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  • 1
    Publication Date: 2014-06-17
    Description: Disease tolerance is the ability of the host to reduce the effect of infection on host fitness. Analysis of disease tolerance pathways could provide new approaches for treating infections and other inflammatory diseases. Typically, an initial exposure to bacterial lipopolysaccharide (LPS) induces a state of refractoriness to further LPS challenge (endotoxin tolerance). We found that a first exposure of mice to LPS activated the ligand-operated transcription factor aryl hydrocarbon receptor (AhR) and the hepatic enzyme tryptophan 2,3-dioxygenase, which provided an activating ligand to the former, to downregulate early inflammatory gene expression. However, on LPS rechallenge, AhR engaged in long-term regulation of systemic inflammation only in the presence of indoleamine 2,3-dioxygenase 1 (IDO1). AhR-complex-associated Src kinase activity promoted IDO1 phosphorylation and signalling ability. The resulting endotoxin-tolerant state was found to protect mice against immunopathology in Gram-negative and Gram-positive infections, pointing to a role for AhR in contributing to host fitness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098076/" 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/PMC4098076/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bessede, Alban -- Gargaro, Marco -- Pallotta, Maria T -- Matino, Davide -- Servillo, Giuseppe -- Brunacci, Cinzia -- Bicciato, Silvio -- Mazza, Emilia M C -- Macchiarulo, Antonio -- Vacca, Carmine -- Iannitti, Rossana -- Tissi, Luciana -- Volpi, Claudia -- Belladonna, Maria L -- Orabona, Ciriana -- Bianchi, Roberta -- Lanz, Tobias V -- Platten, Michael -- Della Fazia, Maria A -- Piobbico, Danilo -- Zelante, Teresa -- Funakoshi, Hiroshi -- Nakamura, Toshikazu -- Gilot, David -- Denison, Michael S -- Guillemin, Gilles J -- DuHadaway, James B -- Prendergast, George C -- Metz, Richard -- Geffard, Michel -- Boon, Louis -- Pirro, Matteo -- Iorio, Alfonso -- Veyret, Bernard -- Romani, Luigina -- Grohmann, Ursula -- Fallarino, Francesca -- Puccetti, Paolo -- P30 CA056036/CA/NCI NIH HHS/ -- R01 CA109542/CA/NCI NIH HHS/ -- R01 ES007685/ES/NIEHS NIH HHS/ -- R01ES007685/ES/NIEHS NIH HHS/ -- England -- Nature. 2014 Jul 10;511(7508):184-90. doi: 10.1038/nature13323.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2] IMS Laboratory, University of Bordeaux, 33607 Pessac, France [3]. ; 1] Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy [2]. ; Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. ; Center for Genome Research, University of Modena and Reggio Emilia, 41125 Modena, Italy. ; Department of Chemistry and Technology of Drugs, University of Perugia, 06123 Perugia, Italy. ; 1] Experimental Neuroimmunology Unit, German Cancer Research Center, 69120 Heidelberg, Germany [2] Department of Neurooncology, University Hospital, 69120 Heidelberg, Germany. ; Center for Advanced Research and Education, Asahikawa Medical University, 078-8510 Asahikawa, Japan. ; Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 565-0871 Osaka, Japan. ; CNRS UMR6290, Institut de Genetique et Developpement de Rennes, Universite de Rennes 1, 35043 Rennes, France. ; Department of Environmental Toxicology, University of California, Davis, 95616 California, USA. ; Australian School of Advanced Medicine (ASAM), Macquarie University, 2109 New South Wales, Australia. ; Lankenau Institute for Medical Research, Wynnewood, 19096 Pennsylvania, USA. ; New Link Genetics Corporation, Ames, 50010 Iowa, USA. ; IMS Laboratory, University of Bordeaux, 33607 Pessac, France. ; Bioceros, 3584 Utrecht, The Netherlands. ; Department of Medicine, University of Perugia, 06132 Perugia, Italy. ; Department of Clinical Epidemiology & Biostatistics, McMaster University, Ontario L8S 4K1, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24930766" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacterial Infections/immunology/metabolism ; Disease Resistance/drug effects/*genetics/*immunology ; Endotoxemia/genetics/immunology/metabolism ; Enzyme Activation/drug effects ; Gene Expression Regulation/drug effects ; Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism ; Inflammation/enzymology/genetics/metabolism ; Kynurenine/metabolism ; Lipopolysaccharides/pharmacology ; Mice ; Phosphorylation ; Receptors, Aryl Hydrocarbon/genetics/*metabolism ; Signal Transduction ; Tryptophan Oxygenase/metabolism ; src-Family Kinases/metabolism
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  • 2
    Publication Date: 2014-05-30
    Description: Targeted genome editing by artificial nucleases has brought the goal of site-specific transgene integration and gene correction within the reach of gene therapy. However, its application to long-term repopulating haematopoietic stem cells (HSCs) has remained elusive. Here we show that poor permissiveness to gene transfer and limited proficiency of the homology-directed DNA repair pathway constrain gene targeting in human HSCs. By tailoring delivery platforms and culture conditions we overcame these barriers and provide stringent evidence of targeted integration in human HSCs by long-term multilineage repopulation of transplanted mice. We demonstrate the therapeutic potential of our strategy by targeting a corrective complementary DNA into the IL2RG gene of HSCs from healthy donors and a subject with X-linked severe combined immunodeficiency (SCID-X1). Gene-edited HSCs sustained normal haematopoiesis and gave rise to functional lymphoid cells that possess a selective growth advantage over those carrying disruptive IL2RG mutations. These results open up new avenues for treating SCID-X1 and other diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4082311/" 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/PMC4082311/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Genovese, Pietro -- Schiroli, Giulia -- Escobar, Giulia -- Di Tomaso, Tiziano -- Firrito, Claudia -- Calabria, Andrea -- Moi, Davide -- Mazzieri, Roberta -- Bonini, Chiara -- Holmes, Michael C -- Gregory, Philip D -- van der Burg, Mirjam -- Gentner, Bernhard -- Montini, Eugenio -- Lombardo, Angelo -- Naldini, Luigi -- 249845/European Research Council/International -- TGT11D02/Telethon/Italy -- England -- Nature. 2014 Jun 12;510(7504):235-40. doi: 10.1038/nature13420. Epub 2014 May 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] Vita Salute San Raffaele University, 20132 Milan, Italy. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland 4102, Australia. ; Experimental Hematology Unit, San Raffaele Scientific Institute, 20132 Milan, Italy. ; Sangamo BioSciences Inc., Richmond, California 94804, USA. ; Department of Immunology Erasmus MC, University Medical Center, 3015 Rotterdam, The Netherlands. ; 1] TIGET, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, 20132 Milan, Italy [2] Vita Salute San Raffaele University, 20132 Milan, Italy [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870228" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD34/metabolism ; DNA, Complementary/genetics ; Endonucleases/metabolism ; Fetal Blood/cytology/metabolism/transplantation ; Gene Targeting/*methods ; Genome, Human/*genetics ; Hematopoiesis/genetics ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/*metabolism ; Humans ; Interleukin Receptor Common gamma Subunit/genetics ; Male ; Mice ; Mutation/genetics ; Targeted Gene Repair/*methods ; X-Linked Combined Immunodeficiency Diseases/*genetics/therapy
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  • 3
    Publication Date: 2014-12-04
    Description: The TRIM37 (also known as MUL) gene is located in the 17q23 chromosomal region, which is amplified in up to approximately 40% of breast cancers. TRIM37 contains a RING finger domain, a hallmark of E3 ubiquitin ligases, but its protein substrate(s) is unknown. Here we report that TRIM37 mono-ubiquitinates histone H2A, a chromatin modification associated with transcriptional repression. We find that in human breast cancer cell lines containing amplified 17q23, TRIM37 is upregulated and, reciprocally, the major H2A ubiquitin ligase RNF2 (also known as RING1B) is downregulated. Genome-wide chromatin immunoprecipitation (ChIP)-chip experiments in 17q23-amplified breast cancer cells identified many genes, including multiple tumour suppressors, whose promoters were bound by TRIM37 and enriched for ubiquitinated H2A. However, unlike RNF2, which is a subunit of polycomb repressive complex 1 (PRC1), we find that TRIM37 associates with polycomb repressive complex 2 (PRC2). TRIM37, PRC2 and PRC1 are co-bound to specific target genes, resulting in their transcriptional silencing. RNA-interference-mediated knockdown of TRIM37 results in loss of ubiquitinated H2A, dissociation of PRC1 and PRC2 from target promoters, and transcriptional reactivation of silenced genes. Knockdown of TRIM37 in human breast cancer cells containing amplified 17q23 substantially decreases tumour growth in mouse xenografts. Conversely, ectopic expression of TRIM37 renders non-transformed cells tumorigenic. Collectively, our results reveal TRIM37 as an oncogenic H2A ubiquitin ligase that is overexpressed in a subset of breast cancers and promotes transformation by facilitating silencing of tumour suppressors and other genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4269325/" 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/PMC4269325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhatnagar, Sanchita -- Gazin, Claude -- Chamberlain, Lynn -- Ou, Jianhong -- Zhu, Xiaochun -- Tushir, Jogender S -- Virbasius, Ching-Man -- Lin, Ling -- Zhu, Lihua J -- Wajapeyee, Narendra -- Green, Michael R -- R01 GM033977/GM/NIGMS NIH HHS/ -- R01GM033977/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 4;516(7529):116-20. doi: 10.1038/nature13955. Epub 2014 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Howard Hughes Medical Institute, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; CEA/DSV/iRCM/LEFG, Genopole G2, and Universite Paris Diderot, 91057 Evry, France. ; Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut 06877, USA. ; 1] Programs in Gene Function and Expression and Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA [2] Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470042" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*enzymology/*genetics ; Female ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Gene Silencing ; Heterografts ; Histones/metabolism ; Humans ; MCF-7 Cells ; Mice ; NIH 3T3 Cells ; Nuclear Proteins/*genetics/*metabolism ; Oncogene Proteins/*genetics/metabolism ; Polycomb Repressive Complex 1/*genetics/metabolism
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  • 4
    Publication Date: 2014-08-28
    Description: Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668/" 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/PMC4248668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schneider, David M -- Nelson, Anders -- Mooney, Richard -- NS079929/NS/NINDS NIH HHS/ -- R01 DC013826/DC/NIDCD NIH HHS/ -- R21 NS079929/NS/NINDS NIH HHS/ -- T32 GM008441/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Sep 11;513(7517):189-94. doi: 10.1038/nature13724. Epub 2014 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA [2]. ; Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25162524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Auditory Cortex/*physiology ; Electrical Synapses/*physiology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/*physiology ; Optogenetics ; Sensory Receptor Cells/metabolism
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  • 5
    Publication Date: 2014-04-18
    Description: Fertilization occurs when sperm and egg recognize each other and fuse to form a new, genetically distinct organism. The molecular basis of sperm-egg recognition is unknown, but is likely to require interactions between receptor proteins displayed on their surface. Izumo1 is an essential sperm cell-surface protein, but its receptor on the egg has not been described. Here we identify folate receptor 4 (Folr4) as the receptor for Izumo1 on the mouse egg, and propose to rename it Juno. We show that the Izumo1-Juno interaction is conserved within several mammalian species, including humans. Female mice lacking Juno are infertile and Juno-deficient eggs do not fuse with normal sperm. Rapid shedding of Juno from the oolemma after fertilization suggests a mechanism for the membrane block to polyspermy, ensuring eggs normally fuse with just a single sperm. Our discovery of an essential receptor pair at the nexus of conception provides opportunities for the rational development of new fertility treatments and contraceptives.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998876/" 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/PMC3998876/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bianchi, Enrica -- Doe, Brendan -- Goulding, David -- Wright, Gavin J -- 098051/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 24;508(7497):483-7. doi: 10.1038/nature13203. Epub 2014 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. ; Mouse Production Team, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK. ; Electron and Advanced Light Microscopy Suite, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739963" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conserved Sequence ; Evolution, Molecular ; Female ; Fertility/genetics ; Fertilization/genetics/*physiology ; Genes, Essential ; Glycosylphosphatidylinositols/metabolism ; Humans ; Immunoglobulins/*metabolism ; Infertility, Female/genetics ; Male ; Mammals ; Membrane Proteins/*metabolism ; Mice ; Oocytes/cytology/metabolism ; Ovum/cytology/*metabolism ; Parthenogenesis ; Receptors, Cell Surface/deficiency/genetics/*metabolism ; Sperm Injections, Intracytoplasmic ; Spermatozoa/*metabolism ; Time Factors
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  • 6
    Publication Date: 2014-03-29
    Description: Huntington's disease is an autosomal dominant disease associated with a mutation in the gene encoding huntingtin (Htt) leading to expanded polyglutamine repeats of mutant Htt (mHtt) that elicit oxidative stress, neurotoxicity, and motor and behavioural changes. Huntington's disease is characterized by highly selective and profound damage to the corpus striatum, which regulates motor function. Striatal selectivity of Huntington's disease may reflect the striatally selective small G protein Rhes binding to mHtt and enhancing its neurotoxicity. Specific molecular mechanisms by which mHtt elicits neurodegeneration have been hard to determine. Here we show a major depletion of cystathionine gamma-lyase (CSE), the biosynthetic enzyme for cysteine, in Huntington's disease tissues, which may mediate Huntington's disease pathophysiology. The defect occurs at the transcriptional level and seems to reflect influences of mHtt on specificity protein 1, a transcriptional activator for CSE. Consistent with the notion of loss of CSE as a pathogenic mechanism, supplementation with cysteine reverses abnormalities in cultures of Huntington's disease tissues and in intact mouse models of Huntington's disease, suggesting therapeutic potential.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4349202/" 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/PMC4349202/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paul, Bindu D -- Sbodio, Juan I -- Xu, Risheng -- Vandiver, M Scott -- Cha, Jiyoung Y -- Snowman, Adele M -- Snyder, Solomon H -- MH18501/MH/NIMH NIH HHS/ -- R01 MH018501/MH/NIMH NIH HHS/ -- T32 GM007309/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 1;509(7498):96-100. doi: 10.1038/nature13136. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670645" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/enzymology ; Corpus Striatum/drug effects/enzymology/metabolism/pathology ; Cystathionine gamma-Lyase/*deficiency/genetics ; Cysteine/administration & dosage/biosynthesis/pharmacology/therapeutic use ; Dietary Supplements ; Disease Models, Animal ; Drinking Water/chemistry ; Gene Deletion ; Gene Expression Regulation, Enzymologic/genetics ; Huntington Disease/drug therapy/*enzymology/genetics/*pathology ; Male ; Mice ; Mutant Proteins/genetics/metabolism ; Nerve Tissue Proteins/genetics/metabolism ; Neuroprotective Agents/administration & ; dosage/metabolism/pharmacology/therapeutic use ; Oxidative Stress/drug effects ; Sp1 Transcription Factor/antagonists & inhibitors/metabolism ; Transcription, Genetic/genetics
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  • 7
    Publication Date: 2014-12-04
    Description: T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORgammat, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORgammat in response to TGF-beta signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rutz, Sascha -- Kayagaki, Nobuhiko -- Phung, Qui T -- Eidenschenk, Celine -- Noubade, Rajkumar -- Wang, Xiaoting -- Lesch, Justin -- Lu, Rongze -- Newton, Kim -- Huang, Oscar W -- Cochran, Andrea G -- Vasser, Mark -- Fauber, Benjamin P -- DeVoss, Jason -- Webster, Joshua -- Diehl, Lauri -- Modrusan, Zora -- Kirkpatrick, Donald S -- Lill, Jennie R -- Ouyang, Wenjun -- Dixit, Vishva M -- England -- Nature. 2015 Feb 19;518(7539):417-21. doi: 10.1038/nature13979. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470037" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Enzyme Stability ; Female ; Inflammation/genetics/pathology ; Interleukin-17/*biosynthesis ; Intestine, Small/metabolism/pathology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; *Protein Biosynthesis ; Signal Transduction ; Substrate Specificity ; Th17 Cells/*metabolism ; Transforming Growth Factor beta/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Specific Proteases/biosynthesis/deficiency/genetics/*metabolism ; Ubiquitination
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  • 8
    Publication Date: 2014-11-20
    Description: Emerging evidence suggests that the ribosome has a regulatory function in directing how the genome is translated in time and space. However, how this regulation is encoded in the messenger RNA sequence remains largely unknown. Here we uncover unique RNA regulons embedded in homeobox (Hox) 5' untranslated regions (UTRs) that confer ribosome-mediated control of gene expression. These structured RNA elements, resembling viral internal ribosome entry sites (IRESs), are found in subsets of Hox mRNAs. They facilitate ribosome recruitment and require the ribosomal protein RPL38 for their activity. Despite numerous layers of Hox gene regulation, these IRES elements are essential for converting Hox transcripts into proteins to pattern the mammalian body plan. This specialized mode of IRES-dependent translation is enabled by an additional regulatory element that we term the translation inhibitory element (TIE), which blocks cap-dependent translation of transcripts. Together, these data uncover a new paradigm for ribosome-mediated control of gene expression and organismal development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4353651/" 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/PMC4353651/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, Shifeng -- Tian, Siqi -- Fujii, Kotaro -- Kladwang, Wipapat -- Das, Rhiju -- Barna, Maria -- 7DP2OD00850902/OD/NIH HHS/ -- DP2 OD008509/OD/NIH HHS/ -- R01 GM102519/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Jan 1;517(7532):33-8. doi: 10.1038/nature14010. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Developmental Biology, Stanford University, Stanford, California 94305, USA [2] Department of Genetics, Stanford University, Stanford, California 94305, USA [3] Tetrad Graduate Program, University of California, San Francisco, San Francisco, California 94158, USA. ; Department of Biochemistry, Stanford University, Stanford, California 94305, USA. ; 1] Department of Developmental Biology, Stanford University, Stanford, California 94305, USA [2] Department of Genetics, Stanford University, Stanford, California 94305, USA. ; 1] Department of Biochemistry, Stanford University, Stanford, California 94305, USA [2] Department of Physics, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409156" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/*genetics ; Animals ; Bone and Bones/embryology/metabolism ; Cell Line ; Conserved Sequence ; Evolution, Molecular ; Gene Expression Regulation/*genetics ; Genes, Homeobox/*genetics ; Mice ; Molecular Sequence Data ; Protein Biosynthesis/genetics ; RNA Caps/metabolism ; Regulatory Sequences, Ribonucleic Acid/*genetics ; Ribosomal Proteins/metabolism ; Ribosomes/chemistry/*metabolism ; Substrate Specificity ; Zebrafish/genetics
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  • 9
    Publication Date: 2014-12-24
    Description: The kinetochore is the crucial apparatus regulating chromosome segregation in mitosis and meiosis. Particularly in meiosis I, unlike in mitosis, sister kinetochores are captured by microtubules emanating from the same spindle pole (mono-orientation) and centromeric cohesion mediated by cohesin is protected in the following anaphase. Although meiotic kinetochore factors have been identified only in budding and fission yeasts, these molecules and their functions are thought to have diverged earlier. Therefore, a conserved mechanism for meiotic kinetochore regulation remains elusive. Here we have identified in mouse a meiosis-specific kinetochore factor that we termed MEIKIN, which functions in meiosis I but not in meiosis II or mitosis. MEIKIN plays a crucial role in both mono-orientation and centromeric cohesion protection, partly by stabilizing the localization of the cohesin protector shugoshin. These functions are mediated mainly by the activity of Polo-like kinase PLK1, which is enriched to kinetochores in a MEIKIN-dependent manner. Our integrative analysis indicates that the long-awaited key regulator of meiotic kinetochore function is Meikin, which is conserved from yeasts to humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jihye -- Ishiguro, Kei-ichiro -- Nambu, Aya -- Akiyoshi, Bungo -- Yokobayashi, Shihori -- Kagami, Ayano -- Ishiguro, Tadashi -- Pendas, Alberto M -- Takeda, Naoki -- Sakakibara, Yogo -- Kitajima, Tomoya S -- Tanno, Yuji -- Sakuno, Takeshi -- Watanabe, Yoshinori -- England -- Nature. 2015 Jan 22;517(7535):466-71. doi: 10.1038/nature14097. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1Yayoi, Tokyo 113-0032, Japan. ; Instituto de Biologia Molecular y Celular del Cancer (CSIC-USAL), 37007 Salamanca, Spain. ; Center for Animal Resources and Development, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 Japan. ; Laboratory for Chromosome Segregation, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533956" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle Proteins/metabolism ; Centromere/metabolism ; Chromosomal Proteins, Non-Histone/deficiency/genetics/*metabolism ; *Conserved Sequence ; Female ; Humans ; Infertility/genetics/metabolism ; Kinetochores/*metabolism ; Male ; *Meiosis ; Mice ; Molecular Sequence Data ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Schizosaccharomyces pombe Proteins/metabolism
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  • 10
    Publication Date: 2014-10-23
    Description: The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7alpha-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" 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/PMC4354891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buffie, Charlie G -- Bucci, Vanni -- Stein, Richard R -- McKenney, Peter T -- Ling, Lilan -- Gobourne, Asia -- No, Daniel -- Liu, Hui -- Kinnebrew, Melissa -- Viale, Agnes -- Littmann, Eric -- van den Brink, Marcel R M -- Jenq, Robert R -- Taur, Ying -- Sander, Chris -- Cross, Justin R -- Toussaint, Nora C -- Xavier, Joao B -- Pamer, Eric G -- AI95706/AI/NIAID NIH HHS/ -- DP2 OD008440/OD/NIH HHS/ -- DP2OD008440/OD/NIH HHS/ -- K23 AI095398/AI/NIAID NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI042135/AI/NIAID NIH HHS/ -- R01 AI095706/AI/NIAID NIH HHS/ -- R01 AI42135/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32 GM007739/GM/NIGMS NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- U54 CA148967/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):205-8. doi: 10.1038/nature13828. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA [2] Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA. ; Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA. ; Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Bile Acids and Salts/*metabolism ; Biological Evolution ; Clostridium/metabolism ; Clostridium difficile/drug effects/*physiology ; Colitis/metabolism/microbiology/prevention & control/therapy ; Disease Susceptibility/*microbiology ; Feces/microbiology ; Female ; Humans ; Intestines/drug effects/*metabolism/*microbiology ; Metagenome/genetics ; Mice ; Mice, Inbred C57BL ; Microbiota/drug effects/genetics/*physiology ; Symbiosis
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  • 11
    Publication Date: 2014-12-24
    Description: Broadly, tissue regeneration is achieved in two ways: by proliferation of common differentiated cells and/or by deployment of specialized stem/progenitor cells. Which of these pathways applies is both organ- and injury-specific. Current models in the lung posit that epithelial repair can be attributed to cells expressing mature lineage markers. By contrast, here we define the regenerative role of previously uncharacterized, rare lineage-negative epithelial stem/progenitor (LNEP) cells present within normal distal lung. Quiescent LNEPs activate a DeltaNp63 (a p63 splice variant) and cytokeratin 5 remodelling program after influenza or bleomycin injury in mice. Activated cells proliferate and migrate widely to occupy heavily injured areas depleted of mature lineages, at which point they differentiate towards mature epithelium. Lineage tracing revealed scant contribution of pre-existing mature epithelial cells in such repair, whereas orthotopic transplantation of LNEPs, isolated by a definitive surface profile identified through single-cell sequencing, directly demonstrated the proliferative capacity and multipotency of this population. LNEPs require Notch signalling to activate the DeltaNp63 and cytokeratin 5 program, and subsequent Notch blockade promotes an alveolar cell fate. Persistent Notch signalling after injury led to parenchymal 'micro-honeycombing' (alveolar cysts), indicative of failed regeneration. Lungs from patients with fibrosis show analogous honeycomb cysts with evidence of hyperactive Notch signalling. Our findings indicate that distinct stem/progenitor cell pools repopulate injured tissue depending on the extent of the injury, and the outcomes of regeneration or fibrosis may depend in part on the dynamics of LNEP Notch signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312207/" 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/PMC4312207/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vaughan, Andrew E -- Brumwell, Alexis N -- Xi, Ying -- Gotts, Jeffrey E -- Brownfield, Doug G -- Treutlein, Barbara -- Tan, Kevin -- Tan, Victor -- Liu, Feng Chun -- Looney, Mark R -- Matthay, Michael A -- Rock, Jason R -- Chapman, Harold A -- F32 HL117600-01/HL/NHLBI NIH HHS/ -- R01 HL44712/HL/NHLBI NIH HHS/ -- U01 HL099995/HL/NHLBI NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- U01 HL111054/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 29;517(7536):621-5. doi: 10.1038/nature14112. Epub 2014 Dec 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Cardiovascular Research Institute, University of California, San Francisco (UCSF), San Francisco, California 94143, USA. ; Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Max Planck Institute for Evolutionary Anthropology, Department of Evolutionary Genetics, Deutscher Platz 6, 04103 Leipzig, Germany. ; Department of Anatomy, School of Medicine, University of California, San Francisco (UCSF), San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25533958" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bleomycin ; Cell Lineage ; Cell Proliferation ; Cell Separation ; Cysts/metabolism/pathology ; Epithelial Cells/*cytology/metabolism/*pathology ; Female ; Humans ; Keratin-5/metabolism ; Lung/*cytology/*pathology/physiology ; Lung Injury/chemically induced/*pathology/virology ; Male ; Mice ; Orthomyxoviridae Infections/pathology/virology ; Phosphoproteins/genetics/metabolism ; *Re-Epithelialization ; Receptors, Notch/metabolism ; Signal Transduction ; Stem Cell Transplantation ; Stem Cells/*cytology/metabolism ; Trans-Activators/genetics/metabolism
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  • 12
    Publication Date: 2014-11-20
    Description: TP53 is commonly altered in human cancer, and Tp53 reactivation suppresses tumours in vivo in mice (TP53 and Tp53 are also known as p53). This strategy has proven difficult to implement therapeutically, and here we examine an alternative strategy by manipulating the p53 family members, Tp63 and Tp73 (also known as p63 and p73, respectively). The acidic transactivation-domain-bearing (TA) isoforms of p63 and p73 structurally and functionally resemble p53, whereas the DeltaN isoforms (lacking the acidic transactivation domain) of p63 and p73 are frequently overexpressed in cancer and act primarily in a dominant-negative fashion against p53, TAp63 and TAp73 to inhibit their tumour-suppressive functions. The p53 family interacts extensively in cellular processes that promote tumour suppression, such as apoptosis and autophagy, thus a clear understanding of this interplay in cancer is needed to treat tumours with alterations in the p53 pathway. Here we show that deletion of the DeltaN isoforms of p63 or p73 leads to metabolic reprogramming and regression of p53-deficient tumours through upregulation of IAPP, the gene that encodes amylin, a 37-amino-acid peptide co-secreted with insulin by the beta cells of the pancreas. We found that IAPP is causally involved in this tumour regression and that amylin functions through the calcitonin receptor (CalcR) and receptor activity modifying protein 3 (RAMP3) to inhibit glycolysis and induce reactive oxygen species and apoptosis. Pramlintide, a synthetic analogue of amylin that is currently used to treat type 1 and type 2 diabetes, caused rapid tumour regression in p53-deficient thymic lymphomas, representing a novel strategy to target p53-deficient cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4312210/" 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/PMC4312210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatanarayan, Avinashnarayan -- Raulji, Payal -- Norton, William -- Chakravarti, Deepavali -- Coarfa, Cristian -- Su, Xiaohua -- Sandur, Santosh K -- Ramirez, Marc S -- Lee, Jaehuk -- Kingsley, Charles V -- Sananikone, Eliot F -- Rajapakshe, Kimal -- Naff, Katherine -- Parker-Thornburg, Jan -- Bankson, James A -- Tsai, Kenneth Y -- Gunaratne, Preethi H -- Flores, Elsa R -- CA-16672/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P50CA136411/CA/NCI NIH HHS/ -- R01 CA134796/CA/NCI NIH HHS/ -- R01 CA160394/CA/NCI NIH HHS/ -- R01CA134796/CA/NCI NIH HHS/ -- R01CA160394/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 29;517(7536):626-30. doi: 10.1038/nature13910. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Graduate School of Biomedical Sciences, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [4] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Veterinary Medicine and Surgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Molecular and Cellular Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [3] Metastasis Research Center, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [4] Radiation Biology &Health Sciences Division, Bhabha Atomic Research Center, Mumbai 400085, India. ; Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Genetics, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; 1] Department of Translational Molecular Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA [2] Department of Dermatology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. ; Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/pathology ; DNA-Binding Proteins/genetics/metabolism ; Female ; Genes, Tumor Suppressor ; Humans ; Islet Amyloid Polypeptide/*metabolism/pharmacology/secretion/therapeutic use ; Lymphoma/drug therapy/genetics/*metabolism/*pathology ; Male ; Mice ; Nuclear Proteins/genetics/metabolism ; Phosphoproteins/genetics/metabolism ; Receptor Activity-Modifying Protein 3/metabolism ; Receptors, Calcitonin/metabolism ; Thymus Gland/metabolism/pathology ; Trans-Activators/genetics/metabolism ; Tumor Suppressor Protein p53/*deficiency/genetics ; Tumor Suppressor Proteins/genetics/metabolism
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  • 13
    Publication Date: 2014-11-11
    Description: Lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis involve the progressive and inexorable destruction of oxygen exchange surfaces and airways, and have emerged as a leading cause of death worldwide. Mitigating therapies, aside from impractical organ transplantation, remain limited and the possibility of regenerative medicine has lacked empirical support. However, it is clinically known that patients who survive sudden, massive loss of lung tissue from necrotizing pneumonia or acute respiratory distress syndrome often recover full pulmonary function within six months. Correspondingly, we recently demonstrated lung regeneration in mice following H1N1 influenza virus infection, and linked distal airway stem cells expressing Trp63 (p63) and keratin 5, called DASC(p63/Krt5), to this process. Here we show that pre-existing, intrinsically committed DASC(p63/Krt5) undergo a proliferative expansion in response to influenza-induced lung damage, and assemble into nascent alveoli at sites of interstitial lung inflammation. We also show that the selective ablation of DASC(p63/Krt5) in vivo prevents this regeneration, leading to pre-fibrotic lesions and deficient oxygen exchange. Finally, we demonstrate that single DASC(p63/Krt5)-derived pedigrees differentiate to type I and type II pneumocytes as well as bronchiolar secretory cells following transplantation to infected lung and also minimize the structural consequences of endogenous stem cell loss on this process. The ability to propagate these cells in culture while maintaining their intrinsic lineage commitment suggests their potential in stem cell-based therapies for acute and chronic lung diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zuo, Wei -- Zhang, Ting -- Wu, Daniel Zheng'An -- Guan, Shou Ping -- Liew, Audrey-Ann -- Yamamoto, Yusuke -- Wang, Xia -- Lim, Siew Joo -- Vincent, Matthew -- Lessard, Mark -- Crum, Christopher P -- Xian, Wa -- McKeon, Frank -- England -- Nature. 2015 Jan 29;517(7536):616-20. doi: 10.1038/nature13903. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Institute of Singapore, A-STAR, 138672 Singapore. ; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA. ; Advanced Cell Technologies, Marlborough, Massachusetts 01752, USA. ; The Jackson Laboratory, Bar Harbor, Maine 04609, USA. ; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Genome Institute of Singapore, A-STAR, 138672 Singapore [2] The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA [3] Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA [4] Department of Medicine, National University Health System, 119228 Singapore [5] Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; 1] Genome Institute of Singapore, A-STAR, 138672 Singapore [2] The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06032, USA [3] Department of Medicine, National University Health System, 119228 Singapore.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383540" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bronchioles/cytology/virology ; Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Dogs ; Humans ; Influenza A Virus, H1N1 Subtype/pathogenicity ; Keratin-5/*metabolism ; Lung/*cytology/pathology/*physiology/virology ; Madin Darby Canine Kidney Cells ; Mice ; Orthomyxoviridae Infections/metabolism/pathology/virology ; Oxygen/metabolism ; Pedigree ; Phosphoproteins/*metabolism ; Pneumonia/metabolism/pathology/virology ; Pulmonary Alveoli/cytology/pathology/virology ; Re-Epithelialization ; *Regeneration ; Stem Cell Transplantation ; Stem Cells/*cytology/*metabolism ; Trans-Activators/*metabolism
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  • 14
    Publication Date: 2014-11-11
    Description: DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance. Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B, and the methylation patterns vary with developmental stages and cell types. DNA methyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a. Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation. The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro, whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 A resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalytic domain (CD) through blocking its DNA-binding affinity. Histone H3 (but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome. Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Xue -- Wang, Ling -- Li, Jie -- Ding, Zhanyu -- Xiao, Jianxiong -- Yin, Xiaotong -- He, Shuang -- Shi, Pan -- Dong, Liping -- Li, Guohong -- Tian, Changlin -- Wang, Jiawei -- Cong, Yao -- Xu, Yanhui -- England -- Nature. 2015 Jan 29;517(7536):640-4. doi: 10.1038/nature13899. Epub 2014 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China [2] State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China. ; Fudan University Shanghai Cancer Center, Institute of Biomedical Sciences, Shanghai Medical College of Fudan University, Shanghai 200032, China. ; National Center for Protein Science Shanghai, State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; 1] High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei 230031, China [2] National Laboratory for Physical Science at the Microscale, University of Science and Technology of China, Hefei 230026, China [3] School of Life Sciences, University of Science and Technology of China, Hefei 230026, China. ; 1] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China [2] University of Chinese Academy of Science, Beijing 100049, China. ; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Science, Beijing 100101, China. ; State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Life Sciences, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Catalytic Domain ; Crystallography, X-Ray ; DNA/metabolism ; DNA (Cytosine-5-)-Methyltransferase/*antagonists & ; inhibitors/*chemistry/*metabolism ; DNA Methylation ; Enzyme Activation ; Histones/*chemistry/*metabolism ; Humans ; Mice ; Models, Molecular ; Protein Structure, Tertiary ; Xenopus laevis
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  • 15
    Publication Date: 2014-12-04
    Description: Filamentous actin (F-actin) is the major protein of muscle thin filaments, and actin microfilaments are the main component of the eukaryotic cytoskeleton. Mutations in different actin isoforms lead to early-onset autosomal dominant non-syndromic hearing loss, familial thoracic aortic aneurysms and dissections, and multiple variations of myopathies. In striated muscle fibres, the binding of myosin motors to actin filaments is mainly regulated by tropomyosin and troponin. Tropomyosin also binds to F-actin in smooth muscle and in non-muscle cells and stabilizes and regulates the filaments there in the absence of troponin. Although crystal structures for monomeric actin (G-actin) are available, a high-resolution structure of F-actin is still missing, hampering our understanding of how disease-causing mutations affect the function of thin muscle filaments and microfilaments. Here we report the three-dimensional structure of F-actin at a resolution of 3.7 A in complex with tropomyosin at a resolution of 6.5 A, determined by electron cryomicroscopy. The structure reveals that the D-loop is ordered and acts as a central region for hydrophobic and electrostatic interactions that stabilize the F-actin filament. We clearly identify map density corresponding to ADP and Mg(2+) and explain the possible effect of prominent disease-causing mutants. A comparison of F-actin with G-actin reveals the conformational changes during filament formation and identifies the D-loop as their key mediator. We also confirm that negatively charged tropomyosin interacts with a positively charged groove on F-actin. Comparison of the position of tropomyosin in F-actin-tropomyosin with its position in our previously determined F-actin-tropomyosin-myosin structure reveals a myosin-induced transition of tropomyosin. Our results allow us to understand the role of individual mutations in the genesis of actin- and tropomyosin-related diseases and will serve as a strong foundation for the targeted development of drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477711/" 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/PMC4477711/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von der Ecken, Julian -- Muller, Mirco -- Lehman, William -- Manstein, Dietmar J -- Penczek, Pawel A -- Raunser, Stefan -- R01 60635/PHS HHS/ -- R01 GM060635/GM/NIGMS NIH HHS/ -- R37HL036153/HL/NHLBI NIH HHS/ -- U54 094598/PHS HHS/ -- U54 GM094598/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):114-7. doi: 10.1038/nature14033. Epub 2014 Dec 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, 44227 Dortmund, Germany. ; Institute for Biophysical Chemistry, Hannover Medical School, 30625 Hannover, Germany. ; Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts 02118, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas, Houston Medical School, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470062" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/*chemistry/genetics/*metabolism ; Adenosine Diphosphate/metabolism ; Animals ; Cryoelectron Microscopy ; Magnesium/metabolism ; Mice ; Models, Molecular ; Mutation/genetics ; Protein Conformation ; Rabbits ; Static Electricity ; Tropomyosin/*chemistry/genetics/*metabolism
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  • 16
    Publication Date: 2014-11-05
    Description: Establishing the hippocampal cellular ensemble that represents an animal's environment involves the emergence and disappearance of place fields in specific CA1 pyramidal neurons, and the acquisition of different spatial firing properties across the active population. While such firing flexibility and diversity have been linked to spatial memory, attention and task performance, the cellular and network origin of these place cell features is unknown. Basic integrate-and-fire models of place firing propose that such features result solely from varying inputs to place cells, but recent studies suggest instead that place cells themselves may play an active role through regenerative dendritic events. However, owing to the difficulty of performing functional recordings from place cell dendrites, no direct evidence of regenerative dendritic events exists, leaving any possible connection to place coding unknown. Using multi-plane two-photon calcium imaging of CA1 place cell somata, axons and dendrites in mice navigating a virtual environment, here we show that regenerative dendritic events do exist in place cells of behaving mice, and, surprisingly, their prevalence throughout the arbour is highly spatiotemporally variable. Furthermore, we show that the prevalence of such events predicts the spatial precision and persistence or disappearance of place fields. This suggests that the dynamics of spiking throughout the dendritic arbour may play a key role in forming the hippocampal representation of space.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289090/" 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/PMC4289090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheffield, Mark E J -- Dombeck, Daniel A -- 1R01MH101297/MH/NIMH NIH HHS/ -- R01 MH101297/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):200-4. doi: 10.1038/nature13871. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Northwestern University, Evanston, Illinois 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363782" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Axons/metabolism ; Calcium/*metabolism ; *Calcium Signaling ; Dendrites/*metabolism ; Hippocampus/*cytology/*physiology ; Male ; Memory, Long-Term/physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity/physiology ; Space Perception/*physiology ; Time Factors
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  • 17
    Publication Date: 2014-12-04
    Description: Cytotoxic chemotherapy is effective in debulking tumour masses initially; however, in some patients tumours become progressively unresponsive after multiple treatment cycles. Previous studies have demonstrated that cancer stem cells (CSCs) are selectively enriched after chemotherapy through enhanced survival. Here we reveal a new mechanism by which bladder CSCs actively contribute to therapeutic resistance via an unexpected proliferative response to repopulate residual tumours between chemotherapy cycles, using human bladder cancer xenografts. Further analyses demonstrate the recruitment of a quiescent label-retaining pool of CSCs into cell division in response to chemotherapy-induced damages, similar to mobilization of normal stem cells during wound repair. While chemotherapy effectively induces apoptosis, associated prostaglandin E2 (PGE2) release paradoxically promotes neighbouring CSC repopulation. This repopulation can be abrogated by a PGE2-neutralizing antibody and celecoxib drug-mediated blockade of PGE2 signalling. In vivo administration of the cyclooxygenase-2 (COX2) inhibitor celecoxib effectively abolishes a PGE2- and COX2-mediated wound response gene signature, and attenuates progressive manifestation of chemoresistance in xenograft tumours, including primary xenografts derived from a patient who was resistant to chemotherapy. Collectively, these findings uncover a new underlying mechanism that models the progressive development of clinical chemoresistance, and implicate an adjunctive therapy to enhance chemotherapeutic response of bladder urothelial carcinomas by abrogating early tumour repopulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465385/" 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/PMC4465385/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kurtova, Antonina V -- Xiao, Jing -- Mo, Qianxing -- Pazhanisamy, Senthil -- Krasnow, Ross -- Lerner, Seth P -- Chen, Fengju -- Roh, Terrence T -- Lay, Erica -- Ho, Philip Levy -- Chan, Keith Syson -- AI036211/AI/NIAID NIH HHS/ -- CA125123/CA/NCI NIH HHS/ -- CA129640/CA/NCI NIH HHS/ -- CA175397/CA/NCI NIH HHS/ -- R00 CA129640/CA/NCI NIH HHS/ -- R01 CA175397/CA/NCI NIH HHS/ -- RR024574/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):209-13. doi: 10.1038/nature14034. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Dan L Duncan Cancer Center and Center for Cell Gene &Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; 1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Summer Medical and Research Training (SMART) Program, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. ; 1] Department of Molecular &Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [2] Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [3] Dan L Duncan Cancer Center and Center for Cell Gene &Therapy, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA [4] Scott Department of Urology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470039" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Neutralizing/immunology/pharmacology ; Apoptosis/drug effects ; Celecoxib ; Cell Proliferation/drug effects ; Cyclooxygenase 2/metabolism ; Cyclooxygenase 2 Inhibitors/pharmacology ; Dinoprostone/*antagonists & inhibitors/immunology/metabolism/secretion ; Drug Resistance, Neoplasm/*drug effects ; Female ; Humans ; Male ; Mice ; Neoplastic Stem Cells/*drug effects/metabolism/*pathology ; Pyrazoles/pharmacology ; Signal Transduction/drug effects ; Sulfonamides/pharmacology ; Urinary Bladder Neoplasms/*drug therapy/*pathology ; Wound Healing/genetics ; Xenograft Model Antitumor Assays
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  • 18
    Publication Date: 2014-08-26
    Description: Aging-associated cognitive decline is affected by factors produced inside and outside the brain. By using multiorgan genome-wide analysis of aged mice, we found that the choroid plexus, an interface between the brain and the circulation, shows a type I interferon (IFN-I)-dependent gene expression profile that was also found in aged human brains. In aged mice, this response was induced by brain-derived signals, present in the cerebrospinal fluid. Blocking IFN-I signaling within the aged brain partially restored cognitive function and hippocampal neurogenesis and reestablished IFN-II-dependent choroid plexus activity, which is lost in aging. Our data identify a chronic aging-induced IFN-I signature, often associated with antiviral response, at the brain's choroid plexus and demonstrate its negative influence on brain function, thereby suggesting a target for ameliorating cognitive decline in aging.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baruch, Kuti -- Deczkowska, Aleksandra -- David, Eyal -- Castellano, Joseph M -- Miller, Omer -- Kertser, Alexander -- Berkutzki, Tamara -- Barnett-Itzhaki, Zohar -- Bezalel, Dana -- Wyss-Coray, Tony -- Amit, Ido -- Schwartz, Michal -- AG045034/AG/NIA NIH HHS/ -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):89-93. doi: 10.1126/science.1252945. Epub 2014 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. ; Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. michal.schwartz@weizmann.ac.il ido.amit@weizmann.ac.il. ; Department of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. michal.schwartz@weizmann.ac.il ido.amit@weizmann.ac.il.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25147279" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/genetics/*pathology ; Animals ; Brain/*physiology ; Choroid Plexus/*metabolism ; *Cognition ; *Gene Expression Regulation ; Hippocampus/cytology ; Interferon Regulatory Factors/*genetics ; Interferon Type I/*physiology ; Mice ; Mice, Transgenic ; Neurogenesis ; Receptors, Interferon/genetics
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  • 19
    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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  • 20
    Publication Date: 2014-09-23
    Description: The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arimura, Sumimasa -- Okada, Takashi -- Tezuka, Tohru -- Chiyo, Tomoko -- Kasahara, Yuko -- Yoshimura, Toshiro -- Motomura, Masakatsu -- Yoshida, Nobuaki -- Beeson, David -- Takeda, Shin'ichi -- Yamanashi, Yuji -- G0701521/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. ; Department of Occupational Therapy, Nagasaki University School of Health Sciences, Nagasaki, Japan. ; Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan. ; Laboratory of Developmental Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. ; Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. yyamanas@ims.u-tokyo.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237101" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dependovirus ; Disease Models, Animal ; Female ; Genetic Therapy/*methods ; Genetic Vectors/administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Proteins/*genetics ; Muscle, Skeletal/*innervation/physiopathology ; Muscular Dystrophies, Limb-Girdle/genetics/*pathology/*therapy ; Neuromuscular Junction/*pathology
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  • 21
    Publication Date: 2014-10-04
    Description: After an infection, pathogen-specific tissue-resident memory T cells (T(RM) cells) persist in nonlymphoid tissues to provide rapid control upon reinfection, and vaccination strategies that create T(RM) cell pools at sites of pathogen entry are therefore attractive. However, it is not well understood how T(RM) cells provide such pathogen protection. Here, we demonstrate that activated T(RM) cells in mouse skin profoundly alter the local tissue environment by inducing a number of broadly active antiviral and antibacterial genes. This "pathogen alert" allows skin T(RM) cells to protect against an antigenically unrelated virus. These data describe a mechanism by which tissue-resident memory CD8(+) T cells protect previously infected sites that is rapid, amplifies the activation of a small number of cells into an organ-wide response, and has the capacity to control escape variants.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ariotti, Silvia -- Hogenbirk, Marc A -- Dijkgraaf, Feline E -- Visser, Lindy L -- Hoekstra, Mirjam E -- Song, Ji-Ying -- Jacobs, Heinz -- Haanen, John B -- Schumacher, Ton N -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):101-5. doi: 10.1126/science.1254803. Epub 2014 Aug 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Division of Biological Stress Response, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Experimental Animal Pathology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Division of Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. t.schumacher@nki.nl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278612" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD8-Positive T-Lymphocytes/*immunology ; Female ; Immunologic Memory/genetics/*immunology ; Male ; Mice ; Skin/*immunology/microbiology/virology ; Transcriptome
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  • 22
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-02-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaiser, Jocelyn -- New York, N.Y. -- Science. 2014 Jan 31;343(6170):477. doi: 10.1126/science.343.6170.477.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24482460" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylcysteine/administration & dosage/*adverse effects ; Animals ; Antioxidants/administration & dosage/*adverse effects ; Carcinogens/toxicity ; DNA Damage ; Dietary Supplements/adverse effects ; Genes, Neoplasm/*drug effects ; Humans ; Lung Neoplasms/*chemically induced/prevention & control ; Mice ; Smoking/adverse effects ; Tumor Suppressor Protein p53/genetics/metabolism ; Vitamin E/administration & dosage/*adverse effects ; Vitamins/administration & dosage/*adverse effects
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  • 23
    Publication Date: 2014-03-15
    Description: Vertebrate limbs first emerge as small buds at specific locations along the trunk. Although a fair amount is known about the molecular regulation of limb initiation and outgrowth, the cellular events underlying these processes have remained less clear. We show that the mesenchymal limb progenitors arise through localized epithelial-to-mesenchymal transition (EMT) of the coelomic epithelium specifically within the presumptive limb fields. This EMT is regulated at least in part by Tbx5 and Fgf10, two genes known to control limb initiation. This work shows that limb buds initiate earlier than previously thought, as a result of localized EMT rather than differential proliferation rates.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4097009/" 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/PMC4097009/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gros, Jerome -- Tabin, Clifford J -- R01 HD045499/HD/NICHD NIH HHS/ -- R01-HD045499/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1253-6. doi: 10.1126/science.1248228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24626928" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cadherins/metabolism ; Chick Embryo ; *Epithelial-Mesenchymal Transition ; Extremities/*embryology ; Fibroblast Growth Factor 10/genetics/metabolism ; Limb Buds/*cytology/metabolism ; Mice ; Mice, Mutant Strains ; Protein Kinase C/metabolism ; T-Box Domain Proteins/genetics/metabolism ; Vimentin/metabolism ; beta Catenin/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 24
    Publication Date: 2014-05-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Couzin-Frankel, Jennifer -- New York, N.Y. -- Science. 2014 May 16;344(6185):679. doi: 10.1126/science.344.6185.679.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24833367" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Experimentation/*standards ; Animals ; Biomedical Research/*standards ; Cells ; Female ; Male ; Mice ; National Institutes of Health (U.S.) ; Sex Factors ; United States ; X Chromosome ; Y Chromosome
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  • 25
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-10-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clery, Daniel -- New York, N.Y. -- Science. 2014 Oct 17;346(6207):290-1. doi: 10.1126/science.346.6207.290.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25324365" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Chemistry ; Mice ; Microscopy, Fluorescence/*methods ; *Nobel Prize ; Organelles/ultrastructure ; United States
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  • 26
    Publication Date: 2014-04-15
    Description: Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4096908/" 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/PMC4096908/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gibson, Erin M -- Purger, David -- Mount, Christopher W -- Goldstein, Andrea K -- Lin, Grant L -- Wood, Lauren S -- Inema, Ingrid -- Miller, Sarah E -- Bieri, Gregor -- Zuchero, J Bradley -- Barres, Ben A -- Woo, Pamelyn J -- Vogel, Hannes -- Monje, Michelle -- 1S10RR02678001/RR/NCRR NIH HHS/ -- K08 NS070926/NS/NINDS NIH HHS/ -- K08NS070926/NS/NINDS NIH HHS/ -- R01 EY10257/EY/NEI NIH HHS/ -- T32 MH020016/MH/NIMH NIH HHS/ -- UL1 RR025744/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 May 2;344(6183):1252304. doi: 10.1126/science.1252304. Epub 2014 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Neurology, Neurosurgery, and Pediatrics, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24727982" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Thy-1/genetics ; Behavior, Animal/physiology ; *Cell Differentiation ; Cell Lineage ; Cell Proliferation ; Corpus Callosum/cytology/physiology ; Mice ; Mice, Mutant Strains ; Motor Activity/physiology ; Motor Cortex/cytology/*physiology ; Myelin Sheath/*metabolism ; Nerve Fibers, Myelinated/*metabolism ; Neural Stem Cells/*physiology ; Neurons/*physiology ; Oligodendroglia/*cytology ; Rhodopsin/genetics
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  • 27
    Publication Date: 2014-01-25
    Description: Episodic memory requires associations of temporally discontiguous events. In the entorhinal-hippocampal network, temporal associations are driven by a direct pathway from layer III of the medial entorhinal cortex (MECIII) to the hippocampal CA1 region. However, the identification of neural circuits that regulate this association has remained unknown. In layer II of entorhinal cortex (ECII), we report clusters of excitatory neurons called island cells, which appear in a curvilinear matrix of bulblike structures, directly project to CA1, and activate interneurons that target the distal dendrites of CA1 pyramidal neurons. Island cells suppress the excitatory MECIII input through the feed-forward inhibition to control the strength and duration of temporal association in trace fear memory. Together, the two EC inputs compose a control circuit for temporal association memory.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kitamura, Takashi -- Pignatelli, Michele -- Suh, Junghyup -- Kohara, Keigo -- Yoshiki, Atsushi -- Abe, Kuniya -- Tonegawa, Susumu -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 21;343(6173):896-901. doi: 10.1126/science.1244634. Epub 2014 Jan 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24457215" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Association ; CA1 Region, Hippocampal/cytology/*physiology ; Entorhinal Cortex/cytology/*physiology ; GABAergic Neurons/physiology ; Interneurons/physiology ; Membrane Proteins/genetics ; *Memory, Episodic ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Nerve Net ; Neurons/*physiology
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  • 28
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    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-03-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Silvente-Poirot, Sandrine -- Poirot, Marc -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1445-6. doi: 10.1126/science.1252787.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UMR 1037 INSERM-University Toulouse III, Cancer Research Center of Toulouse, and Institut Claudius Regaud, 31052 Toulouse, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24675946" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*metabolism/*pathology ; Cholesterol/*metabolism ; Cholesterol, Dietary/administration & dosage/metabolism ; Disease Models, Animal ; Female ; Humans ; Hypercholesterolemia/metabolism ; Metabolic Networks and Pathways ; Mice
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  • 29
    Publication Date: 2014-11-15
    Description: Activators of innate immunity may have the potential to combat a broad range of infectious agents. We report that treatment with bacterial flagellin prevented rotavirus (RV) infection in mice and cured chronically RV-infected mice. Protection was independent of adaptive immunity and interferon (IFN, type I and II) and required flagellin receptors Toll-like receptor 5 (TLR5) and NOD-like receptor C4 (NLRC4). Flagellin-induced activation of TLR5 on dendritic cells elicited production of the cytokine interleukin-22 (IL-22), which induced a protective gene expression program in intestinal epithelial cells. Flagellin also induced NLRC4-dependent production of IL-18 and immediate elimination of RV-infected cells. Administration of IL-22 and IL-18 to mice fully recapitulated the capacity of flagellin to prevent or eliminate RV infection and thus holds promise as a broad-spectrum antiviral agent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Benyue -- Chassaing, Benoit -- Shi, Zhenda -- Uchiyama, Robin -- Zhang, Zhan -- Denning, Timothy L -- Crawford, Sue E -- Pruijssers, Andrea J -- Iskarpatyoti, Jason A -- Estes, Mary K -- Dermody, Terence S -- Ouyang, Wenjun -- Williams, Ifor R -- Vijay-Kumar, Matam -- Gewirtz, Andrew T -- AI038296/AI/NIAID NIH HHS/ -- AI080656/AI/NIAID NIH HHS/ -- AI107943/AI/NIAID NIH HHS/ -- DK061417/DK/NIDDK NIH HHS/ -- DK064730/DK/NIDDK NIH HHS/ -- DK56338/DK/NIDDK NIH HHS/ -- R01 AI038296/AI/NIAID NIH HHS/ -- R37 AI038296/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2014 Nov 14;346(6211):861-5. doi: 10.1126/science.1256999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Elizabeth B. Lamb Center for Pediatric Research, Vanderbilt University School of Medicine, Nashville, TN, USA. Departments of Pediatrics, Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA. ; Department of Immunology, Genentech, South San Francisco, CA, USA. ; Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. ; Department of Nutritional Sciences and Medicine, Pennsylvania State University, University Park, PA 16802, USA. ; Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University, Atlanta, GA, USA. Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA. agewirtz@gsu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25395539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diarrhea/immunology/therapy/virology ; Disease Models, Animal ; Feces/virology ; Flagellin/*administration & dosage/immunology ; Homeodomain Proteins/genetics ; *Immunity, Innate ; Interleukin-18/administration & dosage/genetics/*immunology ; Interleukins/administration & dosage/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Mutation ; Rotavirus Infections/immunology/*prevention & control/therapy ; Toll-Like Receptor 5/genetics/*physiology ; Virus Shedding
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  • 30
    Publication Date: 2014-05-07
    Description: Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral "rejuvenating" factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104429/" 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/PMC4104429/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sinha, Manisha -- Jang, Young C -- Oh, Juhyun -- Khong, Danika -- Wu, Elizabeth Y -- Manohar, Rohan -- Miller, Christine -- Regalado, Samuel G -- Loffredo, Francesco S -- Pancoast, James R -- Hirshman, Michael F -- Lebowitz, Jessica -- Shadrach, Jennifer L -- Cerletti, Massimiliano -- Kim, Mi-Jeong -- Serwold, Thomas -- Goodyear, Laurie J -- Rosner, Bernard -- Lee, Richard T -- Wagers, Amy J -- 1DP2 OD004345/OD/NIH HHS/ -- 1R01 AG033053/AG/NIA NIH HHS/ -- 1R01 AG040019/AG/NIA NIH HHS/ -- 5U01 HL100402/HL/NHLBI NIH HHS/ -- DP2 OD004345/OD/NIH HHS/ -- P30 AG038072/AG/NIA NIH HHS/ -- R01 AG032977/AG/NIA NIH HHS/ -- R01 AG033053/AG/NIA NIH HHS/ -- R01 AG040019/AG/NIA NIH HHS/ -- R01 AR042238/AR/NIAMS NIH HHS/ -- R01 AR42238/AR/NIAMS NIH HHS/ -- T32 DE007057/DE/NIDCR NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 May 9;344(6184):649-52. doi: 10.1126/science.1251152. Epub 2014 May 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard Stem Cell Institute and Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24797481" target="_blank"〉PubMed〈/a〉
    Keywords: Age Factors ; Aging/blood/drug effects/*physiology ; Animals ; Bone Morphogenetic Proteins/administration & dosage/blood/*physiology ; Growth Differentiation Factors/administration & dosage/blood/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Skeletal/*blood supply/drug effects/*physiology ; Myoblasts, Skeletal/drug effects/*physiology ; Parabiosis ; *Regeneration ; *Rejuvenation
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  • 31
    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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  • 32
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-06-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, Elizabeth -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1072. doi: 10.1126/science.344.6188.1072.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904133" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Nucleus/metabolism ; Cells/*metabolism ; Humans ; Inflammation ; Mice ; Mice, Knockout ; Neoplasms ; Pain ; RNA, Long Noncoding/genetics/*metabolism
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  • 33
    Publication Date: 2014-08-26
    Description: Riboswitches are ligand-binding elements contained within the 5' untranslated regions of bacterial transcripts, which generally regulate expression of downstream open reading frames. Here, we show that in Listeria monocytogenes, a riboswitch that binds vitamin B12 controls expression of a noncoding regulatory RNA, Rli55. Rli55, in turn, controls expression of the eut genes, whose products enable ethanolamine utilization and require B12 as a cofactor. Defects in ethanolamine utilization, or in its regulation by Rli55, significantly attenuate Listeria virulence in mice. Rli55 functions by sequestering the two-component response regulator EutV by means of a EutV-binding site contained within the RNA. Thus, Rli55 is a riboswitch-regulated member of the small group of regulatory RNAs that function by sequestering a protein and reveals a distinctive mechanism of signal integration in bacterial gene regulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mellin, J R -- Koutero, Mikael -- Dar, Daniel -- Nahori, Marie-Anne -- Sorek, Rotem -- Cossart, Pascale -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Aug 22;345(6199):940-3. doi: 10.1126/science.1255083.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unite des Interactions Bacteries-Cellules, Institut Pasteur, F-75015 Paris, France. INSERM, U604, Paris, F-75015 France. INRA, USC2020, F-75015 Paris, France. ; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel. ; Unite des Interactions Bacteries-Cellules, Institut Pasteur, F-75015 Paris, France. INSERM, U604, Paris, F-75015 France. INRA, USC2020, F-75015 Paris, France. pcossart@pasteur.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25146292" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions ; Animals ; Ethanolamine/*metabolism ; *Gene Expression Regulation, Bacterial ; Listeria monocytogenes/*genetics/metabolism/virology ; Mice ; Mice, Inbred BALB C ; Operon ; RNA, Untranslated/*metabolism ; Response Elements ; *Riboswitch ; Vitamin B 12/*metabolism
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  • 34
    Publication Date: 2014-02-18
    Description: The human neocortex has numerous specialized functional areas whose formation is poorly understood. Here, we describe a 15-base pair deletion mutation in a regulatory element of GPR56 that selectively disrupts human cortex surrounding the Sylvian fissure bilaterally including "Broca's area," the primary language area, by disrupting regional GPR56 expression and blocking RFX transcription factor binding. GPR56 encodes a heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptor required for normal cortical development and is expressed in cortical progenitor cells. GPR56 expression levels regulate progenitor proliferation. GPR56 splice forms are highly variable between mice and humans, and the regulatory element of gyrencephalic mammals directs restricted lateral cortical expression. Our data reveal a mechanism by which control of GPR56 expression pattern by multiple alternative promoters can influence stem cell proliferation, gyral patterning, and, potentially, neocortex evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4480613/" 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/PMC4480613/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bae, Byoung-Il -- Tietjen, Ian -- Atabay, Kutay D -- Evrony, Gilad D -- Johnson, Matthew B -- Asare, Ebenezer -- Wang, Peter P -- Murayama, Ayako Y -- Im, Kiho -- Lisgo, Steven N -- Overman, Lynne -- Sestan, Nenad -- Chang, Bernard S -- Barkovich, A James -- Grant, P Ellen -- Topcu, Meral -- Politsky, Jeffrey -- Okano, Hideyuki -- Piao, Xianhua -- Walsh, Christopher A -- 2R01NS035129/NS/NINDS NIH HHS/ -- G0700089/Medical Research Council/United Kingdom -- GR082557/Wellcome Trust/United Kingdom -- HHSN275200900011C/PHS HHS/ -- N01-HD-9-0011/HD/NICHD NIH HHS/ -- R01 NS035129/NS/NINDS NIH HHS/ -- U01 MH081896/MH/NIMH NIH HHS/ -- U01MH081896/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2014 Feb 14;343(6172):764-8. doi: 10.1126/science.1244392.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics and Genomics, Manton Center for Orphan Disease, and Howard Hughes Medical Institute, Boston Children's Hospital, Broad Institute of MIT and Harvard, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531968" target="_blank"〉PubMed〈/a〉
    Keywords: *Alternative Splicing ; Animals ; Base Sequence ; Biological Evolution ; Body Patterning/*genetics ; Cats ; Cell Proliferation ; Cerebral Cortex/anatomy & histology/cytology/*embryology ; Codon, Nonsense ; Frontal Lobe/anatomy & histology/cytology/embryology ; Genetic Variation ; Haplotypes ; Humans ; Mice ; Molecular Sequence Data ; Neural Stem Cells/cytology/*physiology ; Pedigree ; Promoter Regions, Genetic/genetics ; Receptors, G-Protein-Coupled/*genetics ; Sequence Deletion
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  • 35
    facet.materialart.
    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-04-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jon -- New York, N.Y. -- Science. 2014 Apr 18;344(6181):244-5. doi: 10.1126/science.344.6181.244.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24744351" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antiviral Agents/administration & dosage/*toxicity ; Arabinofuranosyluracil/administration & dosage/*analogs & derivatives/toxicity ; Chimera ; Hepatocytes/drug effects/metabolism/transplantation ; Humans ; Liver/cytology/*drug effects/metabolism ; Liver Transplantation ; Mice ; Mice, Transgenic ; *Models, Animal ; Toxicity Tests/*methods
    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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  • 36
    Publication Date: 2014-12-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pennisi, Elizabeth -- Kaiser, Jocelyn -- Service, Robert F -- Gibbons, Ann -- Vogel, Gretchen -- Underwood, Emily -- Hand, Eric -- New York, N.Y. -- Science. 2014 Dec 19;346(6216):1444-9. doi: 10.1126/science.346.6216.1444. Epub 2014 Dec 18.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25525224" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/*trends ; Humans ; Mice
    Print ISSN: 0036-8075
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  • 37
    Publication Date: 2014-05-31
    Description: Netrins are secreted proteins that regulate axon guidance and neuronal migration. Deleted in colorectal cancer (DCC) is a well-established netrin-1 receptor mediating attractive responses. We provide evidence that its close relative neogenin is also a functional netrin-1 receptor that acts with DCC to mediate guidance in vivo. We determined the structures of a functional netrin-1 region, alone and in complexes with neogenin or DCC. Netrin-1 has a rigid elongated structure containing two receptor-binding sites at opposite ends through which it brings together receptor molecules. The ligand/receptor complexes reveal two distinct architectures: a 2:2 heterotetramer and a continuous ligand/receptor assembly. The differences result from different lengths of the linker connecting receptor domains fibronectin type III domain 4 (FN4) and FN5, which differs among DCC and neogenin splice variants, providing a basis for diverse signaling outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4369087/" 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/PMC4369087/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Kai -- Wu, Zhuhao -- Renier, Nicolas -- Antipenko, Alexander -- Tzvetkova-Robev, Dorothea -- Xu, Yan -- Minchenko, Maria -- Nardi-Dei, Vincenzo -- Rajashankar, Kanagalaghatta R -- Himanen, Juha -- Tessier-Lavigne, Marc -- Nikolov, Dimitar B -- P41 GM103403/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 13;344(6189):1275-9. doi: 10.1126/science.1255149. Epub 2014 May 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. ; Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA. ; Department of Chemistry and Chemical Biology, Cornell University and Northeastern Collaborative Access Team, Advanced Photon Source, Argonne, IL 60439, USA. ; Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu. ; Structural Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. nikolovd@mskcc.org marctl@mail.rockefeller.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24876346" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/*physiology ; Cell Movement ; Fibronectins/chemistry ; Ligands ; Membrane Proteins/*chemistry/genetics/ultrastructure ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Nerve Growth Factors/*chemistry/genetics/ultrastructure ; Neurons/physiology ; Protein Multimerization ; Protein Structure, Tertiary ; Receptors, Cell Surface/*chemistry/genetics/ultrastructure ; Tumor Suppressor Proteins/*chemistry/genetics/ultrastructure
    Print ISSN: 0036-8075
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  • 38
    Publication Date: 2014-08-26
    Description: Sensory systems define an animal's capacity for perception and can evolve to promote survival in new environmental niches. We have uncovered a noncanonical mechanism for sweet taste perception that evolved in hummingbirds since their divergence from insectivorous swifts, their closest relatives. We observed the widespread absence in birds of an essential subunit (T1R2) of the only known vertebrate sweet receptor, raising questions about how specialized nectar feeders such as hummingbirds sense sugars. Receptor expression studies revealed that the ancestral umami receptor (the T1R1-T1R3 heterodimer) was repurposed in hummingbirds to function as a carbohydrate receptor. Furthermore, the molecular recognition properties of T1R1-T1R3 guided taste behavior in captive and wild hummingbirds. We propose that changing taste receptor function enabled hummingbirds to perceive and use nectar, facilitating the massive radiation of hummingbird species.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4302410/" 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/PMC4302410/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baldwin, Maude W -- Toda, Yasuka -- Nakagita, Tomoya -- O'Connell, Mary J -- Klasing, Kirk C -- Misaka, Takumi -- Edwards, Scott V -- Liberles, Stephen D -- R01 DC013289/DC/NIDCD NIH HHS/ -- R01DC013289/DC/NIDCD NIH HHS/ -- New York, N.Y. -- Science. 2014 Aug 22;345(6199):929-33. doi: 10.1126/science.1255097.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Organismic and Evolutionary Biology, Harvard University, and Museum of Comparative Zoology, Cambridge, MA 02138, USA. maudebaldwin@gmail.com stephen_liberles@hms.harvard.edu. ; Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, Japan. ; Bioinformatics and Molecular Evolution Group, School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Ireland. ; Department of Animal Science, University of California, Davis, Davis, CA 95616, USA. ; Department of Organismic and Evolutionary Biology, Harvard University, and Museum of Comparative Zoology, Cambridge, MA 02138, USA. ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. maudebaldwin@gmail.com stephen_liberles@hms.harvard.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25146290" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Evolution, Molecular ; Mice ; Molecular Sequence Data ; Plant Nectar ; Protein Structure, Tertiary ; Receptors, G-Protein-Coupled/chemistry/classification/*genetics ; Taste/*physiology ; Taste Perception/genetics/*physiology
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  • 39
    facet.materialart.
    Unknown
    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-09-13
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hall, Stephen S -- New York, N.Y. -- Science. 2014 Sep 12;345(6202):1234-7. doi: 10.1126/science.345.6202.1234.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25214587" target="_blank"〉PubMed〈/a〉
    Keywords: *Aging ; Animals ; *Blood ; Bone Morphogenetic Proteins/administration & dosage/physiology ; Brain/physiology ; Growth Differentiation Factors/administration & dosage/physiology ; Heart/drug effects/physiology ; Humans ; Liver/physiology ; Mice ; Muscle, Skeletal/physiology ; Rejuvenation/*physiology
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  • 40
    Publication Date: 2014-09-13
    Description: Fucosylation of intestinal epithelial cells, catalyzed by fucosyltransferase 2 (Fut2), is a major glycosylation mechanism of host-microbiota symbiosis. Commensal bacteria induce epithelial fucosylation, and epithelial fucose is used as a dietary carbohydrate by many of these bacteria. However, the molecular and cellular mechanisms that regulate the induction of epithelial fucosylation are unknown. Here, we show that type 3 innate lymphoid cells (ILC3) induced intestinal epithelial Fut2 expression and fucosylation in mice. This induction required the cytokines interleukin-22 and lymphotoxin in a commensal bacteria-dependent and -independent manner, respectively. Disruption of intestinal fucosylation led to increased susceptibility to infection by Salmonella typhimurium. Our data reveal a role for ILC3 in shaping the gut microenvironment through the regulation of epithelial glycosylation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4774895/" 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/PMC4774895/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Goto, Yoshiyuki -- Obata, Takashi -- Kunisawa, Jun -- Sato, Shintaro -- Ivanov, Ivaylo I -- Lamichhane, Aayam -- Takeyama, Natsumi -- Kamioka, Mariko -- Sakamoto, Mitsuo -- Matsuki, Takahiro -- Setoyama, Hiromi -- Imaoka, Akemi -- Uematsu, Satoshi -- Akira, Shizuo -- Domino, Steven E -- Kulig, Paulina -- Becher, Burkhard -- Renauld, Jean-Christophe -- Sasakawa, Chihiro -- Umesaki, Yoshinori -- Benno, Yoshimi -- Kiyono, Hiroshi -- 1R01DK098378/DK/NIDDK NIH HHS/ -- R01 DK098378/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2014 Sep 12;345(6202):1254009. doi: 10.1126/science.1254009. Epub 2014 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Laboratory of Vaccine Materials, National Institute of Biomedical Innovation, Osaka 567-0085, Japan. Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. ; Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032, USA. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Nippon Institute for Biological Science, Tokyo 198-0024, Japan. ; Microbe Division/Japan Collection of Microorganisms, RIKEN BioResource Center, Tsukuba 305-0074, Japan. ; Yakult Central Institute, Tokyo 186-8650, Japan. ; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Department of Mucosal Immunology, School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba, 260-8670, Japan. ; Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. ; Department of Obstetrics and Gynecology, Cellular and Molecular Biology Program, University of Michigan Medical Center, Ann Arbor, MI 48109-5617, USA. ; Institute of Experimental Immunology, University of Zurich, Winterthurerstrasse 190, Zurich CH-8057, Switzerland. ; Ludwig Institute for Cancer Research and Universite Catholique de Louvain, Brussels B-1200, Belgium. ; Nippon Institute for Biological Science, Tokyo 198-0024, Japan. Division of Bacterial Infection, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan. ; Benno Laboratory, Innovation Center, RIKEN, Wako, Saitama 351-0198, Japan. ; Division of Mucosal Immunology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan. Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Saitama 332-0012, Japan. Division of Mucosal Immunology, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25214634" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Disease Models, Animal ; Fucose/*metabolism ; Fucosyltransferases/genetics/metabolism ; Germ-Free Life ; Glycosylation ; Goblet Cells/enzymology/immunology/microbiology ; Ileum/enzymology/immunology/microbiology ; *Immunity, Innate ; Interleukins/immunology ; Intestinal Mucosa/enzymology/*immunology/microbiology ; Lymphocytes/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Microbiota/*immunology ; Molecular Sequence Data ; Paneth Cells/enzymology/immunology/microbiology ; Salmonella Infections/*immunology/microbiology ; *Salmonella typhimurium
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  • 41
    Publication Date: 2014-04-12
    Description: Many neurologic and psychiatric disorders are marked by imbalances between neural excitation and inhibition. In the cerebral cortex, inhibition is mediated largely by GABAergic (gamma-aminobutyric acid-secreting) interneurons, a cell type that originates in the embryonic ventral telencephalon and populates the cortex through long-distance tangential migration. Remarkably, when transplanted from embryos or in vitro culture preparations, immature interneurons disperse and integrate into host brain circuits, both in the cerebral cortex and in other regions of the central nervous system. These features make interneuron transplantation a powerful tool for the study of neurodevelopmental processes such as cell specification, cell death, and cortical plasticity. Moreover, interneuron transplantation provides a novel strategy for modifying neural circuits in rodent models of epilepsy, Parkinson's disease, mood disorders, and chronic pain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056344/" 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/PMC4056344/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Southwell, Derek G -- Nicholas, Cory R -- Basbaum, Allan I -- Stryker, Michael P -- Kriegstein, Arnold R -- Rubenstein, John L -- Alvarez-Buylla, Arturo -- HD032116/HD/NICHD NIH HHS/ -- MH049428/MH/NIMH NIH HHS/ -- NS14627/NS/NINDS NIH HHS/ -- NS28478/NS/NINDS NIH HHS/ -- NS78326/NS/NINDS NIH HHS/ -- R01 EY002874/EY/NEI NIH HHS/ -- R01 MH049428/MH/NIMH NIH HHS/ -- R01 NS014627/NS/NINDS NIH HHS/ -- R01 NS028478/NS/NINDS NIH HHS/ -- R01 NS078326/NS/NINDS NIH HHS/ -- R01-EY02874/EY/NEI NIH HHS/ -- R37 HD032116/HD/NICHD NIH HHS/ -- T32 GM008568/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Apr 11;344(6180):1240622. doi: 10.1126/science.1240622.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24723614" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; Cell Separation ; *Cell- and Tissue-Based Therapy ; Cerebral Cortex/cytology/growth & development/physiology ; *Embryonic Development ; Humans ; Interneurons/*physiology/*transplantation ; Mental Disorders/*therapy ; Mice ; Nervous System Diseases/*therapy
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  • 42
    Publication Date: 2014-03-01
    Description: Epigenetic gene silencing is seen in several repeat-expansion diseases. In fragile X syndrome, the most common genetic form of mental retardation, a CGG trinucleotide-repeat expansion adjacent to the fragile X mental retardation 1 (FMR1) gene promoter results in its epigenetic silencing. Here, we show that FMR1 silencing is mediated by the FMR1 mRNA. The FMR1 mRNA contains the transcribed CGG-repeat tract as part of the 5' untranslated region, which hybridizes to the complementary CGG-repeat portion of the FMR1 gene to form an RNA.DNA duplex. Disrupting the interaction of the mRNA with the CGG-repeat portion of the FMR1 gene prevents promoter silencing. Thus, our data link trinucleotide-repeat expansion to a form of RNA-directed gene silencing mediated by direct interactions of the trinucleotide-repeat RNA and DNA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357282/" 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/PMC4357282/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colak, Dilek -- Zaninovic, Nikica -- Cohen, Michael S -- Rosenwaks, Zev -- Yang, Wang-Yong -- Gerhardt, Jeannine -- Disney, Matthew D -- Jaffrey, Samie R -- R01 GM079235/GM/NIGMS NIH HHS/ -- R01 MH80420/MH/NIMH NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 28;343(6174):1002-5. doi: 10.1126/science.1245831.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, Weill Cornell Medical College, Cornell University, New York, NY 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24578575" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; DNA Methylation ; Embryonic Stem Cells/metabolism ; Fragile X Mental Retardation Protein/*genetics ; Fragile X Syndrome/*genetics ; *Gene Silencing ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Neurons/metabolism ; Nuclear Proteins/genetics ; Promoter Regions, Genetic/genetics ; RNA, Messenger/*genetics ; RNA, Small Interfering/genetics ; Trinucleotide Repeats/*genetics
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  • 43
    Publication Date: 2014-06-07
    Description: How sleep helps learning and memory remains unknown. We report in mouse motor cortex that sleep after motor learning promotes the formation of postsynaptic dendritic spines on a subset of branches of individual layer V pyramidal neurons. New spines are formed on different sets of dendritic branches in response to different learning tasks and are protected from being eliminated when multiple tasks are learned. Neurons activated during learning of a motor task are reactivated during subsequent non-rapid eye movement sleep, and disrupting this neuronal reactivation prevents branch-specific spine formation. These findings indicate that sleep has a key role in promoting learning-dependent synapse formation and maintenance on selected dendritic branches, which contribute to memory storage.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4447313/" 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/PMC4447313/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Guang -- Lai, Cora Sau Wan -- Cichon, Joseph -- Ma, Lei -- Li, Wei -- Gan, Wen-Biao -- P01 NS074972/NS/NINDS NIH HHS/ -- R01 NS047325/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jun 6;344(6188):1173-8. doi: 10.1126/science.1249098.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. Department of Anesthesiology, New York University School of Medicine, New York, NY 10016, USA. ; Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. ; Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. ; Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School, Shenzhen, 518055, China. ; Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA. gan@saturn.med.nyu.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24904169" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dendritic Spines/*physiology ; Female ; Learning/*physiology ; Male ; Mice ; Mice, Mutant Strains ; Motor Cortex/*physiology ; Sleep, REM/*physiology
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  • 44
    Publication Date: 2014-10-18
    Description: Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain's white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a "complex wheel" with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McKenzie, Ian A -- Ohayon, David -- Li, Huiliang -- de Faria, Joana Paes -- Emery, Ben -- Tohyama, Koujiro -- Richardson, William D -- 100269/Wellcome Trust/United Kingdom -- G0800575/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 17;346(6207):318-22. doi: 10.1126/science.1254960.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. ; Department of Anatomy and Neuroscience and the Florey Institute for Neuroscience and Mental Health, University of Melbourne, Melbourne, Victoria 3010, Australia. ; The Center for Electron Microscopy and Bio-Imaging Research, Iwate Medical University, 19-1 Uchimuru, Morioka, Iwate 020-8505, Japan. ; The Wolfson Institute for Biomedical Research, University College London, Gower Street, London WC1E 6BT, UK. w.richardson@ucl.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25324381" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/*cytology/metabolism ; *Cell Proliferation ; Gene Deletion ; Humans ; *Learning ; Male ; Mental Recall ; Mice ; Mice, Transgenic ; Motor Skills/*physiology ; Myelin Sheath/genetics/*metabolism ; Oligodendroglia/cytology/metabolism/*physiology ; Synaptic Transmission ; Transcription Factors/genetics/metabolism
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  • 45
    Publication Date: 2014-02-08
    Description: Cellular responses elicited by cell surface receptors differ according to stimulus strength. We investigated how the high-affinity receptor for immunoglobulin E (IgE) modulates the response of mast cells to a high- or low-affinity stimulus. Both high- and low-affinity stimuli elicited similar receptor phosphorylation; however, differences were observed in receptor cluster size, mobility, distribution, and the cells' effector responses. Low-affinity stimulation increased receptor association with the Src family kinase Fgr and shifted signals from the adapter LAT1 to the related adapter LAT2. LAT1-dependent calcium signals required for mast cell degranulation were dampened, but the role of LAT2 in chemokine production was enhanced, altering immune cell recruitment at the site of inflammation. These findings uncover how receptor discrimination of stimulus strength can be interpreted as distinct in vivo outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4188507/" 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/PMC4188507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suzuki, Ryo -- Leach, Sarah -- Liu, Wenhua -- Ralston, Evelyn -- Scheffel, Jorg -- Zhang, Weiguo -- Lowell, Clifford A -- Rivera, Juan -- R01 AI065495/AI/NIAID NIH HHS/ -- R01 AI068150/AI/NIAID NIH HHS/ -- ZIA AR041101-20/Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Feb 28;343(6174):1021-5. doi: 10.1126/science.1246976. Epub 2014 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, MD 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24505132" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Amino Acid Transport System y+/metabolism ; Animals ; Antigens, CD98 Light Chains/metabolism ; Cattle ; Cell Movement ; Chemokines/metabolism ; Dinitrophenols ; Immunoglobulin E/*metabolism ; Inflammation/immunology ; Mast Cells/*immunology ; Membrane Proteins/metabolism ; Mice ; Phosphoproteins/metabolism ; Proto-Oncogene Proteins/metabolism ; Receptors, IgE/*metabolism ; src-Family Kinases/metabolism
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  • 46
    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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  • 47
    Publication Date: 2014-10-25
    Description: During cell entry, capsids of incoming influenza A viruses (IAVs) must be uncoated before viral ribonucleoproteins (vRNPs) can enter the nucleus for replication. After hemagglutinin-mediated membrane fusion in late endocytic vacuoles, the vRNPs and the matrix proteins dissociate from each other and disperse within the cytosol. Here, we found that for capsid disassembly, IAV takes advantage of the host cell's aggresome formation and disassembly machinery. The capsids mimicked misfolded protein aggregates by carrying unanchored ubiquitin chains that activated a histone deacetylase 6 (HDAC6)-dependent pathway. The ubiquitin-binding domain was essential for recruitment of HDAC6 to viral fusion sites and for efficient uncoating and infection. That other components of the aggresome processing machinery, including dynein, dynactin, and myosin II, were also required suggested that physical forces generated by microtubule- and actin-associated motors are essential for IAV entry.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banerjee, Indranil -- Miyake, Yasuyuki -- Nobs, Samuel Philip -- Schneider, Christoph -- Horvath, Peter -- Kopf, Manfred -- Matthias, Patrick -- Helenius, Ari -- Yamauchi, Yohei -- New York, N.Y. -- Science. 2014 Oct 24;346(6208):473-7. doi: 10.1126/science.1257037.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry, Eidgenossische Technische Hochschule (ETH) Zurich, Switzerland. ; Epigenetics, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. ; Institute of Molecular Health Sciences, ETH Zurich, Switzerland. ; Synthetic and Systems Biology Unit, Biological Research Center, Szeged, Hungary. ; Epigenetics, Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland. Faculty of Sciences, University of Basel, Basel, Switzerland. ; Institute of Biochemistry, Eidgenossische Technische Hochschule (ETH) Zurich, Switzerland. ari.helenius@bc.biol.ethz.ch yohei.yamauchi@bc.biol.ethz.ch.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25342804" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Capsid/*metabolism ; Cell Line, Tumor ; Cell Nucleus/virology ; Dyneins/metabolism ; Gene Knockout Techniques ; Histone Deacetylases/genetics/*physiology ; Host-Pathogen Interactions ; Humans ; Influenza A virus/*physiology ; Influenza, Human/genetics/metabolism/*virology ; Membrane Fusion/genetics/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/metabolism ; Microtubules/metabolism ; Myosin Type II/metabolism ; Protein Binding ; Protein Folding ; Protein Structure, Tertiary ; RNA Interference ; Ribonucleoproteins/metabolism ; Ubiquitin/chemistry/metabolism ; *Virus Internalization ; Virus Replication
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  • 48
    Publication Date: 2014-05-24
    Description: Novel vaccines are urgently needed to reduce the burden of severe malaria. Using a differential whole-proteome screening method, we identified Plasmodium falciparum schizont egress antigen-1 (PfSEA-1), a 244-kilodalton parasite antigen expressed in schizont-infected red blood cells (RBCs). Antibodies to PfSEA-1 decreased parasite replication by arresting schizont rupture, and conditional disruption of PfSEA-1 resulted in a profound parasite replication defect. Vaccination of mice with recombinant Plasmodium berghei PbSEA-1 significantly reduced parasitemia and delayed mortality after lethal challenge with the Plasmodium berghei strain ANKA. Tanzanian children with antibodies to recombinant PfSEA-1A (rPfSEA-1A) did not experience severe malaria, and Kenyan adolescents and adults with antibodies to rPfSEA-1A had significantly lower parasite densities than individuals without these antibodies. By blocking schizont egress, PfSEA-1 may synergize with other vaccines targeting hepatocyte and RBC invasion.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184151/" 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/PMC4184151/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raj, Dipak K -- Nixon, Christian P -- Nixon, Christina E -- Dvorin, Jeffrey D -- DiPetrillo, Christen G -- Pond-Tor, Sunthorn -- Wu, Hai-Wei -- Jolly, Grant -- Pischel, Lauren -- Lu, Ailin -- Michelow, Ian C -- Cheng, Ling -- Conteh, Solomon -- McDonald, Emily A -- Absalon, Sabrina -- Holte, Sarah E -- Friedman, Jennifer F -- Fried, Michal -- Duffy, Patrick E -- Kurtis, Jonathan D -- 1K08AI100997-01A1/AI/NIAID NIH HHS/ -- DP2 AI112219/AI/NIAID NIH HHS/ -- DP2-AI112219/AI/NIAID NIH HHS/ -- K08 AI100997/AI/NIAID NIH HHS/ -- P20GM103421/GM/NIGMS NIH HHS/ -- P30 AI042853/AI/NIAID NIH HHS/ -- P30AI042853/AI/NIAID NIH HHS/ -- R01 AI102907/AI/NIAID NIH HHS/ -- R01-AI076353/AI/NIAID NIH HHS/ -- R01-AI102907/AI/NIAID NIH HHS/ -- R01-AI52059/AI/NIAID NIH HHS/ -- T32-DA013911/DA/NIDA NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 May 23;344(6186):871-7. doi: 10.1126/science.1254417.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. ; Division of Infectious Diseases, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA. ; Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Department of Pediatrics, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. ; Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02906, USA. ; Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20892, USA. ; Fred Hutchinson Cancer Research Center Program in Biostatistics and Biomathematics, Department of Biostatistics and Global Health, University of Washington, Seattle, WA 98109, USA. ; Center for International Health Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Department of Pathology and Laboratory Medicine, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, Providence, RI 02906, USA. jonathan_kurtis@brown.edu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24855263" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Animals ; Antibodies, Protozoan/blood/*immunology ; Antigens, Protozoan/*immunology ; Child ; Erythrocytes/*parasitology ; Hepatocytes/immunology/parasitology ; Humans ; Immunoglobulin G/blood/immunology ; Kenya ; Malaria/prevention & control ; Malaria Vaccines/*immunology ; Malaria, Falciparum/*prevention & control ; Mice ; Plasmodium berghei/immunology ; Plasmodium falciparum/*growth & development/immunology ; Protozoan Proteins/*immunology ; Recombinant Proteins/immunology ; Schizonts/*growth & development ; Young Adult
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  • 49
    Publication Date: 2014-08-02
    Description: During limb development, digits emerge from the undifferentiated mesenchymal tissue that constitutes the limb bud. It has been proposed that this process is controlled by a self-organizing Turing mechanism, whereby diffusible molecules interact to produce a periodic pattern of digital and interdigital fates. However, the identities of the molecules remain unknown. By combining experiments and modeling, we reveal evidence that a Turing network implemented by Bmp, Sox9, and Wnt drives digit specification. We develop a realistic two-dimensional simulation of digit patterning and show that this network, when modulated by morphogen gradients, recapitulates the expression patterns of Sox9 in the wild type and in perturbation experiments. Our systems biology approach reveals how a combination of growth, morphogen gradients, and a self-organizing Turing network can achieve robust and reproducible pattern formation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raspopovic, J -- Marcon, L -- Russo, L -- Sharpe, J -- New York, N.Y. -- Science. 2014 Aug 1;345(6196):566-70. doi: 10.1126/science.1252960.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Systems Biology Program, Centre for Genomic Regulation (CRG), and Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, 08003 Barcelona, Spain. ; Systems Biology Program, Centre for Genomic Regulation (CRG), and Universitat Pompeu Fabra (UPF), Dr. Aiguader 88, 08003 Barcelona, Spain. Institucio Catalana de Recerca i Estudis Avancats (ICREA), Passeig Lluis Companys 23, 08010 Barcelona, Spain. james.sharpe@crg.eu.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25082703" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Body Patterning/*genetics ; Bone Morphogenetic Proteins/*metabolism ; Computer Simulation ; Extremities/*embryology ; Female ; *Gene Expression Regulation, Developmental ; Gene Knockdown Techniques ; Green Fluorescent Proteins/genetics/metabolism ; Limb Buds/*embryology ; Mice ; Mice, Inbred Strains ; Models, Biological ; Oligonucleotide Array Sequence Analysis ; SOX9 Transcription Factor/genetics/*metabolism ; Wnt Proteins/*metabolism
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  • 50
    Publication Date: 2014-02-01
    Description: Genetic errors in meiosis can lead to birth defects and spontaneous abortions. Checkpoint mechanisms of hitherto unknown nature eliminate oocytes with unrepaired DNA damage, causing recombination-defective mutant mice to be sterile. Here, we report that checkpoint kinase 2 (Chk2 or Chek2), is essential for culling mouse oocytes bearing unrepaired meiotic or induced DNA double-strand breaks (DSBs). Female infertility caused by a meiotic recombination mutation or irradiation was reversed by mutation of Chk2. Both meiotically programmed and induced DSBs trigger CHK2-dependent activation of TRP53 (p53) and TRP63 (p63), effecting oocyte elimination. These data establish CHK2 as essential for DNA damage surveillance in female meiosis and indicate that the oocyte DSB damage response primarily involves a pathway hierarchy in which ataxia telangiectasia and Rad3-related (ATR) signals to CHK2, which then activates p53 and p63.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4048839/" 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/PMC4048839/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bolcun-Filas, Ewelina -- Rinaldi, Vera D -- White, Michelle E -- Schimenti, John C -- GM45415/GM/NIGMS NIH HHS/ -- R01 GM045415/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Jan 31;343(6170):533-6. doi: 10.1126/science.1247671.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biomedical Sciences, Cornell University, Ithaca, NY 14850, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24482479" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/genetics/metabolism ; Animals ; Cell Cycle Proteins/genetics/metabolism ; Checkpoint Kinase 2/genetics/*physiology ; *DNA Breaks, Double-Stranded ; Female ; HeLa Cells ; Humans ; Infertility, Female/*genetics/pathology ; Meiosis/genetics ; Mice ; Mice, Inbred C57BL ; Mice, Mutant Strains ; Oocytes/*metabolism/pathology ; Phosphoproteins/*metabolism ; Trans-Activators/*metabolism ; Tumor Suppressor Protein p53/*metabolism
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  • 51
    Publication Date: 2014-08-12
    Description: Phospholipids (PLs) with polyunsaturated acyl chains are extremely abundant in a few specialized cellular organelles such as synaptic vesicles and photoreceptor discs, but their effect on membrane properties is poorly understood. Here, we found that polyunsaturated PLs increased the ability of dynamin and endophilin to deform and vesiculate synthetic membranes. When cells incorporated polyunsaturated fatty acids into PLs, the plasma membrane became more amenable to deformation by a pulling force and the rate of endocytosis was accelerated, in particular, under conditions in which cholesterol was limiting. Molecular dynamics simulations and biochemical measurements indicated that polyunsaturated PLs adapted their conformation to membrane curvature. Thus, by reducing the energetic cost of membrane bending and fission, polyunsaturated PLs may help to support rapid endocytosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pinot, Mathieu -- Vanni, Stefano -- Pagnotta, Sophie -- Lacas-Gervais, Sandra -- Payet, Laurie-Anne -- Ferreira, Thierry -- Gautier, Romain -- Goud, Bruno -- Antonny, Bruno -- Barelli, Helene -- New York, N.Y. -- Science. 2014 Aug 8;345(6197):693-7. doi: 10.1126/science.1255288.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Pharmacologie Moleculaire et Cellulaire, Universite Nice Sophia Antipolis and CNRS, 06560 Valbonne, France. Unite Mixte de Recherche 144, Institut Curie and CNRS, F-75248 Paris, France. ; Institut de Pharmacologie Moleculaire et Cellulaire, Universite Nice Sophia Antipolis and CNRS, 06560 Valbonne, France. ; Centre Commun de Microscopie Appliquee, Universite Nice Sophia Antipolis, Parc Valrose, 06000 Nice, France. ; Signalisation et Transports Ioniques Membranaires, Universite de Poitiers and CNRS, Poitiers, France. ; Unite Mixte de Recherche 144, Institut Curie and CNRS, F-75248 Paris, France. ; Institut de Pharmacologie Moleculaire et Cellulaire, Universite Nice Sophia Antipolis and CNRS, 06560 Valbonne, France. antonny@ipmc.cnrs.fr.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25104391" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/chemistry/metabolism ; Animals ; Cell Line, Tumor ; Cell Membrane/chemistry/*physiology ; Dynamins/chemistry/metabolism ; *Endocytosis ; Fatty Acids, Unsaturated/chemistry/*physiology ; Humans ; Membranes, Artificial ; Mice ; Molecular Dynamics Simulation
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  • 52
    Publication Date: 2014-05-24
    Description: Cushing's syndrome is caused by excess cortisol production from the adrenocortical gland. In corticotropin-independent Cushing's syndrome, the excess cortisol production is primarily attributed to an adrenocortical adenoma, in which the underlying molecular pathogenesis has been poorly understood. We report a hotspot mutation (L206R) in PRKACA, which encodes the catalytic subunit of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), in more than 50% of cases with adrenocortical adenomas associated with corticotropin-independent Cushing's syndrome. The L206R PRKACA mutant abolished its binding to the regulatory subunit of PKA (PRKAR1A) that inhibits catalytic activity of PRKACA, leading to constitutive, cAMP-independent PKA activation. These results highlight the major role of cAMP-independent activation of cAMP/PKA signaling by somatic mutations in corticotropin-independent Cushing's syndrome, providing insights into the diagnosis and therapeutics of this syndrome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sato, Yusuke -- Maekawa, Shigekatsu -- Ishii, Ryohei -- Sanada, Masashi -- Morikawa, Teppei -- Shiraishi, Yuichi -- Yoshida, Kenichi -- Nagata, Yasunobu -- Sato-Otsubo, Aiko -- Yoshizato, Tetsuichi -- Suzuki, Hiromichi -- Shiozawa, Yusuke -- Kataoka, Keisuke -- Kon, Ayana -- Aoki, Kosuke -- Chiba, Kenichi -- Tanaka, Hiroko -- Kume, Haruki -- Miyano, Satoru -- Fukayama, Masashi -- Nureki, Osamu -- Homma, Yukio -- Ogawa, Seishi -- New York, N.Y. -- Science. 2014 May 23;344(6186):917-20. doi: 10.1126/science.1252328.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan. ; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. ; Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. ; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Laboratory of DNA Information Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. Laboratory of Sequence Analysis, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. sogawa-tky@umin.ac.jp homma-uro@umin.ac.jp. ; Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan. sogawa-tky@umin.ac.jp homma-uro@umin.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24855271" target="_blank"〉PubMed〈/a〉
    Keywords: Adrenal Cortex Neoplasms/*genetics ; Adrenocortical Adenoma/*genetics ; Adrenocorticotropic Hormone/metabolism ; Animals ; Catalytic Domain/genetics ; Cushing Syndrome/*genetics/metabolism ; Cyclic AMP-Dependent Protein Kinase Catalytic Subunits/*genetics/metabolism ; DNA Mutational Analysis ; GTP-Binding Protein alpha Subunits/genetics ; HEK293 Cells ; Humans ; Mice ; Mutation ; NIH 3T3 Cells ; PC12 Cells ; Rats
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  • 53
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-03-15
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nilsen, Timothy W -- New York, N.Y. -- Science. 2014 Mar 14;343(6176):1207-8. doi: 10.1126/science.1249340.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for RNA Molecular Biology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24626918" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/*metabolism ; Animals ; Cell Nucleus/enzymology ; Cytoplasm/enzymology ; Dioxygenases/genetics/metabolism ; Gene Knockdown Techniques ; Humans ; Membrane Proteins/genetics/metabolism ; Methylation ; Methyltransferases/genetics/metabolism ; Mice ; Proteins/genetics/metabolism ; *RNA Stability ; RNA, Messenger/*metabolism ; RNA-Binding Proteins/genetics/metabolism ; *Transcription, Genetic
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  • 54
    Publication Date: 2014-06-14
    Description: The peripheral autonomic nervous system reaches far throughout the body and includes neurons of diverse functions, such as sympathetic and parasympathetic. We show that the parasympathetic system in mice--including trunk ganglia and the cranial ciliary, pterygopalatine, lingual, submandibular, and otic ganglia--arise from glial cells in nerves, not neural crest cells. The parasympathetic fate is induced in nerve-associated Schwann cell precursors at distal peripheral sites. We used multicolor Cre-reporter lineage tracing to show that most of these neurons arise from bi-potent progenitors that generate both glia and neurons. This nerve origin places cellular elements for generating parasympathetic neurons in diverse tissues and organs, which may enable wiring of the developing parasympathetic nervous system.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dyachuk, Vyacheslav -- Furlan, Alessandro -- Shahidi, Maryam Khatibi -- Giovenco, Marcela -- Kaukua, Nina -- Konstantinidou, Chrysoula -- Pachnis, Vassilis -- Memic, Fatima -- Marklund, Ulrika -- Muller, Thomas -- Birchmeier, Carmen -- Fried, Kaj -- Ernfors, Patrik -- Adameyko, Igor -- MC_U117537087/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Jul 4;345(6192):82-7. doi: 10.1126/science.1253281. Epub 2014 Jun 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. A.V. Zhirmunsky Institute of Marine Biology of the Far Eastern Branch of the Russian Academy of Sciences, Vladivostok, Russia. ; Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. ; Department of Dental Medicine, Karolinska Institutet, Stockholm, Sweden. ; Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden. ; Division of Molecular Neurobiology, Medical Research Council (MRC) National Institute for Medical Research, London, UK. ; Department of Neuroscience, The Max Delbruck Center for Molecular Medicine, Berlin-Buch, Germany. ; Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden. igor.adameyko@ki.se patrik.ernfors@ki.se. ; Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden. igor.adameyko@ki.se patrik.ernfors@ki.se.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24925909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics/metabolism ; Ganglia, Parasympathetic/cytology/embryology ; Mice ; Mice, Mutant Strains ; Neural Stem Cells/*cytology/metabolism ; Neuroanatomical Tract-Tracing Techniques/methods ; *Neurogenesis ; Neuroglia/*cytology/metabolism ; Neurons/*cytology/metabolism ; Parasympathetic Nervous System/cytology/*embryology ; SOXE Transcription Factors/genetics/metabolism ; Schwann Cells/cytology/metabolism
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  • 55
    Publication Date: 2014-03-15
    Description: The intestinal microbiota and tissue-resident myeloid cells promote immune responses that maintain intestinal homeostasis in the host. However, the cellular cues that translate microbial signals into intestinal homeostasis remain unclear. Here, we show that deficient granulocyte-macrophage colony-stimulating factor (GM-CSF) production altered mononuclear phagocyte effector functions and led to reduced regulatory T cell (T(reg)) numbers and impaired oral tolerance. We observed that RORgammat(+) innate lymphoid cells (ILCs) are the primary source of GM-CSF in the gut and that ILC-driven GM-CSF production was dependent on the ability of macrophages to sense microbial signals and produce interleukin-1beta. Our findings reveal that commensal microbes promote a crosstalk between innate myeloid and lymphoid cells that leads to immune homeostasis in the intestine.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4291125/" 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/PMC4291125/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mortha, Arthur -- Chudnovskiy, Aleksey -- Hashimoto, Daigo -- Bogunovic, Milena -- Spencer, Sean P -- Belkaid, Yasmine -- Merad, Miriam -- F30 DK094708/DK/NIDDK NIH HHS/ -- R01 CA154947/CA/NCI NIH HHS/ -- R01 CA154947A/CA/NCI NIH HHS/ -- R01 CA173861/CA/NCI NIH HHS/ -- U01 AI095611/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2014 Mar 28;343(6178):1249288. doi: 10.1126/science.1249288. Epub 2014 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Oncological Sciences, 1470 Madison Avenue, New York, NY 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24625929" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens/immunology ; Eating ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics/*metabolism ; Homeostasis ; *Immune Tolerance ; Immunity, Innate ; Interleukin-1beta/immunology ; Intestines/*immunology/*microbiology ; Macrophages/*immunology/*microbiology ; Mice ; Mice, Mutant Strains ; Microbiota/*immunology ; Mouth/immunology ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; T-Lymphocytes, Regulatory/immunology
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  • 56
    Publication Date: 2014-04-26
    Description: Tissue-resident macrophages are heterogeneous as a consequence of anatomical niche-specific functions. Many populations self-renew independently of bone marrow in the adult, but the molecular mechanisms of this are poorly understood. We determined a transcriptional profile for the major self-renewing population of peritoneal macrophages in mice. These cells specifically expressed the transcription factor Gata6. Selective deficiency of Gata6 in myeloid cells caused substantial alterations in the transcriptome of peritoneal macrophages. Gata6 deficiency also resulted in dysregulated peritoneal macrophage proliferative renewal during homeostasis and in response to inflammation, which was associated with delays in the resolution of inflammation. Our investigations reveal that the tissue macrophage phenotype is under discrete tissue-selective transcriptional control and that this is fundamentally linked to the regulation of their proliferation renewal.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4185421/" 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/PMC4185421/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rosas, Marcela -- Davies, Luke C -- Giles, Peter J -- Liao, Chia-Te -- Kharfan, Bashar -- Stone, Timothy C -- O'Donnell, Valerie B -- Fraser, Donald J -- Jones, Simon A -- Taylor, Philip R -- 094143/Wellcome Trust/United Kingdom -- G0601617/Medical Research Council/United Kingdom -- MR/J002151/1/Medical Research Council/United Kingdom -- MR/K02003X/1/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- New York, N.Y. -- Science. 2014 May 9;344(6184):645-8. doi: 10.1126/science.1251414. Epub 2014 Apr 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiff Institute of Infection and Immunity, Cardiff University School of Medicine, Heath Park, Cardiff CF14 4XN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24762537" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Proliferation ; GATA6 Transcription Factor/genetics/*physiology ; Inflammation/immunology ; Macrophages, Peritoneal/*immunology ; Mice ; Mice, Knockout ; Myeloid Cells/immunology ; Phenotype
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  • 57
    Publication Date: 2014-02-08
    Description: We report that the oxytocin-mediated neuroprotective gamma-aminobutyric acid (GABA) excitatory-inhibitory shift during delivery is abolished in the valproate and fragile X rodent models of autism. During delivery and subsequently, hippocampal neurons in these models have elevated intracellular chloride levels, increased excitatory GABA, enhanced glutamatergic activity, and elevated gamma oscillations. Maternal pretreatment with bumetanide restored in offspring control electrophysiological and behavioral phenotypes. Conversely, blocking oxytocin signaling in naive mothers produced offspring having electrophysiological and behavioral autistic-like features. Our results suggest a chronic deficient chloride regulation in these rodent models of autism and stress the importance of oxytocin-mediated GABAergic inhibition during the delivery process. Our data validate the amelioration observed with bumetanide and oxytocin and point to common pathways in a drug-induced and a genetic rodent model of autism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tyzio, Roman -- Nardou, Romain -- Ferrari, Diana C -- Tsintsadze, Timur -- Shahrokhi, Amene -- Eftekhari, Sanaz -- Khalilov, Ilgam -- Tsintsadze, Vera -- Brouchoud, Corinne -- Chazal, Genevieve -- Lemonnier, Eric -- Lozovaya, Natalia -- Burnashev, Nail -- Ben-Ari, Yehezkel -- New York, N.Y. -- Science. 2014 Feb 7;343(6171):675-9. doi: 10.1126/science.1247190.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24503856" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/*chemically induced/*genetics/metabolism ; Behavior, Animal ; Bumetanide/administration & dosage ; Chlorides/metabolism ; *Cytoprotection ; Disease Models, Animal ; Female ; Fragile X Mental Retardation Protein/genetics ; Maternal-Fetal Exchange ; Mice ; Oxytocin/*metabolism ; Parturition ; Pregnancy ; Rats ; Valproic Acid/pharmacology ; gamma-Aminobutyric Acid/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 58
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-08-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Underwood, Emily -- New York, N.Y. -- Science. 2014 Aug 15;345(6198):750-1. doi: 10.1126/science.345.6198.750.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25124425" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diet ; Female ; Fetus/*physiology ; *Food Preferences ; Humans ; Infant ; Infant, Newborn/*physiology ; Mice ; *Mothers ; Olfactory Receptor Neurons/physiology ; Pregnancy ; *Taste ; Taste Perception
    Print ISSN: 0036-8075
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  • 59
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    American Association for the Advancement of Science (AAAS)
    Publication Date: 2014-01-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Caldecott, Keith W -- MR/J006750/1/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Jan 17;343(6168):260-1. doi: 10.1126/science.1248234.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genome Damage and Stability Centre, University of Sussex, Falmer, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24436412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/metabolism ; DNA/biosynthesis/*chemistry ; *DNA Repair ; *DNA Replication ; DNA-Directed DNA Polymerase/chemistry ; *Genomic Instability ; Humans ; Mice ; RNA/*chemistry ; Ribonucleases/chemistry ; Ribonucleotides/*chemistry ; Ribose/*chemistry
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  • 60
    Publication Date: 2014-10-04
    Description: Colloidal nanoparticle biosensors have received intense scientific attention and offer promising applications in both research and medicine. We review the state of the art in nanoparticle development, surface chemistry, and biosensing mechanisms, discussing how a range of technologies are contributing toward commercial and clinical translation. Recent examples of success include the ultrasensitive detection of cancer biomarkers in human serum and in vivo sensing of methyl mercury. We identify five key materials challenges, including the development of robust mass-scale nanoparticle synthesis methods, and five broader challenges, including the use of simulations and bioinformatics-driven experimental approaches for predictive modeling of biosensor performance. The resultant generation of nanoparticle biosensors will form the basis of high-performance analytical assays, effective multiplexed intracellular sensors, and sophisticated in vivo probes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Howes, Philip D -- Chandrawati, Rona -- Stevens, Molly M -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 3;346(6205):1247390. doi: 10.1126/science.1247390. Epub 2014 Oct 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Materials, Department of Bioengineering, and Institute of Biomedical Engineering, Imperial College London, Exhibition Road, London SW7 2AZ, UK. ; Department of Materials, Department of Bioengineering, and Institute of Biomedical Engineering, Imperial College London, Exhibition Road, London SW7 2AZ, UK. m.stevens@imperial.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25278614" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biosensing Techniques ; *Chemistry Techniques, Analytical ; Colloids ; Humans ; Mice ; *Molecular Diagnostic Techniques ; Nanoparticles/*chemistry ; Sensitivity and Specificity ; Surface Properties
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  • 61
    Publication Date: 2014-09-23
    Description: The small number of hematopoietic stem and progenitor cells in cord blood units limits their widespread use in human transplant protocols. We identified a family of chemically related small molecules that stimulates the expansion ex vivo of human cord blood cells capable of reconstituting human hematopoiesis for at least 6 months in immunocompromised mice. The potent activity of these newly identified compounds, UM171 being the prototype, is independent of suppression of the aryl hydrocarbon receptor, which targets cells with more-limited regenerative potential. The properties of UM171 make it a potential candidate for hematopoietic stem cell transplantation and gene therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4372335/" 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/PMC4372335/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fares, Iman -- Chagraoui, Jalila -- Gareau, Yves -- Gingras, Stephane -- Ruel, Rejean -- Mayotte, Nadine -- Csaszar, Elizabeth -- Knapp, David J H F -- Miller, Paul -- Ngom, Mor -- Imren, Suzan -- Roy, Denis-Claude -- Watts, Kori L -- Kiem, Hans-Peter -- Herrington, Robert -- Iscove, Norman N -- Humphries, R Keith -- Eaves, Connie J -- Cohen, Sandra -- Marinier, Anne -- Zandstra, Peter W -- Sauvageau, Guy -- HL84345/HL/NHLBI NIH HHS/ -- R01 HL084345/HL/NHLBI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1509-12. doi: 10.1126/science.1256337.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Genetics of Stem Cells Laboratory, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada. ; Medicinal Chemistry, IRIC, University of Montreal, Montreal, QC, Canada. ; Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON, Canada. ; Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, BC, Canada. ; Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada. Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, QC, Canada. ; Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. ; Clinical Research Division, Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA. Department of Medicine and Pathology, University of Washington, Seattle, WA, USA. ; Ontario Cancer Institute, University Health Network, Toronto, ON, Canada. ; Ontario Cancer Institute, University Health Network, Toronto, ON, Canada. Department of Immunology, University of Toronto, Toronto, ON, Canada. ; Molecular Genetics of Stem Cells Laboratory, Institute of Research in Immunology and Cancer (IRIC), University of Montreal, Montreal, QC, Canada. Division of Hematology, Maisonneuve-Rosemont Hospital, Montreal, QC, Canada. Department of Medicine, Faculty of Medicine, Universite de Montreal, Montreal, QC, Canada. guy.sauvageau@umontreal.ca.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237102" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Culture Techniques ; Fetal Blood/cytology/*drug effects/physiology ; Genetic Therapy/methods ; Hematopoiesis/*drug effects/physiology ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/*drug effects/physiology ; Humans ; Immunocompromised Host ; Indoles/chemistry/*pharmacology ; Mice ; Pyrimidines/chemistry/*pharmacology ; Receptors, Aryl Hydrocarbon/*antagonists & inhibitors ; Regeneration/*drug effects ; Small Molecule Libraries/chemistry/pharmacology
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  • 62
    Publication Date: 2014-02-07
    Description: Alveoli are gas-exchange sacs lined by squamous alveolar type (AT) 1 cells and cuboidal, surfactant-secreting AT2 cells. Classical studies suggested that AT1 arise from AT2 cells, but recent studies propose other sources. Here we use molecular markers, lineage tracing and clonal analysis to map alveolar progenitors throughout the mouse lifespan. We show that, during development, AT1 and AT2 cells arise directly from a bipotent progenitor, whereas after birth new AT1 cells derive from rare, self-renewing, long-lived, mature AT2 cells that produce slowly expanding clonal foci of alveolar renewal. This stem-cell function is broadly activated by AT1 injury, and AT2 self-renewal is selectively induced by EGFR (epidermal growth factor receptor) ligands in vitro and oncogenic Kras(G12D) in vivo, efficiently generating multifocal, clonal adenomas. Thus, there is a switch after birth, when AT2 cells function as stem cells that contribute to alveolar renewal, repair and cancer. We propose that local signals regulate AT2 stem-cell activity: a signal transduced by EGFR-KRAS controls self-renewal and is hijacked during oncogenesis, whereas another signal controls reprogramming to AT1 fate.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4013278/" 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/PMC4013278/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Desai, Tushar J -- Brownfield, Douglas G -- Krasnow, Mark A -- P30 CA124435/CA/NCI NIH HHS/ -- U01 HL099995/HL/NHLBI NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Mar 13;507(7491):190-4. doi: 10.1038/nature12930. Epub 2014 Feb 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5307, USA [2] Department of Internal Medicine, Division of Pulmonary and Critical Care, Stanford University School of Medicine, Stanford, California 94305-5307, USA. ; Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5307, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24499815" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Division ; Cell Lineage ; Cell Transformation, Neoplastic/metabolism/pathology ; Cells, Cultured ; Cellular Reprogramming ; Clone Cells/cytology ; Female ; Lung/*cytology/embryology/*growth & development/pathology ; Lung Neoplasms/metabolism/*pathology ; Male ; Mice ; Models, Biological ; Multipotent Stem Cells/*cytology/metabolism/*pathology ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Pulmonary Alveoli/*cytology ; Receptor, Epidermal Growth Factor/metabolism ; *Regeneration ; Signal Transduction
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 63
    Publication Date: 2014-07-22
    Description: Cachexia is a wasting disorder of adipose and skeletal muscle tissues that leads to profound weight loss and frailty. About half of all cancer patients suffer from cachexia, which impairs quality of life, limits cancer therapy and decreases survival. One key characteristic of cachexia is higher resting energy expenditure levels than in healthy individuals, which has been linked to greater thermogenesis by brown fat. How tumours induce brown fat activity is unknown. Here, using a Lewis lung carcinoma model of cancer cachexia, we show that tumour-derived parathyroid-hormone-related protein (PTHrP) has an important role in wasting, through driving the expression of genes involved in thermogenesis in adipose tissues. Neutralization of PTHrP in tumour-bearing mice blocked adipose tissue browning and the loss of muscle mass and strength. Our results demonstrate that PTHrP mediates energy wasting in fat tissues and contributes to the broader aspects of cancer cachexia. Thus, neutralization of PTHrP might hold promise for ameliorating cancer cachexia and improving patient survival.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4224962/" 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/PMC4224962/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kir, Serkan -- White, James P -- Kleiner, Sandra -- Kazak, Lawrence -- Cohen, Paul -- Baracos, Vickie E -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- R37 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):100-4. doi: 10.1038/nature13528. Epub 2014 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215, USA. ; Department of Oncology, Division of Palliative Care Medicine, University of Alberta, Edmonton T6G 1Z2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043053" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/cytology/drug effects/*metabolism/pathology ; Animals ; Cachexia/*metabolism/pathology ; Carcinoma, Lewis Lung/genetics/*metabolism/*pathology ; Culture Media, Conditioned/pharmacology ; Energy Metabolism/drug effects ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Male ; Mice ; Muscle, Skeletal/metabolism/pathology ; Organ Size/drug effects ; Parathyroid Hormone-Related Protein/antagonists & inhibitors/*metabolism ; Thermogenesis/drug effects/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 64
    Publication Date: 2014-08-15
    Description: The murine caspase-11 non-canonical inflammasome responds to various bacterial infections. Caspase-11 activation-induced pyroptosis, in response to cytoplasmic lipopolysaccharide (LPS), is critical for endotoxic shock in mice. The mechanism underlying cytosolic LPS sensing and the responsible pattern recognition receptor are unknown. Here we show that human monocytes, epithelial cells and keratinocytes undergo necrosis upon cytoplasmic delivery of LPS. LPS-induced cytotoxicity was mediated by human caspase-4 that could functionally complement murine caspase-11. Human caspase-4 and the mouse homologue caspase-11 (hereafter referred to as caspase-4/11) and also human caspase-5, directly bound to LPS and lipid A with high specificity and affinity. LPS associated with endogenous caspase-11 in pyroptotic cells. Insect-cell purified caspase-4/11 underwent oligomerization upon LPS binding, resulting in activation of the caspases. Underacylated lipid IVa and lipopolysaccharide from Rhodobacter sphaeroides (LPS-RS) could bind to caspase-4/11 but failed to induce their oligomerization and activation. LPS binding was mediated by the CARD domain of the caspase. Binding-deficient CARD-domain point mutants did not respond to LPS with oligomerization or activation and failed to induce pyroptosis upon LPS electroporation or bacterial infections. The function of caspase-4/5/11 represents a new mode of pattern recognition in immunity and also an unprecedented means of caspase activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shi, Jianjin -- Zhao, Yue -- Wang, Yupeng -- Gao, Wenqing -- Ding, Jingjin -- Li, Peng -- Hu, Liyan -- Shao, Feng -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):187-92. doi: 10.1038/nature13683. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, Beijing 102206, China [2] National Institute of Biological Sciences, Beijing 102206, China [3]. ; 1] National Institute of Biological Sciences, Beijing 102206, China [2]. ; National Institute of Biological Sciences, Beijing 102206, China. ; 1] National Institute of Biological Sciences, Beijing 102206, China [2] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. ; 1] Peking University-Tsinghua University-National Institute of Biological Sciences Joint Graduate Program, National Institute of Biological Sciences, Beijing 102206, China [2] National Institute of Biological Sciences, Beijing 102206, China [3] National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China [4] National Institute of Biological Sciences, Beijing, Collaborative Innovation Center for Cancer Medicine, Beijing 102206, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119034" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Caspases/chemistry/genetics/immunology/*metabolism ; Caspases, Initiator/chemistry/genetics/immunology/*metabolism ; Cell Death/drug effects ; Cells, Cultured ; Enzyme Activation/drug effects/genetics ; Epithelial Cells/cytology/metabolism ; Genetic Complementation Test ; Humans ; *Immunity, Innate ; Inflammation/enzymology ; Keratinocytes/cytology/metabolism ; Lipid A/metabolism ; Lipopolysaccharides/immunology/*metabolism/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Mice ; Mutant Proteins/chemistry/metabolism ; Necrosis/chemically induced ; Protein Binding ; Protein Multimerization/drug effects/genetics ; Rhodobacter sphaeroides/chemistry/immunology ; Substrate Specificity ; Surface Plasmon Resonance
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 65
    Publication Date: 2014-08-27
    Description: Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Mitri, Diletta -- Toso, Alberto -- Chen, Jing Jing -- Sarti, Manuela -- Pinton, Sandra -- Jost, Tanja Rezzonico -- D'Antuono, Rocco -- Montani, Erica -- Garcia-Escudero, Ramon -- Guccini, Ilaria -- Da Silva-Alvarez, Sabela -- Collado, Manuel -- Eisenberger, Mario -- Zhang, Zhe -- Catapano, Carlo -- Grassi, Fabio -- Alimonti, Andrea -- England -- Nature. 2014 Nov 6;515(7525):134-7. doi: 10.1038/nature13638. Epub 2014 Aug 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2]. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Faculty of Biology and Medicine, University of Lausanne UNIL, Lausanne CH1011, Switzerland. ; Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland. ; Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland. ; 1] Institute of Oncology Research (IOR), Oncology Institute of Southern Switzerland, Bellinzona CH6500, Switzerland [2] Molecular Oncology Unit, CIEMAT, 28040 Madrid, Spain. ; Laboratory of Stem Cells in Cancer and Aging, (stemCHUS) Health Research Institute of Santiago de Compostela (IDIS), Clinical University Hospital (CHUS), E15706 Santiago de Compostela, Spain. ; Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; Divisions of BioStatistics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21231-1000, USA. ; 1] Institute for Research in Biomedicine (IRB), Bellinzona CH6500, Switzerland [2] Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan I-20100, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25156255" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Aging/drug effects ; *Cell Movement ; Disease Progression ; Drug Resistance, Neoplasm ; Humans ; Immunity, Innate ; Interleukin 1 Receptor Antagonist Protein/deficiency/metabolism/secretion ; Interleukin-1alpha/immunology/metabolism ; Male ; Mice ; Myeloid Cells/*cytology/*metabolism/transplantation ; PTEN Phosphohydrolase/deficiency/genetics/metabolism ; Prostatic Neoplasms/drug therapy/immunology/metabolism/*pathology ; Receptors, Chemokine/*metabolism ; Receptors, Interleukin-8B/antagonists & inhibitors ; Taxoids/pharmacology ; Tumor Escape ; Tumor Microenvironment
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  • 66
    Publication Date: 2014-05-13
    Description: The global shortening of messenger RNAs through alternative polyadenylation (APA) that occurs during enhanced cellular proliferation represents an important, yet poorly understood mechanism of regulated gene expression. The 3' untranslated region (UTR) truncation of growth-promoting mRNA transcripts that relieves intrinsic microRNA- and AU-rich-element-mediated repression has been observed to correlate with cellular transformation; however, the importance to tumorigenicity of RNA 3'-end-processing factors that potentially govern APA is unknown. Here we identify CFIm25 as a broad repressor of proximal poly(A) site usage that, when depleted, increases cell proliferation. Applying a regression model on standard RNA-sequencing data for novel APA events, we identified at least 1,450 genes with shortened 3' UTRs after CFIm25 knockdown, representing 11% of significantly expressed mRNAs in human cells. Marked increases in the expression of several known oncogenes, including cyclin D1, are observed as a consequence of CFIm25 depletion. Importantly, we identified a subset of CFIm25-regulated APA genes with shortened 3' UTRs in glioblastoma tumours that have reduced CFIm25 expression. Downregulation of CFIm25 expression in glioblastoma cells enhances their tumorigenic properties and increases tumour size, whereas CFIm25 overexpression reduces these properties and inhibits tumour growth. These findings identify a pivotal role of CFIm25 in governing APA and reveal a previously unknown connection between CFIm25 and glioblastoma tumorigenicity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4128630/" 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/PMC4128630/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Masamha, Chioniso P -- Xia, Zheng -- Yang, Jingxuan -- Albrecht, Todd R -- Li, Min -- Shyu, Ann-Bin -- Li, Wei -- Wagner, Eric J -- CA166274/CA/NCI NIH HHS/ -- CA167752/CA/NCI NIH HHS/ -- GM046454/GM/NIGMS NIH HHS/ -- R01 GM046454/GM/NIGMS NIH HHS/ -- R01 HG007538/HG/NHGRI NIH HHS/ -- R01HG007538/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):412-6. doi: 10.1038/nature13261. Epub 2014 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA [2]. ; 1] Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA [2]. ; The Vivian L. Smith Department of Neurosurgery, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. ; Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, Texas 77030, USA. ; Division of Biostatistics, Dan L Duncan Cancer Center and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030 Texas, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24814343" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions ; Animals ; Carcinogenesis/*genetics/metabolism ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Glioblastoma/*physiopathology ; HeLa Cells ; Heterografts ; Humans ; Male ; Mice ; *Polyadenylation ; RNA, Messenger/*metabolism ; Regression Analysis ; mRNA Cleavage and Polyadenylation Factors/*metabolism
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  • 67
    Publication Date: 2014-06-12
    Description: Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" 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/PMC4112218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viros, Amaya -- Sanchez-Laorden, Berta -- Pedersen, Malin -- Furney, Simon J -- Rae, Joel -- Hogan, Kate -- Ejiama, Sarah -- Girotti, Maria Romina -- Cook, Martin -- Dhomen, Nathalie -- Marais, Richard -- A12738/Cancer Research UK/United Kingdom -- A13540/Cancer Research UK/United Kingdom -- A17240/Cancer Research UK/United Kingdom -- A7091/Cancer Research UK/United Kingdom -- A7192/Cancer Research UK/United Kingdom -- C107/A10433/Cancer Research UK/United Kingdom -- C5759/A12328/Cancer Research UK/United Kingdom -- England -- Nature. 2014 Jul 24;511(7510):478-82. doi: 10.1038/nature13298. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2]. ; 1] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919155" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Transformation, Neoplastic/*genetics/*radiation effects ; DNA Damage/genetics ; Disease Models, Animal ; Female ; Humans ; Melanocytes/metabolism/pathology/radiation effects ; Melanoma/etiology/*genetics/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mutagenesis/genetics/*radiation effects ; Mutation/genetics/radiation effects ; Nevus/etiology/genetics/metabolism/pathology ; Proto-Oncogene Proteins B-raf/*genetics/metabolism ; Skin Neoplasms/etiology/genetics/metabolism/pathology ; Sunburn/complications/etiology/genetics ; Sunscreening Agents/pharmacology ; Tumor Suppressor Protein p53/*genetics/metabolism ; Ultraviolet Rays/*adverse effects
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  • 68
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    Nature Publishing Group (NPG)
    Publication Date: 2014-03-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perrin, Steve -- England -- Nature. 2014 Mar 27;507(7493):423-5.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24678540" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis/genetics/pathology/therapy ; Animals ; Cause of Death ; Clinical Trials as Topic/economics/standards ; *Disease Models, Animal ; Disease Progression ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical/economics/*methods/*standards ; False Positive Reactions ; Guidelines as Topic ; Half-Life ; Humans ; Mice ; Organ Specificity ; Reproducibility of Results ; *Research Design ; Superoxide Dismutase/deficiency/genetics/metabolism ; Survival Analysis ; Translational Medical Research/economics/*methods/*standards ; Treatment Failure
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  • 69
    Publication Date: 2014-01-28
    Description: The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117212/" 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/PMC4117212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Westphalen, Kristin -- Gusarova, Galina A -- Islam, Mohammad N -- Subramanian, Manikandan -- Cohen, Taylor S -- Prince, Alice S -- Bhattacharya, Jahar -- HL57556/HL/NHLBI NIH HHS/ -- HL64896/HL/NHLBI NIH HHS/ -- HL73989/HL/NHLBI NIH HHS/ -- HL78645/HL/NHLBI NIH HHS/ -- R01 HL057556/HL/NHLBI NIH HHS/ -- R01 HL064896/HL/NHLBI NIH HHS/ -- R01 HL073989/HL/NHLBI NIH HHS/ -- R01 HL078645/HL/NHLBI NIH HHS/ -- R01 HL079395/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):503-6. doi: 10.1038/nature12902. Epub 2014 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463523" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bronchoalveolar Lavage Fluid/immunology ; Calcium/metabolism ; Cell Adhesion ; *Cell Communication ; Connexin 43/deficiency/genetics/metabolism ; Cytokines/immunology/secretion ; Female ; Gap Junctions/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages, Alveolar/*cytology/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophil Infiltration ; Neutrophils/immunology ; Pneumonia/chemically induced/immunology/pathology ; Pulmonary Alveoli/*cytology/*immunology ; Respiratory Mucosa/*cytology/*immunology
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  • 70
    Publication Date: 2014-10-03
    Description: Systemic infection induces conserved physiological responses that include both resistance and 'tolerance of infection' mechanisms. Temporary anorexia associated with an infection is often beneficial, reallocating energy from food foraging towards resistance to infection or depriving pathogens of nutrients. However, it imposes a stress on intestinal commensals, as they also experience reduced substrate availability; this affects host fitness owing to the loss of caloric intake and colonization resistance (protection from additional infections). We hypothesized that the host might utilize internal resources to support the gut microbiota during the acute phase of the disease. Here we show that systemic exposure to Toll-like receptor (TLR) ligands causes rapid alpha(1,2)-fucosylation of small intestine epithelial cells (IECs) in mice, which requires the sensing of TLR agonists, as well as the production of interleukin (IL)-23 by dendritic cells, activation of innate lymphoid cells and expression of fucosyltransferase 2 (Fut2) by IL-22-stimulated IECs. Fucosylated proteins are shed into the lumen and fucose is liberated and metabolized by the gut microbiota, as shown by reporter bacteria and community-wide analysis of microbial gene expression. Fucose affects the expression of microbial metabolic pathways and reduces the expression of bacterial virulence genes. It also improves host tolerance of the mild pathogen Citrobacter rodentium. Thus, rapid IEC fucosylation appears to be a protective mechanism that utilizes the host's resources to maintain host-microbial interactions during pathogen-induced stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4214913/" 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/PMC4214913/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pickard, Joseph M -- Maurice, Corinne F -- Kinnebrew, Melissa A -- Abt, Michael C -- Schenten, Dominik -- Golovkina, Tatyana V -- Bogatyrev, Said R -- Ismagilov, Rustem F -- Pamer, Eric G -- Turnbaugh, Peter J -- Chervonsky, Alexander V -- AI42135/AI/NIAID NIH HHS/ -- AI96706/AI/NIAID NIH HHS/ -- DK42086/DK/NIDDK NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- P50 GM068763/GM/NIGMS NIH HHS/ -- R01 AI090084/AI/NIAID NIH HHS/ -- R01 AI095706/AI/NIAID NIH HHS/ -- T32 AI007090/AI/NIAID NIH HHS/ -- T32 AI065382/AI/NIAID NIH HHS/ -- T32 GM007739/GM/NIGMS NIH HHS/ -- UL1 TR000430/TR/NCATS NIH HHS/ -- England -- Nature. 2014 Oct 30;514(7524):638-41. doi: 10.1038/nature13823. Epub 2014 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Committee on Immunology, The University of Chicago, Chicago, Illinois 60637, USA. ; FAS Center for Systems Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; The University of Arizona, Tucson, Arizona 85721, USA. ; Department of Microbiology, The University of Chicago, Chicago, Illinois 60637, USA. ; California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274297" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anorexia/complications/microbiology ; Bacteria/genetics/metabolism/pathogenicity ; Citrobacter rodentium/immunology ; Dendritic Cells/immunology/metabolism ; *Disease ; Eating ; Epithelium/*metabolism/*microbiology ; Fatty Acids/chemistry/metabolism ; Female ; Fucose/*metabolism ; Fucosyltransferases/metabolism ; Gene Expression Regulation, Bacterial ; Glycosylation ; Immune Tolerance ; Immunity, Innate ; Interleukins/biosynthesis/immunology ; Intestine, Small/*metabolism/*microbiology ; Ligands ; Male ; Metabolic Networks and Pathways/genetics ; Mice ; Microbiota/physiology ; Protective Factors ; *Symbiosis ; Toll-Like Receptors/agonists/immunology/metabolism ; Virulence Factors/genetics
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  • 71
    Publication Date: 2014-04-11
    Description: The BRAF kinase is mutated, typically Val 600--〉Glu (V600E), to induce an active oncogenic state in a large fraction of melanomas, thyroid cancers, hairy cell leukaemias and, to a smaller extent, a wide spectrum of other cancers. BRAF(V600E) phosphorylates and activates the MEK1 and MEK2 kinases, which in turn phosphorylate and activate the ERK1 and ERK2 kinases, stimulating the mitogen-activated protein kinase (MAPK) pathway to promote cancer. Targeting MEK1/2 is proving to be an important therapeutic strategy, given that a MEK1/2 inhibitor provides a survival advantage in metastatic melanoma, an effect that is increased when administered together with a BRAF(V600E) inhibitor. We previously found that copper (Cu) influx enhances MEK1 phosphorylation of ERK1/2 through a Cu-MEK1 interaction. Here we show decreasing the levels of CTR1 (Cu transporter 1), or mutations in MEK1 that disrupt Cu binding, decreased BRAF(V600E)-driven signalling and tumorigenesis in mice and human cell settings. Conversely, a MEK1-MEK5 chimaera that phosphorylated ERK1/2 independently of Cu or an active ERK2 restored the tumour growth of murine cells lacking Ctr1. Cu chelators used in the treatment of Wilson disease decreased tumour growth of human or murine cells transformed by BRAF(V600E) or engineered to be resistant to BRAF inhibition. Taken together, these results suggest that Cu-chelation therapy could be repurposed to treat cancers containing the BRAF(V600E) mutation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138975/" 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/PMC4138975/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Brady, Donita C -- Crowe, Matthew S -- Turski, Michelle L -- Hobbs, G Aaron -- Yao, Xiaojie -- Chaikuad, Apirat -- Knapp, Stefan -- Xiao, Kunhong -- Campbell, Sharon L -- Thiele, Dennis J -- Counter, Christopher M -- 092809/Wellcome Trust/United Kingdom -- 092809/Z/10/Z/Wellcome Trust/United Kingdom -- CA094184/CA/NCI NIH HHS/ -- CA172104/CA/NCI NIH HHS/ -- CA178145/CA/NCI NIH HHS/ -- DK074192/DK/NIDDK NIH HHS/ -- HL075443/HL/NHLBI NIH HHS/ -- K01 CA178145/CA/NCI NIH HHS/ -- P01 HL075443/HL/NHLBI NIH HHS/ -- P30 CA014236/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- R01 CA089614/CA/NCI NIH HHS/ -- R01 CA094184/CA/NCI NIH HHS/ -- R01 DK074192/DK/NIDDK NIH HHS/ -- R21 CA172104/CA/NCI NIH HHS/ -- T32 GM007184/GM/NIGMS NIH HHS/ -- T32 GM008570/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 May 22;509(7501):492-6. doi: 10.1038/nature13180. Epub 2014 Apr 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Nuffield Department of Clinical Medicine, Target Discovery Institute and Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK. ; 1] Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717435" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cation Transport Proteins/deficiency/genetics ; Cell Line, Tumor ; *Cell Transformation, Neoplastic/drug effects ; Chelating Agents/pharmacology/therapeutic use ; Copper/*metabolism/pharmacology ; Disease Models, Animal ; Drug Repositioning ; Drug Resistance, Neoplasm/drug effects ; Female ; Hepatolenticular Degeneration/drug therapy ; Humans ; Indoles/pharmacology ; Lung Neoplasms/drug therapy/genetics/metabolism/pathology ; *MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Mitogen-Activated Protein Kinase Kinases/antagonists & ; inhibitors/genetics/metabolism ; Phosphorylation/drug effects ; Proto-Oncogene Proteins B-raf/antagonists & inhibitors/genetics/*metabolism ; Sulfonamides/pharmacology ; Survival Analysis
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  • 72
    Publication Date: 2014-11-20
    Description: Intestinal microbial communities have profound effects on host physiology. Whereas the symbiotic contribution of commensal bacteria is well established, the role of eukaryotic viruses that are present in the gastrointestinal tract under homeostatic conditions is undefined. Here we demonstrate that a common enteric RNA virus can replace the beneficial function of commensal bacteria in the intestine. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice restored intestinal morphology and lymphocyte function without inducing overt inflammation and disease. The presence of MNV also suppressed an expansion of group 2 innate lymphoid cells observed in the absence of bacteria, and induced transcriptional changes in the intestine associated with immune development and type I interferon (IFN) signalling. Consistent with this observation, the IFN-alpha receptor was essential for the ability of MNV to compensate for bacterial depletion. Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection. These data indicate that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similarly to commensal bacteria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257755/" 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/PMC4257755/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kernbauer, Elisabeth -- Ding, Yi -- Cadwell, Ken -- J 3435/Austrian Science Fund FWF/Austria -- P30CA016087/CA/NCI NIH HHS/ -- R01 DK093668/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):94-8. doi: 10.1038/nature13960. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA [2] Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA. ; 1] New York Presbyterian Hospital, New York, New York 10065, USA [2] Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Bacterial Physiological Phenomena/*immunology ; Citrobacter rodentium/physiology ; Enterobacteriaceae Infections/immunology ; Enterovirus/immunology/*physiology ; Female ; Gene Expression Profiling ; Gene Expression Regulation/immunology ; Immunity, Innate/immunology ; Immunity, Mucosal/*immunology ; Interferon Type I/immunology ; Intestinal Mucosa/cytology/drug effects/*immunology/*virology ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Norovirus/immunology/physiology ; Signal Transduction/immunology ; Specific Pathogen-Free Organisms
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  • 73
    Publication Date: 2014-06-12
    Description: High-throughput single-cell transcriptomics offers an unbiased approach for understanding the extent, basis and function of gene expression variation between seemingly identical cells. Here we sequence single-cell RNA-seq libraries prepared from over 1,700 primary mouse bone-marrow-derived dendritic cells spanning several experimental conditions. We find substantial variation between identically stimulated dendritic cells, in both the fraction of cells detectably expressing a given messenger RNA and the transcript's level within expressing cells. Distinct gene modules are characterized by different temporal heterogeneity profiles. In particular, a 'core' module of antiviral genes is expressed very early by a few 'precocious' cells in response to uniform stimulation with a pathogenic component, but is later activated in all cells. By stimulating cells individually in sealed microfluidic chambers, analysing dendritic cells from knockout mice, and modulating secretion and extracellular signalling, we show that this response is coordinated by interferon-mediated paracrine signalling from these precocious cells. Notably, preventing cell-to-cell communication also substantially reduces variability between cells in the expression of an early-induced 'peaked' inflammatory module, suggesting that paracrine signalling additionally represses part of the inflammatory program. Our study highlights the importance of cell-to-cell communication in controlling cellular heterogeneity and reveals general strategies that multicellular populations can use to establish complex dynamic responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4193940/" 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/PMC4193940/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shalek, Alex K -- Satija, Rahul -- Shuga, Joe -- Trombetta, John J -- Gennert, Dave -- Lu, Diana -- Chen, Peilin -- Gertner, Rona S -- Gaublomme, Jellert T -- Yosef, Nir -- Schwartz, Schraga -- Fowler, Brian -- Weaver, Suzanne -- Wang, Jing -- Wang, Xiaohui -- Ding, Ruihua -- Raychowdhury, Raktima -- Friedman, Nir -- Hacohen, Nir -- Park, Hongkun -- May, Andrew P -- Regev, Aviv -- 1F32HD075541-01/HD/NICHD NIH HHS/ -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003893-03/OD/NIH HHS/ -- DP1 CA174427/CA/NCI NIH HHS/ -- DP1OD003958-01/OD/NIH HHS/ -- F32 HD075541/HD/NICHD NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 19;510(7505):363-9. doi: 10.1038/nature13437. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA [3] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [4]. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2]. ; 1] Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA [2]. ; Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Fluidigm Corporation, 7000 Shoreline Court, Suite 100, South San Francisco, California 94080, USA. ; 1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA. ; School of Computer Science and Engineering, Hebrew University, 91904 Jerusalem, Israel. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Center for Immunology and Inflammatory Diseases & Department of Medicine, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA. ; 1] Department of Chemistry & Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA [2] Department of Physics, Harvard University, 17 Oxford Street, Cambridge, Massachusetts 02138, USA [3] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02140, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919153" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Viral/pharmacology ; Base Sequence ; Cell Communication ; Dendritic Cells/drug effects/*immunology ; Gene Expression Profiling ; Gene Expression Regulation/*immunology ; Immunity/*genetics ; Interferon-beta/genetics ; Mice ; Microfluidic Analytical Techniques ; *Paracrine Communication ; Principal Component Analysis ; RNA, Messenger/chemistry/genetics ; Single-Cell Analysis
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  • 74
    Publication Date: 2014-08-28
    Description: The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169316/" 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/PMC4169316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redondo, Roger L -- Kim, Joshua -- Arons, Autumn L -- Ramirez, Steve -- Liu, Xu -- Tonegawa, Susumu -- P50 MH058880/MH/NIMH NIH HHS/ -- R01 MH078821/MH/NIMH NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 18;513(7518):426-30. doi: 10.1038/nature13725. Epub 2014 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3]. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2]. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25162525" target="_blank"〉PubMed〈/a〉
    Keywords: Affect ; Amygdala/physiology ; Animals ; Avoidance Learning ; Conditioning, Classical/physiology ; Cues ; Dentate Gyrus/physiology ; Fear ; Female ; Hippocampus/*physiology ; Male ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity/physiology ; Optogenetics ; Reward
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  • 75
    Publication Date: 2014-04-11
    Description: How we sense touch remains fundamentally unknown. The Merkel cell-neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Abeta sensory fibres to encode fine details of objects. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago. However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown. Synapse-like junctions are observed between Merkel cells and associated afferents, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel-cell mechanosensitivity completely depends on Piezo2. In these mice, slowly adapting responses in vivo mediated by the Merkel cell-neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4039622/" 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/PMC4039622/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Woo, Seung-Hyun -- Ranade, Sanjeev -- Weyer, Andy D -- Dubin, Adrienne E -- Baba, Yoshichika -- Qiu, Zhaozhu -- Petrus, Matt -- Miyamoto, Takashi -- Reddy, Kritika -- Lumpkin, Ellen A -- Stucky, Cheryl L -- Patapoutian, Ardem -- P30 AR044535/AR/NIAMS NIH HHS/ -- R01 AR051219/AR/NIAMS NIH HHS/ -- R01 DE022358/DE/NIDCR NIH HHS/ -- R01 NS040538/NS/NINDS NIH HHS/ -- R01AR051219/AR/NIAMS NIH HHS/ -- R01DE022358/DE/NIDCR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 29;509(7502):622-6. doi: 10.1038/nature13251. Epub 2014 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA. ; Departments of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. ; Departments of Dermatology & Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA. ; 1] Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA [2] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; 1] Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA [2] Gladstone Institute of Neurological Disease, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717433" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Electric Conductivity ; Female ; In Vitro Techniques ; Ion Channels/deficiency/genetics/*metabolism ; Male ; *Mechanotransduction, Cellular/genetics ; Merkel Cells/*metabolism ; Mice ; Mice, Knockout ; Neurites/metabolism ; Neurons, Afferent/metabolism ; Skin/cytology/innervation ; Touch/genetics/*physiology
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  • 76
    Publication Date: 2014-10-14
    Description: The semi-conservative centrosome duplication in cycling cells gives rise to a centrosome composed of a mother and a newly formed daughter centriole. Both centrioles are regarded as equivalent in their ability to form new centrioles and their symmetric duplication is crucial for cell division homeostasis. Multiciliated cells do not use the archetypal duplication program and instead form more than a hundred centrioles that are required for the growth of motile cilia and the efficient propelling of physiological fluids. The majority of these new centrioles are thought to appear de novo, that is, independently from the centrosome, around electron-dense structures called deuterosomes. Their origin remains unknown. Using live imaging combined with correlative super-resolution light and electron microscopy, we show that all new centrioles derive from the pre-existing progenitor cell centrosome through multiple rounds of procentriole seeding. Moreover, we establish that only the daughter centrosomal centriole contributes to deuterosome formation, and thus to over ninety per cent of the final centriole population. This unexpected centriolar asymmetry grants new perspectives when studying cilia-related diseases and pathological centriole amplification observed in cycling cells and associated with microcephaly and cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Al Jord, Adel -- Lemaitre, Anne-Iris -- Delgehyr, Nathalie -- Faucourt, Marion -- Spassky, Nathalie -- Meunier, Alice -- England -- Nature. 2014 Dec 4;516(7529):104-7. doi: 10.1038/nature13770. Epub 2014 Oct 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Ecole Normale Superieure, Institut de Biologie de l'ENS, IBENS, F-75005 Paris, France [2] Inserm, U1024, F-75005 Paris, France [3] CNRS, UMR 8197, F-75005 Paris, France. ; 1] Ecole Normale Superieure, Institut de Biologie de l'ENS, IBENS, F-75005 Paris, France [2] Inserm, U1024, F-75005 Paris, France [3] CNRS, UMR 8197, F-75005 Paris, France [4].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25307055" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Centrioles/*physiology/ultrastructure ; Centrosome/*physiology/ultrastructure ; Cilia/*physiology/ultrastructure ; Mice ; Microscopy, Electron, Transmission
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  • 77
    Publication Date: 2014-08-15
    Description: The pluripotency factor Lin28 inhibits the biogenesis of the let-7 family of mammalian microRNAs. Lin28 is highly expressed in embryonic stem cells and has a fundamental role in regulation of development, glucose metabolism and tissue regeneration. Overexpression of Lin28 is correlated with the onset of numerous cancers, whereas let-7, a tumour suppressor, silences several human oncogenes. Lin28 binds to precursor let-7 (pre-let-7) hairpins, triggering the 3' oligo-uridylation activity of TUT4 and TUT7 (refs 10-12). The oligoU tail added to pre-let-7 serves as a decay signal, as it is rapidly degraded by Dis3l2 (refs 13, 14), a homologue of the catalytic subunit of the RNA exosome. The molecular basis of Lin28-mediated recruitment of TUT4 and TUT7 to pre-let-7 and its subsequent degradation by Dis3l2 is largely unknown. To examine the mechanism of Dis3l2 substrate recognition we determined the structure of mouse Dis3l2 in complex with an oligoU RNA to mimic the uridylated tail of pre-let-7. Three RNA-binding domains form an open funnel on one face of the catalytic domain that allows RNA to navigate a path to the active site different from that of its exosome counterpart. The resulting path reveals an extensive network of uracil-specific interactions spanning the first 12 nucleotides of an oligoU-tailed RNA. We identify three U-specificity zones that explain how Dis3l2 recognizes, binds and processes uridylated pre-let-7 in the final step of the Lin28-let-7 pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4192074/" 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/PMC4192074/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faehnle, Christopher R -- Walleshauser, Jack -- Joshua-Tor, Leemor -- P30 CA045508/CA/NCI NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- T32 GM065094/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Oct 9;514(7521):252-6. doi: 10.1038/nature13553. Epub 2014 Aug 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3]. ; 1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3] Watson School of Biological Science, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA [4]. ; 1] W. M. Keck Structural Biology Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [2] Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA [3] Watson School of Biological Science, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA [4] Howard Hughes Medical Institute, Cold Spring Harbor, 1 Bungtown Road, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119025" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Catalytic Domain ; Crystallography, X-Ray ; Exoribonucleases/*chemistry/*metabolism ; Exosome Multienzyme Ribonuclease Complex/chemistry ; Mice ; MicroRNAs/chemistry/genetics/*metabolism ; Models, Molecular ; Oligoribonucleotides/chemistry/metabolism ; RNA-Binding Proteins/chemistry/*metabolism ; Schizosaccharomyces pombe Proteins/chemistry ; Substrate Specificity ; Uracil Nucleotides/chemistry/metabolism
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  • 78
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    Nature Publishing Group (NPG)
    Publication Date: 2014-04-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2014 Apr 10;508(7495):158-9. doi: 10.1038/508158a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717486" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/therapeutic use ; Citric Acid Cycle/genetics ; Clinical Trials as Topic ; Glucose/metabolism ; Glutarates/metabolism ; Humans ; Isocitrate Dehydrogenase/antagonists & inhibitors/genetics/metabolism ; *Metabolic Networks and Pathways/genetics ; Mice ; Neoplasms/*drug therapy/enzymology/genetics/*metabolism ; Pyruvate Kinase/antagonists & inhibitors/metabolism
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  • 79
    Publication Date: 2014-05-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayden, Erika Check -- England -- Nature. 2014 May 8;509(7499):146. doi: 10.1038/509146a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805325" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Drug Industry/economics/organization & administration ; Humans ; Mice ; *Technology Transfer ; Translational Medical Research/economics/organization & administration ; Universities/*economics/*organization & administration
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  • 80
    Publication Date: 2014-11-28
    Description: The immune system influences the fate of developing cancers by not only functioning as a tumour promoter that facilitates cellular transformation, promotes tumour growth and sculpts tumour cell immunogenicity, but also as an extrinsic tumour suppressor that either destroys developing tumours or restrains their expansion. Yet, clinically apparent cancers still arise in immunocompetent individuals in part as a consequence of cancer-induced immunosuppression. In many individuals, immunosuppression is mediated by cytotoxic T-lymphocyte associated antigen-4 (CTLA-4) and programmed death-1 (PD-1), two immunomodulatory receptors expressed on T cells. Monoclonal-antibody-based therapies targeting CTLA-4 and/or PD-1 (checkpoint blockade) have yielded significant clinical benefits-including durable responses--to patients with different malignancies. However, little is known about the identity of the tumour antigens that function as the targets of T cells activated by checkpoint blockade immunotherapy and whether these antigens can be used to generate vaccines that are highly tumour-specific. Here we use genomics and bioinformatics approaches to identify tumour-specific mutant proteins as a major class of T-cell rejection antigens following anti-PD-1 and/or anti-CTLA-4 therapy of mice bearing progressively growing sarcomas, and we show that therapeutic synthetic long-peptide vaccines incorporating these mutant epitopes induce tumour rejection comparably to checkpoint blockade immunotherapy. Although mutant tumour-antigen-specific T cells are present in progressively growing tumours, they are reactivated following treatment with anti-PD-1 and/or anti-CTLA-4 and display some overlapping but mostly treatment-specific transcriptional profiles, rendering them capable of mediating tumour rejection. These results reveal that tumour-specific mutant antigens are not only important targets of checkpoint blockade therapy, but they can also be used to develop personalized cancer-specific vaccines and to probe the mechanistic underpinnings of different checkpoint blockade treatments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279952/" 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/PMC4279952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gubin, Matthew M -- Zhang, Xiuli -- Schuster, Heiko -- Caron, Etienne -- Ward, Jeffrey P -- Noguchi, Takuro -- Ivanova, Yulia -- Hundal, Jasreet -- Arthur, Cora D -- Krebber, Willem-Jan -- Mulder, Gwenn E -- Toebes, Mireille -- Vesely, Matthew D -- Lam, Samuel S K -- Korman, Alan J -- Allison, James P -- Freeman, Gordon J -- Sharpe, Arlene H -- Pearce, Erika L -- Schumacher, Ton N -- Aebersold, Ruedi -- Rammensee, Hans-Georg -- Melief, Cornelis J M -- Mardis, Elaine R -- Gillanders, William E -- Artyomov, Maxim N -- Schreiber, Robert D -- P01 AI054456/AI/NIAID NIH HHS/ -- P30 AR048335/AR/NIAMS NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30 CA091842/CA/NCI NIH HHS/ -- P50 CA101942/CA/NCI NIH HHS/ -- R01 AI091965/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- R01 CA190700/CA/NCI NIH HHS/ -- R37 CA043059/CA/NCI NIH HHS/ -- T32 CA009547/CA/NCI NIH HHS/ -- T32 CA00954729/CA/NCI NIH HHS/ -- U01 CA141541/CA/NCI NIH HHS/ -- England -- Nature. 2014 Nov 27;515(7528):577-81. doi: 10.1038/nature13988.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; Department of Surgery, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; Department of Immunology, Institute of Cell Biology, and German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ) Partner Site Tubingen, Auf der Morgenstelle 15, 72076 Tubingen, Germany. ; Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland. ; 1] Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA [2] Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA. ; The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA. ; ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands. ; Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands. ; Bristol-Myers Squibb, 700 Bay Road, Redwood City, California 94063, USA. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Biology, Institute of Molecular Systems Biology, ETH Zurich, 8093 Zurich, Switzerland [2] Faculty of Science, University of Zurich, Zurich, 8093 Zurich, Switzerland. ; 1] ISA Therapeutics B.V., 2333 CH Leiden, The Netherlands [2] Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, 2333ZA Leiden, The Netherlands. ; 1] The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA [2] Department of Genetics, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428507" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Monoclonal/*therapeutic use ; Antigens, Neoplasm/*genetics/*immunology ; CD8-Positive T-Lymphocytes/*immunology ; Cancer Vaccines/*therapeutic use ; Cell Cycle Checkpoints/*immunology ; Epitopes/genetics ; *Immunotherapy ; Male ; Mice ; Sarcoma/immunology/*therapy ; Vaccines, Synthetic/therapeutic use
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  • 81
    Publication Date: 2014-07-18
    Description: Corneal epithelial homeostasis and regeneration are sustained by limbal stem cells (LSCs), and LSC deficiency is a major cause of blindness worldwide. Transplantation is often the only therapeutic option available to patients with LSC deficiency. However, while transplant success depends foremost on LSC frequency within grafts, a gene allowing for prospective LSC enrichment has not been identified so far. Here we show that ATP-binding cassette, sub-family B, member 5 (ABCB5) marks LSCs and is required for LSC maintenance, corneal development and repair. Furthermore, we demonstrate that prospectively isolated human or murine ABCB5-positive LSCs possess the exclusive capacity to fully restore the cornea upon grafting to LSC-deficient mice in xenogeneic or syngeneic transplantation models. ABCB5 is preferentially expressed on label-retaining LSCs in mice and p63alpha-positive LSCs in humans. Consistent with these findings, ABCB5-positive LSC frequency is reduced in LSC-deficient patients. Abcb5 loss of function in Abcb5 knockout mice causes depletion of quiescent LSCs due to enhanced proliferation and apoptosis, and results in defective corneal differentiation and wound healing. Our results from gene knockout studies, LSC tracing and transplantation models, as well as phenotypic and functional analyses of human biopsy specimens, provide converging lines of evidence that ABCB5 identifies mammalian LSCs. Identification and prospective isolation of molecularly defined LSCs with essential functions in corneal development and repair has important implications for the treatment of corneal disease, particularly corneal blindness due to LSC deficiency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4246512/" 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/PMC4246512/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ksander, Bruce R -- Kolovou, Paraskevi E -- Wilson, Brian J -- Saab, Karim R -- Guo, Qin -- Ma, Jie -- McGuire, Sean P -- Gregory, Meredith S -- Vincent, William J B -- Perez, Victor L -- Cruz-Guilloty, Fernando -- Kao, Winston W Y -- Call, Mindy K -- Tucker, Budd A -- Zhan, Qian -- Murphy, George F -- Lathrop, Kira L -- Alt, Clemens -- Mortensen, Luke J -- Lin, Charles P -- Zieske, James D -- Frank, Markus H -- Frank, Natasha Y -- DP2 OD007483/OD/NIH HHS/ -- DP2OD007483/OD/NIH HHS/ -- EY08098/EY/NEI NIH HHS/ -- I01 BX000516/BX/BLRD VA/ -- I01 RX000989/RX/RRD VA/ -- K08 NS051349/NS/NINDS NIH HHS/ -- K08NS051349/NS/NINDS NIH HHS/ -- P30 EY014801/EY/NEI NIH HHS/ -- P30EY014801/EY/NEI NIH HHS/ -- P41EB015903/EB/NIBIB NIH HHS/ -- R01 CA113796/CA/NCI NIH HHS/ -- R01 CA138231/CA/NCI NIH HHS/ -- R01 CA158467/CA/NCI NIH HHS/ -- R01 EB017274/EB/NIBIB NIH HHS/ -- R01CA113796/CA/NCI NIH HHS/ -- R01CA138231/CA/NCI NIH HHS/ -- R01CA158467/CA/NCI NIH HHS/ -- R01EY018624/EY/NEI NIH HHS/ -- R01EY021768/EY/NEI NIH HHS/ -- U01HL100402/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 17;511(7509):353-7. doi: 10.1038/nature13426. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA [2]. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA [2] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Ophthalmology, Schepens Eye Research Institute, Massachusetts Eye & Ear Infirmary and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Bascom Palmer Eye Institute and the Department of Ophthalmology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA. ; Department of Ophthalmology, University of Cincinnati Medical Center, Cincinnati, Ohio 45229, USA. ; Stephen A Wynn Institute for Vision Research, Carver College of Medicine, Department of Ophthalmology and Visual Sciences, University of Iowa, Iowa City, Iowa 52242, USA. ; Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. ; Department of Ophthalmology, University of Pittsburgh School of Medicine & Department of Bioengineering, University of Pittsburgh Swanson School of Engineering, Pittsburgh, Pennsylvania 15213, USA. ; Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA [4]. ; 1] Department of Medicine, VA Boston Healthcare System, Boston, Massachusetts 02130, USA [2] Transplant Research Program, Division of Nephrology, Boston Children's Hospital, Boston, Massachusetts 02115, USA [3] Harvard Stem Cell Institute, Harvard Medical School, Boston, Massachusetts 02138, USA [4] Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [5].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25030174" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/deficiency/*metabolism ; Animals ; Apoptosis ; Biomarkers/metabolism ; Cell Differentiation ; Cell Proliferation ; Female ; Humans ; Limbus Corneae/*cytology/*physiology ; Male ; Mice ; Mice, Knockout ; Molecular Sequence Data ; P-Glycoprotein/deficiency/*metabolism ; *Regeneration ; Stem Cell Transplantation ; Stem Cells/cytology/*metabolism ; Transcription Factors/metabolism ; Tumor Suppressor Proteins/metabolism ; *Wound Healing
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  • 82
    Publication Date: 2014-05-09
    Description: During immune responses, B lymphocytes clonally expand and undergo secondary diversification of their immunoglobulin genes in germinal centres (GCs). High-affinity B cells are expanded through iterative interzonal cycles of division and hypermutation in the GC dark zone followed by migration to the GC light zone, where they are selected on the basis of affinity to return to the dark zone. Here we combine a transgenic strategy to measure cell division and a photoactivatable fluorescent reporter to examine whether the extent of clonal expansion and hypermutation are regulated during interzonal GC cycles. We find that both cell division and hypermutation are directly proportional to the amount of antigen captured and presented by GC B cells to follicular helper T cells in the light zone. Our data explain how GC B cells with the highest affinity for antigen are selectively expanded and diversified.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271732/" 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/PMC4271732/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gitlin, Alexander D -- Shulman, Ziv -- Nussenzweig, Michel C -- 1UM1 AI100663-01/AI/NIAID NIH HHS/ -- AI037526-19/AI/NIAID NIH HHS/ -- AI072529-06/AI/NIAID NIH HHS/ -- R01 AI037526/AI/NIAID NIH HHS/ -- R01 AI072529/AI/NIAID NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- UM1 AI100663/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 29;509(7502):637-40. doi: 10.1038/nature13300. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA. ; 1] Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10065, USA [2] Howard Hughes Medical Institute, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805232" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Affinity/immunology ; Antigen Presentation/immunology ; Antigens/immunology ; B-Lymphocytes/*cytology/immunology/*metabolism ; Cell Movement ; Cell Proliferation ; *Clonal Selection, Antigen-Mediated/immunology ; Clone Cells/cytology/immunology/metabolism ; Genes, Reporter/genetics ; Germinal Center/*cytology/*immunology ; Male ; Mice ; S Phase ; Somatic Hypermutation, Immunoglobulin/*genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology ; Time Factors
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  • 83
    Publication Date: 2014-07-06
    Description: Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayer-Barber, Katrin D -- Andrade, Bruno B -- Oland, Sandra D -- Amaral, Eduardo P -- Barber, Daniel L -- Gonzales, Jacqueline -- Derrick, Steven C -- Shi, Ruiru -- Kumar, Nathella Pavan -- Wei, Wang -- Yuan, Xing -- Zhang, Guolong -- Cai, Ying -- Babu, Subash -- Catalfamo, Marta -- Salazar, Andres M -- Via, Laura E -- Barry, Clifton E 3rd -- Sher, Alan -- Intramural NIH HHS/ -- England -- Nature. 2014 Jul 3;511(7507):99-103. doi: 10.1038/nature13489. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; 1] Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Department of Immunology, Biomedical Sciences Institutes, University of Sao Paulo, 05508-900 Sao Paulo, Brazil. ; T Lymphocyte Biology Unit, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. ; Henan Chest Hospital, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] National Institute for Research in Tuberculosis (NIRT), 600 031 Chennai, India. ; Sino-US International Research Center for Tuberculosis, and Henan Public Health Center, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] Helminth Immunology Section, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Oncovir Inc., Washington, Washington DC 20008, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990750" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dinoprostone/antagonists & inhibitors/biosynthesis/metabolism ; Disease Models, Animal ; Female ; Humans ; Immunity, Innate/immunology ; *Immunotherapy ; Interferon Type I/antagonists & inhibitors/biosynthesis/*immunology ; Interleukin-1/*immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/*immunology ; Tuberculosis, Pulmonary/*immunology/microbiology/*therapy
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  • 84
    Publication Date: 2014-04-30
    Description: Replication fork stalling can promote genomic instability, predisposing to cancer and other diseases. Stalled replication forks may be processed by sister chromatid recombination (SCR), generating error-free or error-prone homologous recombination (HR) outcomes. In mammalian cells, a long-standing hypothesis proposes that the major hereditary breast/ovarian cancer predisposition gene products, BRCA1 and BRCA2, control HR/SCR at stalled replication forks. Although BRCA1 and BRCA2 affect replication fork processing, direct evidence that BRCA gene products regulate homologous recombination at stalled chromosomal replication forks is lacking, due to a dearth of tools for studying this process. Here we report that the Escherichia coli Tus/Ter complex can be engineered to induce site-specific replication fork stalling and chromosomal HR/SCR in mouse cells. Tus/Ter-induced homologous recombination entails processing of bidirectionally arrested forks. We find that the Brca1 carboxy (C)-terminal tandem BRCT repeat and regions of Brca1 encoded by exon 11-two Brca1 elements implicated in tumour suppression-control Tus/Ter-induced homologous recombination. Inactivation of either Brca1 or Brca2 increases the absolute frequency of 'long-tract' gene conversions at Tus/Ter-stalled forks, an outcome not observed in response to a site-specific endonuclease-mediated chromosomal double-strand break. Therefore, homologous recombination at stalled forks is regulated differently from homologous recombination at double-strand breaks arising independently of a replication fork. We propose that aberrant long-tract homologous recombination at stalled replication forks contributes to genomic instability and breast/ovarian cancer predisposition in BRCA mutant cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118467/" 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/PMC4118467/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Willis, Nicholas A -- Chandramouly, Gurushankar -- Huang, Bin -- Kwok, Amy -- Follonier, Cindy -- Deng, Chuxia -- Scully, Ralph -- 5T32CA081156/CA/NCI NIH HHS/ -- R01 CA095175/CA/NCI NIH HHS/ -- R01 GM026938/GM/NIGMS NIH HHS/ -- R01 GM043265/GM/NIGMS NIH HHS/ -- R01 GM073894/GM/NIGMS NIH HHS/ -- R01CA095175/CA/NCI NIH HHS/ -- R01GM073894/GM/NIGMS NIH HHS/ -- R21 CA144017/CA/NCI NIH HHS/ -- R21CA144017/CA/NCI NIH HHS/ -- R37 GM026938/GM/NIGMS NIH HHS/ -- R37GM26938/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Jun 26;510(7506):556-9. doi: 10.1038/nature13295. Epub 2014 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. ; 1] Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Temple University, 1801 North Broad Street, Philadelphia, Pennsylvania 19122, USA (G.C.); Brandeis University, 415 South Street, Waltham, Massachusetts 02453, USA (B.H.); University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, Massachusetts 01655, USA (A.K.). ; Princeton University, 101 Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA. ; NIDDK, National Institutes of Health, Building 10, Room 9N105, 10 Center Drive, Bethesda, Maryland 20814, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24776801" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; BRCA1 Protein/chemistry/genetics/*metabolism ; BRCA2 Protein/genetics/metabolism ; DNA Breaks, Double-Stranded ; *DNA Replication ; Escherichia coli/genetics ; Escherichia coli Proteins/genetics/*metabolism ; Exons/genetics ; Gene Conversion/genetics ; Genomic Instability/genetics ; Hereditary Breast and Ovarian Cancer Syndrome/genetics ; *Homologous Recombination ; Mice
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  • 85
    facet.materialart.
    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2014-03-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2014 Feb 27;506(7489):407.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24579097" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Welfare/ethics/*standards ; Animals ; Animals, Laboratory/*physiology/*psychology ; *Emotions ; Euthanasia, Animal/*ethics/methods ; Mice ; Zebrafish/embryology/genetics/*physiology
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  • 86
    Publication Date: 2014-05-09
    Description: How does the mammalian retina detect motion? This classic problem in visual neuroscience has remained unsolved for 50 years. In search of clues, here we reconstruct Off-type starburst amacrine cells (SACs) and bipolar cells (BCs) in serial electron microscopic images with help from EyeWire, an online community of 'citizen neuroscientists'. On the basis of quantitative analyses of contact area and branch depth in the retina, we find evidence that one BC type prefers to wire with a SAC dendrite near the SAC soma, whereas another BC type prefers to wire far from the soma. The near type is known to lag the far type in time of visual response. A mathematical model shows how such 'space-time wiring specificity' could endow SAC dendrites with receptive fields that are oriented in space-time and therefore respond selectively to stimuli that move in the outward direction from the soma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4074887/" 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/PMC4074887/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jinseop S -- Greene, Matthew J -- Zlateski, Aleksandar -- Lee, Kisuk -- Richardson, Mark -- Turaga, Srinivas C -- Purcaro, Michael -- Balkam, Matthew -- Robinson, Amy -- Behabadi, Bardia F -- Campos, Michael -- Denk, Winfried -- Seung, H Sebastian -- EyeWirers -- R01 NS076467/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 15;509(7500):331-6. doi: 10.1038/nature13240. Epub 2014 May 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2]. ; Electrical Engineering and Computer Science Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Brain & Cognitive Sciences Department, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] 601 N 42nd Street, Seattle, Washington 98103, USA (M.R.); Princeton Neuroscience Institute and Computer Science Deptartment, Princeton, New Jersey 08544, USA (H.S.S.); Gatsby Computational Neuroscience Unit, London WC1N 3AR, UK (S.C.T.). ; Qualcomm Research, 5775 Morehouse Drive, San Diego, California 92121, USA. ; Max-Planck Institute for Medical Research, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24805243" target="_blank"〉PubMed〈/a〉
    Keywords: Amacrine Cells/cytology/physiology/ultrastructure ; Animals ; Artificial Intelligence ; *Brain Mapping ; Crowdsourcing ; Dendrites/metabolism ; Mice ; *Models, Neurological ; Motion ; Neural Pathways/*physiology ; Presynaptic Terminals/metabolism ; Retina/*cytology/*physiology ; Retinal Bipolar Cells/cytology/physiology/ultrastructure ; *Spatio-Temporal Analysis
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  • 87
    Publication Date: 2014-05-23
    Description: Deregulation of lysine methylation signalling has emerged as a common aetiological factor in cancer pathogenesis, with inhibitors of several histone lysine methyltransferases (KMTs) being developed as chemotherapeutics. The largely cytoplasmic KMT SMYD3 (SET and MYND domain containing protein 3) is overexpressed in numerous human tumours. However, the molecular mechanism by which SMYD3 regulates cancer pathways and its relationship to tumorigenesis in vivo are largely unknown. Here we show that methylation of MAP3K2 by SMYD3 increases MAP kinase signalling and promotes the formation of Ras-driven carcinomas. Using mouse models for pancreatic ductal adenocarcinoma and lung adenocarcinoma, we found that abrogating SMYD3 catalytic activity inhibits tumour development in response to oncogenic Ras. We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. In cancer cell lines, SMYD3-mediated methylation of MAP3K2 at lysine 260 potentiates activation of the Ras/Raf/MEK/ERK signalling module and SMYD3 depletion synergizes with a MEK inhibitor to block Ras-driven tumorigenesis. Finally, the PP2A phosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation. Together, our results elucidate a new role for lysine methylation in integrating cytoplasmic kinase-signalling cascades and establish a pivotal role for SMYD3 in the regulation of oncogenic Ras signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122675/" 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/PMC4122675/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mazur, Pawel K -- Reynoird, Nicolas -- Khatri, Purvesh -- Jansen, Pascal W T C -- Wilkinson, Alex W -- Liu, Shichong -- Barbash, Olena -- Van Aller, Glenn S -- Huddleston, Michael -- Dhanak, Dashyant -- Tummino, Peter J -- Kruger, Ryan G -- Garcia, Benjamin A -- Butte, Atul J -- Vermeulen, Michiel -- Sage, Julien -- Gozani, Or -- DP2 OD007447/OD/NIH HHS/ -- R01 CA172560/CA/NCI NIH HHS/ -- T32 GM007276/GM/NIGMS NIH HHS/ -- U19 AI109662/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jun 12;510(7504):283-7. doi: 10.1038/nature13320. Epub 2014 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA [3]. ; 1] Department of Biology, Stanford University, California 94305, USA [2]. ; Institute for Immunity, Transplantation and Infection, and Department of Medicine, Stanford University School of Medicine, California 94305, USA. ; Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. ; Department of Biology, Stanford University, California 94305, USA. ; Epigenetics Program and Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA. ; 1] Cancer Epigenetics DPU, Oncology R&D, GlaxoSmithKline, Collegeville, Pennsylvania 19426 USA [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.). ; 1] Department of Pediatrics, Stanford University School of Medicine, California 94305, USA [2] Department of Genetics, Stanford University School of Medicine, California 94305, USA. ; 1] Department of Molecular Cancer Research and Department of Medical Oncology, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands [2] Janssen Research and Development, 1400 McKean Road, Spring House, Pennsylvania 19477, USA (D.D.); Department of Molecular Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University, 6525GA Nijmegen, The Netherlands (M.V.).〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24847881" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/enzymology/genetics/metabolism/pathology ; Animals ; Cell Line, Tumor ; Cell Transformation, Neoplastic/genetics/*metabolism/pathology ; Disease Models, Animal ; Histone-Lysine N-Methyltransferase/*metabolism ; Humans ; Lung Neoplasms/enzymology/genetics/metabolism/pathology ; Lysine/*metabolism ; MAP Kinase Kinase Kinase 2/chemistry/*metabolism ; MAP Kinase Kinase Kinases/chemistry/*metabolism ; Methylation ; Mice ; Mitogen-Activated Protein Kinases/metabolism ; Oncogene Protein p21(ras)/genetics/*metabolism ; Pancreatic Neoplasms/enzymology/genetics/metabolism/pathology ; Protein Phosphatase 2/antagonists & inhibitors/metabolism ; Proto-Oncogene Proteins A-raf/metabolism ; Signal Transduction
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  • 88
    Publication Date: 2014-09-19
    Description: Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suez, Jotham -- Korem, Tal -- Zeevi, David -- Zilberman-Schapira, Gili -- Thaiss, Christoph A -- Maza, Ori -- Israeli, David -- Zmora, Niv -- Gilad, Shlomit -- Weinberger, Adina -- Kuperman, Yael -- Harmelin, Alon -- Kolodkin-Gal, Ilana -- Shapiro, Hagit -- Halpern, Zamir -- Segal, Eran -- Elinav, Eran -- England -- Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. ; 1] Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel [2]. ; 1] Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel [2]. ; Day Care Unit and the Laboratory of Imaging and Brain Stimulation, Kfar Shaul hospital, Jerusalem Center for Mental Health, Jerusalem 91060, Israel. ; 1] Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel [2] Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel [3] Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. ; The Nancy and Stephen Grand Israel National Center for Personalized Medicine (INCPM), Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. ; 1] Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel [2] Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231862" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Aspartame/adverse effects ; Body Weight/drug effects ; Diet, High-Fat ; Dietary Fats/pharmacology ; Feces/microbiology ; Female ; Gastrointestinal Tract/*drug effects/*microbiology ; Germ-Free Life ; Glucose/metabolism ; Glucose Intolerance/*chemically induced/metabolism/*microbiology ; Humans ; Male ; Metabolic Syndrome X/chemically induced/metabolism/microbiology ; Mice ; Mice, Inbred C57BL ; Microbiota/*drug effects ; Saccharin/administration & dosage/adverse effects ; Sucrose/adverse effects/analogs & derivatives ; Sweetening Agents/*adverse effects ; Waist-Hip Ratio
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  • 89
    Publication Date: 2014-04-18
    Description: Social behaviours, such as aggression or mating, proceed through a series of appetitive and consummatory phases that are associated with increasing levels of arousal. How such escalation is encoded in the brain, and linked to behavioural action selection, remains an unsolved problem in neuroscience. The ventrolateral subdivision of the murine ventromedial hypothalamus (VMHvl) contains neurons whose activity increases during male-male and male-female social encounters. Non-cell-type-specific optogenetic activation of this region elicited attack behaviour, but not mounting. We have identified a subset of VMHvl neurons marked by the oestrogen receptor 1 (Esr1), and investigated their role in male social behaviour. Optogenetic manipulations indicated that Esr1(+) (but not Esr1(-)) neurons are sufficient to initiate attack, and that their activity is continuously required during ongoing agonistic behaviour. Surprisingly, weaker optogenetic activation of these neurons promoted mounting behaviour, rather than attack, towards both males and females, as well as sniffing and close investigation. Increasing photostimulation intensity could promote a transition from close investigation and mounting to attack, within a single social encounter. Importantly, time-resolved optogenetic inhibition experiments revealed requirements for Esr1(+) neurons in both the appetitive (investigative) and the consummatory phases of social interactions. Combined optogenetic activation and calcium imaging experiments in vitro, as well as c-Fos analysis in vivo, indicated that increasing photostimulation intensity increases both the number of active neurons and the average level of activity per neuron. These data suggest that Esr1(+) neurons in VMHvl control the progression of a social encounter from its appetitive through its consummatory phases, in a scalable manner that reflects the number or type of active neurons in the population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4098836/" 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/PMC4098836/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Hyosang -- Kim, Dong-Wook -- Remedios, Ryan -- Anthony, Todd E -- Chang, Angela -- Madisen, Linda -- Zeng, Hongkui -- Anderson, David J -- 1F32HD055198-01/HD/NICHD NIH HHS/ -- 1K99NS074077/NS/NINDS NIH HHS/ -- R01 MH085082/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 29;509(7502):627-32. doi: 10.1038/nature13169. Epub 2014 Apr 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Biology and Biological Engineering 156-29, California Institute of Technology, Pasadena, California 91125, USA [2] Howard Hughes Medical Institute, Pasadena, California 91125, USA. ; Computation and Neural Systems, California Institute of Technology, Pasadena, California 91125, USA. ; Division of Biology and Biological Engineering 156-29, California Institute of Technology, Pasadena, California 91125, USA. ; Allen Institute for Brain Science, Seattle, Washington 98103, USA. ; 1] Division of Biology and Biological Engineering 156-29, California Institute of Technology, Pasadena, California 91125, USA [2] Howard Hughes Medical Institute, Pasadena, California 91125, USA [3] Computation and Neural Systems, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739975" target="_blank"〉PubMed〈/a〉
    Keywords: Aggression/*physiology ; Animals ; Estrogen Receptor alpha/*metabolism ; Female ; Integrases/genetics/metabolism ; Male ; Mice ; Neurons/*metabolism ; Optogenetics ; Sexual Behavior, Animal/*physiology ; Ventromedial Hypothalamic Nucleus/*cytology/*physiology
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  • 90
    Publication Date: 2014-04-04
    Description: The formation of precise connections between retina and lateral geniculate nucleus (LGN) involves the activity-dependent elimination of some synapses, with strengthening and retention of others. Here we show that the major histocompatibility complex (MHC) class I molecule H2-D(b) is necessary and sufficient for synapse elimination in the retinogeniculate system. In mice lacking both H2-K(b) and H2-D(b) (K(b)D(b)(-/-)), despite intact retinal activity and basal synaptic transmission, the developmentally regulated decrease in functional convergence of retinal ganglion cell synaptic inputs to LGN neurons fails and eye-specific layers do not form. Neuronal expression of just H2-D(b) in K(b)D(b)(-/-) mice rescues both synapse elimination and eye-specific segregation despite a compromised immune system. When patterns of stimulation mimicking endogenous retinal waves are used to probe synaptic learning rules at retinogeniculate synapses, long-term potentiation (LTP) is intact but long-term depression (LTD) is impaired in K(b)D(b)(-/-) mice. This change is due to an increase in Ca(2+)-permeable AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors. Restoring H2-D(b) to K(b)D(b)(-/-) neurons renders AMPA receptors Ca(2+) impermeable and rescues LTD. These observations reveal an MHC-class-I-mediated link between developmental synapse pruning and balanced synaptic learning rules enabling both LTD and LTP, and demonstrate a direct requirement for H2-D(b) in functional and structural synapse pruning in CNS neurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016165/" 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/PMC4016165/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Hanmi -- Brott, Barbara K -- Kirkby, Lowry A -- Adelson, Jaimie D -- Cheng, Sarah -- Feller, Marla B -- Datwani, Akash -- Shatz, Carla J -- EY02858/EY/NEI NIH HHS/ -- R01 EY002858/EY/NEI NIH HHS/ -- R01 EY013528/EY/NEI NIH HHS/ -- R01 EY13528/EY/NEI NIH HHS/ -- R01 MH071666/MH/NIMH NIH HHS/ -- T32 MH020016/MH/NIMH NIH HHS/ -- England -- Nature. 2014 May 8;509(7499):195-200. doi: 10.1038/nature13154. Epub 2014 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA. ; Department of Molecular and Cell Biology & Helen Wills Neuroscience Institute, University of California, Berkeley, California 94720, USA. ; 1] Departments of Biology and Neurobiology and Bio-X, James H. Clark Center, 318 Campus Drive, Stanford, California 94305, USA [2] Sage Bionetworks, 1100 Fairview Avenue N., Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695230" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Geniculate Bodies/*cytology/*physiology ; H-2 Antigens/genetics/immunology/metabolism ; Histocompatibility Antigen H-2D/genetics/immunology/*metabolism ; Long-Term Potentiation/physiology ; Long-Term Synaptic Depression ; Mice ; *Neural Pathways ; Receptors, N-Methyl-D-Aspartate/metabolism ; Retina/*cytology/*physiology ; Retinal Ganglion Cells/cytology/physiology ; Synapses/*metabolism ; Synaptic Transmission
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  • 91
    Publication Date: 2014-08-15
    Description: The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaoting -- Ota, Naruhisa -- Manzanillo, Paolo -- Kates, Lance -- Zavala-Solorio, Jose -- Eidenschenk, Celine -- Zhang, Juan -- Lesch, Justin -- Lee, Wyne P -- Ross, Jed -- Diehl, Lauri -- van Bruggen, Nicholas -- Kolumam, Ganesh -- Ouyang, Wenjun -- England -- Nature. 2014 Oct 9;514(7521):237-41. doi: 10.1038/nature13564. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Immunology, Genentech, South San Francisco, California 94080, USA [2]. ; Department of Immunology, Genentech, South San Francisco, California 94080, USA. ; Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119041" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/drug effects/metabolism ; Animals ; CD4-Positive T-Lymphocytes/immunology/secretion ; Chronic Disease ; Citrobacter rodentium/drug effects/immunology/physiology ; Colon/drug effects/immunology/microbiology ; Diabetes Mellitus/*immunology/*metabolism/pathology ; Diet, High-Fat ; Female ; Hyperglycemia/diet therapy/drug therapy/metabolism ; *Immunity, Mucosal/drug effects ; Inflammation/drug therapy/metabolism/pathology ; Insulin/metabolism ; Insulin Resistance ; Interleukin-23/immunology/metabolism/pharmacology ; Interleukins/*immunology/*metabolism/pharmacology/therapeutic use ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Male ; Metabolic Diseases/diet therapy/drug therapy/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/metabolism ; Receptors, Interleukin/deficiency/metabolism ; Receptors, Leptin/deficiency/metabolism
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  • 92
    Publication Date: 2014-12-05
    Description: The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell-neurite complexes. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4380172/" 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/PMC4380172/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ranade, Sanjeev S -- Woo, Seung-Hyun -- Dubin, Adrienne E -- Moshourab, Rabih A -- Wetzel, Christiane -- Petrus, Matt -- Mathur, Jayanti -- Begay, Valerie -- Coste, Bertrand -- Mainquist, James -- Wilson, A J -- Francisco, Allain G -- Reddy, Kritika -- Qiu, Zhaozhu -- Wood, John N -- Lewin, Gary R -- Patapoutian, Ardem -- 101054/Wellcome Trust/United Kingdom -- R01 DE022358/DE/NIDCR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 4;516(7529):121-5. doi: 10.1038/nature13980.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA. ; 1] Department of Neuroscience, Max-Delbruck Center for Molecular Medicine, Robert-Rossle Strasse 10, D-13092 Berlin, Germany [2] Klinik fur Anasthesiologie mit Schwerpunkt Operative Intensivmedizin, Campus Charite Mitte and Virchow-Klinikum Charite, Universitatsmedizin Berlin, Augustburgerplatz 1, 13353 Berlin, Germany. ; Department of Neuroscience, Max-Delbruck Center for Molecular Medicine, Robert-Rossle Strasse 10, D-13092 Berlin, Germany. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; 1] Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA [2] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA. ; Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25471886" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ion Channels/genetics/*metabolism ; Mechanoreceptors/metabolism ; Mechanotransduction, Cellular/genetics/*physiology ; Merkel Cells/physiology ; Mice ; Mice, Knockout ; Sensory Receptor Cells/physiology ; Skin/*innervation ; Touch/genetics/*physiology
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  • 93
    Publication Date: 2014-08-01
    Description: In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell-type-specific regulation directed by DNA binding factors. This comparatively static landscape is in marked contrast with the events of fertilization, during which the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, although methylation remains detectable at several notable features. These dynamics have been extensively characterized in the mouse, with only limited observations available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of residual maintenance are primarily restricted to gene bodies. Although most features share similar dynamics to those in mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island promoters that extend beyond known imprint control regions. Retrotransposon regulation is also highly diverse, and transitions from maternally to embryonically expressed elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178976/" 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/PMC4178976/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Zachary D -- Chan, Michelle M -- Humm, Kathryn C -- Karnik, Rahul -- Mekhoubad, Shila -- Regev, Aviv -- Eggan, Kevin -- Meissner, Alexander -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003958/OD/NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 31;511(7511):611-5. doi: 10.1038/nature13581. Epub 2014 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [4] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA [5]. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3]. ; 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Division of Reproductive Endocrinology &Infertility, Department of Obstetrics &Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [3] Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02215, USA [4] Boston IVF, Waltham, Massachusetts 02451, USA [5] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [6]. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [4] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA [5] Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079558" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blastocyst/*metabolism ; Cell Line ; CpG Islands/physiology ; DNA/metabolism ; *DNA Methylation ; Embryonic Stem Cells ; Female ; Gene Expression Regulation, Developmental ; Humans ; Male ; Mice ; Mice, Inbred C57BL
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  • 94
    Publication Date: 2014-11-11
    Description: Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARalpha and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARalpha reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARalpha knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARalpha and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267857/" 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/PMC4267857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Wagner, Martin -- Xiao, Rui -- Kim, Kang Ho -- Feng, Dan -- Lazar, Mitchell A -- Moore, David D -- DK43806/DK/NIDDK NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30DX56338-05A2/PHS HHS/ -- P39CA125123-04/CA/NCI NIH HHS/ -- R01 DK049780/DK/NIDDK NIH HHS/ -- R01 DK49780/DK/NIDDK NIH HHS/ -- R37 DK043806/DK/NIDDK NIH HHS/ -- S10RR027783-01A1/RR/NCRR NIH HHS/ -- U54HD-07495-39/HD/NICHD NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):112-5. doi: 10.1038/nature13961. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Cell Line ; Cells, Cultured ; Fasting/physiology ; Gene Expression Regulation ; Hepatocytes/metabolism ; Liver/cytology/*metabolism/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/metabolism ; PPAR alpha ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
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  • 95
    Publication Date: 2014-10-03
    Description: Bone-marrow transplantation is an effective cell therapy but requires myeloablation, which increases infection risk and mortality. Recent lineage-tracing studies documenting that resident macrophage populations self-maintain independently of haematological progenitors prompted us to consider organ-targeted, cell-specific therapy. Here, using granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor-beta-deficient (Csf2rb(-/-)) mice that develop a myeloid cell disorder identical to hereditary pulmonary alveolar proteinosis (hPAP) in children with CSF2RA or CSF2RB mutations, we show that pulmonary macrophage transplantation (PMT) of either wild-type or Csf2rb-gene-corrected macrophages without myeloablation was safe and well-tolerated and that one administration corrected the lung disease, secondary systemic manifestations and normalized disease-related biomarkers, and prevented disease-specific mortality. PMT-derived alveolar macrophages persisted for at least one year as did therapeutic effects. Our findings identify mechanisms regulating alveolar macrophage population size in health and disease, indicate that GM-CSF is required for phenotypic determination of alveolar macrophages, and support translation of PMT as the first specific therapy for children with hPAP.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4236859/" 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/PMC4236859/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suzuki, Takuji -- Arumugam, Paritha -- Sakagami, Takuro -- Lachmann, Nico -- Chalk, Claudia -- Sallese, Anthony -- Abe, Shuichi -- Trapnell, Cole -- Carey, Brenna -- Moritz, Thomas -- Malik, Punam -- Lutzko, Carolyn -- Wood, Robert E -- Trapnell, Bruce C -- 8UL1TR000077-05/TR/NCATS NIH HHS/ -- AR-47363/AR/NIAMS NIH HHS/ -- DK78392/DK/NIDDK NIH HHS/ -- DK90971/DK/NIDDK NIH HHS/ -- P30 AR047363/AR/NIAMS NIH HHS/ -- R01 HL069549/HL/NHLBI NIH HHS/ -- R01 HL085453/HL/NHLBI NIH HHS/ -- R01 HL118342/HL/NHLBI NIH HHS/ -- R01HL085453/HL/NHLBI NIH HHS/ -- R01HL118342/HL/NHLBI NIH HHS/ -- R21 HL106134/HL/NHLBI NIH HHS/ -- U54 HL127672/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Oct 23;514(7523):450-4. doi: 10.1038/nature13807. Epub 2014 Oct 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. ; Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. ; RG Reprograming and Gene Therapy, Institute of Experimental Hematology, Hannover Medical School, Carl Neuberg-Str. 1, 30625 Hannover, Germany. ; 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02138, USA. ; Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA. ; 1] Division of Pulmonary Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA [2] Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA [3] Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274301" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Separation ; *Cell Transplantation ; Cytokine Receptor Common beta Subunit/deficiency/*genetics ; Female ; *Genetic Therapy ; Lung/*cytology/metabolism/pathology ; Macrophages, Alveolar/*metabolism/*transplantation ; Male ; Mice ; Oligonucleotide Array Sequence Analysis ; Phenotype ; Pulmonary Alveolar Proteinosis/genetics/pathology/*therapy ; Time Factors
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  • 96
    Publication Date: 2014-04-25
    Description: Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 and I-BET762 two selective small-molecule inhibitors that target the amino-terminal bromodomains of BRD4, have been shown to exhibit anti-proliferative effects in a range of malignancies. Here we show that AR-signalling-competent human CRPC cell lines are preferentially sensitive to bromodomain and extraterminal (BET) inhibition. BRD4 physically interacts with the N-terminal domain of AR and can be disrupted by JQ1 (refs 11, 13). Like the direct AR antagonist MDV3100, JQ1 disrupted AR recruitment to target gene loci. By contrast with MDV3100, JQ1 functions downstream of AR, and more potently abrogated BRD4 localization to AR target loci and AR-mediated gene transcription, including induction of the TMPRSS2-ERG gene fusion and its oncogenic activity. In vivo, BET bromodomain inhibition was more efficacious than direct AR antagonism in CRPC xenograft mouse models. Taken together, these studies provide a novel epigenetic approach for the concerted blockade of oncogenic drivers in advanced prostate cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4075966/" 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/PMC4075966/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asangani, Irfan A -- Dommeti, Vijaya L -- Wang, Xiaoju -- Malik, Rohit -- Cieslik, Marcin -- Yang, Rendong -- Escara-Wilke, June -- Wilder-Romans, Kari -- Dhanireddy, Sudheer -- Engelke, Carl -- Iyer, Mathew K -- Jing, Xiaojun -- Wu, Yi-Mi -- Cao, Xuhong -- Qin, Zhaohui S -- Wang, Shaomeng -- Feng, Felix Y -- Chinnaiyan, Arul M -- P50 CA069568/CA/NCI NIH HHS/ -- P50CA69568/CA/NCI NIH HHS/ -- T32 GM007863/GM/NIGMS NIH HHS/ -- U01 CA111275/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jun 12;510(7504):278-82. doi: 10.1038/nature13229. Epub 2014 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics and Bioinformatics, Emory University, Atlanta, Georgia 30329, USA. ; Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Departments of Internal Medicine, Pharmacology, and Medicinal Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; 1] Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [2] Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [3] Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [4] Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA [5] Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759320" target="_blank"〉PubMed〈/a〉
    Keywords: Androgen Antagonists/pharmacology ; Androgens/metabolism ; Animals ; Azepines/*pharmacology/therapeutic use ; Cell Line, Tumor ; Disease Models, Animal ; Epigenesis, Genetic ; Humans ; Male ; Mice ; Nuclear Proteins/*chemistry ; Oncogene Proteins, Fusion/genetics/metabolism ; Prostatic Neoplasms, Castration-Resistant/*drug therapy/genetics ; Protein Structure, Tertiary/drug effects ; Receptors, Androgen/chemistry/metabolism ; Signal Transduction/drug effects ; Transcription Factors/*chemistry ; Triazoles/*pharmacology/therapeutic use
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  • 97
    Publication Date: 2014-11-21
    Description: To broaden our understanding of the evolution of gene regulation mechanisms, we generated occupancy profiles for 34 orthologous transcription factors (TFs) in human-mouse erythroid progenitor, lymphoblast and embryonic stem-cell lines. By combining the genome-wide transcription factor occupancy repertoires, associated epigenetic signals, and co-association patterns, here we deduce several evolutionary principles of gene regulatory features operating since the mouse and human lineages diverged. The genomic distribution profiles, primary binding motifs, chromatin states, and DNA methylation preferences are well conserved for TF-occupied sequences. However, the extent to which orthologous DNA segments are bound by orthologous TFs varies both among TFs and with genomic location: binding at promoters is more highly conserved than binding at distal elements. Notably, occupancy-conserved TF-occupied sequences tend to be pleiotropic; they function in several tissues and also co-associate with many TFs. Single nucleotide variants at sites with potential regulatory functions are enriched in occupancy-conserved TF-occupied sequences.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4343047/" 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/PMC4343047/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheng, Yong -- Ma, Zhihai -- Kim, Bong-Hyun -- Wu, Weisheng -- Cayting, Philip -- Boyle, Alan P -- Sundaram, Vasavi -- Xing, Xiaoyun -- Dogan, Nergiz -- Li, Jingjing -- Euskirchen, Ghia -- Lin, Shin -- Lin, Yiing -- Visel, Axel -- Kawli, Trupti -- Yang, Xinqiong -- Patacsil, Dorrelyn -- Keller, Cheryl A -- Giardine, Belinda -- Mouse ENCODE Consortium -- Kundaje, Anshul -- Wang, Ting -- Pennacchio, Len A -- Weng, Zhiping -- Hardison, Ross C -- Snyder, Michael P -- 1U54HG00699/HG/NHGRI NIH HHS/ -- 3RC2HG005602/HG/NHGRI NIH HHS/ -- 5U54HG006996/HG/NHGRI NIH HHS/ -- R01 DK065806/DK/NIDDK NIH HHS/ -- R01 DK096266/DK/NIDDK NIH HHS/ -- R01 ES024992/ES/NIEHS NIH HHS/ -- R01 EY021482/EY/NEI NIH HHS/ -- R01 GM083337/GM/NIGMS NIH HHS/ -- R01 HG003988/HG/NHGRI NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG007175/HG/NHGRI NIH HHS/ -- R01 HG007348/HG/NHGRI NIH HHS/ -- R01 HG007354/HG/NHGRI NIH HHS/ -- R01DK065806/DK/NIDDK NIH HHS/ -- R01HG003988/HG/NHGRI NIH HHS/ -- R37 DK044746/DK/NIDDK NIH HHS/ -- RC2 HG005573/HG/NHGRI NIH HHS/ -- RC2 HG005602/HG/NHGRI NIH HHS/ -- RC2HG005573/HG/NHGRI NIH HHS/ -- U01 DE024427/DE/NIDCR NIH HHS/ -- U41 HG007234/HG/NHGRI NIH HHS/ -- U54 HG006996/HG/NHGRI NIH HHS/ -- U54 HG006997/HG/NHGRI NIH HHS/ -- U54 HG006998/HG/NHGRI NIH HHS/ -- U54 HG007004/HG/NHGRI NIH HHS/ -- U54HG006997/HG/NHGRI NIH HHS/ -- England -- Nature. 2014 Nov 20;515(7527):371-5. doi: 10.1038/nature13985.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Stanford University, Stanford, California 94305, USA. ; Program in Bioinformatics and Integrative Biology, Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; 1] Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA [2] BRCF Bioinformatics Core, University of Michigan, Ann Arbor, Michigan 48105, USA. ; Department of Genetics, Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St Louis, Missouri 63108, USA. ; Center for Comparative Genomics and Bioinformatics, Huck Institutes of the Life Sciences, Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA. ; 1] Department of Genetics, Stanford University, Stanford, California 94305, USA [2] Division of Cardiovascular Medicine, Stanford University, Stanford, California 94304, USA. ; 1] Department of Genetics, Stanford University, Stanford, California 94305, USA [2] Department of Surgery, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; 1] Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, California 94701, USA [2] Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA [3] School of Natural Sciences, University of California, Merced, California 95343, USA. ; 1] Lawrence Berkeley National Laboratory, Genomics Division, Berkeley, California 94701, USA [2] Department of Energy Joint Genome Institute, Walnut Creek, California 94598, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409826" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Chromatin/genetics/metabolism ; Conserved Sequence/*genetics ; Enhancer Elements, Genetic/genetics ; Genome/*genetics ; *Genomics ; Humans ; Mice ; Polymorphism, Single Nucleotide/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Transcription Factors/*metabolism
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 98
    Publication Date: 2014-08-15
    Description: The aryl hydrocarbon receptor (AhR) is a highly conserved ligand-dependent transcription factor that senses environmental toxins and endogenous ligands, thereby inducing detoxifying enzymes and modulating immune cell differentiation and responses. We hypothesized that AhR evolved to sense not only environmental pollutants but also microbial insults. We characterized bacterial pigmented virulence factors, namely the phenazines from Pseudomonas aeruginosa and the naphthoquinone phthiocol from Mycobacterium tuberculosis, as ligands of AhR. Upon ligand binding, AhR activation leads to virulence factor degradation and regulated cytokine and chemokine production. The relevance of AhR to host defence is underlined by heightened susceptibility of AhR-deficient mice to both P. aeruginosa and M. tuberculosis. Thus, we demonstrate that AhR senses distinct bacterial virulence factors and controls antibacterial responses, supporting a previously unidentified role for AhR as an intracellular pattern recognition receptor, and identify bacterial pigments as a new class of pathogen-associated molecular patterns.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moura-Alves, Pedro -- Fae, Kellen -- Houthuys, Erica -- Dorhoi, Anca -- Kreuchwig, Annika -- Furkert, Jens -- Barison, Nicola -- Diehl, Anne -- Munder, Antje -- Constant, Patricia -- Skrahina, Tatsiana -- Guhlich-Bornhof, Ute -- Klemm, Marion -- Koehler, Anne-Britta -- Bandermann, Silke -- Goosmann, Christian -- Mollenkopf, Hans-Joachim -- Hurwitz, Robert -- Brinkmann, Volker -- Fillatreau, Simon -- Daffe, Mamadou -- Tummler, Burkhard -- Kolbe, Michael -- Oschkinat, Hartmut -- Krause, Gerd -- Kaufmann, Stefan H E -- England -- Nature. 2014 Aug 28;512(7515):387-92. doi: 10.1038/nature13684. Epub 2014 Aug 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Max Planck Institute for Infection Biology, Department of Immunology, Chariteplatz 1, 10117 Berlin, Germany [2]. ; Leibniz Institute for Molecular Pharmacology (FMP), Robert-Rossle-Strasse 10, 13125 Berlin, Germany. ; Max Planck Institute for Infection Biology, Structural Systems Biology, Chariteplatz 1, 10117 Berlin, Germany. ; Clinical Research Group, Clinic for Pediatric Pneumology, Allergology and Neonatology, OE 6710, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ; Institute of Pharmacology and Structural Biology (IPBS), CNRS and University of Toulouse (Toulouse III), 205 Route de Narbonne, 31077, Toulouse cedex 04, Toulouse, France. ; Max Planck Institute for Infection Biology, Department of Immunology, Chariteplatz 1, 10117 Berlin, Germany. ; Microscopy Core Facility, Max Planck Institute for Infection Biology, Department of Immunology, Chariteplatz 1, 10117 Berlin, Germany. ; Microarray Core Facility, Max Planck Institute for Infection Biology, Department of Immunology, Chariteplatz 1, 10117 Berlin, Germany. ; Protein Purification Core Facility, Max Planck Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, Germany. ; German Rheumatism Research Centre Berlin (DRFZ), a Leibniz Institute, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119038" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/metabolism ; Basic Helix-Loop-Helix Transcription Factors/*metabolism ; Bone Marrow Cells/cytology ; Cytokines/immunology/metabolism ; Feedback, Physiological ; Humans ; Ligands ; Macrophage Activation ; Mice ; Mycobacterium tuberculosis/growth & development/*immunology/metabolism ; Phenazines/metabolism ; Pigments, Biological/chemistry/*metabolism ; Pseudomonas Infections/metabolism ; Pseudomonas aeruginosa/*immunology/metabolism ; Pyocyanine/metabolism ; Receptors, Aryl Hydrocarbon/*metabolism ; Receptors, Pattern Recognition/*metabolism ; Virulence Factors/chemistry/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 99
    Publication Date: 2014-03-22
    Description: The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kusumbe, Anjali P -- Ramasamy, Saravana K -- Adams, Ralf H -- England -- Nature. 2014 Mar 20;507(7492):323-8. doi: 10.1038/nature13145. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2]. ; 1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2] University of Munster, Faculty of Medicine, D-48149 Munster, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24646994" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/metabolism/pathology ; Animals ; Blood Vessels/anatomy & histology/cytology/growth & development/*physiology ; Bone and Bones/*blood supply/cytology ; Endothelial Cells/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/*physiology ; Osteoblasts/cytology/metabolism ; Osteogenesis/*physiology ; Oxygen/metabolism ; Stem Cells/cytology/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
    Publication Date: 2014-03-29
    Description: Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976267/" 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/PMC3976267/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hall, Catherine N -- Reynell, Clare -- Gesslein, Bodil -- Hamilton, Nicola B -- Mishra, Anusha -- Sutherland, Brad A -- O'Farrell, Fergus M -- Buchan, Alastair M -- Lauritzen, Martin -- Attwell, David -- 075232/Wellcome Trust/United Kingdom -- G0500495/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 3;508(7494):55-60. doi: 10.1038/nature13165. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK [2]. ; 1] Department of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen N, Denmark [2]. ; Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. ; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. ; 1] Department of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen N, Denmark [2] Department of Clinical Neurophysiology, Glostrup University Hospital, DK-2600 Glostrup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670647" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/physiology ; Blood-Brain Barrier/pathology/physiopathology ; Brain Ischemia/pathology ; Capillaries/*cytology/drug effects ; Cell Death ; Cerebellum/blood supply ; Cerebral Cortex/blood supply/cytology ; Cerebrovascular Circulation/drug effects/*physiology ; Dinoprostone/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Functional Neuroimaging ; Glutamic Acid/pharmacology ; Hydroxyeicosatetraenoic Acids/biosynthesis ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Pericytes/cytology/drug effects/pathology/*physiology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Glutamate/metabolism ; Signal Transduction/drug effects ; Stroke/pathology ; Vasoconstriction ; Vasodilation/drug effects
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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