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  • Signal Transduction  (1,508)
  • Cells, Cultured  (1,353)
  • American Association for the Advancement of Science (AAAS)  (2,717)
  • American Institute of Physics (AIP)
  • Springer
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  • 1
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    [This Week in Science] Tugging on Notch receptor tunes signaling (2017)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2017-03-25
    Description: Author: L. Bryan Ray
    Keywords: Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    [This Week in Science] How hypoxia controls the kinase Akt (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-09-03
    Description: Author: L. Bryan Ray
    Keywords: Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    [This Week in Science] The secrets of making signaling responsive (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-05-20
    Description: Author: L. Bryan Ray
    Keywords: Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 4
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    [This Week in Science] Phase separation organizes signaling (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-04-29
    Description: Author: L. Bryan Ray
    Keywords: Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 5
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    Sequential ionic and conformational signaling by calcium channels drives neuronal gene expression (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Voltage-gated CaV1.2 channels (L-type calcium channel alpha1C subunits) are critical mediators of transcription-dependent neural plasticity. Whether these channels signal via the influx of calcium ion (Ca(2+)), voltage-dependent conformational change (VDeltaC), or a combination of the two has thus far been equivocal. We fused CaV1.2 to a ligand-gated Ca(2+)-permeable channel, enabling independent control of localized Ca(2+) and VDeltaC signals. This revealed an unexpected dual requirement: Ca(2+) must first mobilize actin-bound Ca(2+)/calmodulin-dependent protein kinase II, freeing it for subsequent VDeltaC-mediated accumulation. Neither signal alone sufficed to activate transcription. Signal order was crucial: Efficiency peaked when Ca(2+) preceded VDeltaC by 10 to 20 seconds. CaV1.2 VDeltaC synergistically augmented signaling by N-methyl-d-aspartate receptors. Furthermore, VDeltaC mistuning correlated with autistic symptoms in Timothy syndrome. Thus, nonionic VDeltaC signaling is vital to the function of CaV1.2 in synaptic and neuropsychiatric processes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Boxing -- Tadross, Michael R -- Tsien, Richard W -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):863-7. doi: 10.1126/science.aad3647.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. ; Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA. Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, VA 20147, USA. tadrossm@janelia.hhmi.org. ; Department of Neuroscience and Physiology and New York University Neuroscience Institute, New York, NY 10016, USA. Department of Molecular and Cellular Physiology, Beckman Center, School of Medicine, Stanford University, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912895" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/genetics/metabolism ; Calcium Channel Blockers/pharmacology ; Calcium Channels, L-Type/chemistry/*metabolism ; *Calcium Signaling ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism ; Cells, Cultured ; Cyclic AMP Response Element-Binding Protein/metabolism ; *Gene Expression Regulation ; HEK293 Cells ; Hippocampus/cytology ; Humans ; Long QT Syndrome/genetics/metabolism ; Neuronal Plasticity/*genetics ; Neurons/drug effects/*metabolism ; Nimodipine/pharmacology ; Protein Conformation/drug effects ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate/metabolism ; Synapses/metabolism ; Syndactyly/genetics/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 6
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    Lineage-specific enhancers activate self-renewal genes in macrophages and embryonic stem cells (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-23
    Description: Differentiated macrophages can self-renew in tissues and expand long term in culture, but the gene regulatory mechanisms that accomplish self-renewal in the differentiated state have remained unknown. Here we show that in mice, the transcription factors MafB and c-Maf repress a macrophage-specific enhancer repertoire associated with a gene network that controls self-renewal. Single-cell analysis revealed that, in vivo, proliferating resident macrophages can access this network by transient down-regulation of Maf transcription factors. The network also controls embryonic stem cell self-renewal but is associated with distinct embryonic stem cell-specific enhancers. This indicates that distinct lineage-specific enhancer platforms regulate a shared network of genes that control self-renewal potential in both stem and mature cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucie, Erinn L -- Weng, Ziming -- Geirsdottir, Laufey -- Molawi, Kaaweh -- Maurizio, Julien -- Fenouil, Romain -- Mossadegh-Keller, Noushine -- Gimenez, Gregory -- VanHille, Laurent -- Beniazza, Meryam -- Favret, Jeremy -- Berruyer, Carole -- Perrin, Pierre -- Hacohen, Nir -- Andrau, J-C -- Ferrier, Pierre -- Dubreuil, Patrice -- Sidow, Arend -- Sieweke, Michael H -- P01AG036695/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):aad5510. doi: 10.1126/science.aad5510. Epub 2016 Jan 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. ; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Institut de Genetique Moleculaire de Montpellier, CNRS UMR 5535, 1919 Route de Mende, 34293 Montpellier, France. ; Centre de Recherche en Cancerologie de Marseille, INSERM (U1068), CNRS (U7258), Universite Aix-Marseille (UM105), Marseille, France. ; Department of Pathology, Stanford University, Stanford, CA 94305-5324, USA. Department of Genetics, Stanford University, Stanford, CA 94305, USA. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu. ; Centre d'Immunologie de Marseille-Luminy, Universite Aix-Marseille, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France. INSERM, U1104, Marseille, France. CNRS, UMR 7280, Marseille, France. Max-Delbruck-Centrum fur Molekulare Medizin in der Helmholtz-Gemeinschaft, 10 Robert-Rossle-Strasse, 13125 Berlin, Germany. sieweke@ciml.univ-mrs.fr erinn.soucie@inserm.fr arend@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26797145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation/*genetics ; Cell Lineage/*genetics ; Cell Proliferation ; Cells, Cultured ; Down-Regulation ; Embryonic Stem Cells/*cytology ; Enhancer Elements, Genetic/*physiology ; *Gene Expression Regulation ; Gene Regulatory Networks ; Macrophages/*cytology ; MafB Transcription Factor/metabolism ; Mice ; Proto-Oncogene Proteins c-maf/metabolism ; Single-Cell Analysis ; Transcriptional Activation
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 7
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    Phase separation of signaling molecules promotes T cell receptor signal transduction (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-04-09
    Description: Activation of various cell surface receptors triggers the reorganization of downstream signaling molecules into micrometer- or submicrometer-sized clusters. However, the functional consequences of such clustering have been unclear. We biochemically reconstituted a 12-component signaling pathway on model membranes, beginning with T cell receptor (TCR) activation and ending with actin assembly. When TCR phosphorylation was triggered, downstream signaling proteins spontaneously separated into liquid-like clusters that promoted signaling outputs both in vitro and in human Jurkat T cells. Reconstituted clusters were enriched in kinases but excluded phosphatases and enhanced actin filament assembly by recruiting and organizing actin regulators. These results demonstrate that protein phase separation can create a distinct physical and biochemical compartment that facilitates signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaolei -- Ditlev, Jonathon A -- Hui, Enfu -- Xing, Wenmin -- Banjade, Sudeep -- Okrut, Julia -- King, David S -- Taunton, Jack -- Rosen, Michael K -- Vale, Ronald D -- 5-F32-DK101188/DK/NIDDK NIH HHS/ -- F32 DK101188/DK/NIDDK NIH HHS/ -- R01 GM056322/GM/NIGMS NIH HHS/ -- R01-GM56322/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Apr 29;352(6285):595-9. doi: 10.1126/science.aad9964. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ; HHMI Mass Spectrometry Laboratory and Department of Molecular and Cellular Biology, University of California, Berkeley, CA 94720, USA. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Biophysics and Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu. ; Howard Hughes Medical Institute (HHMI) Summer Institute, Marine Biological Laboratory, Woods Hole, MA 02543, USA. Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, CA 94158, USA. ron.vale@ucsf.edu michael.rosen@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27056844" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*metabolism ; Adaptor Proteins, Signal Transducing/*metabolism ; Fluorescence Recovery After Photobleaching ; Humans ; Jurkat Cells ; Membrane Proteins/*metabolism ; Mitogen-Activated Protein Kinase Kinases ; Phosphorylation ; Polymerization ; Receptors, Antigen, T-Cell/*agonists ; Signal Transduction ; T-Lymphocytes/*metabolism
    Print ISSN: 0036-8075
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  • 8
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    Prostaglandin E(2) constrains systemic inflammation through an innate lymphoid cell-IL-22 axis (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-03-19
    Description: Systemic inflammation, which results from the massive release of proinflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are not fully understood. We observed that prostaglandin E2 (PGE2), through its receptor EP4, is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treatment with EP4 agonists. Mechanistically, we demonstrate that PGE2-EP4 signaling acts directly on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC-IL-22 axis impairs PGE2-mediated inhibition of systemic inflammation. Hence, the ILC-IL-22 axis is essential in protecting against gut barrier dysfunction, enabling PGE2-EP4 signaling to impede systemic inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4841390/" 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/PMC4841390/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duffin, Rodger -- O'Connor, Richard A -- Crittenden, Siobhan -- Forster, Thorsten -- Yu, Cunjing -- Zheng, Xiaozhong -- Smyth, Danielle -- Robb, Calum T -- Rossi, Fiona -- Skouras, Christos -- Tang, Shaohui -- Richards, James -- Pellicoro, Antonella -- Weller, Richard B -- Breyer, Richard M -- Mole, Damian J -- Iredale, John P -- Anderton, Stephen M -- Narumiya, Shuh -- Maizels, Rick M -- Ghazal, Peter -- Howie, Sarah E -- Rossi, Adriano G -- Yao, Chengcan -- 106122/Wellcome Trust/United Kingdom -- BB/K091121/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- DK37097/DK/NIDDK NIH HHS/ -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1333-8. doi: 10.1126/science.aad9903.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK. ; Division of Pathway Medicine, Edinburgh Infectious Diseases, The University of Edinburgh, Edinburgh EH16 4SB, UK. ; Institute for Immunology and Infection Research, The University of Edinburgh, Edinburgh EH9 3JT, UK. ; MRC Centre for Regenerative Medicine, The University of Edinburgh, Edinburgh EH16 4UU, UK. ; Department of Gastroenterology, First Affiliated Hospital of Jinan University, Guangzhou 510630, China. ; Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN 37212, USA. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. ; Center for Innovation in Immunoregulative Technology and Therapeutics (AK Project), Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan. Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Agency (JST), Tokyo 102-0075, Japan. ; Division of Pathway Medicine, Edinburgh Infectious Diseases, The University of Edinburgh, Edinburgh EH16 4SB, UK. Centre for Synthetic and Systems Biology (SynthSys), The University of Edinburgh, Edinburgh EH9 3JD, UK. ; Medical Research Council (MRC) Centre for Inflammation Research, Queen's Medical Research Institute, The University of Edinburgh, Edinburgh EH16 4TJ, UK. chengcan.yao@ed.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26989254" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Infections/genetics/immunology ; Dinoprostone/*immunology ; Gene Expression ; Humans ; Immunity, Innate ; Inflammation/drug therapy/*immunology/microbiology ; Interleukins/*immunology ; Intestines/*immunology/microbiology ; Lymphocytes/*immunology ; Mice ; Receptors, Prostaglandin E, EP4 Subtype/antagonists & ; inhibitors/genetics/*immunology ; Signal Transduction
    Print ISSN: 0036-8075
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  • 9
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    Oligodendrocyte precursors migrate along vasculature in the developing nervous system (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-23
    Description: Oligodendrocytes myelinate axons in the central nervous system and develop from oligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Hui-Hsin -- Niu, Jianqin -- Munji, Roeben -- Davalos, Dimitrios -- Chang, Junlei -- Zhang, Haijing -- Tien, An-Chi -- Kuo, Calvin J -- Chan, Jonah R -- Daneman, Richard -- Fancy, Stephen P J -- 1P01 NS083513/NS/NINDS NIH HHS/ -- 1R01NS064517/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 22;351(6271):379-84. doi: 10.1126/science.aad3839.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, University of California at San Francisco (UCSF), San Francisco, CA 94158, USA. ; Departments of Pharmacology and Neuroscience, University of California at San Diego (UCSD), San Diego, CA 92093, USA. ; Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. ; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. ; Division of Hematology, Department of Medicine, Stanford University, Stanford, CA 94305, USA. Department of Urology, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. Howard Hughes Medical Institute (HHMI), Chevy Chase, MD 20815, USA. Duke University School of Medicine, Durham, NC 27710, USA. ; Department of Neurology, UCSF, San Francisco, CA 94158, USA. ; Department of Pediatrics, University of California at San Francisco (UCSF), San Francisco, CA 94158, USA. Department of Neurology, UCSF, San Francisco, CA 94158, USA. Division of Neonatology, UCSF, San Francisco, CA 94158, USA. Newborn Brain Research Institute, UCSF, San Francisco, CA 94158, USA. stephen.fancy@ucsf.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26798014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Vessels/cytology/embryology ; *Cell Movement ; Cerebral Cortex/blood supply/*embryology ; Endothelium, Vascular/cytology ; Humans ; Mice ; Neural Stem Cells/cytology/*physiology ; *Neurogenesis ; Oligodendroglia/cytology/*physiology ; *Organogenesis ; Pericytes/cytology/physiology ; Receptors, CXCR4/metabolism ; Signal Transduction ; Spinal Cord/blood supply/cytology/*embryology ; Wnt Proteins/metabolism
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  • 10
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    Neurons diversify astrocytes in the adult brain through sonic hedgehog signaling (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Astrocytes are specialized and heterogeneous cells that contribute to central nervous system function and homeostasis. However, the mechanisms that create and maintain differences among astrocytes and allow them to fulfill particular physiological roles remain poorly defined. We reveal that neurons actively determine the features of astrocytes in the healthy adult brain and define a role for neuron-derived sonic hedgehog (Shh) in regulating the molecular and functional profile of astrocytes. Thus, the molecular and physiological program of astrocytes is not hardwired during development but, rather, depends on cues from neurons that drive and sustain their specialized properties.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farmer, W Todd -- Abrahamsson, Therese -- Chierzi, Sabrina -- Lui, Christopher -- Zaelzer, Cristian -- Jones, Emma V -- Bally, Blandine Ponroy -- Chen, Gary G -- Theroux, Jean-Francois -- Peng, Jimmy -- Bourque, Charles W -- Charron, Frederic -- Ernst, Carl -- Sjostrom, P Jesper -- Murai, Keith K -- FDN 143337/Canadian Institutes of Health Research/Canada -- MOP 111152/Canadian Institutes of Health Research/Canada -- MOP 123390/Canadian Institutes of Health Research/Canada -- MOP 126137/Canadian Institutes of Health Research/Canada -- NIA 288936/Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 Feb 19;351(6275):849-54. doi: 10.1126/science.aab3103.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada. ; Department of Psychiatry, McGill University, Montreal, Quebec, Canada. McGill Group for Suicide Studies, Douglas Hospital, Montreal, Quebec, Canada. ; Molecular Biology of Neural Development, Institut de Recherches Cliniques de Montreal, Department of Medicine, University of Montreal, Montreal, Quebec, Canada. Department of Biology, McGill University, Montreal, Quebec, Canada. ; Department of Psychiatry, McGill University, Montreal, Quebec, Canada. McGill Group for Suicide Studies, Douglas Hospital, Montreal, Quebec, Canada. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. Douglas Hospital Research Institute, Verdun, Quebec, Canada. ; Centre for Research in Neuroscience, Department of Neurology and Neurosurgery, Brain Repair and Integrative Neuroscience Program, The Research Institute of the McGill University Health Centre, Montreal General Hospital, Montreal, Quebec, Canada. keith.murai@mcgill.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912893" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/*metabolism ; Cerebellar Cortex/*cytology ; Female ; Gene Deletion ; Hedgehog Proteins/genetics/*metabolism ; Male ; Mice ; Mice, Mutant Strains ; Neurons/*metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Signal Transduction
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  • 11
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    Spatial colocalization and functional link of purinosomes with mitochondria (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-26
    Description: Purine biosynthetic enzymes organize into dynamic cellular bodies called purinosomes. Little is known about the spatiotemporal control of these structures. Using super-resolution microscopy, we demonstrated that purinosomes colocalized with mitochondria, and these results were supported by isolation of purinosome enzymes with mitochondria. Moreover, the number of purinosome-containing cells responded to dysregulation of mitochondrial function and metabolism. To explore the role of intracellular signaling, we performed a kinome screen using a label-free assay and found that mechanistic target of rapamycin (mTOR) influenced purinosome assembly. mTOR inhibition reduced purinosome-mitochondria colocalization and suppressed purinosome formation stimulated by mitochondria dysregulation. Collectively, our data suggest an mTOR-mediated link between purinosomes and mitochondria, and a general means by which mTOR regulates nucleotide metabolism by spatiotemporal control over protein association.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉French, Jarrod B -- Jones, Sara A -- Deng, Huayun -- Pedley, Anthony M -- Kim, Doory -- Chan, Chung Yu -- Hu, Haibei -- Pugh, Raymond J -- Zhao, Hong -- Zhang, Youxin -- Huang, Tony Jun -- Fang, Ye -- Zhuang, Xiaowei -- Benkovic, Stephen J -- 1R33EB019785-01/EB/NIBIB NIH HHS/ -- GM024129/GM/NIGMS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Feb 12;351(6274):733-7. doi: 10.1126/science.aac6054.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Cell Biology, Department of Chemistry, Stony Brook University, Stony Brook, NY 11794, USA. jarrod.french@stonybrook.edu fangy2@corning.com zhuang@chemistry.harvard.edu sjb1@psu.edu. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. ; Biochemical Technologies, Science and Technology Division, Corning Incorporated, Corning, NY 14831, USA. ; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA. ; Department of Engineering Science and Mechanics, The Pennsylvania State University, University Park, PA 16802, USA. ; Biochemical Technologies, Science and Technology Division, Corning Incorporated, Corning, NY 14831, USA. jarrod.french@stonybrook.edu fangy2@corning.com zhuang@chemistry.harvard.edu sjb1@psu.edu. ; Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA. Howard Hughes Medical Institute, Harvard University, Cambridge, MA 02138, USA. Department of Physics, Harvard University, Cambridge, MA 02138, USA. jarrod.french@stonybrook.edu fangy2@corning.com zhuang@chemistry.harvard.edu sjb1@psu.edu. ; Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA. jarrod.french@stonybrook.edu fangy2@corning.com zhuang@chemistry.harvard.edu sjb1@psu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26912862" target="_blank"〉PubMed〈/a〉
    Keywords: HeLa Cells ; Humans ; Microscopy ; Mitochondria/*metabolism/ultrastructure ; Purines/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism
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  • 12
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    Cyclic programmed cell death stimulates hormone signaling and root development in Arabidopsis (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-01-23
    Description: The plant root cap, surrounding the very tip of the growing root, perceives and transmits environmental signals to the inner root tissues. In Arabidopsis thaliana, auxin released by the root cap contributes to the regular spacing of lateral organs along the primary root axis. Here, we show that the periodicity of lateral organ induction is driven by recurrent programmed cell death at the most distal edge of the root cap. We suggest that synchronous bursts of cell death in lateral root cap cells release pulses of auxin to surrounding root tissues, establishing the pattern for lateral root formation. The dynamics of root cap turnover may therefore coordinate primary root growth with root branching in order to optimize the uptake of water and nutrients from the soil.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xuan, Wei -- Band, Leah R -- Kumpf, Robert P -- Van Damme, Daniel -- Parizot, Boris -- De Rop, Gieljan -- Opdenacker, Davy -- Moller, Barbara K -- Skorzinski, Noemi -- Njo, Maria F -- De Rybel, Bert -- Audenaert, Dominique -- Nowack, Moritz K -- Vanneste, Steffen -- Beeckman, Tom -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2016 Jan 22;351(6271):384-7. doi: 10.1126/science.aad2776.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Technologiepark 927, 9052 Ghent, Belgium. Department of Plant Biotechnology and Bioinformatics, Gent University, Technologiepark 927, 9052 Ghent, Belgium. State Key Laboratory of Crop Genetics and Germplasm Enhancement and MOA Key Laboratory of Plant Nutrition and Fertilization in Lower-Middle Reaches of the Yangtze River, Nanjing Agricultural University, Weigang No. 1, Nanjing 210095, PR China. ; Centre for Plant Integrative Biology, University of Nottingham, Nottingham LE12 5RD, UK. ; Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Technologiepark 927, 9052 Ghent, Belgium. Department of Plant Biotechnology and Bioinformatics, Gent University, Technologiepark 927, 9052 Ghent, Belgium. ; Max Planck Institute for Developmental Biology, Spemannstrasse 35, 72076 Tubingen, Germany. ; Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Technologiepark 927, 9052 Ghent, Belgium. Department of Plant Biotechnology and Bioinformatics, Gent University, Technologiepark 927, 9052 Ghent, Belgium. Laboratory of Biochemistry, Wageningen University, Dreijenlaan 3, 6703HA Wageningen, Netherlands. ; Department of Plant Systems Biology, Vlaams Instituut voor Biotechnologie (VIB), Technologiepark 927, 9052 Ghent, Belgium. Department of Plant Biotechnology and Bioinformatics, Gent University, Technologiepark 927, 9052 Ghent, Belgium. tobee@psb.vib-ugent.be.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26798015" target="_blank"〉PubMed〈/a〉
    Keywords: *Apoptosis ; Arabidopsis/cytology/*growth & development/metabolism ; Indoleacetic Acids/*metabolism ; Plant Epidermis/cytology/growth & development/metabolism ; Plant Root Cap/cytology/*growth & development/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/metabolism ; Signal Transduction ; Soil ; Water/metabolism
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  • 13
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    Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut (2016)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2016-02-06
    Description: The intestinal epithelium forms an essential barrier between a host and its microbiota. Protozoa and helminths are members of the gut microbiota of mammals, including humans, yet the many ways that gut epithelial cells orchestrate responses to these eukaryotes remain unclear. Here we show that tuft cells, which are taste-chemosensory epithelial cells, accumulate during parasite colonization and infection. Disruption of chemosensory signaling through the loss of TRMP5 abrogates the expansion of tuft cells, goblet cells, eosinophils, and type 2 innate lymphoid cells during parasite colonization. Tuft cells are the primary source of the parasite-induced cytokine interleukin-25, which indirectly induces tuft cell expansion by promoting interleukin-13 production by innate lymphoid cells. Our results identify intestinal tuft cells as critical sentinels in the gut epithelium that promote type 2 immunity in response to intestinal parasites.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howitt, Michael R -- Lavoie, Sydney -- Michaud, Monia -- Blum, Arthur M -- Tran, Sara V -- Weinstock, Joel V -- Gallini, Carey Ann -- Redding, Kevin -- Margolskee, Robert F -- Osborne, Lisa C -- Artis, David -- Garrett, Wendy S -- F31DK105653/DK/NIDDK NIH HHS/ -- F32DK098826/DK/NIDDK NIH HHS/ -- R01 CA154426/CA/NCI NIH HHS/ -- R01 GM099531/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 18;351(6279):1329-33. doi: 10.1126/science.aaf1648. Epub 2016 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. ; Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111, USA. ; Monell Chemical Senses Center, Philadelphia, PA 19104, USA. ; Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medical College, Cornell University, New York, NY 10021, USA. ; Departments of Immunology and Infectious Diseases and Genetics and Complex Diseases, Harvard T. H. Chan School of Public Health, Boston, MA 02115, USA. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. wgarrett@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26847546" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemoreceptor Cells/*immunology ; Eosinophils/immunology ; Goblet Cells/immunology ; Helminthiasis/immunology/parasitology ; Helminths/immunology ; Immunity, Mucosal ; Interleukin-13/immunology ; Interleukin-17/immunology ; Intestinal Diseases, Parasitic/*immunology/parasitology ; Intestinal Mucosa/*immunology/*parasitology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microbiota/*immunology ; Protein-Serine-Threonine Kinases/immunology ; Protozoan Infections/immunology/parasitology ; Signal Transduction ; TRPM Cation Channels/*immunology ; Taste ; Transducin/genetics/immunology ; Tritrichomonas/immunology
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 14
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    CLK2 inhibition ameliorates autistic features associated with SHANK3 deficiency (2016)
    American Association for the Advancement of Science (AAAS)
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    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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  • 15
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    Hypoxic control of metastasis (2016)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2016-04-29
    Description: Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rankin, Erinn B -- Giaccia, Amato J -- CA-197713/CA/NCI NIH HHS/ -- CA-198291/CA/NCI NIH HHS/ -- CA-67166/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2016 Apr 8;352(6282):175-80. doi: 10.1126/science.aaf4405. Epub 2016 Apr 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305-5152, USA. Department of Obstetrics and Gynecology, Stanford University Medical Center, Stanford, CA 94305-5152, USA. ; Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA 94305-5152, USA. giaccia@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27124451" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/*metabolism ; Biomarkers, Tumor/analysis/metabolism ; Cell Hypoxia ; Cell Movement ; Disease Progression ; Drug Resistance, Neoplasm ; Epithelial-Mesenchymal Transition ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis/*pathology/*therapy ; Radiation Tolerance ; Signal Transduction ; *Tumor Microenvironment
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  • 16
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    Schedule-dependent interaction between anticancer treatments (2016)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2016-03-12
    Description: The oncogene MDMX is overexpressed in many cancers, leading to suppression of the tumor suppressor p53. Inhibitors of the oncogene product MDMX therefore might help reactivate p53 and enhance the efficacy of DNA-damaging drugs. However, we currently lack a quantitative understanding of how MDMX inhibition affects the p53 signaling pathway and cell sensitivity to DNA damage. Live cell imaging showed that MDMX depletion triggered two distinct phases of p53 accumulation in single cells: an initial postmitotic pulse, followed by low-amplitude oscillations. The response to DNA damage was sharply different in these two phases; in the first phase, MDMX depletion was synergistic with DNA damage in causing cell death, whereas in the second phase, depletion of MDMX inhibited cell death. Thus a quantitative understanding of signal dynamics and cellular states is important for designing an optimal schedule of dual-drug administration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Sheng-Hong -- Forrester, William -- Lahav, Galit -- F32GM105205/GM/NIGMS NIH HHS/ -- GM083303/GM/NIGMS NIH HHS/ -- R01 GM083303/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2016 Mar 11;351(6278):1204-8. doi: 10.1126/science.aac5610. Epub 2016 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, MA, USA. ; Developmental and Molecular Pathways, Novartis Institutes for Biomedical Research, Cambridge, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26965628" target="_blank"〉PubMed〈/a〉
    Keywords: Antineoplastic Agents/*administration & dosage ; Apoptosis ; *DNA Damage ; Gene Knockdown Techniques ; Humans ; MCF-7 Cells ; Molecular Imaging ; Neoplasms/*drug therapy ; Proto-Oncogene Proteins c-mdm2/*antagonists & inhibitors/genetics ; RNA, Small Interfering/genetics ; Signal Transduction ; Time Factors ; Tumor Suppressor Protein p53/*metabolism
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    [Editors' Choice] Testing a cell signaling circuit (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-08-16
    Description: Author: L. Bryan Ray
    Keywords: Signal Transduction
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    [This Week in Science] A function for multisite phosphorylation (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
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    Publication Date: 2016-10-14
    Description: Authors: Caroline Ash, L. Bryan Ray
    Keywords: Signal Transduction
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    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
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    [Perspective] Multisite phosphorylation by MAPK (2016)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2016-10-14
    Description: Reversible protein phosphorylation plays a fundamental role in signal transduction networks. Phosphorylation alters protein function by regulating enzymatic activity, stability, cellular localization, or binding partners. Over three-quarters of human proteins may be phosphorylated, with many targeted at multiple sites. Such multisite phosphorylation substantially increases the scope for modulating protein function—a protein with n phosphorylation sites has the potential to exist in 2n distinct phosphorylation states, each of which could, in theory, display modified functionality. Proteins can be substrates for several protein kinases, thereby integrating distinct signals to provide a coherent biological response. However, they can also be phosphorylated at multiple sites by a single protein kinase to promote a specific functional output that can be reversed by dephosphorylation by protein phosphatases. On page 233 of this issue, Mylona et al. (1) reveal an unexpected role for multisite phosphorylation, whereby a protein kinase progressively phosphorylates sites on a transcription factor to promote and then subsequently limit its activity independently of dephosphorylation. Authors: Alan J. Whitmarsh, Roger J. Davis
    Keywords: Signal Transduction
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    Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-04-11
    Description: Protein phosphorylation regulates virtually all biological processes. Although protein kinases are popular drug targets, targeting protein phosphatases remains a challenge. Here, we describe Sephin1 (selective inhibitor of a holophosphatase), a small molecule that safely and selectively inhibited a regulatory subunit of protein phosphatase 1 in vivo. Sephin1 selectively bound and inhibited the stress-induced PPP1R15A, but not the related and constitutive PPP1R15B, to prolong the benefit of an adaptive phospho-signaling pathway, protecting cells from otherwise lethal protein misfolding stress. In vivo, Sephin1 safely prevented the motor, morphological, and molecular defects of two otherwise unrelated protein-misfolding diseases in mice, Charcot-Marie-Tooth 1B, and amyotrophic lateral sclerosis. Thus, regulatory subunits of phosphatases are drug targets, a property exploited here to safely prevent two protein misfolding diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4490275/" 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/PMC4490275/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Das, Indrajit -- Krzyzosiak, Agnieszka -- Schneider, Kim -- Wrabetz, Lawrence -- D'Antonio, Maurizio -- Barry, Nicholas -- Sigurdardottir, Anna -- Bertolotti, Anne -- 309516/European Research Council/International -- MC_U105185860/Medical Research Council/United Kingdom -- R01-NS55256/NS/NINDS NIH HHS/ -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Apr 10;348(6231):239-42. doi: 10.1126/science.aaa4484.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. ; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge, CB2 0QH, UK. aberto@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25859045" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/drug therapy/metabolism/pathology ; Animals ; Cells, Cultured ; Charcot-Marie-Tooth Disease/drug therapy/metabolism/pathology ; Disease Models, Animal ; Endoplasmic Reticulum Stress/drug effects ; Enzyme Inhibitors/metabolism/pharmacokinetics/*pharmacology/toxicity ; Guanabenz/*analogs & derivatives/chemical ; synthesis/metabolism/pharmacology/toxicity ; HeLa Cells ; Humans ; Mice ; Mice, Transgenic ; Molecular Targeted Therapy ; Phosphorylation ; Protein Folding ; Protein Phosphatase 1/*antagonists & inhibitors ; Proteostasis Deficiencies/*drug therapy/*prevention & control ; Signal Transduction
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 21
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    SIGNAL TRANSDUCTION. Membrane potential modulates plasma membrane phospholipid dynamics and K-Ras signaling (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-22
    Description: Plasma membrane depolarization can trigger cell proliferation, but how membrane potential influences mitogenic signaling is uncertain. Here, we show that plasma membrane depolarization induces nanoscale reorganization of phosphatidylserine and phosphatidylinositol 4,5-bisphosphate but not other anionic phospholipids. K-Ras, which is targeted to the plasma membrane by electrostatic interactions with phosphatidylserine, in turn undergoes enhanced nanoclustering. Depolarization-induced changes in phosphatidylserine and K-Ras plasma membrane organization occur in fibroblasts, excitable neuroblastoma cells, and Drosophila neurons in vivo and robustly amplify K-Ras-dependent mitogen-activated protein kinase (MAPK) signaling. Conversely, plasma membrane repolarization disrupts K-Ras nanoclustering and inhibits MAPK signaling. By responding to voltage-induced changes in phosphatidylserine spatiotemporal dynamics, K-Ras nanoclusters set up the plasma membrane as a biological field-effect transistor, allowing membrane potential to control the gain in mitogenic signaling circuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687752/" 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/PMC4687752/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Yong -- Wong, Ching-On -- Cho, Kwang-jin -- van der Hoeven, Dharini -- Liang, Hong -- Thakur, Dhananiay P -- Luo, Jialie -- Babic, Milos -- Zinsmaier, Konrad E -- Zhu, Michael X -- Hu, Hongzhen -- Venkatachalam, Kartik -- Hancock, John F -- R01 NS081301/NS/NINDS NIH HHS/ -- R01NS081301/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):873-6. doi: 10.1126/science.aaa5619.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. ; Department of Diagnostic and Biomedical Sciences, Dental School, University of Texas Health Science Center at Houston, Houston, TX 77054, USA. ; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA. ; Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Program in Cell and Regulatory Biology, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. ; Department of Integrative Biology and Pharmacology, Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Program in Cell and Regulatory Biology, University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA. john.f.hancock@uth.tmc.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293964" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Membrane/metabolism/*physiology ; Cricetinae ; Drosophila melanogaster ; Fibroblasts ; *Membrane Potentials ; Mice ; Neurons ; Phosphatidylinositol 4,5-Diphosphate/*metabolism ; Phosphatidylserines/*metabolism ; Signal Transduction ; ras Proteins/*metabolism
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  • 22
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    Chromosomes. A comprehensive Xist interactome reveals cohesin repulsion and an RNA-directed chromosome conformation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-20
    Description: The inactive X chromosome (Xi) serves as a model to understand gene silencing on a global scale. Here, we perform "identification of direct RNA interacting proteins" (iDRiP) to isolate a comprehensive protein interactome for Xist, an RNA required for Xi silencing. We discover multiple classes of interactors-including cohesins, condensins, topoisomerases, RNA helicases, chromatin remodelers, and modifiers-that synergistically repress Xi transcription. Inhibiting two or three interactors destabilizes silencing. Although Xist attracts some interactors, it repels architectural factors. Xist evicts cohesins from the Xi and directs an Xi-specific chromosome conformation. Upon deleting Xist, the Xi acquires the cohesin-binding and chromosomal architecture of the active X. Our study unveils many layers of Xi repression and demonstrates a central role for RNA in the topological organization of mammalian chromosomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Minajigi, Anand -- Froberg, John E -- Wei, Chunyao -- Sunwoo, Hongjae -- Kesner, Barry -- Colognori, David -- Lessing, Derek -- Payer, Bernhard -- Boukhali, Myriam -- Haas, Wilhelm -- Lee, Jeannie T -- R01-DA-38695/DA/NIDA NIH HHS/ -- R03-MH97478/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 17;349(6245). pii: aab2276. doi: 10.1126/science.aab2276. Epub 2015 Jun 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. ; Massachusetts General Hospital Cancer Center, Charlestown, Boston, MA; Department of Medicine, Harvard Medical School, Boston, MA, USA. ; Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA; Department of Genetics, Harvard Medical School, Boston, MA, USA. lee@molbio.mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089354" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Animals ; Cell Cycle Proteins/*metabolism ; Cells, Cultured ; Chromatin Assembly and Disassembly ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins/metabolism ; Embryonic Stem Cells/metabolism ; Fibroblasts/metabolism ; Gene Knockdown Techniques ; Gene Silencing ; Mice ; Multiprotein Complexes/metabolism ; Nucleic Acid Conformation ; Proteomics ; RNA Helicases/metabolism ; RNA, Long Noncoding/*metabolism ; X Chromosome/chemistry/genetics/*metabolism ; *X Chromosome Inactivation
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 23
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    RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-19
    Description: Prostate cancer is initially responsive to androgen deprivation, but the effectiveness of androgen receptor (AR) inhibitors in recurrent disease is variable. Biopsy of bone metastases is challenging; hence, sampling circulating tumor cells (CTCs) may reveal drug-resistance mechanisms. We established single-cell RNA-sequencing (RNA-Seq) profiles of 77 intact CTCs isolated from 13 patients (mean six CTCs per patient), by using microfluidic enrichment. Single CTCs from each individual display considerable heterogeneity, including expression of AR gene mutations and splicing variants. Retrospective analysis of CTCs from patients progressing under treatment with an AR inhibitor, compared with untreated cases, indicates activation of noncanonical Wnt signaling (P = 0.0064). Ectopic expression of Wnt5a in prostate cancer cells attenuates the antiproliferative effect of AR inhibition, whereas its suppression in drug-resistant cells restores partial sensitivity, a correlation also evident in an established mouse model. Thus, single-cell analysis of prostate CTCs reveals heterogeneity in signaling pathways that could contribute to treatment failure.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyamoto, David T -- Zheng, Yu -- Wittner, Ben S -- Lee, Richard J -- Zhu, Huili -- Broderick, Katherine T -- Desai, Rushil -- Fox, Douglas B -- Brannigan, Brian W -- Trautwein, Julie -- Arora, Kshitij S -- Desai, Niyati -- Dahl, Douglas M -- Sequist, Lecia V -- Smith, Matthew R -- Kapur, Ravi -- Wu, Chin-Lee -- Shioda, Toshi -- Ramaswamy, Sridhar -- Ting, David T -- Toner, Mehmet -- Maheswaran, Shyamala -- Haber, Daniel A -- 2R01CA129933/CA/NCI NIH HHS/ -- EB008047/EB/NIBIB NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 18;349(6254):1351-6. doi: 10.1126/science.aab0917.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Urology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Center for Bioengineering in Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu. ; Massachusetts General Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA. haber@helix.mgh.harvard.edu smaheswaran@mgh.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26383955" target="_blank"〉PubMed〈/a〉
    Keywords: Androgen Antagonists/pharmacology/*therapeutic use ; Animals ; Cell Line, Tumor ; Drug Resistance, Neoplasm/*genetics ; Humans ; Male ; Mice ; Neoplastic Cells, Circulating/drug effects/*metabolism ; Phenylthiohydantoin/*analogs & derivatives/pharmacology/therapeutic use ; Prostate/drug effects/metabolism/pathology ; Prostatic Neoplasms/*drug therapy/*pathology ; Proto-Oncogene Proteins/genetics/metabolism ; RNA Splicing ; Receptors, Androgen/*genetics ; Sequence Analysis, RNA/methods ; Signal Transduction ; Single-Cell Analysis/methods ; Transcriptome ; Wnt Proteins/genetics/*metabolism ; Xenograft Model Antitumor Assays
    Print ISSN: 0036-8075
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  • 24
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    SIGNAL TRANSDUCTION. Structural basis for nucleotide exchange in heterotrimeric G proteins (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-20
    Description: G protein-coupled receptors (GPCRs) relay diverse extracellular signals into cells by catalyzing nucleotide release from heterotrimeric G proteins, but the mechanism underlying this quintessential molecular signaling event has remained unclear. Here we use atomic-level simulations to elucidate the nucleotide-release mechanism. We find that the G protein alpha subunit Ras and helical domains-previously observed to separate widely upon receptor binding to expose the nucleotide-binding site-separate spontaneously and frequently even in the absence of a receptor. Domain separation is necessary but not sufficient for rapid nucleotide release. Rather, receptors catalyze nucleotide release by favoring an internal structural rearrangement of the Ras domain that weakens its nucleotide affinity. We use double electron-electron resonance spectroscopy and protein engineering to confirm predictions of our computationally determined mechanism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dror, Ron O -- Mildorf, Thomas J -- Hilger, Daniel -- Manglik, Aashish -- Borhani, David W -- Arlow, Daniel H -- Philippsen, Ansgar -- Villanueva, Nicolas -- Yang, Zhongyu -- Lerch, Michael T -- Hubbell, Wayne L -- Kobilka, Brian K -- Sunahara, Roger K -- Shaw, David E -- P30EY00331/EY/NEI NIH HHS/ -- R01EY05216/EY/NEI NIH HHS/ -- R01GM083118/GM/NIGMS NIH HHS/ -- T32 GM008294/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jun 19;348(6241):1361-5. doi: 10.1126/science.aaa5264.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉D. E. Shaw Research, New York, NY 10036, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com. ; D. E. Shaw Research, New York, NY 10036, USA. ; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. ; Jules Stein Eye Institute and Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA. ; D. E. Shaw Research, New York, NY 10036, USA. Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA. ron.dror@deshawresearch.com david.shaw@deshawresearch.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26089515" target="_blank"〉PubMed〈/a〉
    Keywords: GTP-Binding Protein alpha Subunits, Gi-Go/*chemistry ; GTP-Binding Protein alpha Subunits, Gs/*chemistry ; Guanine Nucleotide Exchange Factors/*chemistry ; Humans ; Models, Chemical ; Molecular Dynamics Simulation ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/*chemistry ; Signal Transduction
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    PARASITIC PLANTS. Probing strigolactone receptors in Striga hermonthica with fluorescence (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-22
    Description: Elucidating the signaling mechanism of strigolactones has been the key to controlling the devastating problem caused by the parasitic plant Striga hermonthica. To overcome the genetic intractability that has previously interfered with identification of the strigolactone receptor, we developed a fluorescence turn-on probe, Yoshimulactone Green (YLG), which activates strigolactone signaling and illuminates signal perception by the strigolactone receptors. Here we describe how strigolactones bind to and act via ShHTLs, the diverged family of alpha/beta hydrolase-fold proteins in Striga. Live imaging using YLGs revealed that a dynamic wavelike propagation of strigolactone perception wakes up Striga seeds. We conclude that ShHTLs function as the strigolactone receptors mediating seed germination in Striga. Our findings enable access to strigolactone receptors and observation of the regulatory dynamics for strigolactone signal transduction in Striga.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsuchiya, Yuichiro -- Yoshimura, Masahiko -- Sato, Yoshikatsu -- Kuwata, Keiko -- Toh, Shigeo -- Holbrook-Smith, Duncan -- Zhang, Hua -- McCourt, Peter -- Itami, Kenichiro -- Kinoshita, Toshinori -- Hagihara, Shinya -- New York, N.Y. -- Science. 2015 Aug 21;349(6250):864-8. doi: 10.1126/science.aab3831.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Department of Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada. yuichiro@itbm.nagoya-u.ac.jp hagi@itbm.nagoya-u.ac.jp. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Department of Cell and Systems Biology, University of Toronto, 25 Willcocks Street, Toronto, Ontario M5S 3B2, Canada. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Japan Science and Technology Agency-Exploratory Research for Advanced Technology, Itami Molecular Nanocarbon Project, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. ; Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. Graduate School of Science, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8602, Japan. yuichiro@itbm.nagoya-u.ac.jp hagi@itbm.nagoya-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26293962" target="_blank"〉PubMed〈/a〉
    Keywords: Fluoresceins/chemistry/metabolism ; Fluorescence ; Fluorescent Dyes/chemistry/metabolism ; *Germination ; Hydrolases/metabolism ; Hydrolysis ; Lactones/*metabolism ; Molecular Imaging/methods ; Molecular Sequence Data ; Plant Growth Regulators/*metabolism ; Plant Proteins/genetics/*metabolism ; Receptors, Cell Surface/genetics/*metabolism ; Seeds/*growth & development/metabolism ; Signal Transduction ; Striga/*growth & development/metabolism
    Print ISSN: 0036-8075
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  • 26
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    Circadian rhythms. Decoupling circadian clock protein turnover from circadian period determination (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-31
    Description: The mechanistic basis of eukaryotic circadian oscillators in model systems as diverse as Neurospora, Drosophila, and mammalian cells is thought to be a transcription-and-translation-based negative feedback loop, wherein progressive and controlled phosphorylation of one or more negative elements ultimately elicits their own proteasome-mediated degradation, thereby releasing negative feedback and determining circadian period length. The Neurospora crassa circadian negative element FREQUENCY (FRQ) exemplifies such proteins; it is progressively phosphorylated at more than 100 sites, and strains bearing alleles of frq with anomalous phosphorylation display abnormal stability of FRQ that is well correlated with altered periods or apparent arrhythmicity. Unexpectedly, we unveiled normal circadian oscillations that reflect the allelic state of frq but that persist in the absence of typical degradation of FRQ. This manifest uncoupling of negative element turnover from circadian period length determination is not consistent with the consensus eukaryotic circadian model.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4432837/" 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/PMC4432837/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Larrondo, Luis F -- Olivares-Yanez, Consuelo -- Baker, Christopher L -- Loros, Jennifer J -- Dunlap, Jay C -- P01 GM68087/GM/NIGMS NIH HHS/ -- R01 GM034985/GM/NIGMS NIH HHS/ -- R01 GM083336/GM/NIGMS NIH HHS/ -- R01 GM34985/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 30;347(6221):1257277. doi: 10.1126/science.1257277.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. ; Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA. jay.c.dunlap@dartmouth.edu llarrondo@bio.puc.cl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25635104" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine/analogs & derivatives/pharmacology ; Alleles ; *Circadian Clocks ; *Circadian Rhythm ; Feedback, Physiological ; Fungal Proteins/biosynthesis/*genetics/*metabolism ; Half-Life ; Neurospora crassa/*physiology ; Phosphorylation ; Proteasome Endopeptidase Complex/metabolism ; Protein Kinase Inhibitors/pharmacology ; Protein Stability ; Proteolysis ; Signal Transduction
    Print ISSN: 0036-8075
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  • 27
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    Ebola virus. Two-pore channels control Ebola virus host cell entry and are drug targets for disease treatment (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-28
    Description: Ebola virus causes sporadic outbreaks of lethal hemorrhagic fever in humans, but there is no currently approved therapy. Cells take up Ebola virus by macropinocytosis, followed by trafficking through endosomal vesicles. However, few factors controlling endosomal virus movement are known. Here we find that Ebola virus entry into host cells requires the endosomal calcium channels called two-pore channels (TPCs). Disrupting TPC function by gene knockout, small interfering RNAs, or small-molecule inhibitors halted virus trafficking and prevented infection. Tetrandrine, the most potent small molecule that we tested, inhibited infection of human macrophages, the primary target of Ebola virus in vivo, and also showed therapeutic efficacy in mice. Therefore, TPC proteins play a key role in Ebola virus infection and may be effective targets for antiviral therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550587/" 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/PMC4550587/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sakurai, Yasuteru -- Kolokoltsov, Andrey A -- Chen, Cheng-Chang -- Tidwell, Michael W -- Bauta, William E -- Klugbauer, Norbert -- Grimm, Christian -- Wahl-Schott, Christian -- Biel, Martin -- Davey, Robert A -- R01 AI063513/AI/NIAID NIH HHS/ -- R01AI063513/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 27;347(6225):995-8. doi: 10.1126/science.1258758.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Texas Biomedical Research Institute, San Antonio, TX, USA. ; The University of Texas Medical Branch, Galveston, TX, USA. ; Center for Integrated Protein Science Munich (CIPSM) at the Department of Pharmacy-Center for Drug Research, Ludwig-Maximilians-Universitat Munchen, Munich, Germany. ; Southwest Research Institute, San Antonio, TX, USA. ; Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-Universitat Freiburg, Freiburg, Germany. ; Texas Biomedical Research Institute, San Antonio, TX, USA. rdavey@txbiomed.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25722412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiviral Agents/*pharmacology/therapeutic use ; BALB 3T3 Cells ; Benzylisoquinolines/pharmacology/therapeutic use ; Calcium Channel Blockers/*pharmacology/therapeutic use ; Calcium Channels/genetics/*physiology ; Ebolavirus/drug effects/*physiology ; Female ; Gene Knockout Techniques ; HeLa Cells ; Hemorrhagic Fever, Ebola/drug therapy/*therapy/virology ; Humans ; Macrophages/drug effects/virology ; Mice ; *Molecular Targeted Therapy ; NADP/analogs & derivatives/metabolism ; RNA Interference ; Signal Transduction ; Verapamil/pharmacology/therapeutic use ; Virus Internalization/*drug effects
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 28
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    Malaria. A forward genetic screen identifies erythrocyte CD55 as essential for Plasmodium falciparum invasion (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-05-09
    Description: Efforts to identify host determinants for malaria have been hindered by the absence of a nucleus in erythrocytes, which precludes genetic manipulation in the cell in which the parasite replicates. We used cultured red blood cells derived from hematopoietic stem cells to carry out a forward genetic screen for Plasmodium falciparum host determinants. We found that CD55 is an essential host factor for P. falciparum invasion. CD55-null erythrocytes were refractory to invasion by all isolates of P. falciparum because parasites failed to attach properly to the erythrocyte surface. Thus, CD55 is an attractive target for the development of malaria therapeutics. Hematopoietic stem cell-based forward genetic screens may be valuable for the identification of additional host determinants of malaria pathogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465434/" 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/PMC4465434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Egan, Elizabeth S -- Jiang, Rays H Y -- Moechtar, Mischka A -- Barteneva, Natasha S -- Weekes, Michael P -- Nobre, Luis V -- Gygi, Steven P -- Paulo, Joao A -- Frantzreb, Charles -- Tani, Yoshihiko -- Takahashi, Junko -- Watanabe, Seishi -- Goldberg, Jonathan -- Paul, Aditya S -- Brugnara, Carlo -- Root, David E -- Wiegand, Roger C -- Doench, John G -- Duraisingh, Manoj T -- 100140/Wellcome Trust/United Kingdom -- 1K08AI103034-01A1/AI/NIAID NIH HHS/ -- K01 DK098285/DK/NIDDK NIH HHS/ -- K01DK098285/DK/NIDDK NIH HHS/ -- K08 AI103034/AI/NIAID NIH HHS/ -- K12-HD000850/HD/NICHD NIH HHS/ -- R01AI091787/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 May 8;348(6235):711-4. doi: 10.1126/science.aaa3526.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Division of Infectious Diseases, Boston Children's Hospital, Boston, MA, USA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. Department of Global Health and Center for Drug Discovery and Innovation, University of South Florida, Tampa, FL, USA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. ; Department of Pediatrics, Harvard Medical School and Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA. ; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK. ; Department of Cell Biology, Harvard Medical School, Boston, MA, USA. ; Japanese Red Cross Kinki Block Blood Center, Osaka, Japan. ; Japanese Red Cross Kyushu Block Blood Center, Fukuoka, Japan. ; Department of Laboratory Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. ; The Broad Institute of Harvard and Massachussetts Insititute of Technology, Cambridge, MA, USAA. ; Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, MA, USA. The Broad Institute of Harvard and Massachussetts Insititute of Technology, Cambridge, MA, USAA. mduraisi@hsph.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25954012" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD44/genetics ; Antigens, CD55/*genetics ; Cell Differentiation/genetics ; Cells, Cultured ; Erythrocytes/cytology/metabolism/*parasitology ; Genetic Testing ; Hematopoietic Stem Cells/cytology ; Host-Parasite Interactions/*genetics ; Humans ; Malaria, Falciparum/*genetics/*parasitology ; Plasmodium falciparum/*pathogenicity ; RNA, Small Interfering/genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    HEART DISEASE. Titin mutations in iPS cells define sarcomere insufficiency as a cause of dilated cardiomyopathy (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-01
    Description: Human mutations that truncate the massive sarcomere protein titin [TTN-truncating variants (TTNtvs)] are the most common genetic cause for dilated cardiomyopathy (DCM), a major cause of heart failure and premature death. Here we show that cardiac microtissues engineered from human induced pluripotent stem (iPS) cells are a powerful system for evaluating the pathogenicity of titin gene variants. We found that certain missense mutations, like TTNtvs, diminish contractile performance and are pathogenic. By combining functional analyses with RNA sequencing, we explain why truncations in the A-band domain of TTN cause DCM, whereas truncations in the I band are better tolerated. Finally, we demonstrate that mutant titin protein in iPS cell-derived cardiomyocytes results in sarcomere insufficiency, impaired responses to mechanical and beta-adrenergic stress, and attenuated growth factor and cell signaling activation. Our findings indicate that titin mutations cause DCM by disrupting critical linkages between sarcomerogenesis and adaptive remodeling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4618316/" 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/PMC4618316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hinson, John T -- Chopra, Anant -- Nafissi, Navid -- Polacheck, William J -- Benson, Craig C -- Swist, Sandra -- Gorham, Joshua -- Yang, Luhan -- Schafer, Sebastian -- Sheng, Calvin C -- Haghighi, Alireza -- Homsy, Jason -- Hubner, Norbert -- Church, George -- Cook, Stuart A -- Linke, Wolfgang A -- Chen, Christopher S -- Seidman, J G -- Seidman, Christine E -- EB017103/EB/NIBIB NIH HHS/ -- HG005550/HG/NHGRI NIH HHS/ -- HL007374/HL/NHLBI NIH HHS/ -- HL115553/HL/NHLBI NIH HHS/ -- HL125807/HL/NHLBI NIH HHS/ -- K08 HL125807/HL/NHLBI NIH HHS/ -- T32 HL007208/HL/NHLBI NIH HHS/ -- Department of Health/United Kingdom -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):982-6. doi: 10.1126/science.aaa5458.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu. ; Department of Biomedical Engineering, Boston University, Boston, MA 02215, USA. The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. ; Department of Cardiovascular Physiology, Ruhr University Bochum, MA 3/56 D-44780, Bochum, Germany. ; The Wyss Institute for Biologically Inspired Engineering at Harvard University, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. ; Cardiovascular and Metabolic Sciences, Max Delbruck Center for Molecular Medicine, Berlin, Germany. DZHK (German Center for Cardiovascular Research), Partner Site Berlin, Berlin, Germany. ; National Institute for Health Research (NIHR) Biomedical Research Unit in Cardiovascular Disease at Royal Brompton and Harefield National Health Service (NHS) Foundation Trust, Imperial College London, London, UK. National Heart Centre and Duke-National University, Singapore, Singapore. ; Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. jthinson@partners.org cseidman@genetics.med.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315439" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenergic beta-Agonists/pharmacology ; Cardiomyopathy, Dilated/*genetics/pathology/*physiopathology ; Cells, Cultured ; Connectin/chemistry/*genetics/*physiology ; Heart Rate ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Isoproterenol/pharmacology ; Mutant Proteins/chemistry/physiology ; *Mutation, Missense ; Myocardial Contraction ; Myocytes, Cardiac/*physiology ; RNA/genetics/metabolism ; Sarcomeres/*physiology/ultrastructure ; Sequence Analysis, RNA ; Signal Transduction ; Stress, Physiological
    Print ISSN: 0036-8075
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    CELL DIVISION CYCLE. Competition between MPS1 and microtubules at kinetochores regulates spindle checkpoint signaling (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-06-13
    Description: Cell division progresses to anaphase only after all chromosomes are connected to spindle microtubules through kinetochores and the spindle assembly checkpoint (SAC) is satisfied. We show that the amino-terminal localization module of the SAC protein kinase MPS1 (monopolar spindle 1) directly interacts with the HEC1 (highly expressed in cancer 1) calponin homology domain in the NDC80 (nuclear division cycle 80) kinetochore complex in vitro, in a phosphorylation-dependent manner. Microtubule polymers disrupted this interaction. In cells, MPS1 binding to kinetochores or to ectopic NDC80 complexes was prevented by end-on microtubule attachment, independent of known kinetochore protein-removal mechanisms. Competition for kinetochore binding between SAC proteins and microtubules provides a direct and perhaps evolutionarily conserved way to detect a properly organized spindle ready for cell division.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hiruma, Yoshitaka -- Sacristan, Carlos -- Pachis, Spyridon T -- Adamopoulos, Athanassios -- Kuijt, Timo -- Ubbink, Marcellus -- von Castelmur, Eleonore -- Perrakis, Anastassis -- Kops, Geert J P L -- New York, N.Y. -- Science. 2015 Jun 12;348(6240):1264-7. doi: 10.1126/science.aaa4055. Epub 2015 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Leiden Institute of Chemistry, Leiden University, Post Office Box 9502, 2300 RA Leiden, Netherlands. ; Division of Biochemistry, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl. ; Molecular Cancer Research, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, Netherlands. g.j.p.l.kops@umcutrecht.nl a.perrakis@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26068855" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; Binding, Competitive ; Calcium-Binding Proteins/genetics/metabolism ; *Cell Cycle Checkpoints ; Cell Cycle Proteins/*metabolism ; HeLa Cells ; Humans ; Kinetochores/*metabolism ; Microfilament Proteins/genetics/metabolism ; Microtubules/*metabolism ; Nuclear Proteins/chemistry/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/*metabolism ; Protein-Tyrosine Kinases/*metabolism ; Signal Transduction ; Spindle Apparatus/*metabolism
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    A brain circuit that synchronizes growth and maturation revealed through Dilp8 binding to Lgr3 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-10-03
    Description: Body-size constancy and symmetry are signs of developmental stability. Yet, it is unclear exactly how developing animals buffer size variation. Drosophila insulin-like peptide Dilp8 is responsive to growth perturbations and controls homeostatic mechanisms that coordinately adjust growth and maturation to maintain size within the normal range. Here we show that Lgr3 is a Dilp8 receptor. Through the use of functional and adenosine 3',5'-monophosphate assays, we defined a pair of Lgr3 neurons that mediate homeostatic regulation. These neurons have extensive axonal arborizations, and genetic and green fluorescent protein reconstitution across synaptic partners show that these neurons connect with the insulin-producing cells and prothoracicotropic hormone-producing neurons to attenuate growth and maturation. This previously unrecognized circuit suggests how growth and maturation rate are matched and co-regulated according to Dilp8 signals to stabilize organismal size.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vallejo, Diana M -- Juarez-Carreno, Sergio -- Bolivar, Jorge -- Morante, Javier -- Dominguez, Maria -- OD010949-10/OD/NIH HHS/ -- P40OD018537/OD/NIH HHS/ -- R01-GM084947/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):aac6767. doi: 10.1126/science.aac6767. Epub 2015 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, Campus de Sant Joan, Apartado 18, 03550 Sant Joan, Alicante, Spain. ; Departamento de Biomedicina, Biotecnologia y Salud Publica, Facultad de Ciencias, Universidad de Cadiz, Poligono Rio San Pedro s/n, 11510 Puerto Real, Spain. ; Instituto de Neurociencias, Consejo Superior de Investigaciones Cientificas and Universidad Miguel Hernandez, Campus de Sant Joan, Apartado 18, 03550 Sant Joan, Alicante, Spain. m.dominguez@umh.es j.morante@umh.es.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26429885" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Monophosphate/metabolism ; Animals ; Body Size ; Brain/cytology/*growth & development/metabolism ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*growth & development/metabolism ; Homeostasis ; Insect Hormones/genetics/metabolism ; Insulin/*metabolism ; Intercellular Signaling Peptides and Proteins/genetics/*metabolism ; Nerve Net/cytology/metabolism ; Neurons/*metabolism ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Receptors, Peptide/genetics/*metabolism ; Signal Transduction ; Synapses/metabolism
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    Cell nonautonomous activation of flavin-containing monooxygenase promotes longevity and health span (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-11-21
    Description: Stabilization of the hypoxia-inducible factor 1 (HIF-1) increases life span and health span in nematodes through an unknown mechanism. We report that neuronal stabilization of HIF-1 mediates these effects in Caenorhabditis elegans through a cell nonautonomous signal to the intestine, which results in activation of the xenobiotic detoxification enzyme flavin-containing monooxygenase-2 (FMO-2). This prolongevity signal requires the serotonin biosynthetic enzyme TPH-1 in neurons and the serotonin receptor SER-7 in the intestine. Intestinal FMO-2 is also activated by dietary restriction (DR) and is necessary for DR-mediated life-span extension, which suggests that this enzyme represents a point of convergence for two distinct longevity pathways. FMOs are conserved in eukaryotes and induced by multiple life span-extending interventions in mice, which suggests that these enzymes may play a critical role in promoting health and longevity across phyla.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Leiser, Scott F -- Miller, Hillary -- Rossner, Ryan -- Fletcher, Marissa -- Leonard, Alison -- Primitivo, Melissa -- Rintala, Nicholas -- Ramos, Fresnida J -- Miller, Dana L -- Kaeberlein, Matt -- P30AG013280/AG/NIA NIH HHS/ -- R00AGA0033050/PHS HHS/ -- R01AG038518/AG/NIA NIH HHS/ -- T32AG000057/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Dec 11;350(6266):1375-8. doi: 10.1126/science.aac9257. Epub 2015 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of Washington, Seattle, WA 98195, USA. ; Department of Biochemistry, University of Washington, Seattle, WA 98195, USA. ; Department of Pathology, University of Washington, Seattle, WA 98195, USA. kaeber@uw.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586189" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Caenorhabditis elegans/genetics/metabolism/*physiology ; Caenorhabditis elegans Proteins/chemistry/genetics/metabolism/*physiology ; Diet ; Intestines/*enzymology ; Longevity/genetics/*physiology ; Mice ; Neurons/*metabolism ; Oxygenases/genetics/*physiology ; Protein Stability ; RNA Interference ; Receptors, Serotonin/metabolism ; Signal Transduction ; Transcription Factors/chemistry/*metabolism ; Tryptophan Hydroxylase/metabolism
    Print ISSN: 0036-8075
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    Human oocytes. Error-prone chromosome-mediated spindle assembly favors chromosome segregation defects in human oocytes (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-06-06
    Description: Aneuploidy in human eggs is the leading cause of pregnancy loss and several genetic disorders such as Down syndrome. Most aneuploidy results from chromosome segregation errors during the meiotic divisions of an oocyte, the egg's progenitor cell. The basis for particularly error-prone chromosome segregation in human oocytes is not known. We analyzed meiosis in more than 100 live human oocytes and identified an error-prone chromosome-mediated spindle assembly mechanism as a major contributor to chromosome segregation defects. Human oocytes assembled a meiotic spindle independently of either centrosomes or other microtubule organizing centers. Instead, spindle assembly was mediated by chromosomes and the small guanosine triphosphatase Ran in a process requiring ~16 hours. This unusually long spindle assembly period was marked by intrinsic spindle instability and abnormal kinetochore-microtubule attachments, which favor chromosome segregation errors and provide a possible explanation for high rates of aneuploidy in human eggs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477045/" 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/PMC4477045/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Holubcova, Zuzana -- Blayney, Martyn -- Elder, Kay -- Schuh, Melina -- MC_U105192711/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jun 5;348(6239):1143-7. doi: 10.1126/science.aaa9529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Bourn Hall Clinic, Bourn, Cambridge CB23 2TN, UK. ; Medical Research Council, Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. mschuh@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26045437" target="_blank"〉PubMed〈/a〉
    Keywords: Anaphase ; *Aneuploidy ; Animals ; Cells, Cultured ; *Chromosome Segregation ; Female ; Green Fluorescent Proteins/genetics/metabolism ; Humans ; Kinetochores/metabolism ; *Meiosis ; Mice ; Microtubule-Associated Proteins/genetics/metabolism ; Microtubule-Organizing Center/metabolism ; Oocytes/*pathology ; Spindle Apparatus/*metabolism ; ran GTP-Binding Protein/metabolism
    Print ISSN: 0036-8075
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    Farm dust and endotoxin protect against allergy through A20 induction in lung epithelial cells (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-05
    Description: Growing up on a dairy farm protects children from allergy, hay fever, and asthma. A mechanism linking exposure to this endotoxin (bacterial lipopolysaccharide)-rich environment with protection has remained elusive. Here we show that chronic exposure to low-dose endotoxin or farm dust protects mice from developing house dust mite (HDM)-induced asthma. Endotoxin reduced epithelial cell cytokines that activate dendritic cells (DCs), thus suppressing type 2 immunity to HDMs. Loss of the ubiquitin-modifying enzyme A20 in lung epithelium abolished the protective effect. A single-nucleotide polymorphism in the gene encoding A20 was associated with allergy and asthma risk in children growing up on farms. Thus, the farming environment protects from allergy by modifying the communication between barrier epithelial cells and DCs through A20 induction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schuijs, Martijn J -- Willart, Monique A -- Vergote, Karl -- Gras, Delphine -- Deswarte, Kim -- Ege, Markus J -- Madeira, Filipe Branco -- Beyaert, Rudi -- van Loo, Geert -- Bracher, Franz -- von Mutius, Erika -- Chanez, Pascal -- Lambrecht, Bart N -- Hammad, Hamida -- New York, N.Y. -- Science. 2015 Sep 4;349(6252):1106-10. doi: 10.1126/science.aac6623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. ; Department of Respiratory Medicine, Assistance Publique Hopitaux de Marseille, UMR INSERM U1067 CNRS 7333, Aix Marseille University, Marseille, France. ; Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universitat, Munich, Germany. ; Unit of Molecular Signal Transduction, VIB Inflammation Research Center, Ghent, Belgium. Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. ; Center for Drug Research, Department of Pharmacy, Ludwig Maximilians University, Butenandtstrasse 5-13, D-81377 Munich, Germany. ; Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. Department of Pulmonary Medicine, Erasmus Medical Center, Rotterdam, Netherlands. hamida.hammad@ugent.be bart.lambrecht@ugent.be. ; Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium. Department of Internal Medicine, Ghent University, Ghent, Belgium. hamida.hammad@ugent.be bart.lambrecht@ugent.be.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26339029" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/immunology/prevention & control ; Cells, Cultured ; Child ; DNA-Binding Proteins/*biosynthesis ; Dairying ; Dendritic Cells/immunology ; Dust/*immunology ; Female ; Humans ; Hygiene Hypothesis ; Hypersensitivity/enzymology/immunology/*prevention & control ; Inhalation Exposure ; Intracellular Signaling Peptides and Proteins/*biosynthesis ; Lipopolysaccharides/*immunology ; Lung/*enzymology/immunology ; Mice ; Mice, Inbred C57BL ; Nuclear Proteins/*biosynthesis ; Pyroglyphidae/*immunology ; Respiratory Mucosa/*enzymology/immunology
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    Aging. Lysosomal signaling molecules regulate longevity in Caenorhabditis elegans (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-01-03
    Description: Lysosomes are crucial cellular organelles for human health that function in digestion and recycling of extracellular and intracellular macromolecules. We describe a signaling role for lysosomes that affects aging. In the worm Caenorhabditis elegans, the lysosomal acid lipase LIPL-4 triggered nuclear translocalization of a lysosomal lipid chaperone LBP-8, which promoted longevity by activating the nuclear hormone receptors NHR-49 and NHR-80. We used high-throughput metabolomic analysis to identify several lipids in which abundance was increased in worms constitutively overexpressing LIPL-4. Among them, oleoylethanolamide directly bound to LBP-8 and NHR-80 proteins, activated transcription of target genes of NHR-49 and NHR-80, and promoted longevity in C. elegans. These findings reveal a lysosome-to-nucleus signaling pathway that promotes longevity and suggest a function of lysosomes as signaling organelles in metazoans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4425353/" 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/PMC4425353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Folick, Andrew -- Oakley, Holly D -- Yu, Yong -- Armstrong, Eric H -- Kumari, Manju -- Sanor, Lucas -- Moore, David D -- Ortlund, Eric A -- Zechner, Rudolf -- Wang, Meng C -- F30 AG046043/AG/NIA NIH HHS/ -- F30AG046043/AG/NIA NIH HHS/ -- R00 AG034988/AG/NIA NIH HHS/ -- R00AG034988/AG/NIA NIH HHS/ -- R01 AG045183/AG/NIA NIH HHS/ -- R01 DK095750/DK/NIDDK NIH HHS/ -- R01AG045183/AG/NIA NIH HHS/ -- R01DK095750/DK/NIDDK NIH HHS/ -- T32 GM008602/GM/NIGMS NIH HHS/ -- T32GM008602/GM/NIGMS NIH HHS/ -- T32HD055200/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 2;347(6217):83-6. doi: 10.1126/science.1258857.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. ; Department of Biochemistry, Discovery and Developmental Therapeutics, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. ; Institute of Molecular Biosciences, University of Graz, Graz, A-8010, Austria. ; Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA. ; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA. Huffington Center on Aging, Baylor College of Medicine, Houston, TX 77030, USA. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA. wmeng@bcm.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25554789" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Caenorhabditis elegans/genetics/*physiology ; Caenorhabditis elegans Proteins/genetics/*metabolism ; Cell Nucleus/metabolism ; Lipase/metabolism ; Lipid Metabolism ; Longevity/genetics/*physiology ; Lysosomes/*metabolism ; Molecular Chaperones/genetics/*metabolism ; Receptors, Cytoplasmic and Nuclear/metabolism ; Signal Transduction
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    SYNTHETIC BIOLOGY. Emergent genetic oscillations in a synthetic microbial consortium (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-09-01
    Description: A challenge of synthetic biology is the creation of cooperative microbial systems that exhibit population-level behaviors. Such systems use cellular signaling mechanisms to regulate gene expression across multiple cell types. We describe the construction of a synthetic microbial consortium consisting of two distinct cell types-an "activator" strain and a "repressor" strain. These strains produced two orthogonal cell-signaling molecules that regulate gene expression within a synthetic circuit spanning both strains. The two strains generated emergent, population-level oscillations only when cultured together. Certain network topologies of the two-strain circuit were better at maintaining robust oscillations than others. The ability to program population-level dynamics through the genetic engineering of multiple cooperative strains points the way toward engineering complex synthetic tissues and organs with multiple cell types.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4597888/" 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/PMC4597888/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Ye -- Kim, Jae Kyoung -- Hirning, Andrew J -- Josic, Kresimir -- Bennett, Matthew R -- R01 GM104974/GM/NIGMS NIH HHS/ -- R01GM104974/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 28;349(6251):986-9. doi: 10.1126/science.aaa3794.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biosciences, Rice University, Houston, TX 77005, USA. ; Department of Mathematical Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Korea. Mathematical Biosciences Institute, The Ohio State University, Columbus, OH 43210, USA. ; Department of Mathematics, University of Houston, Houston, TX 77204, USA. Department of Biology and Biochemistry, University of Houston, Houston, TX 77204, USA. ; Department of Biosciences, Rice University, Houston, TX 77005, USA. Institute of Biosciences and Bioengineering, Rice University, Houston, TX 77005, USA. matthew.bennett@rice.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26315440" target="_blank"〉PubMed〈/a〉
    Keywords: 4-Butyrolactone/analogs & derivatives/metabolism ; Escherichia coli/*genetics/*physiology ; Escherichia coli Proteins/genetics/metabolism ; Feedback, Physiological ; *Gene Expression Regulation, Bacterial ; *Gene Regulatory Networks ; Genetic Engineering ; Lab-On-A-Chip Devices ; Microbial Consortia/*genetics/*physiology ; Microbial Interactions ; Models, Biological ; Promoter Regions, Genetic ; Quorum Sensing ; Signal Transduction ; Synthetic Biology ; Transcription, Genetic
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    TDP-43 repression of nonconserved cryptic exons is compromised in ALS-FTD (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-08-08
    Description: Cytoplasmic aggregation of TDP-43, accompanied by its nuclear clearance, is a key common pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD). However, a limited understanding of this RNA-binding protein (RBP) impedes the clarification of pathogenic mechanisms underlying TDP-43 proteinopathy. In contrast to RBPs that regulate splicing of conserved exons, we found that TDP-43 repressed the splicing of nonconserved cryptic exons, maintaining intron integrity. When TDP-43 was depleted from mouse embryonic stem cells, these cryptic exons were spliced into messenger RNAs, often disrupting their translation and promoting nonsense-mediated decay. Moreover, enforced repression of cryptic exons prevented cell death in TDP-43-deficient cells. Furthermore, repression of cryptic exons was impaired in ALS-FTD cases, suggesting that this splicing defect could potentially underlie TDP-43 proteinopathy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ling, Jonathan P -- Pletnikova, Olga -- Troncoso, Juan C -- Wong, Philip C -- P50AG05146/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2015 Aug 7;349(6248):650-5. doi: 10.1126/science.aab0983.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. wong@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26250685" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/*genetics ; Animals ; Base Sequence ; Cells, Cultured ; Cysteine Endopeptidases/genetics ; DNA-Binding Proteins/genetics/*physiology ; Embryonic Stem Cells ; Exons/*genetics ; Frontotemporal Dementia/*genetics ; Gene Knockout Techniques ; HeLa Cells ; Humans ; Mice ; Molecular Sequence Data ; Protein Isoforms/genetics ; *RNA Splicing ; RNA Stability ; RNA, Messenger/metabolism ; Sequence Analysis, DNA
    Print ISSN: 0036-8075
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    Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    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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    Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    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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    Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-07-18
    Description: Secretion of the cytokine interleukin-1beta (IL-1beta) by macrophages, a major driver of pathogenesis in atherosclerosis, requires two steps: Priming signals promote transcription of immature IL-1beta, and then endogenous "danger" signals activate innate immune signaling complexes called inflammasomes to process IL-1beta for secretion. Although cholesterol crystals are known to act as danger signals in atherosclerosis, what primes IL-1beta transcription remains elusive. Using a murine model of atherosclerosis, we found that cholesterol crystals acted both as priming and danger signals for IL-1beta production. Cholesterol crystals triggered neutrophils to release neutrophil extracellular traps (NETs). NETs primed macrophages for cytokine release, activating T helper 17 (TH17) cells that amplify immune cell recruitment in atherosclerotic plaques. Therefore, danger signals may drive sterile inflammation, such as that seen in atherosclerosis, through their interactions with neutrophils.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warnatsch, Annika -- Ioannou, Marianna -- Wang, Qian -- Papayannopoulos, Venizelos -- MC_UP_1202/13/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2015 Jul 17;349(6245):316-20. doi: 10.1126/science.aaa8064. Epub 2015 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. ; Mill Hill Laboratory, Francis Crick Institute, London NW7 1AA, UK. veni.p@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26185250" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*immunology ; Cells, Cultured ; Cholesterol/chemistry/immunology ; Disease Models, Animal ; Extracellular Traps/*immunology ; Humans ; Inflammasomes/immunology ; Inflammation/immunology ; Interleukin-1beta/*biosynthesis/genetics ; Macrophages/*immunology ; Mice ; Mice, Mutant Strains ; Neutrophils/*immunology ; Signal Transduction ; Th17 Cells/immunology ; Transcription, Genetic
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    Cancer's copper connections (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-07-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garber, Ken -- New York, N.Y. -- Science. 2015 Jul 10;349(6244):129. doi: 10.1126/science.349.6244.129.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26160924" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Oxidoreductases/chemistry/metabolism ; Collagen/metabolism ; Copper/*metabolism ; Humans ; Melanoma/drug therapy/pathology ; Neoplasms/*drug therapy/pathology ; Proto-Oncogene Proteins B-raf/*antagonists & inhibitors/genetics ; Signal Transduction ; Skin Diseases/drug therapy/pathology
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    Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway (2015)
    American Association for the Advancement of Science (AAAS)
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    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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    Spatial navigation. Disruption of the head direction cell network impairs the parahippocampal grid cell signal (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-02-24
    Description: Navigation depends on multiple neural systems that encode the moment-to-moment changes in an animal's direction and location in space. These include head direction (HD) cells representing the orientation of the head and grid cells that fire at multiple locations, forming a repeating hexagonal grid pattern. Computational models hypothesize that generation of the grid cell signal relies upon HD information that ascends to the hippocampal network via the anterior thalamic nuclei (ATN). We inactivated or lesioned the ATN and subsequently recorded single units in the entorhinal cortex and parasubiculum. ATN manipulation significantly disrupted grid and HD cell characteristics while sparing theta rhythmicity in these regions. These results indicate that the HD signal via the ATN is necessary for the generation and function of grid cell activity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476794/" 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/PMC4476794/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Winter, Shawn S -- Clark, Benjamin J -- Taube, Jeffrey S -- NS053907/NS/NINDS NIH HHS/ -- R01 MH048924/MH/NIMH NIH HHS/ -- R01 NS053907/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):870-4. doi: 10.1126/science.1259591. Epub 2015 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA. ; Department of Psychological and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth College, Hanover, NH 03755, USA. jeffrey.taube@dartmouth.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700518" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anterior Thalamic Nuclei/drug effects/*physiology ; Entorhinal Cortex/cytology/*physiology ; Female ; Head ; Hippocampus/cytology/physiology ; Lidocaine/pharmacology ; Nerve Net/cytology/drug effects/*physiology ; Neurons/*physiology ; Orientation/*physiology ; Rats ; Rats, Inbred LEC ; Signal Transduction ; Spatial Navigation/*physiology ; Theta Rhythm
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    A gut-vascular barrier controls the systemic dissemination of bacteria (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-11-14
    Description: In healthy individuals, the intestinal microbiota cannot access the liver, spleen, or other peripheral tissues. Some pathogenic bacteria can reach these sites, however, and can induce a systemic immune response. How such compartmentalization is achieved is unknown. We identify a gut-vascular barrier (GVB) in mice and humans that controls the translocation of antigens into the blood stream and prohibits entry of the microbiota. Salmonella typhimurium can penetrate the GVB in a manner dependent on its pathogenicity island (Spi) 2-encoded type III secretion system and on decreased beta-catenin-dependent signaling in gut endothelial cells. The GVB is modified in celiac disease patients with elevated serum transaminases, which indicates that GVB dismantling may be responsible for liver damage in these patients. Understanding the GVB may provide new insights into the regulation of the gut-liver axis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spadoni, Ilaria -- Zagato, Elena -- Bertocchi, Alice -- Paolinelli, Roberta -- Hot, Edina -- Di Sabatino, Antonio -- Caprioli, Flavio -- Bottiglieri, Luca -- Oldani, Amanda -- Viale, Giuseppe -- Penna, Giuseppe -- Dejana, Elisabetta -- Rescigno, Maria -- New York, N.Y. -- Science. 2015 Nov 13;350(6262):830-4. doi: 10.1126/science.aad0135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. ; The Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. ; First Department of Medicine, St. Matteo Hospital, University of Pavia, Pavia, Italy. ; Unita Operativa Gastroenterologia ed Endoscopia, Fondazione IRCCS Ca Granda, Ospedale Maggiore Policlinico di Milano, and Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Universita degli Studi di Milano, Milan, Italy. ; Department of Pathology and Laboratory Medicine, European Institute of Oncology, Milan, Italy. ; The Italian Foundation for Cancer Research (FIRC) Institute of Molecular Oncology (IFOM), Milan, Italy. Department of Biosciences, Universita degli Studi di Milano, Italy. Department of Genetics, Immunology and Pathology, Uppsala University, Uppsala, Sweden. ; Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. Department of Biosciences, Universita degli Studi di Milano, Italy. maria.rescigno@ieo.eu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26564856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Bacterial/blood/immunology ; Capillary Permeability/*immunology ; Celiac Disease/blood/immunology/microbiology ; Genomic Islands/genetics/immunology ; Humans ; Ileum/blood supply/immunology/microbiology ; Intestinal Mucosa/immunology/microbiology ; Intestines/blood supply/*immunology/*microbiology ; Liver/immunology ; Mice ; Mice, Inbred C57BL ; Microbiota/*immunology ; Salmonella Infections/*immunology ; Salmonella typhimurium/genetics/*immunology/pathogenicity ; Signal Transduction ; Spleen/immunology ; Transaminases/blood ; Type III Secretion Systems/genetics/immunology ; Wnt Signaling Pathway ; beta Catenin/metabolism
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    Proteasomes. A molecular census of 26S proteasomes in intact neurons (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-01-24
    Description: The 26S proteasome is a key player in eukaryotic protein quality control and in the regulation of numerous cellular processes. Here, we describe quantitative in situ structural studies of this highly dynamic molecular machine in intact hippocampal neurons. We used electron cryotomography with the Volta phase plate, which allowed high fidelity and nanometer precision localization of 26S proteasomes. We undertook a molecular census of single- and double-capped proteasomes and assessed the conformational states of individual complexes. Under the conditions of the experiment-that is, in the absence of proteotoxic stress-only 20% of the 26S proteasomes were engaged in substrate processing. The remainder was in the substrate-accepting ground state. These findings suggest that in the absence of stress, the capacity of the proteasome system is not fully used.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asano, Shoh -- Fukuda, Yoshiyuki -- Beck, Florian -- Aufderheide, Antje -- Forster, Friedrich -- Danev, Radostin -- Baumeister, Wolfgang -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):439-42. doi: 10.1126/science.1261197.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany. ; Department of Molecular Structural Biology, Max-Planck Institute of Biochemistry, 82152 Martinsried, Germany. baumeist@biochem.mpg.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25613890" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Hippocampus/*cytology/enzymology ; Neurons/*enzymology/*ultrastructure ; Proteasome Endopeptidase Complex/*chemistry ; Protein Conformation ; Rats ; Stress, Physiological
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    The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-09-26
    Description: Cellular senescence is a terminal stress-activated program controlled by the p53 and p16(INK4a) tumor suppressor proteins. A striking feature of senescence is the senescence-associated secretory phenotype (SASP), a pro-inflammatory response linked to tumor promotion and aging. We have identified the transcription factor GATA4 as a senescence and SASP regulator. GATA4 is stabilized in cells undergoing senescence and is required for the SASP. Normally, GATA4 is degraded by p62-mediated selective autophagy, but this regulation is suppressed during senescence, thereby stabilizing GATA4. GATA4 in turn activates the transcription factor NF-kappaB to initiate the SASP and facilitate senescence. GATA4 activation depends on the DNA damage response regulators ATM and ATR, but not on p53 or p16(INK4a). GATA4 accumulates in multiple tissues, including the aging brain, and could contribute to aging and its associated inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Chanhee -- Xu, Qikai -- Martin, Timothy D -- Li, Mamie Z -- Demaria, Marco -- Aron, Liviu -- Lu, Tao -- Yankner, Bruce A -- Campisi, Judith -- Elledge, Stephen J -- AG009909/AG/NIA NIH HHS/ -- AG017242/AG/NIA NIH HHS/ -- AG046174/AG/NIA NIH HHS/ -- DP1 OD006849/OD/NIH HHS/ -- DP1OD006849/OD/NIH HHS/ -- GM44664/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2015 Sep 25;349(6255):aaa5612. doi: 10.1126/science.aaa5612.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. ; Buck Institute for Research on Aging, Novato, CA 94945, USA. ; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics, Harvard Medical School, Division of Genetics, Brigham and Women's Hospital, Howard Hughes Medical Institute, Boston, MA 02115, USA. selledge@genetics.med.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26404840" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*genetics/metabolism ; Animals ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Autophagy/*genetics ; Brain/metabolism ; Cell Aging/*genetics ; Cell Cycle/genetics ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16 ; *DNA Damage ; Fibroblasts ; GATA4 Transcription Factor/genetics/*metabolism ; Gene Expression Profiling ; Humans ; Inflammation/*genetics ; Interleukin-1alpha/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics/metabolism ; NF-kappa B/metabolism ; Phenotype ; Promoter Regions, Genetic ; Tumor Necrosis Factor Receptor-Associated Peptides and ; Proteins/genetics/metabolism ; Tumor Suppressor Protein p53/metabolism
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    Dopamine and serotonin signals for reward across time scales (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-10-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jeremiah Y -- New York, N.Y. -- Science. 2015 Oct 2;350(6256):47. doi: 10.1126/science.aad3003.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, Brain Science Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. jeremiah.cohen@jhmi.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26430113" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*physiology ; Dopamine/*metabolism ; Dopaminergic Neurons/*metabolism ; Electric Stimulation ; Humans ; Mice ; Neurophysiology/trends ; *Reward ; Serotonin/*metabolism ; Signal Transduction ; Time Factors ; Ventral Tegmental Area/*cytology
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    Insulin granules. Insulin secretory granules control autophagy in pancreatic beta cells (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-02-24
    Description: Pancreatic beta cells lower insulin release in response to nutrient depletion. The question of whether starved beta cells induce macroautophagy, a predominant mechanism maintaining energy homeostasis, remains poorly explored. We found that, in contrast to many mammalian cells, macroautophagy in pancreatic beta cells was suppressed upon starvation. Instead, starved beta cells induced lysosomal degradation of nascent secretory insulin granules, which was controlled by protein kinase D (PKD), a key player in secretory granule biogenesis. Starvation-induced nascent granule degradation triggered lysosomal recruitment and activation of mechanistic target of rapamycin that suppressed macroautophagy. Switching from macroautophagy to insulin granule degradation was important to keep insulin secretion low upon fasting. Thus, beta cells use a PKD-dependent mechanism to adapt to nutrient availability and couple autophagy flux to secretory function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goginashvili, Alexander -- Zhang, Zhirong -- Erbs, Eric -- Spiegelhalter, Coralie -- Kessler, Pascal -- Mihlan, Michael -- Pasquier, Adrien -- Krupina, Ksenia -- Schieber, Nicole -- Cinque, Laura -- Morvan, Joelle -- Sumara, Izabela -- Schwab, Yannick -- Settembre, Carmine -- Ricci, Romeo -- New York, N.Y. -- Science. 2015 Feb 20;347(6224):878-82. doi: 10.1126/science.aaa2628.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM, CNRS, Universite de Strasbourg, 67404 Illkirch, France. ; Cell Biology and Biophysics Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany. ; Dulbecco Telethon Institute and Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy. ; Dulbecco Telethon Institute and Telethon Institute of Genetics and Medicine (TIGEM), 80131 Naples, Italy. Medical Genetics, Department of Medical and Translational Science Unit, Federico II University, Via Pansini 5, 80131 Naples, Italy. ; Institut de Genetique et de Biologie Moleculaire et Cellulaire (IGBMC), INSERM, CNRS, Universite de Strasbourg, 67404 Illkirch, France. Nouvel Hopital Civil, Laboratoire de Biochimie et de Biologie Moleculaire, Universite de Strasbourg, 67091 Strasbourg, France. romeo.ricci@igbmc.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25700520" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Autophagy ; Cells, Cultured ; Fasting ; Humans ; Insulin/*secretion ; Insulin-Secreting Cells/*physiology/secretion/ultrastructure ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 13/genetics ; Protein Kinase C/physiology ; Secretory Vesicles/*physiology/secretion
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    Circuit-specific signaling in astrocyte-neuron networks in basal ganglia pathways (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-08-15
    Description: Astrocytes are important regulatory elements in brain function. They respond to neurotransmitters and release gliotransmitters that modulate synaptic transmission. However, the cell- and synapse-specificity of the functional relationship between astrocytes and neurons in certain brain circuits remains unknown. In the dorsal striatum, which mainly comprises two intermingled subtypes (striatonigral and striatopallidal) of medium spiny neurons (MSNs) and synapses belonging to two neural circuits (the direct and indirect pathways of the basal ganglia), subpopulations of astrocytes selectively responded to specific MSN subtype activity. These subpopulations of astrocytes released glutamate that selectively activated N-methyl-d-aspartate receptors in homotypic, but not heterotypic, MSNs. Likewise, astrocyte subpopulations selectively regulated homotypic synapses through metabotropic glutamate receptor activation. Therefore, bidirectional astrocyte-neuron signaling selectively occurs between specific subpopulations of astrocytes, neurons, and synapses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martin, R -- Bajo-Graneras, R -- Moratalla, R -- Perea, G -- Araque, A -- New York, N.Y. -- Science. 2015 Aug 14;349(6249):730-4. doi: 10.1126/science.aaa7945.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Instituto Cajal, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain. ; Instituto Cajal, Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain. Centro de Investigacion Biomedica en Red Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, 28029 Madrid, Spain. ; Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455, USA. araque@umn.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26273054" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/*physiology ; Basal Ganglia/cytology/*physiology ; Cell Communication ; Glutamates/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Net/physiology ; Neurons/*physiology ; Receptors, Metabotropic Glutamate/agonists/metabolism ; Receptors, N-Methyl-D-Aspartate/agonists/metabolism ; Signal Transduction ; Synapses/*physiology ; *Synaptic Transmission
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    Photochemistry. Chemiexcitation of melanin derivatives induces DNA photoproducts long after UV exposure (2015)
    American Association for the Advancement of Science (AAAS)
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    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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    RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-09-26
    Description: Dying cells initiate adaptive immunity by providing both antigens and inflammatory stimuli for dendritic cells, which in turn activate CD8(+) T cells through a process called antigen cross-priming. To define how different forms of programmed cell death influence immunity, we established models of necroptosis and apoptosis, in which dying cells are generated by receptor-interacting protein kinase-3 and caspase-8 dimerization, respectively. We found that the release of inflammatory mediators, such as damage-associated molecular patterns, by dying cells was not sufficient for CD8(+) T cell cross-priming. Instead, robust cross-priming required receptor-interacting protein kinase-1 (RIPK1) signaling and nuclear factor kappaB (NF-kappaB)-induced transcription within dying cells. Decoupling NF-kappaB signaling from necroptosis or inflammatory apoptosis reduced priming efficiency and tumor immunity. Our results reveal that coordinated inflammatory and cell death signaling pathways within dying cells orchestrate adaptive immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651449/" 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/PMC4651449/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yatim, Nader -- Jusforgues-Saklani, Helene -- Orozco, Susana -- Schulz, Oliver -- Barreira da Silva, Rosa -- Reis e Sousa, Caetano -- Green, Douglas R -- Oberst, Andrew -- Albert, Matthew L -- 5R01AI108685-02/AI/NIAID NIH HHS/ -- AI44848/AI/NIAID NIH HHS/ -- R01 AI108685/AI/NIAID NIH HHS/ -- R01AI108685/AI/NIAID NIH HHS/ -- R21 CA185681/CA/NCI NIH HHS/ -- R21CA185681/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2015 Oct 16;350(6258):328-34. doi: 10.1126/science.aad0395. Epub 2015 Sep 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. Institut National de la Sante et de la Recherche Medicale, U818, 25 Rue du Docteur Roux, 75015 Paris, France. Frontieres du Vivant Doctoral School, Ecole Doctorale 474, Universite Paris Diderot-Paris 7, Sorbonne Paris Cite, 8-10 Rue Charles V, 75004 Paris, France. ; Laboratory of Dendritic Cell Biology, Department of Immunology, Institut Pasteur, 25 Rue du Docteur Roux, 75015 Paris, France. Institut National de la Sante et de la Recherche Medicale, U818, 25 Rue du Docteur Roux, 75015 Paris, France. ; Department of Immunology, University of Washington, Campus Box 358059, 750 Republican Street, Seattle, WA 98109, USA. ; Immunobiology Laboratory, The Francis Crick Institute, Lincoln's Inn Fields Laboratory, 44 Lincoln's Inn Fields, London WC2A 3LY, UK. ; Department of Immunology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26405229" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Caspase 8/metabolism ; Cell Survival ; Cross-Priming ; Dendritic Cells/immunology ; Mice ; Mice, Inbred C57BL ; NF-kappa B/*metabolism ; NIH 3T3 Cells ; Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Control of signaling-mediated clearance of apoptotic cells by the tumor suppressor p53 (2015)
    American Association for the Advancement of Science (AAAS)
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    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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  • 53
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    Stem cell regulation. Bidirectional Notch signaling regulates Drosophila intestinal stem cell multipotency (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-11-21
    Description: Drosophila intestinal stem cells (ISCs) generate enterocytes (ECs) and enteroendocrine (ee) cells. Previous work suggests that different levels of the Notch ligand Delta (Dl) in ISCs unidirectionally activate Notch in daughters to control multipotency. However, the mechanisms driving different outcomes remain unknown. We found that during ee cell formation, the ee cell marker Prospero localizes to the basal side of dividing ISCs. After asymmetric division, the ee daughter cell acts as a source of Dl that induces low Notch activity in the ISC to maintain identity. Alternatively, ISCs expressing Dl induce high Notch activity in daughter cells to promote EC formation. Our data reveal a conserved role for Notch in Drosophila and mammalian ISC maintenance and suggest that bidirectional Notch signaling may regulate multipotency in other systems.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Zheng -- Ohlstein, Benjamin -- New York, N.Y. -- Science. 2015 Nov 20;350(6263). pii: aab0988. doi: 10.1126/science.aab0988.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. ; Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. bo2160@columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26586765" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Division ; Cell Polarity ; Drosophila Proteins/*metabolism ; Drosophila melanogaster/cytology/*growth & development/metabolism ; Enterocytes/*cytology ; Enteroendocrine Cells/*cytology ; Multipotent Stem Cells/*cytology/metabolism ; Nuclear Proteins/*metabolism ; Phosphoproteins/*metabolism ; Receptors, Notch/*metabolism ; Signal Transduction ; Transcription Factors/*metabolism
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  • 54
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    Distinct routes of lineage development reshape the human blood hierarchy across ontogeny (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-11-07
    Description: In a classical view of hematopoiesis, the various blood cell lineages arise via a hierarchical scheme starting with multipotent stem cells that become increasingly restricted in their differentiation potential through oligopotent and then unipotent progenitors. We developed a cell-sorting scheme to resolve myeloid (My), erythroid (Er), and megakaryocytic (Mk) fates from single CD34(+) cells and then mapped the progenitor hierarchy across human development. Fetal liver contained large numbers of distinct oligopotent progenitors with intermingled My, Er, and Mk fates. However, few oligopotent progenitor intermediates were present in the adult bone marrow. Instead, only two progenitor classes predominate, multipotent and unipotent, with Er-Mk lineages emerging from multipotent cells. The developmental shift to an adult "two-tier" hierarchy challenges current dogma and provides a revised framework to understand normal and disease states of human hematopoiesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Notta, Faiyaz -- Zandi, Sasan -- Takayama, Naoya -- Dobson, Stephanie -- Gan, Olga I -- Wilson, Gavin -- Kaufmann, Kerstin B -- McLeod, Jessica -- Laurenti, Elisa -- Dunant, Cyrille F -- McPherson, John D -- Stein, Lincoln D -- Dror, Yigal -- Dick, John E -- Canadian Institutes of Health Research/Canada -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2016 Jan 8;351(6269):aab2116. doi: 10.1126/science.aab2116. Epub 2015 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. ; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. ; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. ; Wellcome Trust, Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, UK. ; Ecole Polytechnique Federale de Lausanne, LMC, Station 12, Lausanne, CH-1015, Switzerland. ; Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. Ontario Institute for Cancer Research, Toronto, Ontario, Canada. ; The Hospital for Sick Children Research Institute, University of Toronto, Ontario, Canada. ; Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada. jdick@uhnres.utoronto.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26541609" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Antigens, CD34/analysis ; Cell Lineage/genetics/*physiology ; Cell Separation ; Cells, Cultured ; Erythroid Cells/*cytology ; Fetal Blood/cytology ; Gene Expression Profiling ; Hematopoiesis/genetics/*physiology ; Humans ; Liver/cytology/embryology ; Megakaryocyte Progenitor Cells/*cytology ; Megakaryocytes/*cytology ; Multipotent Stem Cells/cytology ; Myeloid Cells/*cytology ; Transcription, Genetic
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    Sestrin2 is a leucine sensor for the mTORC1 pathway (2015)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2015-10-10
    Description: Leucine is a proteogenic amino acid that also regulates many aspects of mammalian physiology, in large part by activating the mTOR complex 1 (mTORC1) protein kinase, a master growth controller. Amino acids signal to mTORC1 through the Rag guanosine triphosphatases (GTPases). Several factors regulate the Rags, including GATOR1, aGTPase-activating protein; GATOR2, a positive regulator of unknown function; and Sestrin2, a GATOR2-interacting protein that inhibits mTORC1 signaling. We find that leucine, but not arginine, disrupts the Sestrin2-GATOR2 interaction by binding to Sestrin2 with a dissociation constant of 20 micromolar, which is the leucine concentration that half-maximally activates mTORC1. The leucine-binding capacity of Sestrin2 is required for leucine to activate mTORC1 in cells. These results indicate that Sestrin2 is a leucine sensor for the mTORC1 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4698017/" 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/PMC4698017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolfson, Rachel L -- Chantranupong, Lynne -- Saxton, Robert A -- Shen, Kuang -- Scaria, Sonia M -- Cantor, Jason R -- Sabatini, David M -- AI47389/AI/NIAID NIH HHS/ -- F30 CA189333/CA/NCI NIH HHS/ -- F31 CA180271/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2016 Jan 1;351(6268):43-8. doi: 10.1126/science.aab2674. Epub 2015 Oct 8.〈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. ; 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. ; 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/26449471" target="_blank"〉PubMed〈/a〉
    Keywords: GTPase-Activating Proteins/*metabolism ; HEK293 Cells ; Humans ; Leucine/*metabolism ; Metabolic Networks and Pathways ; Multiprotein Complexes/*metabolism ; Nuclear Proteins/chemistry/genetics/*metabolism ; Protein Binding ; Proteins/chemistry/*metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism
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    Positive feedback within a kinase signaling complex functions as a switch mechanism for NF-kappaB activation (2014)
    American Association for the Advancement of Science (AAAS)
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    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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    Local impermeant anions establish the neuronal chloride concentration (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-02-08
    Description: Neuronal intracellular chloride concentration [Cl(-)](i) is an important determinant of gamma-aminobutyric acid type A (GABA(A)) receptor (GABA(A)R)-mediated inhibition and cytoplasmic volume regulation. Equilibrative cation-chloride cotransporters (CCCs) move Cl(-) across the membrane, but accumulating evidence suggests factors other than the bulk concentrations of transported ions determine [Cl(-)](i). Measurement of [Cl(-)](i) in murine brain slice preparations expressing the transgenic fluorophore Clomeleon demonstrated that cytoplasmic impermeant anions ([A](i)) and polyanionic extracellular matrix glycoproteins ([A](o)) constrain the local [Cl(-)]. CCC inhibition had modest effects on [Cl(-)](i) and neuronal volume, but substantial changes were produced by alterations of the balance between [A](i) and [A](o). Therefore, CCCs are important elements of Cl(-) homeostasis, but local impermeant anions determine the homeostatic set point for [Cl(-)], and hence, neuronal volume and the polarity of local GABA(A)R signaling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4220679/" 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/PMC4220679/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Glykys, J -- Dzhala, V -- Egawa, K -- Balena, T -- Saponjian, Y -- Kuchibhotla, K V -- Bacskai, B J -- Kahle, K T -- Zeuthen, T -- Staley, K J -- NS 40109-06/NS/NINDS NIH HHS/ -- R01 EB000768/EB/NIBIB NIH HHS/ -- R01 NS040109/NS/NINDS NIH HHS/ -- R01 NS074772/NS/NINDS NIH HHS/ -- R25 NS065743/NS/NINDS NIH HHS/ -- S10 RR025645/RR/NCRR NIH HHS/ -- U41 RR019703/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):670-5. doi: 10.1126/science.1245423.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24503855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*metabolism ; Cell Membrane Permeability ; Cell Polarity ; Chloride Channels/*metabolism ; Chlorides/*metabolism ; Cytoplasm/metabolism ; Extracellular Matrix Proteins/metabolism ; Glycoproteins/metabolism ; Mice ; Mice, Transgenic ; Neurons/*metabolism ; Receptors, GABA-A/*metabolism ; Recombinant Fusion Proteins/genetics/metabolism ; Signal Transduction
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    Construction of a vertebrate embryo from two opposing morphogen gradients (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-04-05
    Description: Development of vertebrate embryos involves tightly regulated molecular and cellular processes that progressively instruct proliferating embryonic cells about their identity and behavior. Whereas numerous gene activities have been found to be essential during early embryogenesis, little is known about the minimal conditions and factors that would be sufficient to instruct pluripotent cells to organize the embryo. Here, we show that opposing gradients of bone morphogenetic protein (BMP) and Nodal, two transforming growth factor family members that act as morphogens, are sufficient to induce molecular and cellular mechanisms required to organize, in vivo or in vitro, uncommitted cells of the zebrafish blastula animal pole into a well-developed embryo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Peng-Fei -- Houssin, Nathalie -- Ferri-Lagneau, Karine F -- Thisse, Bernard -- Thisse, Christine -- New York, N.Y. -- Science. 2014 Apr 4;344(6179):87-9. doi: 10.1126/science.1248252.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, University of Virginia, Charlottesville, VA 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24700857" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blastula/*physiology ; Body Patterning ; Bone Morphogenetic Proteins/genetics/*physiology ; Embryo, Nonmammalian/*physiology ; *Embryonic Development ; Gastrula/physiology ; Gastrulation ; Gene Expression Regulation, Developmental ; Morphogenesis ; Nodal Protein/genetics/*physiology ; RNA, Messenger/genetics ; Signal Transduction ; Zebrafish/*embryology/genetics ; Zebrafish Proteins/genetics/*physiology
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    Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-08-30
    Description: Cells use actomyosin contractility to move through three-dimensional (3D) extracellular matrices. Contractility affects the type of protrusions cells use to migrate in 3D, but the mechanisms are unclear. In this work, we found that contractility generated high-pressure lobopodial protrusions in human cells migrating in a 3D matrix. In these cells, the nucleus physically divided the cytoplasm into forward and rear compartments. Actomyosin contractility with the nucleoskeleton-intermediate filament linker protein nesprin-3 pulled the nucleus forward and pressurized the front of the cell. Reducing expression of nesprin-3 decreased and equalized the intracellular pressure. Thus, the nucleus can act as a piston that physically compartmentalizes the cytoplasm and increases the hydrostatic pressure between the nucleus and the leading edge of the cell to drive lamellipodia-independent 3D cell migration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petrie, Ryan J -- Koo, Hyun -- Yamada, Kenneth M -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1062-5. doi: 10.1126/science.1256965.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA. petrier@mail.nih.gov kyamada@mail.nih.gov. ; Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892-4370, USA. Center for Oral Biology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, NY 14642, USA. Biofilm Research Labs, Levy Center for Oral Health, Department of Orthodontics, University of Pennsylvania School of Dental Medicine, Philadelphia, PA 19104-6030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170155" target="_blank"〉PubMed〈/a〉
    Keywords: Actomyosin/physiology ; Cell Movement/*physiology ; Cell Nucleus/*physiology ; Cells, Cultured ; Cytoplasm/physiology ; Extracellular Matrix/*physiology/ultrastructure ; Fibroblasts/*physiology ; Humans ; Hydrostatic Pressure ; Microfilament Proteins ; Pseudopodia/*physiology ; Vimentin/metabolism
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    Neutrophils scan for activated platelets to initiate inflammation (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-12-06
    Description: Immune and inflammatory responses require leukocytes to migrate within and through the vasculature, a process that is facilitated by their capacity to switch to a polarized morphology with an asymmetric distribution of receptors. We report that neutrophil polarization within activated venules served to organize a protruding domain that engaged activated platelets present in the bloodstream. The selectin ligand PSGL-1 transduced signals emanating from these interactions, resulting in the redistribution of receptors that drive neutrophil migration. Consequently, neutrophils unable to polarize or to transduce signals through PSGL-1 displayed aberrant crawling, and blockade of this domain protected mice against thromboinflammatory injury. These results reveal that recruited neutrophils scan for activated platelets, and they suggest that the neutrophils' bipolarity allows the integration of signals present at both the endothelium and the circulation before inflammation proceeds.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280847/" 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/PMC4280847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sreeramkumar, Vinatha -- Adrover, Jose M -- Ballesteros, Ivan -- Cuartero, Maria Isabel -- Rossaint, Jan -- Bilbao, Izaskun -- Nacher, Maria -- Pitaval, Christophe -- Radovanovic, Irena -- Fukui, Yoshinori -- McEver, Rodger P -- Filippi, Marie-Dominique -- Lizasoain, Ignacio -- Ruiz-Cabello, Jesus -- Zarbock, Alexander -- Moro, Maria A -- Hidalgo, Andres -- HL03463/HL/NHLBI NIH HHS/ -- HL085607/HL/NHLBI NIH HHS/ -- HL090676/HL/NHLBI NIH HHS/ -- P01 HL085607/HL/NHLBI NIH HHS/ -- R01 HL034363/HL/NHLBI NIH HHS/ -- R01 HL090676/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2014 Dec 5;346(6214):1234-8. doi: 10.1126/science.1256478. Epub 2014 Dec 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. ; Unidad de Investigacion Neurovascular, Department of Pharmacology, Faculty of Medicine, Universidad Complutense and Instituto de Investigacion Hospital 12 de Octubre (i+12), Madrid, Spain. ; Department of Anesthesiology and Critical Care Medicine, University of Munster and Max Planck Institute Munster, Munster, Germany. ; Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Ciber de Enfermedades Respiratorias (CIBERES), Madrid, Spain. ; Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Faculty of Science, Medicine and Health, University of Wollongong, New South Wales, Australia. ; Division of Immunogenetics, Department of Immunobiology and Neuroscience, Kyushu University, Japan. ; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA. ; Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Research Foundation, University of Cincinnati College of Medicine, Cincinnati, OH, USA. ; Department of Atherothrombosis, Imaging and Epidemiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain. Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany. ahidalgo@cnic.es.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477463" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Circulation ; Blood Platelets/*immunology ; Cell Movement ; Cell Polarity ; Endothelium, Vascular/immunology ; Inflammation/blood/*immunology ; Male ; Membrane Glycoproteins ; Mice ; Mice, Inbred C57BL ; Neutrophils/*immunology ; *Platelet Activation ; Signal Transduction ; Thrombosis/*immunology ; Venules/immunology
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    Perception of root-derived peptides by shoot LRR-RKs mediates systemic N-demand signaling (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-10-18
    Description: Nitrogen (N) is a critical nutrient for plants but is often distributed unevenly in the soil. Plants therefore have evolved a systemic mechanism by which N starvation on one side of the root system leads to a compensatory and increased nitrate uptake on the other side. Here, we study the molecular systems that support perception of N and the long-distance signaling needed to alter root development. Rootlets starved of N secrete small peptides that are translocated to the shoot and received by two leucine-rich repeat receptor kinases (LRR-RKs). Arabidopsis plants deficient in this pathway show growth retardation accompanied with N-deficiency symptoms. Thus, signaling from the root to the shoot helps the plant adapt to fluctuations in local N availability.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tabata, Ryo -- Sumida, Kumiko -- Yoshii, Tomoaki -- Ohyama, Kentaro -- Shinohara, Hidefumi -- Matsubayashi, Yoshikatsu -- New York, N.Y. -- Science. 2014 Oct 17;346(6207):343-6. doi: 10.1126/science.1257800.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. ; Department of Applied Molecular Biosciences, Graduate School of Bio-Agricultural Sciences, Nagoya University, Chikusa, Nagoya 464-8601, Japan. ; Division of Biological Science, Graduate School of Science, Nagoya University, Chikusa, Nagoya 464-8602, Japan. matsu@bio.nagoya-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25324386" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Arabidopsis/genetics/*growth & development/metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Molecular Sequence Data ; Nitrogen/*metabolism ; Peptides/*metabolism ; Plant Roots/genetics/*growth & development/metabolism ; Plant Shoots/genetics/*growth & development/metabolism ; Receptors, Peptide/genetics/*metabolism ; Signal Transduction
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    Intracellular sensing of complement C3 activates cell autonomous immunity (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-09-06
    Description: Pathogens traverse multiple barriers during infection, including cell membranes. We found that during this transition, pathogens carried covalently attached complement C3 into the cell, triggering immediate signaling and effector responses. Sensing of C3 in the cytosol activated mitochondrial antiviral signaling (MAVS)-dependent signaling cascades and induced proinflammatory cytokine secretion. C3 also flagged viruses for rapid proteasomal degradation, preventing their replication. This system could detect both viral and bacterial pathogens but was antagonized by enteroviruses, such as rhinovirus and poliovirus, which cleave C3 using their 3C protease. The antiviral rupintrivir inhibited 3C protease and prevented C3 cleavage, rendering enteroviruses susceptible to intracellular complement sensing. Thus, complement C3 allows cells to detect and disable pathogens that have invaded the cytosol.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172439/" 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/PMC4172439/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tam, Jerry C H -- Bidgood, Susanna R -- McEwan, William A -- James, Leo C -- 281627/European Research Council/International -- MC_U105181010/Medical Research Council/United Kingdom -- U105181010/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1256070. doi: 10.1126/science.1256070. Epub 2014 Sep 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; Medical Research Council Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. lcj@mrc-lmb.cam.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25190799" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoviridae/*immunology ; Adenovirus Infections, Human/*immunology ; Animals ; Antibodies, Viral/immunology ; Complement C3/*immunology ; Cytokines/biosynthesis/genetics ; Dogs ; HEK293 Cells ; Host-Pathogen Interactions/*immunology ; Humans ; *Immunity, Innate ; Interferon Regulatory Factors/metabolism ; NF-kappa B/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Ribonucleoproteins/genetics/metabolism ; Signal Transduction ; Transcription Factor AP-1/metabolism
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    Science & SciLifeLab Prize Essay. Size does matter (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-12-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bar-Peled, Liron -- New York, N.Y. -- Science. 2014 Dec 5;346(6214):1191-2. doi: 10.1126/science.aaa1808.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Scripps Research Institute, La Jolla, CA 92122, USA. lironbp@scripps.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477447" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/*metabolism ; Animals ; *Body Size ; *Cell Enlargement ; *Cell Proliferation ; GTP-Binding Protein Regulators/*metabolism ; Lysosomes/*metabolism ; Monomeric GTP-Binding Proteins/*metabolism ; Multiprotein Complexes/metabolism ; Protein Transport ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism
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    Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-30
    Description: Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M-containing nucleosomes, and its misregulation in Drosophila results in changes of H3K9 methylation levels and heterochromatic silencing defects. We have established histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin signaling pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4508193/" 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/PMC4508193/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Herz, Hans-Martin -- Morgan, Marc -- Gao, Xin -- Jackson, Jessica -- Rickels, Ryan -- Swanson, Selene K -- Florens, Laurence -- Washburn, Michael P -- Eissenberg, Joel C -- Shilatifard, Ali -- CA R01CA089455/CA/NCI NIH HHS/ -- R01 CA089455/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 29;345(6200):1065-70. doi: 10.1126/science.1255104.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. ; Saint Louis University School of Medicine, Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis, MO, USA. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA. ; Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. ash@northwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25170156" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Animals ; Chromatin/*metabolism ; Disease Models, Animal ; Drosophila Proteins/genetics ; Drosophila melanogaster ; Gene Silencing ; Glioma/genetics/metabolism ; Heterochromatin/metabolism ; Histone-Lysine N-Methyltransferase/genetics ; Histones/*genetics/metabolism ; Jumonji Domain-Containing Histone Demethylases/metabolism ; Lysine/*genetics ; Methionine/*genetics ; Methylation ; Mutation ; Signal Transduction
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    Highly multiplexed subcellular RNA sequencing in situ (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-01
    Description: Understanding the spatial organization of gene expression with single-nucleotide resolution requires localizing the sequences of expressed RNA transcripts within a cell in situ. Here, we describe fluorescent in situ RNA sequencing (FISSEQ), in which stably cross-linked complementary DNA (cDNA) amplicons are sequenced within a biological sample. Using 30-base reads from 8102 genes in situ, we examined RNA expression and localization in human primary fibroblasts with a simulated wound-healing assay. FISSEQ is compatible with tissue sections and whole-mount embryos and reduces the limitations of optical resolution and noisy signals on single-molecule detection. Our platform enables massively parallel detection of genetic elements, including gene transcripts and molecular barcodes, and can be used to investigate cellular phenotype, gene regulation, and environment in situ.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4140943/" 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/PMC4140943/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Je Hyuk -- Daugharthy, Evan R -- Scheiman, Jonathan -- Kalhor, Reza -- Yang, Joyce L -- Ferrante, Thomas C -- Terry, Richard -- Jeanty, Sauveur S F -- Li, Chao -- Amamoto, Ryoji -- Peters, Derek T -- Turczyk, Brian M -- Marblestone, Adam H -- Inverso, Samuel A -- Bernard, Amy -- Mali, Prashant -- Rios, Xavier -- Aach, John -- Church, George M -- GM080177/GM/NIGMS NIH HHS/ -- MH098977/MH/NIMH NIH HHS/ -- P50 HG005550/HG/NHGRI NIH HHS/ -- RC2 HL102815/HL/NHLBI NIH HHS/ -- RC2HL102815/HL/NHLBI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32 GM080177/GM/NIGMS NIH HHS/ -- U01 MH098977/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 21;343(6177):1360-3. doi: 10.1126/science.1250212. Epub 2014 Feb 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wyss Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578530" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; Cell Line ; Cells, Cultured ; DNA, Complementary ; Fluorescence ; Gene Expression Profiling/*methods ; Humans ; Induced Pluripotent Stem Cells ; RNA, Messenger/genetics/metabolism ; Sequence Analysis, RNA/*methods ; Single-Cell Analysis ; Transcription Initiation Site ; *Transcriptome ; Wound Healing
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    Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-17
    Description: Neural circuits are shaped by elimination of early-formed redundant synapses during postnatal development. Retrograde signaling from postsynaptic cells regulates synapse elimination. In this work, we identified semaphorins, a family of versatile cell recognition molecules, as retrograde signals for elimination of redundant climbing fiber to Purkinje cell synapses in developing mouse cerebellum. Knockdown of Sema3A, a secreted semaphorin, in Purkinje cells or its receptor in climbing fibers accelerated synapse elimination during postnatal day 8 (P8) to P18. Conversely, knockdown of Sema7A, a membrane-anchored semaphorin, in Purkinje cells or either of its two receptors in climbing fibers impaired synapse elimination after P15. The effect of Sema7A involves signaling by metabotropic glutamate receptor 1, a canonical pathway for climbing fiber synapse elimination. These findings define how semaphorins retrogradely regulate multiple processes of synapse elimination.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Uesaka, Naofumi -- Uchigashima, Motokazu -- Mikuni, Takayasu -- Nakazawa, Takanobu -- Nakao, Harumi -- Hirai, Hirokazu -- Aiba, Atsu -- Watanabe, Masahiko -- Kano, Masanobu -- New York, N.Y. -- Science. 2014 May 30;344(6187):1020-3. doi: 10.1126/science.1252514. Epub 2014 May 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. ; Department of Anatomy, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. ; Laboratory of Animal Resources, Center for Disease Biology and Integrated Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. ; Department of Neurophysiology, Gunma University Graduate School of Medicine, Maebashi, Gunma 371-8511, Japan. ; Department of Neurophysiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan. mkano-tky@m.u-tokyo.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24831527" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/genetics/*metabolism ; Brain/*growth & development/metabolism ; Gene Knockdown Techniques ; Mice ; Mice, Inbred C57BL ; Purkinje Cells/metabolism/*physiology ; RNA Interference ; Rats ; Rats, Sprague-Dawley ; Receptors, Metabotropic Glutamate/genetics/metabolism ; Semaphorin-3A/genetics/*metabolism ; Semaphorins/genetics/*metabolism ; Signal Transduction ; Synapses/genetics/*physiology
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    Cytoneme-mediated contact-dependent transport of the Drosophila decapentaplegic signaling protein (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-01-05
    Description: Decapentaplegic (Dpp), a Drosophila morphogen signaling protein, transfers directly at synapses made at sites of contact between cells that produce Dpp and cytonemes that extend from recipient cells. The Dpp that cytonemes receive moves together with activated receptors toward the recipient cell body in motile puncta. Genetic loss-of-function conditions for diaphanous, shibire, neuroglian, and capricious perturbed cytonemes by reducing their number or only the synapses they make with cells they target, and reduced cytoneme-mediated transport of Dpp and Dpp signaling. These experiments provide direct evidence that cells use cytonemes to exchange signaling proteins, that cytoneme-based exchange is essential for signaling and normal development, and that morphogen distribution and signaling can be contact-dependent, requiring cytoneme synapses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4336149/" 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/PMC4336149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Roy, Sougata -- Huang, Hai -- Liu, Songmei -- Kornberg, Thomas B -- GM030637/GM/NIGMS NIH HHS/ -- K99HL114867/HL/NHLBI NIH HHS/ -- R01 GM030637/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):1244624. doi: 10.1126/science.1244624. Epub 2014 Jan 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24385607" target="_blank"〉PubMed〈/a〉
    Keywords: Air Sacs/cytology/metabolism ; Animals ; Carrier Proteins/genetics/metabolism ; Cell Adhesion Molecules, Neuronal/genetics/metabolism ; *Cell Communication ; Drosophila Proteins/genetics/*metabolism ; Drosophila melanogaster/*cytology/*metabolism ; Dynamins/genetics/metabolism ; Membrane Proteins/genetics/metabolism ; Protein Transport ; Pseudopodia/*metabolism ; Signal Transduction ; Trachea/cytology/metabolism
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    Single beta-actin mRNA detection in neurons reveals a mechanism for regulating its translatability (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-01-25
    Description: The physical manifestation of learning and memory formation in the brain can be expressed by strengthening or weakening of synaptic connections through morphological changes. Local actin remodeling underlies some forms of plasticity and may be facilitated by local beta-actin synthesis, but dynamic information is lacking. In this work, we use single-molecule in situ hybridization to demonstrate that dendritic beta-actin messenger RNA (mRNA) and ribosomes are in a masked, neuron-specific form. Chemically induced long-term potentiation prompts transient mRNA unmasking, which depends on factors active during synaptic activity. Ribosomes and single beta-actin mRNA motility increase after stimulation, indicative of release from complexes. Hence, the single-molecule assays we developed allow for the quantification of activity-induced unmasking and availability for active translation. Further, our work demonstrates that beta-actin mRNA and ribosomes are in a masked state that is alleviated by stimulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121734/" 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/PMC4121734/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buxbaum, Adina R -- Wu, Bin -- Singer, Robert H -- GM84364/GM/NIGMS NIH HHS/ -- NS083085-19/NS/NINDS NIH HHS/ -- R01 NS083085/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jan 24;343(6169):419-22. doi: 10.1126/science.1242939.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24458642" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*biosynthesis/genetics ; Animals ; Cells, Cultured ; Dendrites/metabolism ; In Situ Hybridization, Fluorescence/methods ; Long-Term Potentiation/drug effects/*physiology ; Memory/physiology ; Mice ; Mice, Transgenic ; Neuronal Plasticity/drug effects/physiology ; Neurons/*metabolism ; *Protein Biosynthesis ; RNA, Messenger/analysis/*biosynthesis ; RNA, Ribosomal/metabolism ; Ribosomes/*metabolism ; Synapses/metabolism
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    Dlk1 promotes a fast motor neuron biophysical signature required for peak force execution (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-03-15
    Description: Motor neurons, which relay neural commands to drive skeletal muscle movements, encompass types ranging from "slow" to "fast," whose biophysical properties govern the timing, gradation, and amplitude of muscle force. Here we identify the noncanonical Notch ligand Delta-like homolog 1 (Dlk1) as a determinant of motor neuron functional diversification. Dlk1, expressed by ~30% of motor neurons, is necessary and sufficient to promote a fast biophysical signature in the mouse and chick. Dlk1 suppresses Notch signaling and activates expression of the K(+) channel subunit Kcng4 to modulate delayed-rectifier currents. Dlk1 inactivation comprehensively shifts motor neurons toward slow biophysical and transcriptome signatures, while abolishing peak force outputs. Our findings provide insights into the development of motor neuron functional diversity and its contribution to the execution of movements.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muller, Daniel -- Cherukuri, Pitchaiah -- Henningfeld, Kristine -- Poh, Chor Hoon -- Wittler, Lars -- Grote, Phillip -- Schluter, Oliver -- Schmidt, Jennifer -- Laborda, Jorge -- Bauer, Steven R -- Brownstone, Robert M -- Marquardt, Till -- R01 HD042013/HD/NICHD NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1264-6. doi: 10.1126/science.1246448.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Neurobiology Laboratory, European Neuroscience Institute (ENI-G), Grisebachstrasse 5, 37077 Gottingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24626931" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Gene Expression Regulation ; Intercellular Signaling Peptides and Proteins/genetics/*physiology ; Mice ; Mice, Knockout ; Motor Neurons/*metabolism ; Movement ; Muscle Fibers, Skeletal/physiology ; Muscle, Skeletal/innervation/*physiology ; Potassium Channels, Voltage-Gated/genetics ; Receptors, Notch/*physiology ; Signal Transduction ; Transcriptome
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    Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-08-12
    Description: Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival of motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels of functional SMN protein due to alternative splicing that truncates the transcript. The decreased levels of SMN protein lead to progressive neuromuscular degeneration and high rates of mortality. Through chemical screening and optimization, we identified orally available small molecules that shift the balance of SMN2 splicing toward the production of full-length SMN2 messenger RNA with high selectivity. Administration of these compounds to Delta7 mice, a model of severe SMA, led to an increase in SMN protein levels, improvement of motor function, and protection of the neuromuscular circuit. These compounds also extended the life span of the mice. Selective SMN2 splicing modifiers may have therapeutic potential for patients with SMA.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naryshkin, Nikolai A -- Weetall, Marla -- Dakka, Amal -- Narasimhan, Jana -- Zhao, Xin -- Feng, Zhihua -- Ling, Karen K Y -- Karp, Gary M -- Qi, Hongyan -- Woll, Matthew G -- Chen, Guangming -- Zhang, Nanjing -- Gabbeta, Vijayalakshmi -- Vazirani, Priya -- Bhattacharyya, Anuradha -- Furia, Bansri -- Risher, Nicole -- Sheedy, Josephine -- Kong, Ronald -- Ma, Jiyuan -- Turpoff, Anthony -- Lee, Chang-Sun -- Zhang, Xiaoyan -- Moon, Young-Choon -- Trifillis, Panayiota -- Welch, Ellen M -- Colacino, Joseph M -- Babiak, John -- Almstead, Neil G -- Peltz, Stuart W -- Eng, Loren A -- Chen, Karen S -- Mull, Jesse L -- Lynes, Maureen S -- Rubin, Lee L -- Fontoura, Paulo -- Santarelli, Luca -- Haehnke, Daniel -- McCarthy, Kathleen D -- Schmucki, Roland -- Ebeling, Martin -- Sivaramakrishnan, Manaswini -- Ko, Chien-Ping -- Paushkin, Sergey V -- Ratni, Hasane -- Gerlach, Irene -- Ghosh, Anirvan -- Metzger, Friedrich -- New York, N.Y. -- Science. 2014 Aug 8;345(6197):688-93. doi: 10.1126/science.1250127.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. ; Section of Neurobiology, Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA. ; PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ 07080, USA. friedrich.metzger@roche.com speltz@ptcbio.com. ; SMA Foundation, 888 Seventh Avenue, Suite 400, New York, NY 10019, USA. ; Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. ; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. ; Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche, Grenzacherstrasse 124, 4070 Basel, Switzerland. friedrich.metzger@roche.com speltz@ptcbio.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25104390" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Alternative Splicing/*drug effects ; Animals ; Cells, Cultured ; Coumarins/*administration & dosage/chemistry ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Humans ; Isocoumarins/*administration & dosage/chemistry ; Longevity/*drug effects ; Mice ; Muscular Atrophy, Spinal/*drug therapy/genetics/metabolism ; Pyrimidinones/*administration & dosage/chemistry ; RNA, Messenger/genetics ; Sequence Deletion ; Small Molecule Libraries/*administration & dosage/chemistry ; Survival of Motor Neuron 2 Protein/*genetics/metabolism
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    Activating hotspot L205R mutation in PRKACA and adrenal Cushing's syndrome (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-04-05
    Description: Adrenal Cushing's syndrome is caused by excess production of glucocorticoid from adrenocortical tumors and hyperplasias, which leads to metabolic disorders. We performed whole-exome sequencing of 49 blood-tumor pairs and RNA sequencing of 44 tumors from cortisol-producing adrenocortical adenomas (ACAs), adrenocorticotropic hormone-independent macronodular adrenocortical hyperplasias (AIMAHs), and adrenocortical oncocytomas (ADOs). We identified a hotspot in the PRKACA gene with a L205R mutation in 69.2% (27 out of 39) of ACAs and validated in 65.5% of a total of 87 ACAs. Our data revealed that the activating L205R mutation, which locates in the P+1 loop of the protein kinase A (PKA) catalytic subunit, promoted PKA substrate phosphorylation and target gene expression. Moreover, we discovered the recurrently mutated gene DOT1L in AIMAHs and CLASP2 in ADOs. Collectively, these data highlight potentially functional mutated genes in adrenal Cushing's syndrome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cao, Yanan -- He, Minghui -- Gao, Zhibo -- Peng, Ying -- Li, Yanli -- Li, Lin -- Zhou, Weiwei -- Li, Xiangchun -- Zhong, Xu -- Lei, Yiming -- Su, Tingwei -- Wang, Hang -- Jiang, Yiran -- Yang, Lin -- Wei, Wei -- Yang, Xu -- Jiang, Xiuli -- Liu, Li -- He, Juan -- Ye, Junna -- Wei, Qing -- Li, Yingrui -- Wang, Weiqing -- Wang, Jun -- Ning, Guang -- New York, N.Y. -- Science. 2014 May 23;344(6186):913-7. doi: 10.1126/science.1249480. Epub 2014 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. ; BGI-Shanghai, BGI-Shenzhen, Shenzhen, China. ; Department of Pathology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. ; Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com. ; BGI-Shanghai, BGI-Shenzhen, Shenzhen, China. Department of Biology, University of Copenhagen, Copenhagen, Denmark. King Abdulaziz University, Jeddah, Saudi Arabia. Macau University of Science and Technology, Macau, China. Department of Medicine, University of Hong Kong, Hong Kong. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com. ; Shanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Key Laboratory for Endocrine Tumors, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China. Laboratory of Endocrinology and Metabolism, Institute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS), and Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China. guangning@medmail.com.cn wangj@genomics.org.cn wqingw@hotmail.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24700472" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenal Cortex Neoplasms/*genetics/*metabolism ; Adrenocortical Adenoma/*genetics/*metabolism ; Amino Acid Substitution ; Arginine/genetics ; Catalytic Domain/genetics ; Cells, Cultured ; Cushing Syndrome/*genetics ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/chemistry/*genetics ; Glucocorticoids/metabolism ; Humans ; Hydrocortisone/*metabolism ; Leucine/genetics ; Methyltransferases/genetics ; Microtubule-Associated Proteins/genetics ; Mutation
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    Toddler: an embryonic signal that promotes cell movement via Apelin receptors (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-01-11
    Description: It has been assumed that most, if not all, signals regulating early development have been identified. Contrary to this expectation, we identified 28 candidate signaling proteins expressed during zebrafish embryogenesis, including Toddler, a short, conserved, and secreted peptide. Both absence and overproduction of Toddler reduce the movement of mesendodermal cells during zebrafish gastrulation. Local and ubiquitous production of Toddler promote cell movement, suggesting that Toddler is neither an attractant nor a repellent but acts globally as a motogen. Toddler drives internalization of G protein-coupled APJ/Apelin receptors, and activation of APJ/Apelin signaling rescues toddler mutants. These results indicate that Toddler is an activator of APJ/Apelin receptor signaling, promotes gastrulation movements, and might be the first in a series of uncharacterized developmental signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107353/" 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/PMC4107353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pauli, Andrea -- Norris, Megan L -- Valen, Eivind -- Chew, Guo-Liang -- Gagnon, James A -- Zimmerman, Steven -- Mitchell, Andrew -- Ma, Jiao -- Dubrulle, Julien -- Reyon, Deepak -- Tsai, Shengdar Q -- Joung, J Keith -- Saghatelian, Alan -- Schier, Alexander F -- K99 HD076935/HD/NICHD NIH HHS/ -- R01 GM056211/GM/NIGMS NIH HHS/ -- R01 GM102491/GM/NIGMS NIH HHS/ -- R01 HG005111/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 14;343(6172):1248636. doi: 10.1126/science.1248636. Epub 2014 Jan 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24407481" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Cell Movement ; Chemokine CXCL12/metabolism ; Frameshift Mutation ; Gastrulation/genetics/*physiology ; Molecular Sequence Data ; Receptors, G-Protein-Coupled/genetics/*metabolism ; Signal Transduction ; Zebrafish/*embryology/genetics/metabolism ; Zebrafish Proteins/genetics/*metabolism
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    T cell signaling. Antigen affinity, costimulation, and cytokine inputs sum linearly to amplify T cell expansion (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-29
    Description: T cell responses are initiated by antigen and promoted by a range of costimulatory signals. Understanding how T cells integrate alternative signal combinations and make decisions affecting immune response strength or tolerance poses a considerable theoretical challenge. Here, we report that T cell receptor (TCR) and costimulatory signals imprint an early, cell-intrinsic, division fate, whereby cells effectively count through generations before returning automatically to a quiescent state. This autonomous program can be extended by cytokines. Signals from the TCR, costimulatory receptors, and cytokines add together using a linear division calculus, allowing the strength of a T cell response to be predicted from the sum of the underlying signal components. These data resolve a long-standing costimulation paradox and provide a quantitative paradigm for therapeutically manipulating immune response strength.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marchingo, Julia M -- Kan, Andrey -- Sutherland, Robyn M -- Duffy, Ken R -- Wellard, Cameron J -- Belz, Gabrielle T -- Lew, Andrew M -- Dowling, Mark R -- Heinzel, Susanne -- Hodgkin, Philip D -- New York, N.Y. -- Science. 2014 Nov 28;346(6213):1123-7. doi: 10.1126/science.1260044.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. ; Hamilton Institute, National University of Ireland, Maynooth, Ireland. ; Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. The Royal Melbourne Hospital, Parkville, VIC, Australia. ; Division of Immunology, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia. hodgkin@wehi.edu.au.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25430770" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens/*immunology ; CD8-Positive T-Lymphocytes/cytology/*immunology ; Cell Division ; Cell Proliferation ; Cytokines/*immunology ; *Immune Tolerance ; Lymphocyte Activation ; Mice ; Receptors, Antigen, T-Cell/*immunology ; Signal Transduction
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    Structural basis for assembly and function of a heterodimeric plant immune receptor (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-04-20
    Description: Cytoplasmic plant immune receptors recognize specific pathogen effector proteins and initiate effector-triggered immunity. In Arabidopsis, the immune receptors RPS4 and RRS1 are both required to activate defense to three different pathogens. We show that RPS4 and RRS1 physically associate. Crystal structures of the N-terminal Toll-interleukin-1 receptor/resistance (TIR) domains of RPS4 and RRS1, individually and as a heterodimeric complex (respectively at 2.05, 1.75, and 2.65 angstrom resolution), reveal a conserved TIR/TIR interaction interface. We show that TIR domain heterodimerization is required to form a functional RRS1/RPS4 effector recognition complex. The RPS4 TIR domain activates effector-independent defense, which is inhibited by the RRS1 TIR domain through the heterodimerization interface. Thus, RPS4 and RRS1 function as a receptor complex in which the two components play distinct roles in recognition and signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Williams, Simon J -- Sohn, Kee Hoon -- Wan, Li -- Bernoux, Maud -- Sarris, Panagiotis F -- Segonzac, Cecile -- Ve, Thomas -- Ma, Yan -- Saucet, Simon B -- Ericsson, Daniel J -- Casey, Lachlan W -- Lonhienne, Thierry -- Winzor, Donald J -- Zhang, Xiaoxiao -- Coerdt, Anne -- Parker, Jane E -- Dodds, Peter N -- Kobe, Bostjan -- Jones, Jonathan D G -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):299-303. doi: 10.1126/science.1247357.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Chemistry and Molecular Biosciences and Australian Infectious Diseases Research Centre, University of Queensland, Brisbane, QLD 4072, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744375" target="_blank"〉PubMed〈/a〉
    Keywords: Agrobacterium/physiology ; Amino Acid Motifs ; Arabidopsis/chemistry/*immunology/microbiology ; Arabidopsis Proteins/*chemistry/genetics/metabolism ; Bacterial Proteins/immunology/metabolism ; Cell Death ; Crystallography, X-Ray ; Immunity, Innate ; Models, Molecular ; Mutation ; Plant Diseases/immunology/microbiology ; Plant Leaves/microbiology ; Plant Proteins/*chemistry/genetics/metabolism ; Plants, Genetically Modified ; Protein Interaction Domains and Motifs ; Protein Multimerization ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptors, Immunologic/*chemistry/genetics/metabolism ; Signal Transduction ; Tobacco/genetics/immunology/metabolism/microbiology
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    Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-10-04
    Description: Stem cells fuel tissue development, renewal, and regeneration, and these activities are controlled by the local stem cell microenvironment, the "niche." Wnt signals emanating from the niche can act as self-renewal factors for stem cells in multiple mammalian tissues. Wnt proteins are lipid-modified, which constrains them to act as short-range cellular signals. The locality of Wnt signaling dictates that stem cells exiting the Wnt signaling domain differentiate, spatially delimiting the niche in certain tissues. In some instances, stem cells may act as or generate their own niche, enabling the self-organization of patterned tissues. In this Review, we discuss the various ways by which Wnt operates in stem cell control and, in doing so, identify an integral program for tissue renewal and regeneration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clevers, Hans -- Loh, Kyle M -- Nusse, Roel -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):1248012. doi: 10.1126/science.1248012. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW), University Medical Centre Utrecht and CancerGenomics.nl, 3584CT Utrecht, Netherlands. ; Department of Developmental Biology, Howard Hughes Medical Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. ; Department of Developmental Biology, Howard Hughes Medical Institute, Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. rnusse@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278615" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/physiology ; Cell Division ; Hair Follicle/physiology ; Humans ; Intestines/physiology ; Mammary Glands, Human/physiology ; Regeneration/genetics/*physiology ; Signal Transduction ; Stem Cell Niche/physiology ; Stem Cells/cytology/metabolism/*physiology ; Transcription, Genetic ; Wnt Proteins/*metabolism
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    A critical period of sleep for development of courtship circuitry and behavior in Drosophila (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-04-20
    Description: Most animals sleep more early in life than in adulthood, but the function of early sleep is not known. Using Drosophila, we found that increased sleep in young flies was associated with an elevated arousal threshold and resistance to sleep deprivation. Excess sleep results from decreased inhibition of a sleep-promoting region by a specific dopaminergic circuit. Experimental hyperactivation of this circuit in young flies results in sleep loss and lasting deficits in adult courtship behaviors. These deficits are accompanied by impaired development of a single olfactory glomerulus, VA1v, which normally displays extensive sleep-dependent growth after eclosion. Our results demonstrate that sleep promotes normal brain development that gives rise to an adult behavior critical for species propagation and suggest that rapidly growing regions of the brain are most susceptible to sleep perturbations early in life.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4479292/" 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/PMC4479292/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kayser, Matthew S -- Yue, Zhifeng -- Sehgal, Amita -- R25MH060490/MH/NIMH NIH HHS/ -- T32 HL007713/HL/NHLBI NIH HHS/ -- T32HL07713/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):269-74. doi: 10.1126/science.1250553.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744368" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arousal ; Brain/growth & development/physiology ; Courtship ; Dopamine/metabolism ; Dopaminergic Neurons/*physiology ; Drosophila/genetics/growth & development/*physiology ; Female ; Male ; Models, Animal ; Neural Pathways/physiology ; Olfactory Bulb/growth & development/physiology ; Sexual Behavior, Animal ; Signal Transduction ; *Sleep ; Sleep Deprivation ; Temperature
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    Cell reprogramming. Histone chaperone ASF1A is required for maintenance of pluripotency and cellular reprogramming (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-07-19
    Description: Unfertilized oocytes have the intrinsic capacity to remodel sperm and the nuclei of somatic cells. The discoveries that cells can change their phenotype from differentiated to embryonic state using oocytes or specific transcription factors have been recognized as two major breakthroughs in the biomedical field. Here, we show that ASF1A, a histone-remodeling chaperone specifically enriched in the metaphase II human oocyte, is necessary for reprogramming of human adult dermal fibroblasts (hADFs) into undifferentiated induced pluripotent stem cell. We also show that overexpression of just ASF1A and OCT4 in hADFs exposed to the oocyte-specific paracrine growth factor GDF9 can reprogram hADFs into pluripotent cells. Our Report underscores the importance of studying the unfertilized MII oocyte as a means to understand the molecular pathways governing somatic cell reprogramming.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Munoz, Elena -- Arboleda-Estudillo, Yohanna -- Otu, Hasan H -- Cibelli, Jose B -- New York, N.Y. -- Science. 2014 Aug 15;345(6198):822-5. doi: 10.1126/science.1254745. Epub 2014 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉LARCEL, Laboratorio Andaluz de Reprogramacion Celular, BIONAND, Centro Andaluz de Nanomedicina y Biotecnologia Andalucia, 29590, Spain. ; Department of Genetics and Bioengineering, Istanbul Bilgi University 34060, Istanbul, Turkey. Department of Electrical Engineering, University of Nebraska-Lincoln, Lincoln, NE 68588, USA. ; LARCEL, Laboratorio Andaluz de Reprogramacion Celular, BIONAND, Centro Andaluz de Nanomedicina y Biotecnologia Andalucia, 29590, Spain. Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA. Department of Physiology, Michigan State University, East Lansing, MI 48824, USA. cibelli@msu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25035411" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Cell Cycle Proteins/genetics/*metabolism ; Cell Dedifferentiation ; Cell Differentiation ; *Cellular Reprogramming ; Embryonic Stem Cells/cytology/physiology ; Fibroblasts/cytology/physiology ; Growth Differentiation Factor 9/metabolism ; Histone Chaperones/genetics/*metabolism ; Histones/metabolism ; Humans ; Induced Pluripotent Stem Cells/*physiology ; Metaphase ; Octamer Transcription Factor-3/metabolism ; Oocytes/cytology/physiology ; Signal Transduction ; Transcriptional Activation ; Transcriptome
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    Systems biology. Conditional density-based analysis of T cell signaling in single-cell data (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-10-25
    Description: Cellular circuits sense the environment, process signals, and compute decisions using networks of interacting proteins. To model such a system, the abundance of each activated protein species can be described as a stochastic function of the abundance of other proteins. High-dimensional single-cell technologies, such as mass cytometry, offer an opportunity to characterize signaling circuit-wide. However, the challenge of developing and applying computational approaches to interpret such complex data remains. Here, we developed computational methods, based on established statistical concepts, to characterize signaling network relationships by quantifying the strengths of network edges and deriving signaling response functions. In comparing signaling between naive and antigen-exposed CD4(+) T lymphocytes, we find that although these two cell subtypes had similarly wired networks, naive cells transmitted more information along a key signaling cascade than did antigen-exposed cells. We validated our characterization on mice lacking the extracellular-regulated mitogen-activated protein kinase (MAPK) ERK2, which showed stronger influence of pERK on pS6 (phosphorylated-ribosomal protein S6), in naive cells as compared with antigen-exposed cells, as predicted. We demonstrate that by using cell-to-cell variation inherent in single-cell data, we can derive response functions underlying molecular circuits and drive the understanding of how cells process signals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4334155/" 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/PMC4334155/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krishnaswamy, Smita -- Spitzer, Matthew H -- Mingueneau, Michael -- Bendall, Sean C -- Litvin, Oren -- Stone, Erica -- Pe'er, Dana -- Nolan, Garry P -- 1K01DK095008/DK/NIDDK NIH HHS/ -- 1R01CA130826/CA/NCI NIH HHS/ -- 1U54CA121852-01A1/CA/NCI NIH HHS/ -- CA 09-011/CA/NCI NIH HHS/ -- HHSN268201000034C/HV/NHLBI NIH HHS/ -- HHSN272200700038C/PHS HHS/ -- HV-10-05/HV/NHLBI NIH HHS/ -- K01 DK095008/DK/NIDDK NIH HHS/ -- P01 CA034233/CA/NCI NIH HHS/ -- R00 GM104148/GM/NIGMS NIH HHS/ -- R01 CA130826/CA/NCI NIH HHS/ -- S10RR027582-01/RR/NCRR NIH HHS/ -- U19 AI057229/AI/NIAID NIH HHS/ -- U19 AI100627/AI/NIAID NIH HHS/ -- U54 CA149145/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 28;346(6213):1250689. doi: 10.1126/science.1250689. Epub 2014 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, Department of Systems Biology, Columbia University, New York, NY, USA. ; Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA. ; Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA. ; Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA. ; Department of Biological Sciences, Department of Systems Biology, Columbia University, New York, NY, USA. dpeer@biology.columbia.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25342659" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/*immunology ; Computer Simulation ; Image Cytometry ; Male ; Mice ; Mice, Mutant Strains ; Mitogen-Activated Protein Kinase 1/genetics ; Receptors, Antigen, T-Cell/*metabolism ; Ribosomal Protein S6/metabolism ; Signal Transduction ; Single-Cell Analysis/*methods ; Systems Biology/*methods ; eIF-2 Kinase/metabolism
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    Cell surface ABP1-TMK auxin-sensing complex activates ROP GTPase signaling (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-01
    Description: Auxin-binding protein 1 (ABP1) was discovered nearly 40 years ago and was shown to be essential for plant development and morphogenesis, but its mode of action remains unclear. Here, we report that the plasma membrane-localized transmembrane kinase (TMK) receptor-like kinases interact with ABP1 and transduce auxin signal to activate plasma membrane-associated ROPs [Rho-like guanosine triphosphatases (GTPase) from plants], leading to changes in the cytoskeleton and the shape of leaf pavement cells in Arabidopsis. The interaction between ABP1 and TMK at the cell surface is induced by auxin and requires ABP1 sensing of auxin. These findings show that TMK proteins and ABP1 form a cell surface auxin perception complex that activates ROP signaling pathways, regulating nontranscriptional cytoplasmic responses and associated fundamental processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4166562/" 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/PMC4166562/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Tongda -- Dai, Ning -- Chen, Jisheng -- Nagawa, Shingo -- Cao, Min -- Li, Hongjiang -- Zhou, Zimin -- Chen, Xu -- De Rycke, Riet -- Rakusova, Hana -- Wang, Wuyi -- Jones, Alan M -- Friml, Jiri -- Patterson, Sara E -- Bleecker, Anthony B -- Yang, Zhenbiao -- GM065989/GM/NIGMS NIH HHS/ -- GM081451/GM/NIGMS NIH HHS/ -- R01 GM081451/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 28;343(6174):1025-8. doi: 10.1126/science.1245125.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Plant Cell Biology, Department of Botany and Plant Sciences, University of California, Riverside, CA 92521, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578577" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*enzymology/genetics ; Cell Membrane/*enzymology ; Indoleacetic Acids/*metabolism ; Plant Leaves/enzymology/genetics ; Plant Proteins/*metabolism ; Protein Kinases/genetics/*metabolism ; Receptors, Cell Surface/*metabolism ; Signal Transduction ; rho GTP-Binding Proteins/*metabolism
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    Btk29A promotes Wnt4 signaling in the niche to terminate germ cell proliferation in Drosophila (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-01-18
    Description: Btk29A is the Drosophila ortholog of the mammalian Bruton's tyrosine kinase (Btk), mutations of which in humans cause a heritable immunodeficiency disease. Btk29A mutations stabilized the proliferating cystoblast fate, leading to an ovarian tumor. This phenotype was rescued by overexpression of wild-type Btk29A and phenocopied by the interference of Wnt4-beta-catenin signaling or its putative downstream nuclear protein Piwi in somatic escort cells. Btk29A and mammalian Btk directly phosphorylated tyrosine residues of beta-catenin, leading to the up-regulation of its transcriptional activity. Thus, we identify a transcriptional switch involving the kinase Btk29A/Btk and its phosphorylation target, beta-catenin, which functions downstream of Wnt4 in escort cells to terminate Drosophila germ cell proliferation through up-regulation of piwi expression. This signaling mechanism likely represents a versatile developmental switch.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hamada-Kawaguchi, Noriko -- Nore, Beston F -- Kuwada, Yusuke -- Smith, C I Edvard -- Yamamoto, Daisuke -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):294-7. doi: 10.1126/science.1244512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology and Neurosciences, Tohoku University Graduate School of Life Sciences, Sendai 980-8577, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436419" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/*biosynthesis ; *Cell Proliferation ; DNA Breaks, Double-Stranded ; Drosophila Proteins/*biosynthesis/genetics/*metabolism ; Drosophila melanogaster/genetics/metabolism/*physiology ; Gene Knockdown Techniques ; Genomic Instability ; Germ Cells/cytology/metabolism/*physiology ; Glycoproteins/genetics/*metabolism ; Phosphorylation ; Protein-Tyrosine Kinases/genetics/*metabolism ; RNA, Small Interfering/genetics/metabolism ; Signal Transduction ; Transcription, Genetic ; Tyrosine/genetics/metabolism ; Up-Regulation ; Wnt Proteins/genetics/*metabolism ; beta Catenin/genetics/*metabolism
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    A chloroplast retrograde signal regulates nuclear alternative splicing (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-04-26
    Description: Light is a source of energy and also a regulator of plant physiological adaptations. We show here that light/dark conditions affect alternative splicing of a subset of Arabidopsis genes preferentially encoding proteins involved in RNA processing. The effect requires functional chloroplasts and is also observed in roots when the communication with the photosynthetic tissues is not interrupted, suggesting that a signaling molecule travels through the plant. Using photosynthetic electron transfer inhibitors with different mechanisms of action, we deduce that the reduced pool of plastoquinones initiates a chloroplast retrograde signaling that regulates nuclear alternative splicing and is necessary for proper plant responses to varying light conditions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382720/" 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/PMC4382720/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petrillo, Ezequiel -- Godoy Herz, Micaela A -- Fuchs, Armin -- Reifer, Dominik -- Fuller, John -- Yanovsky, Marcelo J -- Simpson, Craig -- Brown, John W S -- Barta, Andrea -- Kalyna, Maria -- Kornblihtt, Alberto R -- BB/G024979/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- P 26333/Austrian Science Fund FWF/Austria -- Biotechnology and Biological Sciences Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Apr 25;344(6182):427-30. doi: 10.1126/science.1250322. Epub 2014 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratorio de Fisiologia y Biologia Molecular, Departamento de Fisiologia, Biologia Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellon 2, C1428EHA Buenos Aires, Argentina.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24763593" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Arabidopsis/*genetics/metabolism ; Arabidopsis Proteins/genetics/metabolism ; Cell Nucleus/genetics ; Chloroplasts/*metabolism ; Circadian Clocks ; Dibromothymoquinone/pharmacology ; Diuron/pharmacology ; Electron Transport/drug effects ; *Gene Expression Regulation, Plant ; Light ; Models, Biological ; Oxidation-Reduction ; Photosynthesis/drug effects ; Plant Leaves/metabolism ; Plant Roots/metabolism ; Plants, Genetically Modified ; Plastoquinone/*metabolism ; RNA Stability ; RNA, Messenger/genetics/metabolism ; RNA, Plant/genetics/metabolism ; Seedlings/genetics/metabolism ; Signal Transduction
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    Poly-dipeptides encoded by the C9orf72 repeats bind nucleoli, impede RNA biogenesis, and kill cells (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-08-02
    Description: Many RNA regulatory proteins controlling pre-messenger RNA splicing contain serine:arginine (SR) repeats. Here, we found that these SR domains bound hydrogel droplets composed of fibrous polymers of the low-complexity domain of heterogeneous ribonucleoprotein A2 (hnRNPA2). Hydrogel binding was reversed upon phosphorylation of the SR domain by CDC2-like kinases 1 and 2 (CLK1/2). Mutated variants of the SR domains changing serine to glycine (SR-to-GR variants) also bound to hnRNPA2 hydrogels but were not affected by CLK1/2. When expressed in mammalian cells, these variants bound nucleoli. The translation products of the sense and antisense transcripts of the expansion repeats associated with the C9orf72 gene altered in neurodegenerative disease encode GRn and PRn repeat polypeptides. Both peptides bound to hnRNPA2 hydrogels independent of CLK1/2 activity. When applied to cultured cells, both peptides entered cells, migrated to the nucleus, bound nucleoli, and poisoned RNA biogenesis, which caused cell death.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4459787/" 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/PMC4459787/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwon, Ilmin -- Xiang, Siheng -- Kato, Masato -- Wu, Leeju -- Theodoropoulos, Pano -- Wang, Tao -- Kim, Jiwoong -- Yun, Jonghyun -- Xie, Yang -- McKnight, Steven L -- U01 GM107623/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 5;345(6201):1139-45. doi: 10.1126/science.1254917. Epub 2014 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Quantitative Biomedical Research Center, Department of Clinical Sciences, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. ; Department of Biochemistry, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9152, USA. steven.mcknight@utsouthwestern.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25081482" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing ; Amyotrophic Lateral Sclerosis/genetics/*metabolism/pathology ; Astrocytes/*metabolism/pathology ; Cell Death ; Cell Nucleolus/*metabolism ; Cells, Cultured ; Dipeptides/genetics/*metabolism/pharmacology ; Frontotemporal Dementia/genetics/*metabolism/pathology ; Glutamate Plasma Membrane Transport Proteins/genetics ; Heterogeneous-Nuclear Ribonucleoprotein Group A-B/*metabolism ; Humans ; Hydrogel ; Phosphorylation ; Protein Biosynthesis ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/metabolism ; Proteins/*genetics ; RNA, Antisense/antagonists & inhibitors/biosynthesis ; RNA, Messenger/antagonists & inhibitors/biosynthesis ; RNA, Ribosomal/antagonists & inhibitors/biosynthesis ; Repetitive Sequences, Amino Acid ; Transcription, Genetic
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    The cellular and molecular origin of tumor-associated macrophages (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-05-09
    Description: Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being rediscovered as regulators of several diseases, including cancer. Here we show that in mice, mammary tumor growth induces the accumulation of tumor-associated macrophages (TAMs) that are phenotypically and functionally distinct from mammary tissue macrophages (MTMs). TAMs express the adhesion molecule Vcam1 and proliferate upon their differentiation from inflammatory monocytes, but do not exhibit an "alternatively activated" phenotype. TAM terminal differentiation depends on the transcriptional regulator of Notch signaling, RBPJ; and TAM, but not MTM, depletion restores tumor-infiltrating cytotoxic T cell responses and suppresses tumor growth. These findings reveal the ontogeny of TAMs and a discrete tumor-elicited inflammatory response, which may provide new opportunities for cancer immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4204732/" 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/PMC4204732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Franklin, Ruth A -- Liao, Will -- Sarkar, Abira -- Kim, Myoungjoo V -- Bivona, Michael R -- Liu, Kang -- Pamer, Eric G -- Li, Ming O -- AI101251/AI/NIAID NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI101251/AI/NIAID NIH HHS/ -- R37 AI039031/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 May 23;344(6186):921-5. doi: 10.1126/science.1252510. Epub 2014 May 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, NY 10065, USA. ; New York Genome Center, New York, NY 10022, USA. ; Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. ; Department of Microbiology and Immunology, Columbia University, New York, NY 10032, USA. ; Immunology Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. lim@mskcc.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24812208" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation ; Female ; Inflammation/immunology/pathology ; Macrophages/*immunology ; Mammary Neoplasms, Animal/*immunology/*pathology ; Mice ; Mice, Inbred C57BL ; Monocyte-Macrophage Precursor Cells/immunology ; Receptors, Notch/metabolism ; Signal Transduction ; Vascular Cell Adhesion Molecule-1/metabolism
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    Virus entry. Lassa virus entry requires a trigger-induced receptor switch (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-06-28
    Description: Lassa virus spreads from a rodent to humans and can lead to lethal hemorrhagic fever. Despite its broad tropism, chicken cells were reported 30 years ago to resist infection. We found that Lassa virus readily engaged its cell-surface receptor alpha-dystroglycan in avian cells, but virus entry in susceptible species involved a pH-dependent switch to an intracellular receptor, the lysosome-resident protein LAMP1. Iterative haploid screens revealed that the sialyltransferase ST3GAL4 was required for the interaction of the virus glycoprotein with LAMP1. A single glycosylated residue in LAMP1, present in susceptible species but absent in birds, was essential for interaction with the Lassa virus envelope protein and subsequent infection. The resistance of Lamp1-deficient mice to Lassa virus highlights the relevance of this receptor switch in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4239993/" 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/PMC4239993/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jae, Lucas T -- Raaben, Matthijs -- Herbert, Andrew S -- Kuehne, Ana I -- Wirchnianski, Ariel S -- Soh, Timothy K -- Stubbs, Sarah H -- Janssen, Hans -- Damme, Markus -- Saftig, Paul -- Whelan, Sean P -- Dye, John M -- Brummelkamp, Thijn R -- AI081842/AI/NIAID NIH HHS/ -- AI109740/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- T32 AI007245/AI/NIAID NIH HHS/ -- U19 AI109740/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 27;344(6191):1506-10. doi: 10.1126/science.1252480.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. ; Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, Netherlands. Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. ; Biochemisches Institut, Christian Albrechts-Universitat Kiel, 24118 Kiel, Germany. ; Department of Microbiology and Immunobiology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; U.S. Army Medical Research Institute of Infectious Diseases, 1425 Porter Street, Fort Detrick, MD 21702-5011, USA. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu. ; 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, 1066 CX, Amsterdam, Netherlands. t.brummelkamp@nki.nl john.m.dye1.civ@mail.mil sean_whelan@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24970085" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Cell Line ; Cell Membrane/metabolism/virology ; Cells, Cultured ; Chickens ; Dystroglycans/genetics/metabolism ; Glycosylation ; Humans ; Hydrogen-Ion Concentration ; Lassa Fever/virology ; Lassa virus/*physiology ; Lysosomal-Associated Membrane Protein 1/chemistry/*metabolism ; Lysosomes/metabolism/virology ; Mice ; Mice, Knockout ; Molecular Sequence Data ; Protein Binding ; Receptors, Virus/*metabolism ; Sialyltransferases/metabolism ; Viral Envelope Proteins/*metabolism ; *Virus Internalization
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    Border control--a membrane-linked interactome of Arabidopsis (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-05-17
    Description: Cellular membranes act as signaling platforms and control solute transport. Membrane receptors, transporters, and enzymes communicate with intracellular processes through protein-protein interactions. Using a split-ubiquitin yeast two-hybrid screen that covers a test-space of 6.4 x 10(6) pairs, we identified 12,102 membrane/signaling protein interactions from Arabidopsis. Besides confirmation of expected interactions such as heterotrimeric G protein subunit interactions and aquaporin oligomerization, 〉99% of the interactions were previously unknown. Interactions were confirmed at a rate of 32% in orthogonal in planta split-green flourescent protein interaction assays, which was statistically indistinguishable from the confirmation rate for known interactions collected from literature (38%). Regulatory associations in membrane protein trafficking, turnover, and phosphorylation include regulation of potassium channel activity through abscisic acid signaling, transporter activity by a WNK kinase, and a brassinolide receptor kinase by trafficking-related proteins. These examples underscore the utility of the membrane/signaling protein interaction network for gene discovery and hypothesis generation in plants and other organisms.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jones, Alexander M -- Xuan, Yuanhu -- Xu, Meng -- Wang, Rui-Sheng -- Ho, Cheng-Hsun -- Lalonde, Sylvie -- You, Chang Hun -- Sardi, Maria I -- Parsa, Saman A -- Smith-Valle, Erika -- Su, Tianying -- Frazer, Keith A -- Pilot, Guillaume -- Pratelli, Rejane -- Grossmann, Guido -- Acharya, Biswa R -- Hu, Heng-Cheng -- Engineer, Cawas -- Villiers, Florent -- Ju, Chuanli -- Takeda, Kouji -- Su, Zhao -- Dong, Qunfeng -- Assmann, Sarah M -- Chen, Jin -- Kwak, June M -- Schroeder, Julian I -- Albert, Reka -- Rhee, Seung Y -- Frommer, Wolf B -- New York, N.Y. -- Science. 2014 May 16;344(6185):711-6. doi: 10.1126/science.1251358.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Biology, Carnegie Institution for Science, CA 94305, USA. ; Department of Physics, Pennsylvania State University, University Park, PA 16802, USA. ; Department of Plant Biology, Carnegie Institution for Science, CA 94305, USA. Department of Plant Pathology, Physiology, and Weed Science, Virginia Polytechnic University and State University, Blacksburg, VA 24061, USA. ; Department of Biology, Pennsylvania State University, University Park, PA 16802, USA. ; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. ; Cell and Developmental Biology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. ; Department of Biological Sciences, University of North Texas, Denton, TX 76203, USA. ; Department of Plant Biology, Carnegie Institution for Science, CA 94305, USA. Michigan State University-U.S. Department of Energy (MSU-DOE) Plant Research Laboratory and Department of Computer Science and Engineering, Michigan State University, East Lansing, MI 48824, USA. ; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742, USA. Center for Plant Aging Research, Institute for Basic Science, Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu 711-873, Republic of Korea. ; Department of Plant Biology, Carnegie Institution for Science, CA 94305, USA. wfrommer@stanford.edu srhee@carnegiescience.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833385" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/genetics/*metabolism ; Arabidopsis Proteins/genetics/*metabolism ; Cell Membrane/*metabolism ; Membrane Proteins/genetics/*metabolism ; *Protein Interaction Maps ; Signal Transduction ; Two-Hybrid System Techniques
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    Neurodevelopment. Dendrite morphogenesis depends on relative levels of NT-3/TrkC signaling (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-02
    Description: Neurotrophins regulate diverse aspects of neuronal development and plasticity, but their precise in vivo functions during neural circuit assembly in the central brain remain unclear. We show that the neurotrophin receptor tropomyosin-related kinase C (TrkC) is required for dendritic growth and branching of mouse cerebellar Purkinje cells. Sparse TrkC knockout reduced dendrite complexity, but global Purkinje cell knockout had no effect. Removal of the TrkC ligand neurotrophin-3 (NT-3) from cerebellar granule cells, which provide major afferent input to developing Purkinje cell dendrites, rescued the dendrite defects caused by sparse TrkC disruption in Purkinje cells. Our data demonstrate that NT-3 from presynaptic neurons (granule cells) is required for TrkC-dependent competitive dendrite morphogenesis in postsynaptic neurons (Purkinje cells)--a previously unknown mechanism of neural circuit development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4631524/" 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/PMC4631524/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joo, William -- Hippenmeyer, Simon -- Luo, Liqun -- 5 F31 NS071697/NS/NINDS NIH HHS/ -- F31 NS071697/NS/NINDS NIH HHS/ -- R01 NS050835/NS/NINDS NIH HHS/ -- R01-NS050835/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Oct 31;346(6209):626-9. doi: 10.1126/science.1258996.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA. Neurosciences Program, Stanford University, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA. ; Howard Hughes Medical Institute and Department of Biology, Stanford University, Stanford, CA 94305, USA. Neurosciences Program, Stanford University, Stanford, CA 94305, USA. lluo@stanford.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25359972" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dendrites/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Nerve Net/cytology/*growth & development ; *Neurogenesis ; Neurotrophin 3/*metabolism ; Purkinje Cells/*cytology/metabolism ; Receptor, trkC/genetics/*metabolism ; Signal Transduction ; Synapses/physiology
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    Visualization of dynamics of single endogenous mRNA labeled in live mouse (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-01-25
    Description: The transcription and transport of messenger RNA (mRNA) are critical steps in regulating the spatial and temporal components of gene expression, but it has not been possible to observe the dynamics of endogenous mRNA in primary mammalian tissues. We have developed a transgenic mouse in which all beta-actin mRNA is fluorescently labeled. We found that beta-actin mRNA in primary fibroblasts localizes predominantly by diffusion and trapping as single mRNAs. In cultured neurons and acute brain slices, we found that multiple beta-actin mRNAs can assemble together, travel by active transport, and disassemble upon depolarization by potassium chloride. Imaging of brain slices revealed immediate early induction of beta-actin transcription after depolarization. Studying endogenous mRNA in live mouse tissues provides insight into its dynamic regulation within the context of the cellular and tissue microenvironment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111226/" 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/PMC4111226/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Hye Yoon -- Lim, Hyungsik -- Yoon, Young J -- Follenzi, Antonia -- Nwokafor, Chiso -- Lopez-Jones, Melissa -- Meng, Xiuhua -- Singer, Robert H -- EB13571/EB/NIBIB NIH HHS/ -- F32-GM87122/GM/NIGMS NIH HHS/ -- GM84364/GM/NIGMS NIH HHS/ -- NS083085-19/NS/NINDS NIH HHS/ -- R01 EB013571/EB/NIBIB NIH HHS/ -- R01 NS083085/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Jan 24;343(6169):422-4. doi: 10.1126/science.1239200.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24458643" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*biosynthesis/genetics ; Animals ; Brain/cytology/metabolism ; Cells, Cultured ; Fibroblasts/metabolism ; Fluorescent Dyes/chemistry ; Mice ; Mice, Transgenic ; Neuroimaging/*methods ; Neurons/metabolism ; Protein Biosynthesis ; RNA, Messenger/analysis/biosynthesis/*metabolism ; Staining and Labeling
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    Interferon-lambda cures persistent murine norovirus infection in the absence of adaptive immunity (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-29
    Description: Norovirus gastroenteritis is a major public health burden worldwide. Although fecal shedding is important for transmission of enteric viruses, little is known about the immune factors that restrict persistent enteric infection. We report here that although the cytokines interferon-alpha (IFN-alpha) and IFN-beta prevented the systemic spread of murine norovirus (MNoV), only IFN-lambda controlled persistent enteric infection. Infection-dependent induction of IFN-lambda was governed by the MNoV capsid protein and correlated with diminished enteric persistence. Treatment of established infection with IFN-lambda cured mice in a manner requiring nonhematopoietic cell expression of the IFN-lambda receptor, Ifnlr1, and independent of adaptive immunity. These results suggest the therapeutic potential of IFN-lambda for curing virus infections in the gastrointestinal tract.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398891/" 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/PMC4398891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nice, Timothy J -- Baldridge, Megan T -- McCune, Broc T -- Norman, Jason M -- Lazear, Helen M -- Artyomov, Maxim -- Diamond, Michael S -- Virgin, Herbert W -- 5T32A100716334/PHS HHS/ -- 5T32AI007163/AI/NIAID NIH HHS/ -- 5T32CA009547/CA/NCI NIH HHS/ -- F31 CA177194/CA/NCI NIH HHS/ -- F31CA177194-01/CA/NCI NIH HHS/ -- R01 AI084887/AI/NIAID NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- T32 CA009547/CA/NCI NIH HHS/ -- U19 AI083019/AI/NIAID NIH HHS/ -- U19 AI106772/AI/NIAID NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 16;347(6219):269-73. doi: 10.1126/science.1258100. Epub 2014 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. virgin@wustl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25431489" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptive Immunity ; Animals ; Caliciviridae Infections/*drug therapy/*immunology/virology ; Capsid Proteins/immunology/metabolism ; Cells, Cultured ; Cytokines/biosynthesis/*immunology/*therapeutic use ; Feces/virology ; Gastroenteritis/drug therapy/*immunology/virology ; Immunity, Innate ; Interferon-alpha/biosynthesis/immunology ; Interferon-beta/biosynthesis/immunology ; Mice ; Mice, Inbred C57BL ; Norovirus/*immunology/*physiology ; Virus Replication ; Virus Shedding
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Commensal microbes and interferon-lambda determine persistence of enteric murine norovirus infection (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-11-29
    Description: The capacity of human norovirus (NoV), which causes 〉90% of global epidemic nonbacterial gastroenteritis, to infect a subset of people persistently may contribute to its spread. How such enteric viruses establish persistent infections is not well understood. We found that antibiotics prevented persistent murine norovirus (MNoV) infection, an effect that was reversed by replenishment of the bacterial microbiota. Antibiotics did not prevent tissue infection or affect systemic viral replication but acted specifically in the intestine. The receptor for the antiviral cytokine interferon-lambda, Ifnlr1, as well as the transcription factors Stat1 and Irf3, were required for antibiotics to prevent viral persistence. Thus, the bacterial microbiome fosters enteric viral persistence in a manner counteracted by specific components of the innate immune system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409937/" 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/PMC4409937/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baldridge, Megan T -- Nice, Timothy J -- McCune, Broc T -- Yokoyama, Christine C -- Kambal, Amal -- Wheadon, Michael -- Diamond, Michael S -- Ivanova, Yulia -- Artyomov, Maxim -- Virgin, Herbert W -- 1F31CA177194/CA/NCI NIH HHS/ -- 5T32AI007163/AI/NIAID NIH HHS/ -- 5T32CA009547/CA/NCI NIH HHS/ -- F31 CA177194/CA/NCI NIH HHS/ -- R01 AI084887/AI/NIAID NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- T32 CA009547/CA/NCI NIH HHS/ -- U19 AI083019/AI/NIAID NIH HHS/ -- U19 AI106772/AI/NIAID NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2015 Jan 16;347(6219):266-9. doi: 10.1126/science.1258025. Epub 2014 Nov 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Departments of Medicine and Molecular Microbiology, Washington University School of Medicine, St. Louis, MO 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. virgin@wustl.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25431490" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Caliciviridae Infections/drug therapy/immunology/microbiology/*virology ; Cytokines/*physiology ; Female ; Gastroenteritis/drug therapy/immunology/microbiology/*virology ; Intestines/*microbiology/virology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; *Microbiota/drug effects ; Norovirus/immunology/*physiology ; Receptors, Cytokine/genetics/metabolism ; Signal Transduction ; *Symbiosis ; Viral Load ; Virus Replication ; Virus Shedding
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    T cell immunity. Functional heterogeneity of human memory CD4(+) T cell clones primed by pathogens or vaccines (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-12-06
    Description: Distinct types of CD4(+) T cells protect the host against different classes of pathogens. However, it is unclear whether a given pathogen induces a single type of polarized T cell. By combining antigenic stimulation and T cell receptor deep sequencing, we found that human pathogen- and vaccine-specific T helper 1 (T(H)1), T(H)2, and T(H)17 memory cells have different frequencies but comparable diversity and comprise not only clones polarized toward a single fate, but also clones whose progeny have acquired multiple fates. Single naive T cells primed by a pathogen in vitro could also give rise to multiple fates. Our results unravel an unexpected degree of interclonal and intraclonal functional heterogeneity of the human T cell response and suggest that polarized responses result from preferential expansion rather than priming.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Becattini, Simone -- Latorre, Daniela -- Mele, Federico -- Foglierini, Mathilde -- De Gregorio, Corinne -- Cassotta, Antonino -- Fernandez, Blanca -- Kelderman, Sander -- Schumacher, Ton N -- Corti, Davide -- Lanzavecchia, Antonio -- Sallusto, Federica -- New York, N.Y. -- Science. 2015 Jan 23;347(6220):400-6. doi: 10.1126/science.1260668. Epub 2014 Dec 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. Institute of Microbiology, ETH Zurich, Zurich, Switzerland. ; Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. ; Division of Immunology, Netherlands Cancer Institute, Amsterdam, Netherlands. ; Institute for Research in Biomedicine, Bellinzona, Universita della Svizzera Italiana, Lugano, Switzerland. federica.sallusto@irb.usi.ch.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25477212" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; CD4-Positive T-Lymphocytes/*immunology ; Candida albicans/*immunology ; Cells, Cultured ; Clone Cells ; High-Throughput Nucleotide Sequencing ; Host-Pathogen Interactions/*immunology ; Humans ; *Immunologic Memory ; Lymphocyte Activation ; Molecular Sequence Data ; Mycobacterium tuberculosis/*immunology ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocyte Subsets/*immunology ; Th1 Cells/immunology ; Th17 Cells/immunology ; Th2 Cells/immunology ; Vaccines/*immunology
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    Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-08-31
    Description: Invasion of microbial DNA into the cytoplasm of animal cells triggers a cascade of host immune reactions that help clear the infection; however, self DNA in the cytoplasm can cause autoimmune diseases. Biochemical approaches led to the identification of cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) as a cytosolic DNA sensor that triggers innate immune responses. Here, we show that cells from cGAS-deficient (cGas(-/-)) mice, including fibroblasts, macrophages, and dendritic cells, failed to produce type I interferons and other cytokines in response to DNA transfection or DNA virus infection. cGas(-/-) mice were more susceptible to lethal infection with herpes simplex virus 1 (HSV1) than wild-type mice. We also show that cGAMP is an adjuvant that boosts antigen-specific T cell activation and antibody production in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3863637/" 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/PMC3863637/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Xiao-Dong -- Wu, Jiaxi -- Gao, Daxing -- Wang, Hua -- Sun, Lijun -- Chen, Zhijian J -- 5T32AI070116/AI/NIAID NIH HHS/ -- AI-093967/AI/NIAID NIH HHS/ -- R01 AI093967/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Sep 20;341(6152):1390-4. doi: 10.1126/science.1244040. Epub 2013 Aug 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23989956" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/biosynthesis ; DNA, Viral/genetics/immunology ; Dendritic Cells/immunology ; Fibroblasts/immunology ; Herpes Simplex/*immunology ; *Herpesvirus 1, Human ; Interferon Regulatory Factor-3/genetics ; Interferon-beta/*biosynthesis/genetics ; Lymphocyte Activation ; Macrophages/immunology ; Mice ; Mice, Knockout ; Nucleotidyltransferases/genetics/*immunology ; Signal Transduction ; T-Lymphocytes/immunology ; Transfection
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    Interfollicular epidermal stem cells self-renew via autocrine Wnt signaling (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-12-07
    Description: The skin is a classical example of a tissue maintained by stem cells. However, the identity of the stem cells that maintain the interfollicular epidermis and the source of the signals that control their activity remain unclear. Using mouse lineage tracing and quantitative clonal analyses, we showed that the Wnt target gene Axin2 marks interfollicular epidermal stem cells. These Axin2-expressing cells constitute the majority of the basal epidermal layer, compete neutrally, and require Wnt/beta-catenin signaling to proliferate. The same cells contribute robustly to wound healing, with no requirement for a quiescent stem cell subpopulation. By means of double-labeling RNA in situ hybridization in mice, we showed that the Axin2-expressing cells themselves produce Wnt signals as well as long-range secreted Wnt inhibitors, suggesting an autocrine mechanism of stem cell self-renewal.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4081860/" 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/PMC4081860/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, Xinhong -- Tan, Si Hui -- Koh, Winston Lian Chye -- Chau, Rosanna Man Wah -- Yan, Kelley S -- Kuo, Calvin J -- van Amerongen, Renee -- Klein, Allon Moshe -- Nusse, Roel -- 1R01DK085720/DK/NIDDK NIH HHS/ -- 1U01DK085527/DK/NIDDK NIH HHS/ -- 5K08DK096048/DK/NIDDK NIH HHS/ -- K08 DK096048/DK/NIDDK NIH HHS/ -- P30 DK026743/DK/NIDDK NIH HHS/ -- R01 DK085720/DK/NIDDK NIH HHS/ -- U01 DK085527/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1226-30. doi: 10.1126/science.1239730.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, Howard Hughes Medical Institute (HHMI), Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24311688" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Autocrine Communication ; Axin Protein/genetics/metabolism ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Cells, Cultured ; Epidermis/*cytology/injuries/metabolism ; Epithelial Cells/cytology/metabolism ; Gene Expression ; Homeostasis ; Humans ; Intercellular Signaling Peptides and Proteins/metabolism ; Keratinocytes/cytology/metabolism ; Mice ; Regeneration ; Skin/injuries ; Stem Cell Niche ; Stem Cells/cytology/*physiology ; Wnt Proteins/metabolism ; *Wnt Signaling Pathway ; Wound Healing ; beta Catenin/genetics/metabolism
    Print ISSN: 0036-8075
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    B cells use mechanical energy to discriminate antigen affinities (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-05-21
    Description: The generation of high-affinity antibodies depends on the ability of B cells to extract antigens from the surfaces of antigen-presenting cells. B cells that express high-affinity B cell receptors (BCRs) acquire more antigen and obtain better T cell help. However, the mechanisms by which B cells extract antigen remain unclear. Using fluid and flexible membrane substrates to mimic antigen-presenting cells, we showed that B cells acquire antigen by dynamic myosin IIa-mediated contractions that pull out and invaginate the presenting membranes. The forces generated by myosin IIa contractions ruptured most individual BCR-antigen bonds and promoted internalization of only high-affinity, multivalent BCR microclusters. Thus, B cell contractility contributes to affinity discrimination by mechanically testing the strength of antigen binding.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3713314/" 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/PMC3713314/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Natkanski, Elizabeth -- Lee, Wing-Yiu -- Mistry, Bhakti -- Casal, Antonio -- Molloy, Justin E -- Tolar, Pavel -- MC_U117570592/Medical Research Council/United Kingdom -- MC_U117597138/Medical Research Council/United Kingdom -- U117570592/Medical Research Council/United Kingdom -- U117597138/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2013 Jun 28;340(6140):1587-90. doi: 10.1126/science.1237572. Epub 2013 May 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immune Cell Biology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23686338" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Antibody Affinity ; *Antigen Presentation ; Antigens/*immunology ; B-Lymphocytes/*immunology ; Cells, Cultured ; Mechanical Processes ; Mice ; Mice, Inbred C57BL ; Microscopy, Atomic Force ; Nonmuscle Myosin Type IIA/*physiology ; Receptors, Antigen, B-Cell/immunology
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    A mechanism for reorientation of cortical microtubule arrays driven by microtubule severing (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-11-10
    Description: Environmental and hormonal signals cause reorganization of microtubule arrays in higher plants, but the mechanisms driving these transitions have remained elusive. The organization of these arrays is required to direct morphogenesis. We discovered that microtubule severing by the protein katanin plays a crucial and unexpected role in the reorientation of cortical arrays, as triggered by blue light. Imaging and genetic experiments revealed that phototropin photoreceptors stimulate katanin-mediated severing specifically at microtubule intersections, leading to the generation of new microtubules at these locations. We show how this activity serves as the basis for a mechanism that amplifies microtubules orthogonal to the initial array, thereby driving array reorientation. Our observations show how severing is used constructively to build a new microtubule array.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindeboom, Jelmer J -- Nakamura, Masayoshi -- Hibbel, Anneke -- Shundyak, Kostya -- Gutierrez, Ryan -- Ketelaar, Tijs -- Emons, Anne Mie C -- Mulder, Bela M -- Kirik, Viktor -- Ehrhardt, David W -- New York, N.Y. -- Science. 2013 Dec 6;342(6163):1245533. doi: 10.1126/science.1245533. Epub 2013 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Plant Biology, Carnegie Institution for Science, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24200811" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/genetics/*metabolism ; Arabidopsis/genetics/growth & development/*metabolism/*ultrastructure ; Arabidopsis Proteins/genetics/*metabolism ; Hypocotyl/metabolism/ultrastructure ; Light ; Microtubules/*metabolism/ultrastructure ; Phosphoproteins/metabolism ; *Phototropism ; Recombinant Fusion Proteins/metabolism ; Signal Transduction
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Beyond stem cells: self-renewal of differentiated macrophages (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-11-23
    Description: In many mammalian tissues, mature differentiated cells are replaced by self-renewing stem cells, either continuously during homeostasis or in response to challenge and injury. For example, hematopoietic stem cells generate all mature blood cells, including monocytes, which have long been thought to be the major source of tissue macrophages. Recently, however, major macrophage populations were found to be derived from embryonic progenitors and to renew independently of hematopoietic stem cells. This process may not require progenitors, as mature macrophages can proliferate in response to specific stimuli indefinitely and without transformation or loss of functional differentiation. These findings suggest that macrophages are mature differentiated cells that may have a self-renewal potential similar to that of stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sieweke, Michael H -- Allen, Judith E -- MR/J001929/1/Medical Research Council/United Kingdom -- MR/K01207X1/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2013 Nov 22;342(6161):1242974. doi: 10.1126/science.1242974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre d'Immunologie de Marseille-Luminy (CIML), Aix-Marseille Universite, UM2, Campus de Luminy, Case 906, 13288 Marseille Cedex 09, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24264994" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Proliferation ; Cytokines/metabolism ; Embryonic Stem Cells/cytology ; Humans ; Macrophages/*cytology ; Mice ; Monocytes/cytology ; Rats ; Signal Transduction ; Stem Cells/*cytology
    Print ISSN: 0036-8075
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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    Mitochondrial fusion directs cardiomyocyte differentiation via calcineurin and Notch signaling (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-10-05
    Description: Mitochondrial morphology is crucial for tissue homeostasis, but its role in cell differentiation is unclear. We found that mitochondrial fusion was required for proper cardiomyocyte development. Ablation of mitochondrial fusion proteins Mitofusin 1 and 2 in the embryonic mouse heart, or gene-trapping of Mitofusin 2 or Optic atrophy 1 in mouse embryonic stem cells (ESCs), arrested mouse heart development and impaired differentiation of ESCs into cardiomyocytes. Gene expression profiling revealed decreased levels of transcription factors transforming growth factor-beta/bone morphogenetic protein, serum response factor, GATA4, and myocyte enhancer factor 2, linked to increased Ca(2+)-dependent calcineurin activity and Notch1 signaling that impaired ESC differentiation. Orchestration of cardiomyocyte differentiation by mitochondrial morphology reveals how mitochondria, Ca(2+), and calcineurin interact to regulate Notch1 signaling.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kasahara, Atsuko -- Cipolat, Sara -- Chen, Yun -- Dorn, Gerald W 2nd -- Scorrano, Luca -- GPP10005/Telethon/Italy -- R01 HL059888/HL/NHLBI NIH HHS/ -- R01 HL59888/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Nov 8;342(6159):734-7. doi: 10.1126/science.1241359. Epub 2013 Oct 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Physiology and Metabolism, University of Geneva, 1206 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24091702" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcineurin/*metabolism ; Calcineurin Inhibitors ; Cell Differentiation/genetics/*physiology ; GTP Phosphohydrolases/genetics/metabolism ; Gene Expression Profiling ; Heart/embryology ; Mice ; Mice, Knockout ; Mitochondrial Dynamics/genetics/*physiology ; Myocytes, Cardiac/*cytology/ultrastructure ; Receptor, Notch1/*metabolism ; Signal Transduction ; Transcription Factors/genetics/metabolism
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    Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-04-06
    Description: A number of human cancers harbor somatic point mutations in the genes encoding isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These mutations alter residues in the enzyme active sites and confer a gain-of-function in cancer cells, resulting in the accumulation and secretion of the oncometabolite (R)-2-hydroxyglutarate (2HG). We developed a small molecule, AGI-6780, that potently and selectively inhibits the tumor-associated mutant IDH2/R140Q. A crystal structure of AGI-6780 complexed with IDH2/R140Q revealed that the inhibitor binds in an allosteric manner at the dimer interface. The results of steady-state enzymology analysis were consistent with allostery and slow-tight binding by AGI-6780. Treatment with AGI-6780 induced differentiation of TF-1 erythroleukemia and primary human acute myelogenous leukemia cells in vitro. These data provide proof-of-concept that inhibitors targeting mutant IDH2/R140Q could have potential applications as a differentiation therapy for cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Fang -- Travins, Jeremy -- DeLaBarre, Byron -- Penard-Lacronique, Virginie -- Schalm, Stefanie -- Hansen, Erica -- Straley, Kimberly -- Kernytsky, Andrew -- Liu, Wei -- Gliser, Camelia -- Yang, Hua -- Gross, Stefan -- Artin, Erin -- Saada, Veronique -- Mylonas, Elena -- Quivoron, Cyril -- Popovici-Muller, Janeta -- Saunders, Jeffrey O -- Salituro, Francesco G -- Yan, Shunqi -- Murray, Stuart -- Wei, Wentao -- Gao, Yi -- Dang, Lenny -- Dorsch, Marion -- Agresta, Sam -- Schenkein, David P -- Biller, Scott A -- Su, Shinsan M -- de Botton, Stephane -- Yen, Katharine E -- New York, N.Y. -- Science. 2013 May 3;340(6132):622-6. doi: 10.1126/science.1234769. Epub 2013 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Agios Pharmaceuticals, Cambridge, MA 02139-4169, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23558173" target="_blank"〉PubMed〈/a〉
    Keywords: Allosteric Site ; Antineoplastic Agents/chemistry/metabolism/pharmacology ; Catalytic Domain ; Cell Line, Tumor ; Cell Proliferation ; Cells, Cultured ; Crystallography, X-Ray ; Enzyme Inhibitors/chemistry/metabolism/*pharmacology ; Erythropoiesis/drug effects ; Gene Expression Regulation, Leukemic ; Glutarates/metabolism ; Hematopoiesis/*drug effects ; Humans ; Isocitrate Dehydrogenase/*antagonists & inhibitors/chemistry/*genetics/metabolism ; Leukemia, Erythroblastic, Acute ; Leukemia, Myeloid, Acute/drug therapy/*enzymology/genetics/pathology ; Molecular Targeted Therapy ; Mutant Proteins/antagonists & inhibitors/chemistry/metabolism ; Phenylurea Compounds/chemistry/metabolism/*pharmacology ; Point Mutation ; Protein Multimerization ; Protein Structure, Secondary ; Small Molecule Libraries ; Sulfonamides/chemistry/metabolism/*pharmacology
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    Erythropoietin derived by chemical synthesis (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-12-18
    Description: Erythropoietin is a signaling glycoprotein that controls the fundamental process of erythropoiesis, orchestrating the production and maintenance of red blood cells. As administrated clinically, erythropoietin has a polypeptide backbone with complex dishomogeneity in its carbohydrate domains. Here we describe the total synthesis of homogeneous erythropoietin with consensus carbohydrate domains incorporated at all of the native glycosylation sites. The oligosaccharide sectors were built by total synthesis and attached stereospecifically to peptidyl fragments of the wild-type primary sequence, themselves obtained by solid-phase peptide synthesis. The glycopeptidyl constructs were joined by chemical ligation, followed by metal-free dethiylation, and subsequently folded. This homogeneous erythropoietin glycosylated at the three wild-type aspartates with N-linked high-mannose sialic acid-containing oligosaccharides and O-linked glycophorin exhibits Procrit-level in vivo activity in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4080428/" 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/PMC4080428/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Ping -- Dong, Suwei -- Shieh, Jae-Hung -- Peguero, Elizabeth -- Hendrickson, Ronald -- Moore, Malcolm A S -- Danishefsky, Samuel J -- HL025848/HL/NHLBI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 GM109760/GM/NIGMS NIH HHS/ -- R01 HL025848/HL/NHLBI NIH HHS/ -- New York, N.Y. -- Science. 2013 Dec 13;342(6164):1357-60. doi: 10.1126/science.1245095.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24337294" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Aspartic Acid/chemistry ; Cells, Cultured ; Consensus Sequence ; Dose-Response Relationship, Drug ; Erythrocyte Count ; Erythropoietin/*administration & dosage/*chemical synthesis/chemistry ; Glycophorin/chemistry ; Glycosylation ; Injections, Subcutaneous ; Mannose/chemistry ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; N-Acetylneuraminic Acid/chemistry ; Oligosaccharides/chemistry ; Reticulocytes/drug effects
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    An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level (2013)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2013-10-12
    Description: Genome-wide association studies (GWASs) have ascertained numerous trait-associated common genetic variants, frequently localized to regulatory DNA. We found that common genetic variation at BCL11A associated with fetal hemoglobin (HbF) level lies in noncoding sequences decorated by an erythroid enhancer chromatin signature. Fine-mapping uncovers a motif-disrupting common variant associated with reduced transcription factor (TF) binding, modestly diminished BCL11A expression, and elevated HbF. The surrounding sequences function in vivo as a developmental stage-specific, lineage-restricted enhancer. Genome engineering reveals the enhancer is required in erythroid but not B-lymphoid cells for BCL11A expression. These findings illustrate how GWASs may expose functional variants of modest impact within causal elements essential for appropriate gene expression. We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the beta-hemoglobinopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4018826/" 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/PMC4018826/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bauer, Daniel E -- Kamran, Sophia C -- Lessard, Samuel -- Xu, Jian -- Fujiwara, Yuko -- Lin, Carrie -- Shao, Zhen -- Canver, Matthew C -- Smith, Elenoe C -- Pinello, Luca -- Sabo, Peter J -- Vierstra, Jeff -- Voit, Richard A -- Yuan, Guo-Cheng -- Porteus, Matthew H -- Stamatoyannopoulos, John A -- Lettre, Guillaume -- Orkin, Stuart H -- 123382/Canadian Institutes of Health Research/Canada -- K08 DK093705/DK/NIDDK NIH HHS/ -- K08DK093705/DK/NIDDK NIH HHS/ -- P01HL032262/HL/NHLBI NIH HHS/ -- P30 DK049216/DK/NIDDK NIH HHS/ -- P30DK049216/DK/NIDDK NIH HHS/ -- R01 HG005085/HG/NHGRI NIH HHS/ -- R01 HL032259/HL/NHLBI NIH HHS/ -- R01HL032259/HL/NHLBI NIH HHS/ -- U54HG004594/HG/NHGRI NIH HHS/ -- U54HG007010/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2013 Oct 11;342(6155):253-7. doi: 10.1126/science.1242088.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24115442" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/*genetics ; Cell Line, Tumor ; Cells, Cultured ; Chromatin/genetics/metabolism ; Chromatin Immunoprecipitation ; Chromosome Mapping ; *Enhancer Elements, Genetic ; Erythroid Cells/*metabolism ; Fetal Hemoglobin/*biosynthesis/genetics ; *Gene Expression Regulation ; Gene Targeting ; Genetic Engineering ; Genetic Variation ; Genome-Wide Association Study ; Hemoglobinopathies/*genetics/therapy ; Humans ; Mice ; Nuclear Proteins/*genetics ; Precursor Cells, B-Lymphoid/metabolism ; Transcription Factors/genetics/metabolism
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    Mice genetically deficient in vasopressin V1a and V1b receptors are resistant to jet lag (2013)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2013-10-05
    Description: Jet-lag symptoms arise from temporal misalignment between the internal circadian clock and external solar time. We found that circadian rhythms of behavior (locomotor activity), clock gene expression, and body temperature immediately reentrained to phase-shifted light-dark cycles in mice lacking vasopressin receptors V1a and V1b (V1a(-/-)V1b(-/-)). Nevertheless, the behavior of V1a(-/-)V1b(-/-) mice was still coupled to the internal clock, which oscillated normally under standard conditions. Experiments with suprachiasmatic nucleus (SCN) slices in culture suggested that interneuronal communication mediated by V1a and V1b confers on the SCN an intrinsic resistance to external perturbation. Pharmacological blockade of V1a and V1b in the SCN of wild-type mice resulted in accelerated recovery from jet lag, which highlights the potential of vasopressin signaling as a therapeutic target for management of circadian rhythm misalignment, such as jet lag and shift work.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamaguchi, Yoshiaki -- Suzuki, Toru -- Mizoro, Yasutaka -- Kori, Hiroshi -- Okada, Kazuki -- Chen, Yulin -- Fustin, Jean-Michel -- Yamazaki, Fumiyoshi -- Mizuguchi, Naoki -- Zhang, Jing -- Dong, Xin -- Tsujimoto, Gozoh -- Okuno, Yasushi -- Doi, Masao -- Okamura, Hitoshi -- New York, N.Y. -- Science. 2013 Oct 4;342(6154):85-90. doi: 10.1126/science.1238599.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24092737" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidiuretic Hormone Receptor Antagonists ; Body Temperature/genetics ; CLOCK Proteins/genetics ; Cell Communication/drug effects/genetics ; Cells, Cultured ; Circadian Rhythm/genetics ; Gene Expression Regulation ; Jet Lag Syndrome/*genetics/physiopathology ; Mice ; Mice, Knockout ; Motor Activity/genetics ; Receptors, Vasopressin/*genetics ; Suprachiasmatic Nucleus/physiopathology
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