angeles, CA 90089, USA. thandel@ucsd.edu stevens@usc.edu ikufareva@ucsd.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612609" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chemokine CXCL12/chemistry ; Chemokines/*chemistry ; Crystallography, X-Ray ; Drug Design ; Humans ; Models, Chemical ; Molecular Sequence Data ; Protein Binding ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Receptors, CXCR4/agonists/antagonists & inhibitors/*chemistry ; Structural Homology, Protein
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  • 88
    Publication Date: 2015-08-01
    Description: The inefficient clearance of dying cells can lead to abnormal immune responses, such as unresolved inflammation and autoimmune conditions. We show that tumor suppressor p53 controls signaling-mediated phagocytosis of apoptotic cells through its target, Death Domain1alpha (DD1alpha), which suggests that p53 promotes both the proapoptotic pathway and postapoptotic events. DD1alpha appears to function as an engulfment ligand or receptor that engages in homophilic intermolecular interaction at intercellular junctions of apoptotic cells and macrophages, unlike other typical scavenger receptors that recognize phosphatidylserine on the surface of dead cells. DD1alpha-deficient mice showed in vivo defects in clearing dying cells, which led to multiple organ damage indicative of immune dysfunction. p53-induced expression of DD1alpha thus prevents persistence of cell corpses and ensures efficient generation of precise immune responses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoon, Kyoung Wan -- Byun, Sanguine -- Kwon, Eunjeong -- Hwang, So-Young -- Chu, Kiki -- Hiraki, Masatsugu -- Jo, Seung-Hee -- Weins, Astrid -- Hakroush, Samy -- Cebulla, Angelika -- Sykes, David B -- Greka, Anna -- Mundel, Peter -- Fisher, David E -- Mandinova, Anna -- Lee, Sam W -- CA142805/CA/NCI NIH HHS/ -- CA149477/CA/NCI NIH HHS/ -- CA80058/CA/NCI NIH HHS/ -- DK062472/DK/NIDDK NIH HHS/ -- DK091218/DK/NIDDK NIH HHS/ -- DK093378/DK/NIDDK NIH HHS/ -- DK57683/DK/NIDDK NIH HHS/ -- S10RR027673/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 31;349(6247):1261669. doi: 10.1126/science.1261669.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. ; Department of Pathology, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. ; Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA. ; Center for Regenerative Medicine and Technology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA. ; Department of Medicine, Glom-NExT Center for Glomerular Kidney Disease and Novel Experimental Therapeutics, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA. ; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Building 149, 13th Street, Charlestown, MA 02129, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. swlee@mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26228159" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Apoptosis/genetics/*immunology ; Autoimmune Diseases/genetics/immunology ; Cell Line, Tumor ; Female ; Humans ; Inflammation/genetics/immunology ; Macrophages/immunology ; Male ; Membrane Proteins/genetics/*metabolism ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Phagocytosis/*immunology ; Phosphatidylserines/*metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/*metabolism
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  • 89
    Publication Date: 2015-01-24
    Description: The root meristem consists of populations of distal and proximal stem cells and an organizing center known as the quiescent center. During embryogenesis, initiation of the root meristem occurs when an asymmetric cell division of the hypophysis forms the distal stem cells and quiescent center. We have identified NO TRANSMITTING TRACT (NTT) and two closely related paralogs as being required for the initiation of the root meristem. All three genes are expressed in the hypophysis, and their expression is dependent on the auxin-signaling pathway. Expression of these genes is necessary for distal stem cell fate within the root meristem, whereas misexpression is sufficient to transform other stem cell populations to a distal stem cell fate in both the embryo and mature roots.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Crawford, Brian C W -- Sewell, Jared -- Golembeski, Greg -- Roshan, Carmel -- Long, Jeff A -- Yanofsky, Martin F -- 5 R01 GM072764/GM/NIGMS NIH HHS/ -- R01 GM072764/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 6;347(6222):655-9. doi: 10.1126/science.aaa0196. Epub 2015 Jan 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. ; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA. ; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA 90095, USA. marty@ucsd.edu jeffalong@ucla.edu. ; Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA. marty@ucsd.edu jeffalong@ucla.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25612610" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/embryology/genetics ; Arabidopsis Proteins/genetics/*physiology ; *Gene Expression Regulation, Developmental ; *Gene Expression Regulation, Plant ; Indoleacetic Acids/pharmacology ; Meristem/cytology/*embryology ; Mutation ; Plant Development/*genetics ; Stem Cells/cytology/drug effects/*physiology ; Transcription Factors/genetics/*physiology
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  • 90
    Publication Date: 2015-09-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zahn, Laura M -- Travis, John -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):1470-1. doi: 10.1126/science.349.6255.1470.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404821" target="_blank"〉PubMed〈/a〉
    Keywords: *DNA Mutational Analysis ; Disease/*genetics ; Great Britain ; Humans ; Mutation
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  • 91
    Publication Date: 2015-09-01
    Description: The nuclear pore complex (NPC) constitutes the sole gateway for bidirectional nucleocytoplasmic transport. We present the reconstitution and interdisciplinary analyses of the ~425-kilodalton inner ring complex (IRC), which forms the central transport channel and diffusion barrier of the NPC, revealing its interaction network and equimolar stoichiometry. The Nsp1*Nup49*Nup57 channel nucleoporin heterotrimer (CNT) attaches to the IRC solely through the adaptor nucleoporin Nic96. The CNT*Nic96 structure reveals that Nic96 functions as an assembly sensor that recognizes the three-dimensional architecture of the CNT, thereby mediating the incorporation of a defined CNT state into the NPC. We propose that the IRC adopts a relatively rigid scaffold that recruits the CNT to primarily form the diffusion barrier of the NPC, rather than enabling channel dilation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stuwe, Tobias -- Bley, Christopher J -- Thierbach, Karsten -- Petrovic, Stefan -- Schilbach, Sandra -- Mayo, Daniel J -- Perriches, Thibaud -- Rundlet, Emily J -- Jeon, Young E -- Collins, Leslie N -- Huber, Ferdinand M -- Lin, Daniel H -- Paduch, Marcin -- Koide, Akiko -- Lu, Vincent -- Fischer, Jessica -- Hurt, Ed -- Koide, Shohei -- Kossiakoff, Anthony A -- Hoelz, Andre -- ACB-12002/PHS HHS/ -- AGM-12006/PHS HHS/ -- P30-CA014599/CA/NCI NIH HHS/ -- R01-GM090324/GM/NIGMS NIH HHS/ -- R01-GM111461/GM/NIGMS NIH HHS/ -- U01-GM094588/GM/NIGMS NIH HHS/ -- U54-GM087519/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):56-64. doi: 10.1126/science.aac9176. Epub 2015 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉California Institute of Technology, Division of Chemistry and Chemical Engineering, 1200 East California Boulevard, Pasadena, CA 91125, USA. ; Department of Biochemistry and Molecular Biology, The University of Chicago, Chicago, IL 60637, USA. ; Biochemistry Center of Heidelberg University, 69120 Heidelberg, Germany. ; California Institute of Technology, Division of Chemistry and Chemical Engineering, 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/26316600" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Chaetomium/metabolism/*ultrastructure ; Fungal Proteins/chemistry/*ultrastructure ; Molecular Sequence Data ; Nuclear Pore/metabolism/*ultrastructure ; Nuclear Pore Complex Proteins/chemistry/*ultrastructure ; Nuclear Proteins/chemistry/*ultrastructure ; Protein Binding ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary
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  • 92
    Publication Date: 2015-09-19
    Description: A wide variety of RNAs encode small open-reading-frame (smORF/sORF) peptides, but their functions are largely unknown. Here, we show that Drosophila polished-rice (pri) sORF peptides trigger proteasome-mediated protein processing, converting the Shavenbaby (Svb) transcription repressor into a shorter activator. A genome-wide RNA interference screen identifies an E2-E3 ubiquitin-conjugating complex, UbcD6-Ubr3, which targets Svb to the proteasome in a pri-dependent manner. Upon interaction with Ubr3, Pri peptides promote the binding of Ubr3 to Svb. Ubr3 can then ubiquitinate the Svb N terminus, which is degraded by the proteasome. The C-terminal domains protect Svb from complete degradation and ensure appropriate processing. Our data show that Pri peptides control selectivity of Ubr3 binding, which suggests that the family of sORF peptides may contain an extended repertoire of protein regulators.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanet, J -- Benrabah, E -- Li, T -- Pelissier-Monier, A -- Chanut-Delalande, H -- Ronsin, B -- Bellen, H J -- Payre, F -- Plaza, S -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1356-8. doi: 10.1126/science.aac5677.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre de Biologie du Developpement, Universite de Toulouse III-Paul Sabatier, Batiment 4R3, 118 route de Narbonne, F-31062 Toulouse, France. CNRS, UMR5547, Centre de Biologie du Developpement, F-31062 Toulouse, France. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Howard Hughes Medical Institute, Neurological Research Institute, Baylor College of Medicine, Houston, TX 77030, USA. ; Centre de Biologie du Developpement, Universite de Toulouse III-Paul Sabatier, Batiment 4R3, 118 route de Narbonne, F-31062 Toulouse, France. CNRS, UMR5547, Centre de Biologie du Developpement, F-31062 Toulouse, France. francois.payre@univ-tlse3.fr serge.plaza@univ-tlse3.f.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383956" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; DNA-Binding Proteins/chemistry/genetics/*metabolism ; Drosophila Proteins/chemistry/genetics/*metabolism ; Drosophila melanogaster/enzymology/genetics/*metabolism ; Gene Expression Regulation ; Molecular Sequence Data ; Open Reading Frames ; Peptides/genetics/*metabolism ; Proteasome Endopeptidase Complex/*metabolism ; Protein Structure, Tertiary ; *Proteolysis ; RNA Interference ; Transcription Factors/chemistry/genetics/*metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitination
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  • 93
    Publication Date: 2015-01-31
    Description: Translocator proteins (TSPOs) bind steroids and porphyrins, and they are implicated in many human diseases, for which they serve as biomarkers and therapeutic targets. TSPOs have tryptophan-rich sequences that are highly conserved from bacteria to mammals. Here we report crystal structures for Bacillus cereus TSPO (BcTSPO) down to 1.7 A resolution, including a complex with the benzodiazepine-like inhibitor PK11195. We also describe BcTSPO-mediated protoporphyrin IX (PpIX) reactions, including catalytic degradation to a previously undescribed heme derivative. We used structure-inspired mutations to investigate reaction mechanisms, and we showed that TSPOs from Xenopus and man have similar PpIX-directed activities. Although TSPOs have been regarded as transporters, the catalytic activity in PpIX degradation suggests physiological importance for TSPOs in protection against oxidative stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4341906/" 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/PMC4341906/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Youzhong -- Kalathur, Ravi C -- Liu, Qun -- Kloss, Brian -- Bruni, Renato -- Ginter, Christopher -- Kloppmann, Edda -- Rost, Burkhard -- Hendrickson, Wayne A -- GM095315/GM/NIGMS NIH HHS/ -- GM107462/GM/NIGMS NIH HHS/ -- R01 GM107462/GM/NIGMS NIH HHS/ -- U54 GM075026/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):551-5. doi: 10.1126/science.aaa1534.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA. ; The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. Department of Informatics, Bioinformatics and Computational Biology, Technische Universitat Munchen, Garching 85748, Germany. ; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. The New York Consortium on Membrane Protein Structure (NYCOMPS), New York Structural Biology Center, 89 Convent Avenue, New York, NY 10027, USA. New York Structural Biology Center, Synchrotron Beamlines, Brookhaven National Laboratory, Upton, NY 11973, USA. Department of Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA. wayne@xtl.cumc.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635100" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Bacillus cereus/*chemistry ; Bacterial Proteins/*chemistry/*metabolism ; Binding Sites ; Crystallography, X-Ray ; Isoquinolines/metabolism ; Ligands ; Membrane Transport Proteins/*chemistry/*metabolism ; Molecular Sequence Data ; Mutant Proteins/chemistry/metabolism ; Protein Conformation ; Protein Multimerization ; Protein Structure, Secondary ; Protein Subunits/chemistry ; Protoporphyrins/metabolism ; Reactive Oxygen Species/metabolism ; Tryptophan/analysis
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  • 94
    Publication Date: 2015-05-09
    Description: In the fruit fly Drosophila, head formation is driven by a single gene, bicoid, which generates head-to-tail polarity of the main embryonic axis. Bicoid deficiency results in embryos with tail-to-tail polarity and no head. However, most insects lack bicoid, and the molecular mechanism for establishing head-to-tail polarity is poorly understood. We have identified a gene that establishes head-to-tail polarity of the mosquito-like midge, Chironomus riparius. This gene, named panish, encodes a cysteine-clamp DNA binding domain and operates through a different mechanism than bicoid. This finding, combined with the observation that the phylogenetic distributions of panish and bicoid are limited to specific families of flies, reveals frequent evolutionary changes of body axis determinants and a remarkable opportunity to study gene regulatory network evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449817/" 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/PMC4449817/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klomp, Jeff -- Athy, Derek -- Kwan, Chun Wai -- Bloch, Natasha I -- Sandmann, Thomas -- Lemke, Steffen -- Schmidt-Ott, Urs -- 1R03HD67700-01A1/HD/NICHD NIH HHS/ -- R03 HD067700/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2015 May 29;348(6238):1040-2. doi: 10.1126/science.aaa7105. Epub 2015 May 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, USA. ; Division of Signaling and Functional Genomics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Organismal Biology and Anatomy, University of Chicago, Chicago, IL 60637, USA. uschmid@uchicago.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25953821" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Body Patterning/*genetics ; Chironomidae/*embryology/genetics ; DNA-Binding Proteins/classification/genetics/*physiology ; Embryo, Nonmammalian/*embryology ; Evolution, Molecular ; Gene Expression Regulation, Developmental ; Gene Regulatory Networks ; Homeodomain Proteins/classification/genetics/*physiology ; Molecular Sequence Data ; Phylogeny ; Protein Structure, Tertiary/genetics ; Trans-Activators/classification/genetics/*physiology
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  • 95
    Publication Date: 2015-04-18
    Description: Measles is a highly contagious human disease. We used cryo-electron microscopy and single particle-based helical image analysis to determine the structure of the helical nucleocapsid formed by the folded domain of the measles virus nucleoprotein encapsidating an RNA at a resolution of 4.3 angstroms. The resulting pseudoatomic model of the measles virus nucleocapsid offers important insights into the mechanism of the helical polymerization of nucleocapsids of negative-strand RNA viruses, in particular via the exchange subdomains of the nucleoprotein. The structure reveals the mode of the nucleoprotein-RNA interaction and explains why each nucleoprotein of measles virus binds six nucleotides, whereas the respiratory syncytial virus nucleoprotein binds seven. It provides a rational basis for further analysis of measles virus replication and transcription, and reveals potential targets for drug design.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gutsche, Irina -- Desfosses, Ambroise -- Effantin, Gregory -- Ling, Wai Li -- Haupt, Melina -- Ruigrok, Rob W H -- Sachse, Carsten -- Schoehn, Guy -- New York, N.Y. -- Science. 2015 May 8;348(6235):704-7. doi: 10.1126/science.aaa5137. Epub 2015 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. gutsche@embl.fr. ; Structural and Computational Biology Unit, European Molecular Biology Laboratory, 69917 Heidelberg, Germany. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. ; Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France. ; Institut Laue-Langevin, 38000 Grenoble, France. ; CNRS, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, Unit for Virus Host-Cell Interactions, 38042 Grenoble, France. Universite Grenoble Alpes, IBS, 38044 Grenoble, France. CNRS, IBS, 38044 Grenoble, France. CEA, IBS, 38044 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25883315" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cryoelectron Microscopy ; Humans ; Measles/*virology ; Measles virus/chemistry/*ultrastructure ; Molecular Sequence Data ; Nucleic Acid Conformation ; Nucleocapsid/chemistry/*ultrastructure ; Nucleoproteins/chemistry/ultrastructure ; Protein Structure, Secondary ; RNA, Viral/chemistry/ultrastructure ; Viral Proteins/chemistry/ultrastructure
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  • 96
    Publication Date: 2015-11-21
    Description: Eukaryotic cells coordinate growth with the availability of nutrients through the mechanistic target of rapamycin complex 1 (mTORC1), a master growth regulator. Leucine is of particular importance and activates mTORC1 via the Rag guanosine triphosphatases and their regulators GATOR1 and GATOR2. Sestrin2 interacts with GATOR2 and is a leucine sensor. Here we present the 2.7 angstrom crystal structure of Sestrin2 in complex with leucine. Leucine binds through a single pocket that coordinates its charged functional groups and confers specificity for the hydrophobic side chain. A loop encloses leucine and forms a lid-latch mechanism required for binding. A structure-guided mutation in Sestrin2 that decreases its affinity for leucine leads to a concomitant increase in the leucine concentration required for mTORC1 activation in cells. These results provide a structural mechanism of amino acid sensing by the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698039/" 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/PMC4698039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saxton, Robert A -- Knockenhauer, Kevin E -- Wolfson, Rachel L -- Chantranupong, Lynne -- Pacold, Michael E -- Wang, Tim -- Schwartz, Thomas U -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA189333/CA/NCI NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- F31 CA189437/CA/NCI NIH HHS/ -- P41 GM103403/GM/NIGMS NIH HHS/ -- R01 AI047389/AI/NIAID NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01CA103866/CA/NCI NIH HHS/ -- S10 RR029205/RR/NCRR NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):53-8. doi: 10.1126/science.aad2087. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. ; Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA. Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA. Howard Hughes Medical Institute, Department of Biology, MIT, Cambridge, MA 02139, USA. Koch Institute for Integrative Cancer Research, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA. sabatini@wi.mit.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586190" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Binding Sites ; Crystallography, X-Ray ; HEK293 Cells ; Humans ; Leucine/*chemistry/metabolism ; Metabolic Networks and Pathways ; Molecular Sequence Data ; Multiprotein Complexes/chemistry/genetics/*metabolism ; Mutation ; Nuclear Proteins/*chemistry/metabolism ; Protein Binding ; Protein Structure, Secondary ; Protein Structure, Tertiary ; TOR Serine-Threonine Kinases/chemistry/genetics/*metabolism
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  • 97
    Publication Date: 2014-04-12
    Description: Plant embryogenesis initiates with the establishment of an apical-basal axis; however, the molecular mechanisms accompanying this early event remain unclear. Here, we show that a small cysteine-rich peptide family is required for formation of the zygotic basal cell lineage and proembryo patterning in Arabidopsis. EMBRYO SURROUNDING FACTOR 1 (ESF1) peptides accumulate before fertilization in central cell gametes and thereafter in embryo-surrounding endosperm cells. Biochemical and structural analyses revealed cleavage of ESF1 propeptides to form biologically active mature peptides. Further, these peptides act in a non-cell-autonomous manner and synergistically with the receptor-like kinase SHORT SUSPENSOR to promote suspensor elongation through the YODA mitogen-activated protein kinase pathway. Our findings demonstrate that the second female gamete and its sexually derived endosperm regulate early embryonic patterning in flowering plants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Costa, Liliana M -- Marshall, Eleanor -- Tesfaye, Mesfin -- Silverstein, Kevin A T -- Mori, Masashi -- Umetsu, Yoshitaka -- Otterbach, Sophie L -- Papareddy, Ranjith -- Dickinson, Hugh G -- Boutiller, Kim -- VandenBosch, Kathryn A -- Ohki, Shinya -- Gutierrez-Marcos, Jose F -- BB/F008082/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L003023/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/L003023/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Apr 11;344(6180):168-72. doi: 10.1126/science.1243005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Sciences, University of Oxford, South Parks Road, OX1 3RB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24723605" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/*embryology/genetics ; Arabidopsis Proteins/chemistry/genetics/*metabolism ; *Body Patterning ; Endosperm/embryology/genetics ; Flowers/*embryology/genetics ; Gene Duplication ; Gene Expression Regulation, Developmental ; Gene Expression Regulation, Plant ; Gene Knockout Techniques ; Interleukin-1 Receptor-Associated Kinases/metabolism ; MAP Kinase Kinase Kinases/metabolism ; Molecular Sequence Data ; Peptides/chemistry/genetics/metabolism ; Seeds/*embryology/genetics
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  • 98
    Publication Date: 2014-05-17
    Description: A switchlike response in nuclear factor-kappaB (NF-kappaB) activity implies the existence of a threshold in the NF-kappaB signaling module. We show that the CARD-containing MAGUK protein 1 (CARMA1, also called CARD11)-TAK1 (MAP3K7)-inhibitor of NF-kappaB (IkappaB) kinase-beta (IKKbeta) module is a switch mechanism for NF-kappaB activation in B cell receptor (BCR) signaling. Experimental and mathematical modeling analyses showed that IKK activity is regulated by positive feedback from IKKbeta to TAK1, generating a steep dose response to BCR stimulation. Mutation of the scaffolding protein CARMA1 at serine-578, an IKKbeta target, abrogated not only late TAK1 activity, but also the switchlike activation of NF-kappaB in single cells, suggesting that phosphorylation of this residue accounts for the feedback.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shinohara, Hisaaki -- Behar, Marcelo -- Inoue, Kentaro -- Hiroshima, Michio -- Yasuda, Tomoharu -- Nagashima, Takeshi -- Kimura, Shuhei -- Sanjo, Hideki -- Maeda, Shiori -- Yumoto, Noriko -- Ki, Sewon -- Akira, Shizuo -- Sako, Yasushi -- Hoffmann, Alexander -- Kurosaki, Tomohiro -- Okada-Hatakeyama, Mariko -- 5R01CA141722/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 May 16;344(6185):760-4. doi: 10.1126/science.1250020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ; Laboratory for Cell Signaling Dynamics, RIKEN Quantitative Biology Center (QBiC), 6-2-3, Furuedai, Suita, Osaka 565-0874, Japan. Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ; Graduate School of Engineering, Tottori University 4-101, Koyama-minami, Tottori 680-8552, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ; Cellular Informatics Laboratory, RIKEN, 2-1 Hirosawa, Wako 351-0198, Japan. ; Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA. Institute for Quantitative and Computational Biosciences (QC Bio) and Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. Laboratory for Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp. ; Laboratory for Integrated Cellular Systems, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan. ahoffmann@ucla.edu kurosaki@rcai.riken.jp marikoh@rcai.riken.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833394" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/metabolism ; CARD Signaling Adaptor Proteins/genetics/*metabolism ; Cell Line ; Chickens ; Feedback, Physiological ; Guanylate Cyclase/genetics/*metabolism ; I-kappa B Kinase/*metabolism ; MAP Kinase Kinase Kinases/genetics/*metabolism ; Mice ; Mice, Knockout ; Mutation ; NF-kappa B/*agonists ; Phosphorylation ; Receptors, Antigen, B-Cell/genetics/*metabolism ; Serine/genetics/metabolism ; Signal Transduction
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  • 99
    Publication Date: 2014-03-29
    Description: The field of optogenetics uses channelrhodopsins (ChRs) for light-induced neuronal activation. However, optimized tools for cellular inhibition at moderate light levels are lacking. We found that replacement of E90 in the central gate of ChR with positively charged residues produces chloride-conducting ChRs (ChloCs) with only negligible cation conductance. Molecular dynamics modeling unveiled that a high-affinity Cl(-)-binding site had been generated near the gate. Stabilizing the open state dramatically increased the operational light sensitivity of expressing cells (slow ChloC). In CA1 pyramidal cells, ChloCs completely inhibited action potentials triggered by depolarizing current injections or synaptic stimulation. Thus, by inverting the charge of the selectivity filter, we have created a class of directly light-gated anion channels that can be used to block neuronal output in a fully reversible fashion.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wietek, Jonas -- Wiegert, J Simon -- Adeishvili, Nona -- Schneider, Franziska -- Watanabe, Hiroshi -- Tsunoda, Satoshi P -- Vogt, Arend -- Elstner, Marcus -- Oertner, Thomas G -- Hegemann, Peter -- New York, N.Y. -- Science. 2014 Apr 25;344(6182):409-12. doi: 10.1126/science.1249375. Epub 2014 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Biology, Experimental Biophysics, Humboldt Universitat zu Berlin, D-10115 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24674867" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Binding Sites ; CA1 Region, Hippocampal/cytology ; Chloride Channels/*chemistry/*metabolism ; Chlorides/*metabolism ; HEK293 Cells ; Humans ; Hydrogen Bonding ; Ion Channel Gating ; Light ; Models, Molecular ; Molecular Dynamics Simulation ; Mutation ; Patch-Clamp Techniques ; Protein Conformation ; Protein Engineering ; Pyramidal Cells/metabolism ; Rats ; Recombinant Fusion Proteins/chemistry ; Rhodopsin/*chemistry/genetics/*metabolism ; Transfection
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  • 100
    Publication Date: 2014-09-23
    Description: Ribonucleotide reductase (RNR) supplies the balanced pools of deoxynucleotide triphosphates (dNTPs) necessary for DNA replication and maintenance of genomic integrity. RNR is subject to allosteric regulatory mechanisms in all eukaryotes, as well as to control by small protein inhibitors Sml1p and Spd1p in budding and fission yeast, respectively. Here, we show that the metazoan protein IRBIT forms a deoxyadenosine triphosphate (dATP)-dependent complex with RNR, which stabilizes dATP in the activity site of RNR and thus inhibits the enzyme. Formation of the RNR-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. We demonstrate a mechanism for RNR regulation in higher eukaryotes that acts by enhancing allosteric RNR inhibition by dATP.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnaoutov, Alexei -- Dasso, Mary -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1512-5. doi: 10.1126/science.1251550.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA. arnaouta@mail.nih.gov. ; Laboratory of Gene Regulation and Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development, 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/25237103" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Regulation ; Amino Acid Sequence ; Catalytic Domain ; Deoxyadenine Nucleotides/*metabolism ; HeLa Cells ; Humans ; Immunoprecipitation ; Lectins, C-Type/genetics/*metabolism ; Membrane Proteins/genetics/*metabolism ; Molecular Sequence Data ; Phosphorylation ; Ribonucleotide Reductases/*antagonists & inhibitors/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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