ALBERT

Description: The enteric nervous system (ENS) is the largest component of the autonomic nervous system, with neuron numbers surpassing those present in the spinal cord. The ENS has been called the 'second brain' given its autonomy, remarkable neurotransmitter diversity and complex cytoarchitecture. Defects in ENS development are responsible for many human disorders including Hirschsprung disease (HSCR). HSCR is caused by the developmental failure of ENS progenitors to migrate into the gastrointestinal tract, particularly the distal colon. Human ENS development remains poorly understood owing to the lack of an easily accessible model system. Here we demonstrate the efficient derivation and isolation of ENS progenitors from human pluripotent stem (PS) cells, and their further differentiation into functional enteric neurons. ENS precursors derived in vitro are capable of targeted migration in the developing chick embryo and extensive colonization of the adult mouse colon. The in vivo engraftment and migration of human PS-cell-derived ENS precursors rescue disease-related mortality in HSCR mice (Ednrb(s-l/s-l)), although the mechanism of action remains unclear. Finally, EDNRB-null mutant ENS precursors enable modelling of HSCR-related migration defects, and the identification of pepstatin A as a candidate therapeutic target. Our study establishes the first, to our knowledge, human PS-cell-based platform for the study of human ENS development, and presents cell- and drug-based strategies for the treatment of HSCR.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846424/" 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/PMC4846424/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fattahi, Faranak -- Steinbeck, Julius A -- Kriks, Sonja -- Tchieu, Jason -- Zimmer, Bastian -- Kishinevsky, Sarah -- Zeltner, Nadja -- Mica, Yvonne -- El-Nachef, Wael -- Zhao, Huiyong -- de Stanchina, Elisa -- Gershon, Michael D -- Grikscheit, Tracy C -- Chen, Shuibing -- Studer, Lorenz -- DP2 DK098093-01/DK/NIDDK NIH HHS/ -- NS15547/NS/NINDS NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 NS015547/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Mar 3;531(7592):105-9. doi: 10.1038/nature16951. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Center for Stem Cell Biology, New York, New York 10065, USA. ; Developmental Biology Program, Sloan-Kettering Institute for Cancer Research, New York, New York 10065, USA. ; Weill Graduate School of Medical Sciences of Cornell University, New York, New York 10065, USA. ; Molecular Pharmacology Program, New York, New York 10065, USA. ; Department of Pathology and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. ; Children's Hospital Los Angeles, Pediatric Surgery, Los Angeles, California 90027, USA. ; Department of Surgery, Weill Medical College of Cornell University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863197" target="_blank"〉PubMed〈/a〉

Description: Mammalian Wnt proteins are believed to act as short-range signals, yet have not been previously visualized in vivo. Self-renewal, proliferation and differentiation are coordinated along a putative Wnt gradient in the intestinal crypt. Wnt3 is produced specifically by Paneth cells. Here we have generated an epitope-tagged, functional Wnt3 knock-in allele. Wnt3 covers basolateral membranes of neighbouring stem cells. In intestinal organoids, Wnt3-transfer involves direct contact between Paneth cells and stem cells. Plasma membrane localization requires surface expression of Frizzled receptors, which in turn is regulated by the transmembrane E3 ligases Rnf43/Znrf3 and their antagonists Lgr4-5/R-spondin. By manipulating Wnt3 secretion and by arresting stem-cell proliferation, we demonstrate that Wnt3 mainly travels away from its source in a cell-bound manner through cell division, and not through diffusion. We conclude that stem-cell membranes constitute a reservoir for Wnt proteins, while Frizzled receptor turnover and 'plasma membrane dilution' through cell division shape the epithelial Wnt3 gradient.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Farin, Henner F -- Jordens, Ingrid -- Mosa, Mohammed H -- Basak, Onur -- Korving, Jeroen -- Tauriello, Daniele V F -- de Punder, Karin -- Angers, Stephane -- Peters, Peter J -- Maurice, Madelon M -- Clevers, Hans -- England -- Nature. 2016 Feb 18;530(7590):340-3. doi: 10.1038/nature16937. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands. ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands. ; The Maastricht Multimodal Molecular Imaging institute, Maastricht University, 6229ER Maastricht, the Netherlands. ; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863187" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lim, XiaoZhi -- England -- Nature. 2016 Mar 3;531(7592):26-8. doi: 10.1038/531026a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26935679" target="_blank"〉PubMed〈/a〉

Description: Circadian clocks are fundamental to the biology of most eukaryotes, coordinating behaviour and physiology to resonate with the environmental cycle of day and night through complex networks of clock-controlled genes. A fundamental knowledge gap exists, however, between circadian gene expression cycles and the biochemical mechanisms that ultimately facilitate circadian regulation of cell biology. Here we report circadian rhythms in the intracellular concentration of magnesium ions, [Mg(2+)]i, which act as a cell-autonomous timekeeping component to determine key clock properties both in a human cell line and in a unicellular alga that diverged from each other more than 1 billion years ago. Given the essential role of Mg(2+) as a cofactor for ATP, a functional consequence of [Mg(2+)]i oscillations is dynamic regulation of cellular energy expenditure over the daily cycle. Mechanistically, we find that these rhythms provide bilateral feedback linking rhythmic metabolism to clock-controlled gene expression. The global regulation of nucleotide triphosphate turnover by intracellular Mg(2+) availability has potential to impact upon many of the cell's more than 600 MgATP-dependent enzymes and every cellular system where MgNTP hydrolysis becomes rate limiting. Indeed, we find that circadian control of translation by mTOR is regulated through [Mg(2+)]i oscillations. It will now be important to identify which additional biological processes are subject to this form of regulation in tissues of multicellular organisms such as plants and humans, in the context of health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feeney, Kevin A -- Hansen, Louise L -- Putker, Marrit -- Olivares-Yanez, Consuelo -- Day, Jason -- Eades, Lorna J -- Larrondo, Luis F -- Hoyle, Nathaniel P -- O'Neill, John S -- van Ooijen, Gerben -- 093734/Z/10/Z/Wellcome Trust/United Kingdom -- MC_UP_1201/4/Medical Research Council/United Kingdom -- England -- Nature. 2016 Apr 21;532(7599):375-9. doi: 10.1038/nature17407. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory for Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK. ; School of Biological Sciences, University of Edinburgh, Max Born Crescent, Edinburgh EH9 3BF, UK. ; Millennium Nucleus for Fungal Integrative and Synthetic Biology, Departamento de Genetica Molecular y Microbiologia, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Casilla 114-D, Santiago, Chile. ; Department of Earth Sciences, University of Cambridge, Downing Street, Cambridge CB2 3EQ, UK. ; School of Chemistry, University of Edinburgh, David Brewster Road, Edinburgh EH9 3FJ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074515" target="_blank"〉PubMed〈/a〉

Description: Microglia are damage sensors for the central nervous system (CNS), and the phagocytes responsible for routine non-inflammatory clearance of dead brain cells. Here we show that the TAM receptor tyrosine kinases Mer and Axl regulate these microglial functions. We find that adult mice deficient in microglial Mer and Axl exhibit a marked accumulation of apoptotic cells specifically in neurogenic regions of the CNS, and that microglial phagocytosis of the apoptotic cells generated during adult neurogenesis is normally driven by both TAM receptor ligands Gas6 and protein S. Using live two-photon imaging, we demonstrate that the microglial response to brain damage is also TAM-regulated, as TAM-deficient microglia display reduced process motility and delayed convergence to sites of injury. Finally, we show that microglial expression of Axl is prominently upregulated in the inflammatory environment that develops in a mouse model of Parkinson's disease. Together, these results establish TAM receptors as both controllers of microglial physiology and potential targets for therapeutic intervention in CNS disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fourgeaud, Lawrence -- Traves, Paqui G -- Tufail, Yusuf -- Leal-Bailey, Humberto -- Lew, Erin D -- Burrola, Patrick G -- Callaway, Perri -- Zagorska, Anna -- Rothlin, Carla V -- Nimmerjahn, Axel -- Lemke, Greg -- DP2 NS083038/DP/NCCDPHP CDC HHS/ -- DP2 NS083038/NS/NINDS NIH HHS/ -- P30CA014195/CA/NCI NIH HHS/ -- R01 AI089824/AI/NIAID NIH HHS/ -- R01 AI101400/AI/NIAID NIH HHS/ -- R01 NS085296/NS/NINDS NIH HHS/ -- R01 NS085938/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 14;532(7598):240-4. doi: 10.1038/nature17630. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Instituto de Investigaciones Biomedicas Alberto Sols (CSIC-UAM), Madrid 28029, Spain. ; Waitt Advanced Biophotonics Center, The Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Joint Master in Neuroscience Program, University of Strasbourg, Strasbourg 67081, France. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Immunobiology and Microbial Pathogenesis Laboratory, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049947" target="_blank"〉PubMed〈/a〉

Description: Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Anderson, Mark A -- Burda, Joshua E -- Ren, Yilong -- Ao, Yan -- O'Shea, Timothy M -- Kawaguchi, Riki -- Coppola, Giovanni -- Khakh, Baljit S -- Deming, Timothy J -- Sofroniew, Michael V -- MH099559A/MH/NIMH NIH HHS/ -- MH104069/MH/NIMH NIH HHS/ -- NS057624/NS/NINDS NIH HHS/ -- NS060677/NS/NINDS NIH HHS/ -- NS084030/NS/NINDS NIH HHS/ -- P30 NS062691/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Apr 14;532(7598):195-200. doi: 10.1038/nature17623. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1763, USA. ; Departments of Psychiatry and Neurology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1761, USA. ; Department of Physiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095-1751, USA. ; Departments of Bioengineering, Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California 90095-1600, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027288" target="_blank"〉PubMed〈/a〉

Description: Targeted, temporally regulated neural modulation is invaluable in determining the physiological roles of specific neural populations or circuits. Here we describe a system for non-invasive, temporal activation or inhibition of neuronal activity in vivo and its use to study central nervous system control of glucose homeostasis and feeding in mice. We are able to induce neuronal activation remotely using radio waves or magnetic fields via Cre-dependent expression of a GFP-tagged ferritin fusion protein tethered to the cation-conducting transient receptor potential vanilloid 1 (TRPV1) by a camelid anti-GFP antibody (anti-GFP-TRPV1). Neuronal inhibition via the same stimuli is achieved by mutating the TRPV1 pore, rendering the channel chloride-permeable. These constructs were targeted to glucose-sensing neurons in the ventromedial hypothalamus in glucokinase-Cre mice, which express Cre in glucose-sensing neurons. Acute activation of glucose-sensing neurons in this region increases plasma glucose and glucagon, lowers insulin levels and stimulates feeding, while inhibition reduces blood glucose, raises insulin levels and suppresses feeding. These results suggest that pancreatic hormones function as an effector mechanism of central nervous system circuits controlling blood glucose and behaviour. The method we employ obviates the need for permanent implants and could potentially be applied to study other neural processes or used to regulate other, even dispersed, cell types.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stanley, Sarah A -- Kelly, Leah -- Latcha, Kaamashri N -- Schmidt, Sarah F -- Yu, Xiaofei -- Nectow, Alexander R -- Sauer, Jeremy -- Dyke, Jonathan P -- Dordick, Jonathan S -- Friedman, Jeffrey M -- GM067545/GM/NIGMS NIH HHS/ -- GM095654/GM/NIGMS NIH HHS/ -- MH105941/MH/NIMH NIH HHS/ -- U01 MH105941/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 31;531(7596):647-50. doi: 10.1038/nature17183. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Genetics, Rockefeller University, New York, New York 10065, USA. ; Department of Chemical &Biological Engineering, Center for Biotechnology &Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, New York 12180, USA. ; Department of Radiology, Weill Cornell Medical College, New York, New York 10065, USA. ; Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007848" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnold, Carrie -- England -- Nature. 2016 Apr 21;532(7599):292. doi: 10.1038/nature.2016.19755.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27111610" target="_blank"〉PubMed〈/a〉

Description: Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a pivotal role in maintaining immunological self-tolerance; yet, excessive Treg cell activities suppress anti-tumour immune responses. Compared to the resting Treg (rTreg) cell phenotype in secondary lymphoid organs, Treg cells in non-lymphoid tissues exhibit an activated Treg (aTreg) cell phenotype. However, the function of aTreg cells and whether their generation can be manipulated are largely unexplored. Here we show that the transcription factor Foxo1, previously demonstrated to promote Treg cell suppression of lymphoproliferative diseases, has an unexpected function in inhibiting aTreg-cell-mediated immune tolerance in mice. We find that aTreg cells turned over at a slower rate than rTreg cells, but were not locally maintained in tissues. aTreg cell differentiation was associated with repression of Foxo1-dependent gene transcription, concomitant with reduced Foxo1 expression, cytoplasmic localization and enhanced phosphorylation at the Akt sites. Treg-cell-specific expression of an Akt-insensitive Foxo1 mutant prevented downregulation of lymphoid organ homing molecules, and impeded Treg cell homing to non-lymphoid organs, causing CD8(+) T-cell-mediated autoimmune diseases. Compared to Treg cells from healthy tissues, tumour-infiltrating Treg cells downregulated Foxo1 target genes more substantially. Expression of the Foxo1 mutant at a lower dose was sufficient to deplete tumour-associated Treg cells, activate effector CD8(+) T cells, and inhibit tumour growth without inflicting autoimmunity. Thus, Foxo1 inactivation is essential for the migration of aTreg cells that have a crucial function in suppressing CD8(+) T-cell responses; and the Foxo signalling pathway in Treg cells can be titrated to break tumour immune tolerance preferentially.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luo, Chong T -- Liao, Will -- Dadi, Saida -- Toure, Ahmed -- Li, Ming O -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI102888-01A1/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):532-6. doi: 10.1038/nature16486. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Program, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Louis V. Gerstner Jr Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; New York Genome Center, New York, New York 10013, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26789248" target="_blank"〉PubMed〈/a〉

Description: Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-beta, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bailey, Peter -- Chang, David K -- Nones, Katia -- Johns, Amber L -- Patch, Ann-Marie -- Gingras, Marie-Claude -- Miller, David K -- Christ, Angelika N -- Bruxner, Tim J C -- Quinn, Michael C -- Nourse, Craig -- Murtaugh, L Charles -- Harliwong, Ivon -- Idrisoglu, Senel -- Manning, Suzanne -- Nourbakhsh, Ehsan -- Wani, Shivangi -- Fink, Lynn -- Holmes, Oliver -- Chin, Venessa -- Anderson, Matthew J -- Kazakoff, Stephen -- Leonard, Conrad -- Newell, Felicity -- Waddell, Nick -- Wood, Scott -- Xu, Qinying -- Wilson, Peter J -- Cloonan, Nicole -- Kassahn, Karin S -- Taylor, Darrin -- Quek, Kelly -- Robertson, Alan -- Pantano, Lorena -- Mincarelli, Laura -- Sanchez, Luis N -- Evers, Lisa -- Wu, Jianmin -- Pinese, Mark -- Cowley, Mark J -- Jones, Marc D -- Colvin, Emily K -- Nagrial, Adnan M -- Humphrey, Emily S -- Chantrill, Lorraine A -- Mawson, Amanda -- Humphris, Jeremy -- Chou, Angela -- Pajic, Marina -- Scarlett, Christopher J -- Pinho, Andreia V -- Giry-Laterriere, Marc -- Rooman, Ilse -- Samra, Jaswinder S -- Kench, James G -- Lovell, Jessica A -- Merrett, Neil D -- Toon, Christopher W -- Epari, Krishna -- Nguyen, Nam Q -- Barbour, Andrew -- Zeps, Nikolajs -- Moran-Jones, Kim -- Jamieson, Nigel B -- Graham, Janet S -- Duthie, Fraser -- Oien, Karin -- Hair, Jane -- Grutzmann, Robert -- Maitra, Anirban -- Iacobuzio-Donahue, Christine A -- Wolfgang, Christopher L -- Morgan, Richard A -- Lawlor, Rita T -- Corbo, Vincenzo -- Bassi, Claudio -- Rusev, Borislav -- Capelli, Paola -- Salvia, Roberto -- Tortora, Giampaolo -- Mukhopadhyay, Debabrata -- Petersen, Gloria M -- Australian Pancreatic Cancer Genome Initiative -- Munzy, Donna M -- Fisher, William E -- Karim, Saadia A -- Eshleman, James R -- Hruban, Ralph H -- Pilarsky, Christian -- Morton, Jennifer P -- Sansom, Owen J -- Scarpa, Aldo -- Musgrove, Elizabeth A -- Bailey, Ulla-Maja Hagbo -- Hofmann, Oliver -- Sutherland, Robert L -- Wheeler, David A -- Gill, Anthony J -- Gibbs, Richard A -- Pearson, John V -- Waddell, Nicola -- Biankin, Andrew V -- Grimmond, Sean M -- 103721/Z/14/Z/Wellcome Trust/United Kingdom -- A12481/Cancer Research UK/United Kingdom -- A18076/Cancer Research UK/United Kingdom -- C29717/A17263/Cancer Research UK/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):47-52. doi: 10.1038/nature16965. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1BD, UK. ; The Kinghorn Cancer Centre, 370 Victoria St, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. ; Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. ; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. ; QIMR Berghofer Medical Research Institute, Herston, Queensland 4006, Australia. ; Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Michael DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas 77030, USA. ; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Human Genetics, University of Utah, Salt Lake City, Utah 84112, USA. ; Genetic and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia. ; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia 5000, Australia. ; Harvard Chan Bioinformatics Core, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA. ; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales 2560, Australia. ; Department of Pathology. SydPath, St Vincent's Hospital, Sydney, NSW 2010, Australia. ; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, New South Wales 2052, Australia. ; School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. ; Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. ; University of Sydney, Sydney, New South Wales 2006, Australia. ; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown New South Wales 2050, Australia. ; School of Medicine, University of Western Sydney, Penrith, New South Wales 2175, Australia. ; Fiona Stanley Hospital, Robin Warren Drive, Murdoch, Western Australia 6150, Australia. ; Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. ; Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. ; School of Surgery M507, University of Western Australia, 35 Stirling Hwy, Nedlands 6009, Australia and St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. ; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. ; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. ; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow G12 0YN, UK. ; Department of Pathology, Southern General Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. ; GGC Bio-repository, Pathology Department, Southern General Hospital, 1345 Govan Road, Glasgow G51 4TY, UK. ; Department of Surgery, TU Dresden, Fetscherstr. 74, 01307 Dresden, Germany. ; Departments of Pathology and Translational Molecular Pathology, UT MD Anderson Cancer Center, Houston Texas 77030, USA. ; The David M. Rubenstein Pancreatic Cancer Research Center and Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA. ; ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Pathology and Diagnostics, University of Verona, Verona 37134, Italy. ; Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. ; Department of Medical Oncology, Comprehensive Cancer Centre, University and Hospital Trust of Verona, Verona 37134, Italy. ; Mayo Clinic, Rochester, Minnesota 55905, USA. ; Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. ; Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. ; Institute for Cancer Science, University of Glasgow, Glasgow G12 8QQ, UK. ; University of Melbourne, Parkville, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909576" target="_blank"〉PubMed〈/a〉

Description: Inhibitory neurons regulate the adaptation of neural circuits to sensory experience, but the molecular mechanisms by which experience controls the connectivity between different types of inhibitory neuron to regulate cortical plasticity are largely unknown. Here we show that exposure of dark-housed mice to light induces a gene program in cortical vasoactive intestinal peptide (VIP)-expressing neurons that is markedly distinct from that induced in excitatory neurons and other subtypes of inhibitory neuron. We identify Igf1 as one of several activity-regulated genes that are specific to VIP neurons, and demonstrate that IGF1 functions cell-autonomously in VIP neurons to increase inhibitory synaptic input onto these neurons. Our findings further suggest that in cortical VIP neurons, experience-dependent gene transcription regulates visual acuity by activating the expression of IGF1, thus promoting the inhibition of disinhibitory neurons and affecting inhibition onto cortical pyramidal neurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4823817/" 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/PMC4823817/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mardinly, A R -- Spiegel, I -- Patrizi, A -- Centofante, E -- Bazinet, J E -- Tzeng, C P -- Mandel-Brehm, C -- Harmin, D A -- Adesnik, H -- Fagiolini, M -- Greenberg, M E -- P01 NS047572/NS/NINDS NIH HHS/ -- P30 HD018655/HD/NICHD NIH HHS/ -- R01 NS028829/NS/NINDS NIH HHS/ -- R37 NS028829/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):371-5. doi: 10.1038/nature17187. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, University of California Berkeley, 205 Life Sciences Addition, Berkeley, California 94720, USA. ; Department of Neurobiology, Harvard Medical School, 220 Longwood Ave, Boston, Massachusetts 02115, USA. ; FM Kirby Neurobiology Center, Boston Children's Hospital, 3 Blackfan Circle, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958833" target="_blank"〉PubMed〈/a〉

Description: It has been known for more than 70 years that synaptic strength is dynamically regulated in a use-dependent manner. At synapses with a low initial release probability, closely spaced presynaptic action potentials can result in facilitation, a short-term form of enhancement in which each subsequent action potential evokes greater neurotransmitter release. Facilitation can enhance neurotransmitter release considerably and can profoundly influence information transfer across synapses, but the underlying mechanism remains a mystery. One proposed mechanism is that a specialized calcium sensor for facilitation transiently increases the probability of release, and this sensor is distinct from the fast sensors that mediate rapid neurotransmitter release. Yet such a sensor has never been identified, and its very existence has been disputed. Here we show that synaptotagmin 7 (Syt7) is a calcium sensor that is required for facilitation at several central synapses. In Syt7-knockout mice, facilitation is eliminated even though the initial probability of release and the presynaptic residual calcium signals are unaltered. Expression of wild-type Syt7 in presynaptic neurons restored facilitation, whereas expression of a mutated Syt7 with a calcium-insensitive C2A domain did not. By revealing the role of Syt7 in synaptic facilitation, these results resolve a longstanding debate about a widespread form of short-term plasticity, and will enable future studies that may lead to a deeper understanding of the functional importance of facilitation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4729191/" 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/PMC4729191/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jackman, Skyler L -- Turecek, Josef -- Belinsky, Justine E -- Regehr, Wade G -- NS032405/NS/NINDS NIH HHS/ -- P30 NS072030/NS/NINDS NIH HHS/ -- R01 NS032405/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Jan 7;529(7584):88-91. doi: 10.1038/nature16507.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, 220 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738595" target="_blank"〉PubMed〈/a〉

Description: The bacterial CRISPR/Cas9 system allows sequence-specific gene editing in many organisms and holds promise as a tool to generate models of human diseases, for example, in human pluripotent stem cells. CRISPR/Cas9 introduces targeted double-stranded breaks (DSBs) with high efficiency, which are typically repaired by non-homologous end-joining (NHEJ) resulting in nonspecific insertions, deletions or other mutations (indels). DSBs may also be repaired by homology-directed repair (HDR) using a DNA repair template, such as an introduced single-stranded oligo DNA nucleotide (ssODN), allowing knock-in of specific mutations. Although CRISPR/Cas9 is used extensively to engineer gene knockouts through NHEJ, editing by HDR remains inefficient and can be corrupted by additional indels, preventing its widespread use for modelling genetic disorders through introducing disease-associated mutations. Furthermore, targeted mutational knock-in at single alleles to model diseases caused by heterozygous mutations has not been reported. Here we describe a CRISPR/Cas9-based genome-editing framework that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. We show that HDR accuracy is increased dramatically by incorporating silent CRISPR/Cas-blocking mutations along with pathogenic mutations, and establish a method termed 'CORRECT' for scarless genome editing. By characterizing and exploiting a stereotyped inverse relationship between a mutation's incorporation rate and its distance to the DSB, we achieve predictable control of zygosity. Homozygous introduction requires a guide RNA targeting close to the intended mutation, whereas heterozygous introduction can be accomplished by distance-dependent suboptimal mutation incorporation or by use of mixed repair templates. Using this approach, we generated human induced pluripotent stem cells with heterozygous and homozygous dominant early onset Alzheimer's disease-causing mutations in amyloid precursor protein (APP(Swe)) and presenilin 1 (PSEN1(M146V)) and derived cortical neurons, which displayed genotype-dependent disease-associated phenotypes. Our findings enable efficient introduction of specific sequence changes with CRISPR/Cas9, facilitating study of human disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Paquet, Dominik -- Kwart, Dylan -- Chen, Antonia -- Sproul, Andrew -- Jacob, Samson -- Teo, Shaun -- Olsen, Kimberly Moore -- Gregg, Andrew -- Noggle, Scott -- Tessier-Lavigne, Marc -- 8 UL1 TR000043/TR/NCATS NIH HHS/ -- T32GM007739/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 May 5;533(7601):125-9. doi: 10.1038/nature17664. Epub 2016 Apr 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Brain Development and Repair, The Rockefeller University, 1230 York Avenue, New York, New York 10065, USA. ; The New York Stem Cell Foundation Research Institute, New York, New York 10032, USA. ; Weill Cornell Graduate School of Medical Sciences, The Rockefeller University and Sloan-Kettering Institute Tri-institutional MD-PhD Program, 1300 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27120160" target="_blank"〉PubMed〈/a〉

Description: In bright light, cone-photoreceptors are active and colour vision derives from a comparison of signals in cones with different visual pigments. This comparison begins in the retina, where certain retinal ganglion cells have 'colour-opponent' visual responses-excited by light of one colour and suppressed by another colour. In dim light, rod-photoreceptors are active, but colour vision is impossible because they all use the same visual pigment. Instead, the rod signals are thought to splice into retinal circuits at various points, in synergy with the cone signals. Here we report a new circuit for colour vision that challenges these expectations. A genetically identified type of mouse retinal ganglion cell called JAMB (J-RGC), was found to have colour-opponent responses, OFF to ultraviolet (UV) light and ON to green light. Although the mouse retina contains a green-sensitive cone, the ON response instead originates in rods. Rods and cones both contribute to the response over several decades of light intensity. Remarkably, the rod signal in this circuit is antagonistic to that from cones. For rodents, this UV-green channel may play a role in social communication, as suggested by spectral measurements from the environment. In the human retina, all of the components for this circuit exist as well, and its function can explain certain experiences of colour in dim lights, such as a 'blue shift' in twilight. The discovery of this genetically defined pathway will enable new targeted studies of colour processing in the brain.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joesch, Maximilian -- Meister, Markus -- England -- Nature. 2016 Apr 14;532(7598):236-9. doi: 10.1038/nature17158. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA. ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California 91125, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049951" target="_blank"〉PubMed〈/a〉

Description: How tissue regeneration programs are triggered by injury has received limited research attention. Here we investigate the existence of enhancer regulatory elements that are activated in regenerating tissue. Transcriptomic analyses reveal that leptin b (lepb) is highly induced in regenerating hearts and fins of zebrafish. Epigenetic profiling identified a short DNA sequence element upstream and distal to lepb that acquires open chromatin marks during regeneration and enables injury-dependent expression from minimal promoters. This element could activate expression in injured neonatal mouse tissues and was divisible into tissue-specific modules sufficient for expression in regenerating zebrafish fins or hearts. Simple enhancer-effector transgenes employing lepb-linked sequences upstream of pro- or anti-regenerative factors controlled the efficacy of regeneration in zebrafish. Our findings provide evidence for 'tissue regeneration enhancer elements' (TREEs) that trigger gene expression in injury sites and can be engineered to modulate the regenerative potential of vertebrate organs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844022/" 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/PMC4844022/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kang, Junsu -- Hu, Jianxin -- Karra, Ravi -- Dickson, Amy L -- Tornini, Valerie A -- Nachtrab, Gregory -- Gemberling, Matthew -- Goldman, Joseph A -- Black, Brian L -- Poss, Kenneth D -- F32 HL120494/HL/NHLBI NIH HHS/ -- K08 HL116485/HL/NHLBI NIH HHS/ -- P01 HL089707/HL/NHLBI NIH HHS/ -- R01 GM074057/GM/NIGMS NIH HHS/ -- R01 HL064658/HL/NHLBI NIH HHS/ -- R01 HL081674/HL/NHLBI NIH HHS/ -- R01 HL089707/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Apr 14;532(7598):201-6. doi: 10.1038/nature17644. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California 94143, USA. ; Department of Medicine, 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/27049946" target="_blank"〉PubMed〈/a〉

Description: It has been widely accepted that 5-methylcytosine is the only form of DNA methylation in mammalian genomes. Here we identify N(6)-methyladenine as another form of DNA modification in mouse embryonic stem cells. Alkbh1 encodes a demethylase for N(6)-methyladenine. An increase of N(6)-methyladenine levels in Alkbh1-deficient cells leads to transcriptional silencing. N(6)-methyladenine deposition is inversely correlated with the evolutionary age of LINE-1 transposons; its deposition is strongly enriched at young (〈1.5 million years old) but not old (〉6 million years old) L1 elements. The deposition of N(6)-methyladenine correlates with epigenetic silencing of such LINE-1 transposons, together with their neighbouring enhancers and genes, thereby resisting the gene activation signals during embryonic stem cell differentiation. As young full-length LINE-1 transposons are strongly enriched on the X chromosome, genes located on the X chromosome are also silenced. Thus, N(6)-methyladenine developed a new role in epigenetic silencing in mammalian evolution distinct from its role in gene activation in other organisms. Our results demonstrate that N(6)-methyladenine constitutes a crucial component of the epigenetic regulation repertoire in mammalian genomes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Tao P -- Wang, Tao -- Seetin, Matthew G -- Lai, Yongquan -- Zhu, Shijia -- Lin, Kaixuan -- Liu, Yifei -- Byrum, Stephanie D -- Mackintosh, Samuel G -- Zhong, Mei -- Tackett, Alan -- Wang, Guilin -- Hon, Lawrence S -- Fang, Gang -- Swenberg, James A -- Xiao, Andrew Z -- P20GM103429/GM/NIGMS NIH HHS/ -- P30 ES010126/ES/NIEHS NIH HHS/ -- P42 ES005948/ES/NIEHS NIH HHS/ -- R01 GM114472-01/GM/NIGMS NIH HHS/ -- R01GM106024/GM/NIGMS NIH HHS/ -- R01GM114205-01/GM/NIGMS NIH HHS/ -- S10OD018445/OD/NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):329-33. doi: 10.1038/nature17640. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Pacific Biosciences, 1380 Willow Road, Menlo Park, California 94025, USA. ; Environmental Sciences &Engineering, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. ; Department of Genetics and Genomic Sciences and Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York 10029, USA. ; Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. ; Yale Stem Cell Center and Department of Cell Biology, Yale School of Medicine, New Haven, Connecticut 06520, USA. ; Department of Molecular Biophysics &Biochemistry, Yale Center for Genome Analysis, Yale 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/27027282" target="_blank"〉PubMed〈/a〉

Description: Haematopoietic stem cells (HSCs) are arguably the most extensively characterized tissue stem cells. Since the identification of HSCs by prospective isolation, complex multi-parameter flow cytometric isolation of phenotypic subsets has facilitated studies on many aspects of HSC biology, including self-renewal, differentiation, ageing, niche, and diversity. Here we demonstrate by unbiased multi-step screening, identification of a single gene, homeobox B5 (Hoxb5, also known as Hox-2.1), with expression in the bone marrow that is limited to long-term (LT)-HSCs in mice. Using a mouse single-colour tri-mCherry reporter driven by endogenous Hoxb5 regulation, we show that only the Hoxb5(+) HSCs exhibit long-term reconstitution capacity after transplantation in primary transplant recipients and, notably, in secondary recipients. Only 7-35% of various previously defined immunophenotypic HSCs are LT-HSCs. Finally, by in situ imaging of mouse bone marrow, we show that 〉94% of LT-HSCs (Hoxb5(+)) are directly attached to VE-cadherin(+) cells, implicating the perivascular space as a near-homogenous location of LT-HSCs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, James Y -- Miyanishi, Masanori -- Wang, Sean K -- Yamazaki, Satoshi -- Sinha, Rahul -- Kao, Kevin S -- Seita, Jun -- Sahoo, Debashis -- Nakauchi, Hiromitsu -- Weissman, Irving L -- F30-HL122096/HL/NHLBI NIH HHS/ -- R01 CA086065/CA/NCI NIH HHS/ -- R01 HL058770/HL/NHLBI NIH HHS/ -- T32 GM007365/GM/NIGMS NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):223-7. doi: 10.1038/nature16943.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; Ludwig Center for Cancer Stem Cell Research and Medicine, Stanford University School of Medicine, Stanford, California 94305, USA. ; Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, 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/26863982" target="_blank"〉PubMed〈/a〉

Description: CD8(+) T cells have a central role in antitumour immunity, but their activity is suppressed in the tumour microenvironment. Reactivating the cytotoxicity of CD8(+) T cells is of great clinical interest in cancer immunotherapy. Here we report a new mechanism by which the antitumour response of mouse CD8(+) T cells can be potentiated by modulating cholesterol metabolism. Inhibiting cholesterol esterification in T cells by genetic ablation or pharmacological inhibition of ACAT1, a key cholesterol esterification enzyme, led to potentiated effector function and enhanced proliferation of CD8(+) but not CD4(+) T cells. This is due to the increase in the plasma membrane cholesterol level of CD8(+) T cells, which causes enhanced T-cell receptor clustering and signalling as well as more efficient formation of the immunological synapse. ACAT1-deficient CD8(+) T cells were better than wild-type CD8(+) T cells at controlling melanoma growth and metastasis in mice. We used the ACAT inhibitor avasimibe, which was previously tested in clinical trials for treating atherosclerosis and showed a good human safety profile, to treat melanoma in mice and observed a good antitumour effect. A combined therapy of avasimibe plus an anti-PD-1 antibody showed better efficacy than monotherapies in controlling tumour progression. ACAT1, an established target for atherosclerosis, is therefore also a potential target for cancer immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851431/" 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/PMC4851431/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Wei -- Bai, Yibing -- Xiong, Ying -- Zhang, Jin -- Chen, Shuokai -- Zheng, Xiaojun -- Meng, Xiangbo -- Li, Lunyi -- Wang, Jing -- Xu, Chenguang -- Yan, Chengsong -- Wang, Lijuan -- Chang, Catharine C Y -- Chang, Ta-Yuan -- Zhang, Ti -- Zhou, Penghui -- Song, Bao-Liang -- Liu, Wanli -- Sun, Shao-cong -- Liu, Xiaolong -- Li, Bo-liang -- Xu, Chenqi -- HL 60306./HL/NHLBI NIH HHS/ -- R01 HL060306/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Mar 31;531(7596):651-5. doi: 10.1038/nature17412. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Science Research Center, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; MOE Key Laboratory of Protein Science, School of Life Sciences, Collaborative Innovation Center for Infectious Diseases, Tsinghua University, Beijing 100084, China. ; Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Haven 03755, USA. ; Rheumatology and Immunology Department of ChangZheng Hospital, Second Military Medical University, Shanghai 200433, China. ; Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou 510060, China. ; College of Life Sciences, Wuhan University, Wuhan, Hubei Province 430072, China. ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA. ; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. ; School of Life Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982734" target="_blank"〉PubMed〈/a〉

Description: Cancer is a disease of ageing. Clinically, aged cancer patients tend to have a poorer prognosis than young. This may be due to accumulated cellular damage, decreases in adaptive immunity, and chronic inflammation. However, the effects of the aged microenvironment on tumour progression have been largely unexplored. Since dermal fibroblasts can have profound impacts on melanoma progression, we examined whether age-related changes in dermal fibroblasts could drive melanoma metastasis and response to targeted therapy. Here we find that aged fibroblasts secrete a Wnt antagonist, sFRP2, which activates a multi-step signalling cascade in melanoma cells that results in a decrease in beta-catenin and microphthalmia-associated transcription factor (MITF), and ultimately the loss of a key redox effector, APE1. Loss of APE1 attenuates the response of melanoma cells to DNA damage induced by reactive oxygen species, rendering the cells more resistant to targeted therapy (vemurafenib). Age-related increases in sFRP2 also augment both angiogenesis and metastasis of melanoma cells. These data provide an integrated view of how fibroblasts in the aged microenvironment contribute to tumour progression, offering new possibilities for the design of therapy for the elderly.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833579/" 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/PMC4833579/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaur, Amanpreet -- Webster, Marie R -- Marchbank, Katie -- Behera, Reeti -- Ndoye, Abibatou -- Kugel, Curtis H 3rd -- Dang, Vanessa M -- Appleton, Jessica -- O'Connell, Michael P -- Cheng, Phil -- Valiga, Alexander A -- Morissette, Rachel -- McDonnell, Nazli B -- Ferrucci, Luigi -- Kossenkov, Andrew V -- Meeth, Katrina -- Tang, Hsin-Yao -- Yin, Xiangfan -- Wood, William H 3rd -- Lehrmann, Elin -- Becker, Kevin G -- Flaherty, Keith T -- Frederick, Dennie T -- Wargo, Jennifer A -- Cooper, Zachary A -- Tetzlaff, Michael T -- Hudgens, Courtney -- Aird, Katherine M -- Zhang, Rugang -- Xu, Xiaowei -- Liu, Qin -- Bartlett, Edmund -- Karakousis, Giorgos -- Eroglu, Zeynep -- Lo, Roger S -- Chan, Matthew -- Menzies, Alexander M -- Long, Georgina V -- Johnson, Douglas B -- Sosman, Jeffrey -- Schilling, Bastian -- Schadendorf, Dirk -- Speicher, David W -- Bosenberg, Marcus -- Ribas, Antoni -- Weeraratna, Ashani T -- P01 CA 114046-06/CA/NCI NIH HHS/ -- P01 CA114046/CA/NCI NIH HHS/ -- P30 CA010815/CA/NCI NIH HHS/ -- P50 CA093372/CA/NCI NIH HHS/ -- R01 CA174746/CA/NCI NIH HHS/ -- R01 CA174746-01/CA/NCI NIH HHS/ -- T32 CA009171/CA/NCI NIH HHS/ -- T32 CA9171-36/CA/NCI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2016 Apr 14;532(7598):250-4. doi: 10.1038/nature17392. Epub 2016 Apr 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wistar Institute, Philadelphia, Pennsylvania 19104, USA. ; University of the Sciences, Philadelphia, Pennsylvania 19104, USA. ; Department of Dermatology, University of Zurich, Zurich CH-8006, Switzerland. ; The National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA. ; Department of Dermatology and Pathology, Yale University, New Haven, Connecticut 06511, USA. ; Massachusetts General Hospital Cancer Center, Developmental Therapeutics, Boston 02114, Massachusetts, USA. ; Department of Surgical Oncology, MD Anderson Cancer Center, Houston, Texas 77030, USA. ; Departments of Surgery and Pathology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Medical Oncology, City of Hope Medical Center, Duarte, California 91010, USA. ; Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles, Los Angeles, California 90095, USA. ; Crown Princess Mary Cancer Centre, Westmead Hospital, Westmead 2145, Australia. ; Melanoma Institute Australia and The University of Sydney, Sydney 2000, Australia. ; Department of Medicine, Vanderbilt University Medical Center, Nashville Tennessee 37232, USA. ; Department of Dermatology, University Hospital, West German Cancer Center, University Duesburg-Essen, Essen, Germany. ; German Cancer Consortium (DKTK), Heidelberg 45127, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27042933" target="_blank"〉PubMed〈/a〉

Description: Endoplasmic reticulum (ER) stress is a major contributor to inflammatory diseases, such as Crohn disease and type 2 diabetes. ER stress induces the unfolded protein response, which involves activation of three transmembrane receptors, ATF6, PERK and IRE1alpha. Once activated, IRE1alpha recruits TRAF2 to the ER membrane to initiate inflammatory responses via the NF-kappaB pathway. Inflammation is commonly triggered when pattern recognition receptors (PRRs), such as Toll-like receptors or nucleotide-binding oligomerization domain (NOD)-like receptors, detect tissue damage or microbial infection. However, it is not clear which PRRs have a major role in inducing inflammation during ER stress. Here we show that NOD1 and NOD2, two members of the NOD-like receptor family of PRRs, are important mediators of ER-stress-induced inflammation in mouse and human cells. The ER stress inducers thapsigargin and dithiothreitol trigger production of the pro-inflammatory cytokine IL-6 in a NOD1/2-dependent fashion. Inflammation and IL-6 production triggered by infection with Brucella abortus, which induces ER stress by injecting the type IV secretion system effector protein VceC into host cells, is TRAF2, NOD1/2 and RIP2-dependent and can be reduced by treatment with the ER stress inhibitor tauroursodeoxycholate or an IRE1alpha kinase inhibitor. The association of NOD1 and NOD2 with pro-inflammatory responses induced by the IRE1alpha/TRAF2 signalling pathway provides a novel link between innate immunity and ER-stress-induced inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869892/" 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/PMC4869892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keestra-Gounder, A Marijke -- Byndloss, Mariana X -- Seyffert, Nubia -- Young, Briana M -- Chavez-Arroyo, Alfredo -- Tsai, April Y -- Cevallos, Stephanie A -- Winter, Maria G -- Pham, Oanh H -- Tiffany, Connor R -- de Jong, Maarten F -- Kerrinnes, Tobias -- Ravindran, Resmi -- Luciw, Paul A -- McSorley, Stephen J -- Baumler, Andreas J -- Tsolis, Renee M -- AI044170/AI/NIAID NIH HHS/ -- AI076246/AI/NIAID NIH HHS/ -- AI076278/AI/NIAID NIH HHS/ -- AI096528/AI/NIAID NIH HHS/ -- AI109799/AI/NIAID NIH HHS/ -- AI112258/AI/NIAID NIH HHS/ -- AI117303/AI/NIAID NIH HHS/ -- GM056765/GM/NIGMS NIH HHS/ -- R01 AI044170/AI/NIAID NIH HHS/ -- R01 AI076246/AI/NIAID NIH HHS/ -- R01 AI076278/AI/NIAID NIH HHS/ -- R01 AI096528/AI/NIAID NIH HHS/ -- R01 AI109799/AI/NIAID NIH HHS/ -- R21 AI112258/AI/NIAID NIH HHS/ -- R21 AI117303/AI/NIAID NIH HHS/ -- R25 GM056765/GM/NIGMS NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):394-7. doi: 10.1038/nature17631. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Microbiology and Immunology, School of Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA. ; Center for Comparative Medicine, Schools of Medicine and Veterinary Medicine, University of California at Davis, One Shields Ave, Davis, California 95616, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007849" target="_blank"〉PubMed〈/a〉

Description: The RAS/MAPK (mitogen-activated protein kinase) signalling pathway is frequently deregulated in non-small-cell lung cancer, often through KRAS activating mutations. A single endogenous mutant Kras allele is sufficient to promote lung tumour formation in mice but malignant progression requires additional genetic alterations. We recently showed that advanced lung tumours from Kras(G12D/+);p53-null mice frequently exhibit Kras(G12D) allelic enrichment (Kras(G12D)/Kras(wild-type) 〉 1) (ref. 7), implying that mutant Kras copy gains are positively selected during progression. Here we show, through a comprehensive analysis of mutant Kras homozygous and heterozygous mouse embryonic fibroblasts and lung cancer cells, that these genotypes are phenotypically distinct. In particular, Kras(G12D/G12D) cells exhibit a glycolytic switch coupled to increased channelling of glucose-derived metabolites into the tricarboxylic acid cycle and glutathione biosynthesis, resulting in enhanced glutathione-mediated detoxification. This metabolic rewiring is recapitulated in mutant KRAS homozygous non-small-cell lung cancer cells and in vivo, in spontaneous advanced murine lung tumours (which display a high frequency of Kras(G12D) copy gain), but not in the corresponding early tumours (Kras(G12D) heterozygous). Finally, we demonstrate that mutant Kras copy gain creates unique metabolic dependences that can be exploited to selectively target these aggressive mutant Kras tumours. Our data demonstrate that mutant Kras lung tumours are not a single disease but rather a heterogeneous group comprising two classes of tumours with distinct metabolic profiles, prognosis and therapeutic susceptibility, which can be discriminated on the basis of their relative mutant allelic content. We also provide the first, to our knowledge, in vivo evidence of metabolic rewiring during lung cancer malignant progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4780242/" 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/PMC4780242/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kerr, Emma M -- Gaude, Edoardo -- Turrell, Frances K -- Frezza, Christian -- Martins, Carla P -- MC_UU_12022/4/Medical Research Council/United Kingdom -- MC_UU_12022/6/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2016 Mar 3;531(7592):110-3. doi: 10.1038/nature16967. Epub 2016 Feb 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Cancer Unit, University of Cambridge, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26909577" target="_blank"〉PubMed〈/a〉

Description: Brown and beige adipose tissues can dissipate chemical energy as heat through thermogenic respiration, which requires uncoupling protein 1 (UCP1). Thermogenesis from these adipocytes can combat obesity and diabetes, encouraging investigation of factors that control UCP1-dependent respiration in vivo. Here we show that acutely activated thermogenesis in brown adipose tissue is defined by a substantial increase in levels of mitochondrial reactive oxygen species (ROS). Remarkably, this process supports in vivo thermogenesis, as pharmacological depletion of mitochondrial ROS results in hypothermia upon cold exposure, and inhibits UCP1-dependent increases in whole-body energy expenditure. We further establish that thermogenic ROS alter the redox status of cysteine thiols in brown adipose tissue to drive increased respiration, and that Cys253 of UCP1 is a key target. UCP1 Cys253 is sulfenylated during thermogenesis, while mutation of this site desensitizes the purine-nucleotide-inhibited state of the carrier to adrenergic activation and uncoupling. These studies identify mitochondrial ROS induction in brown adipose tissue as a mechanism that supports UCP1-dependent thermogenesis and whole-body energy expenditure, which opens the way to improved therapeutic strategies for combating metabolic disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chouchani, Edward T -- Kazak, Lawrence -- Jedrychowski, Mark P -- Lu, Gina Z -- Erickson, Brian K -- Szpyt, John -- Pierce, Kerry A -- Laznik-Bogoslavski, Dina -- Vetrivelan, Ramalingam -- Clish, Clary B -- Robinson, Alan J -- Gygi, Steve P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2016 Apr 7;532(7597):112-6. doi: 10.1038/nature17399. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA. ; Department of Neurology, Harvard Medical School, Boston, Massachusetts 02215, USA. ; MRC Mitochondrial Biology Unit, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027295" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chu, Derrick M -- Aagaard, Kjersti M -- England -- Nature. 2016 Apr 21;532(7599):316-7. doi: 10.1038/nature17887. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Departments of Molecular and Human Genetics, Molecular and Cell Biology, and Molecular Physiology and Biophysics, Baylor College of Medicine.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074514" target="_blank"〉PubMed〈/a〉

Description: Cerebral cavernous malformations (CCMs) are common inherited and sporadic vascular malformations that cause strokes and seizures in younger individuals. CCMs arise from endothelial cell loss of KRIT1, CCM2 or PDCD10, non-homologous proteins that form an adaptor complex. How disruption of the CCM complex results in disease remains controversial, with numerous signalling pathways (including Rho, SMAD and Wnt/beta-catenin) and processes such as endothelial-mesenchymal transition (EndMT) proposed to have causal roles. CCM2 binds to MEKK3 (refs 7, 8, 9, 10, 11), and we have recently shown that CCM complex regulation of MEKK3 is essential during vertebrate heart development. Here we investigate this mechanism in CCM disease pathogenesis. Using a neonatal mouse model of CCM disease, we show that expression of the MEKK3 target genes Klf2 and Klf4, as well as Rho and ADAMTS protease activity, are increased in the endothelial cells of early CCM lesions. By contrast, we find no evidence of EndMT or increased SMAD or Wnt signalling during early CCM formation. Endothelial-specific loss of Map3k3 (also known as Mekk3), Klf2 or Klf4 markedly prevents lesion formation, reverses the increase in Rho activity, and rescues lethality. Consistent with these findings in mice, we show that endothelial expression of KLF2 and KLF4 is increased in human familial and sporadic CCM lesions, and that a disease-causing human CCM2 mutation abrogates the MEKK3 interaction without affecting CCM complex formation. These studies identify gain of MEKK3 signalling and KLF2/4 function as causal mechanisms for CCM pathogenesis that may be targeted to develop new CCM therapeutics.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4864035/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Zinan -- Tang, Alan T -- Wong, Weng-Yew -- Bamezai, Sharika -- Goddard, Lauren M -- Shenkar, Robert -- Zhou, Su -- Yang, Jisheng -- Wright, Alexander C -- Foley, Matthew -- Arthur, J Simon C -- Whitehead, Kevin J -- Awad, Issam A -- Li, Dean Y -- Zheng, Xiangjian -- Kahn, Mark L -- P01 HL075215/HL/NHLBI NIH HHS/ -- P01 HL120846/HL/NHLBI NIH HHS/ -- P01 NS092521/NS/NINDS NIH HHS/ -- P01NS092521/NS/NINDS NIH HHS/ -- R01 HL094326/HL/NHLBI NIH HHS/ -- R01HL-084516/HL/NHLBI NIH HHS/ -- R01HL094326/HL/NHLBI NIH HHS/ -- R01NS075168/NS/NINDS NIH HHS/ -- T32HL07439/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 7;532(7597):122-6. doi: 10.1038/nature17178. Epub 2016 Mar 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 3400 Civic Center Blvd, Philadelphia, Pennsylvania 19104, USA. ; Laboratory of Cardiovascular Signaling, Centenary Institute, Sydney, New South Wales 2050, Australia. ; Neurovascular Surgery Program, Section of Neurosurgery, Department of Surgery, The University of Chicago Medicine and Biological Sciences, Chicago, Illinois 60637, USA. ; Department of Radiology, University of Pennsylvania Medical Center, 3400 Spruce Street, Philadelphia, Pennsylvania 19104, USA. ; Sydney Microscopy &Microanalysis, University of Sydney, Sydney, New South Wales 2050, Australia. ; Division of Cell Signaling and Immunology, University of Dundee, Dundee DD1 5EH, UK. ; Division of Cardiovascular Medicine and the Program in Molecular Medicine, University of Utah, Salt Lake City, Utah 84112, USA. ; The Key Laboratory for Human Disease Gene Study of Sichuan Province, Institute of Laboratory Medicine, Sichuan Academy of Medical Sciences &Sichuan Provincial People's Hospital, Chengdu, Sichuan 610072, China. ; Faculty of Medicine, Sydney Medical School, University of Sydney, Sydney, New South Wales 2050, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27027284" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2016 Feb 18;530(7590):264. doi: 10.1038/nature.2016.19335.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887470" target="_blank"〉PubMed〈/a〉

Description: Chronic opiate use induces opiate dependence, which is characterized by extremely unpleasant physical and emotional feelings after drug use is terminated. Both the rewarding effects of a drug and the desire to avoid withdrawal symptoms motivate continued drug use, and the nucleus accumbens is important for orchestrating both processes. While multiple inputs to the nucleus accumbens regulate reward, little is known about the nucleus accumbens circuitry underlying withdrawal. Here we identify the paraventricular nucleus of the thalamus as a prominent input to the nucleus accumbens mediating the expression of opiate-withdrawal-induced physical signs and aversive memory. Activity in the paraventricular nucleus of the thalamus to nucleus accumbens pathway is necessary and sufficient to mediate behavioural aversion. Selectively silencing this pathway abolishes aversive symptoms in two different mouse models of opiate withdrawal. Chronic morphine exposure selectively potentiates excitatory transmission between the paraventricular nucleus of the thalamus and D2-receptor-expressing medium spiny neurons via synaptic insertion of GluA2-lacking AMPA receptors. Notably, in vivo optogenetic depotentiation restores normal transmission at these synapses and robustly suppresses morphine withdrawal symptoms. This links morphine-evoked pathway- and cell-type-specific plasticity in the paraventricular nucleus of the thalamus to nucleus accumbens circuit to opiate dependence, and suggests that reprogramming this circuit holds promise for treating opiate addiction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Yingjie -- Wienecke, Carl F R -- Nachtrab, Gregory -- Chen, Xiaoke -- 5T32DA035165-02/DA/NIDA NIH HHS/ -- T32 DA035165/DA/NIDA NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):219-22. doi: 10.1038/nature16954. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840481" target="_blank"〉PubMed〈/a〉

Description: The integrated stress response (ISR) is a homeostatic mechanism by which eukaryotic cells sense and respond to stress-inducing signals, such as amino acid starvation. General controlled non-repressed (GCN2) kinase is a key orchestrator of the ISR, and modulates protein synthesis in response to amino acid starvation. Here we demonstrate in mice that GCN2 controls intestinal inflammation by suppressing inflammasome activation. Enhanced activation of ISR was observed in intestinal antigen presenting cells (APCs) and epithelial cells during amino acid starvation, or intestinal inflammation. Genetic deletion of Gcn2 (also known as Eif2ka4) in CD11c(+) APCs or intestinal epithelial cells resulted in enhanced intestinal inflammation and T helper 17 cell (TH17) responses, owing to enhanced inflammasome activation and interleukin (IL)-1beta production. This was caused by reduced autophagy in Gcn2(-/-) intestinal APCs and epithelial cells, leading to increased reactive oxygen species (ROS), a potent activator of inflammasomes. Thus, conditional ablation of Atg5 or Atg7 in intestinal APCs resulted in enhanced ROS and TH17 responses. Furthermore, in vivo blockade of ROS and IL-1beta resulted in inhibition of TH17 responses and reduced inflammation in Gcn2(-/-) mice. Importantly, acute amino acid starvation suppressed intestinal inflammation via a mechanism dependent on GCN2. These results reveal a mechanism that couples amino acid sensing with control of intestinal inflammation via GCN2.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854628/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ravindran, Rajesh -- Loebbermann, Jens -- Nakaya, Helder I -- Khan, Nooruddin -- Ma, Hualing -- Gama, Leonardo -- Machiah, Deepa K -- Lawson, Benton -- Hakimpour, Paul -- Wang, Yi-chong -- Li, Shuzhao -- Sharma, Prachi -- Kaufman, Randal J -- Martinez, Jennifer -- Pulendran, Bali -- R01 DK088227/DK/NIDDK NIH HHS/ -- R01 DK103185/DK/NIDDK NIH HHS/ -- R37 AI048638/AI/NIAID NIH HHS/ -- R37 DK042394/DK/NIDDK NIH HHS/ -- R37 DK057665/DK/NIDDK NIH HHS/ -- U19 AI057266/AI/NIAID NIH HHS/ -- U19 AI090023/AI/NIAID NIH HHS/ -- ZIA ES103286-01/Intramural NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):523-7. doi: 10.1038/nature17186. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Emory Vaccine Center, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; School of Pharmaceutical Sciences, University of Sao Paulo, Sao Paulo 05508, Brazil. ; Department of Biotechnology and Bioinformatics, School of Life Sciences, University of Hyderabad, Hyderabad 500 046, India. ; Division of Pathology, Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Virology Core, Emory Vaccine Center and Yerkes National Primate Research Center, 954 Gatewood Road, Atlanta, Georgia 30329, USA. ; Degenerative Disease Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 North Torrey Pines Road, La Jolla, California 92037 USA. ; National Institute of Environmental Health Sciences, Mail Drop D2-01 Research Triangle Park, North Carolina 27709, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982722" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reardon, Sara -- England -- Nature. 2016 May 5;533(7601):15-6. doi: 10.1038/533015a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27147010" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2016 Feb 18;530(7590):254. doi: 10.1038/530254a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26887455" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wagner, Erwin F -- England -- Nature. 2016 Feb 4;530(7588):42-3. doi: 10.1038/530042a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Cancer Research Centre (CNIO), Department of Cancer Cell Biology, E-28029 Madrid, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26842052" target="_blank"〉PubMed〈/a〉

Description: The eye is a complex organ with highly specialized constituent tissues derived from different primordial cell lineages. The retina, for example, develops from neuroectoderm via the optic vesicle, the corneal epithelium is descended from surface ectoderm, while the iris and collagen-rich stroma of the cornea have a neural crest origin. Recent work with pluripotent stem cells in culture has revealed a previously under-appreciated level of intrinsic cellular self-organization, with a focus on the retina and retinal cells. Moreover, we and others have demonstrated the in vitro induction of a corneal epithelial cell phenotype from pluripotent stem cells. These studies, however, have a single, tissue-specific focus and fail to reflect the complexity of whole eye development. Here we demonstrate the generation from human induced pluripotent stem cells of a self-formed ectodermal autonomous multi-zone (SEAM) of ocular cells. In some respects the concentric SEAM mimics whole-eye development because cell location within different zones is indicative of lineage, spanning the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. It thus represents a promising resource for new and ongoing studies of ocular morphogenesis. The approach also has translational potential and to illustrate this we show that cells isolated from the ocular surface ectodermal zone of the SEAM can be sorted and expanded ex vivo to form a corneal epithelium that recovers function in an experimentally induced animal model of corneal blindness.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayashi, Ryuhei -- Ishikawa, Yuki -- Sasamoto, Yuzuru -- Katori, Ryosuke -- Nomura, Naoki -- Ichikawa, Tatsuya -- Araki, Saori -- Soma, Takeshi -- Kawasaki, Satoshi -- Sekiguchi, Kiyotoshi -- Quantock, Andrew J -- Tsujikawa, Motokazu -- Nishida, Kohji -- England -- Nature. 2016 Mar 17;531(7594):376-80. doi: 10.1038/nature17000. Epub 2016 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Stem Cells and Applied Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan. ; Laboratory of Extracellular Matrix Biochemistry, Institute for Protein Research, Osaka University, Suita, Osaka 565-0871, Japan. ; Structural Biophysics Group, School of Optometry and Vision Sciences, College of Biomedical and Life Sciences, Cardiff University, Cardiff CF24 4HQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26958835" target="_blank"〉PubMed〈/a〉

Description: Inflammasomes are intracellular protein complexes that drive the activation of inflammatory caspases. So far, four inflammasomes involving NLRP1, NLRP3, NLRC4 and AIM2 have been described that recruit the common adaptor protein ASC to activate caspase-1, leading to the secretion of mature IL-1beta and IL-18 proteins. The NLRP3 inflammasome has been implicated in the pathogenesis of several acquired inflammatory diseases as well as cryopyrin-associated periodic fever syndromes (CAPS) caused by inherited NLRP3 mutations. Potassium efflux is a common step that is essential for NLRP3 inflammasome activation induced by many stimuli. Despite extensive investigation, the molecular mechanism leading to NLRP3 activation in response to potassium efflux remains unknown. Here we report the identification of NEK7, a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL-1beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the CAPS-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimaeras reconstituted with wild-type, Nek7(-/-) or Nlrp3(-/-) haematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. These studies demonstrate that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉He, Yuan -- Zeng, Melody Y -- Yang, Dahai -- Motro, Benny -- Nunez, Gabriel -- R01AI063331/AI/NIAID NIH HHS/ -- R01DK091191/DK/NIDDK NIH HHS/ -- T32 HL007517/HL/NHLBI NIH HHS/ -- T32DK094775/DK/NIDDK NIH HHS/ -- T32HL007517/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Feb 18;530(7590):354-7. doi: 10.1038/nature16959. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA. ; The State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. ; The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan 52900, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814970" target="_blank"〉PubMed〈/a〉

Description: Lung metastasis is the lethal determinant in many cancers and a number of lines of evidence point to monocytes and macrophages having key roles in its development. Yet little is known about the immediate fate of incoming tumour cells as they colonize this tissue, and even less known about how they make first contact with the immune system. Primary tumours liberate circulating tumour cells (CTCs) into the blood and we have developed a stable intravital two-photon lung imaging model in mice for direct observation of the arrival of CTCs and subsequent host interaction. Here we show dynamic generation of tumour microparticles in shear flow in the capillaries within minutes of CTC entry. Rather than dispersing under flow, many of these microparticles remain attached to the lung vasculature or independently migrate along the inner walls of vessels. Using fluorescent lineage reporters and flow cytometry, we observed 'waves' of distinct myeloid cell subsets that load differentially and sequentially with this CTC-derived material. Many of these tumour-ingesting myeloid cells collectively accumulated in the lung interstitium along with the successful metastatic cells and, as previously understood, promote the development of successful metastases from surviving tumour cells. Although the numbers of these cells rise globally in the lung with metastatic exposure and ingesting myeloid cells undergo phenotypic changes associated with microparticle ingestion, a consistently sparse population of resident conventional dendritic cells, among the last cells to interact with CTCs, confer anti-metastatic protection. This work reveals that CTC fragmentation generates immune-interacting intermediates, and defines a competitive relationship between phagocyte populations for tumour loading during metastatic cell seeding.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Headley, Mark B -- Bins, Adriaan -- Nip, Alyssa -- Roberts, Edward W -- Looney, Mark R -- Gerard, Audrey -- Krummel, Matthew F -- P01 HL024136/HL/NHLBI NIH HHS/ -- R21 CA167601/CA/NCI NIH HHS/ -- R21CA167601/CA/NCI NIH HHS/ -- U54 CA163123/CA/NCI NIH HHS/ -- England -- Nature. 2016 Mar 24;531(7595):513-7. doi: 10.1038/nature16985. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, University of California, San Francisco, 513 Parnassus Ave, HSW512, San Francisco, California 94143-0511, USA. ; Department of Medical Oncology, Academic Medical Center Amsterdam, Meibergdreef, 91105AZ Amsterdam, The Netherlands. ; Departments of Medicine and Laboratory Medicine, University of California, San Francisco, 513 Parnassus Avenue, HSW512, California 94143-0511, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982733" target="_blank"〉PubMed〈/a〉

Description: Blood vessels define local microenvironments in the skeletal system, play crucial roles in osteogenesis and provide niches for haematopoietic stem cells. The properties of niche-forming vessels and their changes in the ageing organism remain incompletely understood. Here we show that Notch signalling in endothelial cells leads to the expansion of haematopoietic stem cell niches in bone, which involves increases in CD31-positive capillaries and platelet-derived growth factor receptor-beta (PDGFRbeta)-positive perivascular cells, arteriole formation and elevated levels of cellular stem cell factor. Although endothelial hypoxia-inducible factor signalling promotes some of these changes, it fails to enhance vascular niche function because of a lack of arterialization and expansion of PDGFRbeta-positive cells. In ageing mice, niche-forming vessels in the skeletal system are strongly reduced but can be restored by activation of endothelial Notch signalling. These findings indicate that vascular niches for haematopoietic stem cells are part of complex, age-dependent microenvironments involving multiple cell populations and vessel subtypes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kusumbe, Anjali P -- Ramasamy, Saravana K -- Itkin, Tomer -- Mae, Maarja Andaloussi -- Langen, Urs H -- Betsholtz, Christer -- Lapidot, Tsvee -- Adams, Ralf H -- England -- Nature. 2016 Apr 21;532(7599):380-4. doi: 10.1038/nature17638. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max-Planck-Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, and University of Munster, Faculty of Medicine, D-48149 Munster, Germany. ; Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ; Vascular Biology Program, Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden. ; Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles vag 2, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074508" target="_blank"〉PubMed〈/a〉

Description: The DNA-binding protein PRDM9 directs positioning of the double-strand breaks (DSBs) that initiate meiotic recombination in mice and humans. Prdm9 is the only mammalian speciation gene yet identified and is responsible for sterility phenotypes in male hybrids of certain mouse subspecies. To investigate PRDM9 binding and its role in fertility and meiotic recombination, we humanized the DNA-binding domain of PRDM9 in C57BL/6 mice. This change repositions DSB hotspots and completely restores fertility in male hybrids. Here we show that alteration of one Prdm9 allele impacts the behaviour of DSBs controlled by the other allele at chromosome-wide scales. These effects correlate strongly with the degree to which each PRDM9 variant binds both homologues at the DSB sites it controls. Furthermore, higher genome-wide levels of such 'symmetric' PRDM9 binding associate with increasing fertility measures, and comparisons of individual hotspots suggest binding symmetry plays a downstream role in the recombination process. These findings reveal that subspecies-specific degradation of PRDM9 binding sites by meiotic drive, which steadily increases asymmetric PRDM9 binding, has impacts beyond simply changing hotspot positions, and strongly support a direct involvement in hybrid infertility. Because such meiotic drive occurs across mammals, PRDM9 may play a wider, yet transient, role in the early stages of speciation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756437/" 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/PMC4756437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Davies, Benjamin -- Hatton, Edouard -- Altemose, Nicolas -- Hussin, Julie G -- Pratto, Florencia -- Zhang, Gang -- Hinch, Anjali Gupta -- Moralli, Daniela -- Biggs, Daniel -- Diaz, Rebeca -- Preece, Chris -- Li, Ran -- Bitoun, Emmanuelle -- Brick, Kevin -- Green, Catherine M -- Camerini-Otero, R Daniel -- Myers, Simon R -- Donnelly, Peter -- 090532/Z/09/Z/Wellcome Trust/United Kingdom -- 095552/Z/11/Z/Wellcome Trust/United Kingdom -- 098387/Z/12/Z/Wellcome Trust/United Kingdom -- Intramural NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):171-6. doi: 10.1038/nature16931. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, University of Oxford, Oxford OX3 7BN, UK. ; Department of Statistics, University of Oxford, 24-29 St. Giles', Oxford OX1 3LB, UK. ; Genetics and Biochemistry Branch, National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840484" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ward, Alyssa -- Baldwin, Thomas O -- Antin, Parker B -- England -- Nature. 2016 Apr 14;532(7598):177. doi: 10.1038/532177d.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. ; University of California, Riverside, USA. ; University of Arizona, Tucson, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075087" target="_blank"〉PubMed〈/a〉

Description: Primary cilia are solitary, generally non-motile, hair-like protrusions that extend from the surface of cells between cell divisions. Their antenna-like structure leads naturally to the assumption that they sense the surrounding environment, the most common hypothesis being sensation of mechanical force through calcium-permeable ion channels within the cilium. This Ca(2+)-responsive mechanosensor hypothesis for primary cilia has been invoked to explain a large range of biological responses, from control of left-right axis determination in embryonic development to adult progression of polycystic kidney disease and some cancers. Here we report the complete lack of mechanically induced calcium increases in primary cilia, in tissues upon which this hypothesis has been based. We developed a transgenic mouse, Arl13b-mCherry-GECO1.2, expressing a ratiometric genetically encoded calcium indicator in all primary cilia. We then measured responses to flow in primary cilia of cultured kidney epithelial cells, kidney thick ascending tubules, crown cells of the embryonic node, kinocilia of inner ear hair cells, and several cell lines. Cilia-specific Ca(2+) influxes were not observed in physiological or even highly supraphysiological levels of fluid flow. We conclude that mechanosensation, if it originates in primary cilia, is not via calcium signalling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4851444/" 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/PMC4851444/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delling, M -- Indzhykulian, A A -- Liu, X -- Li, Y -- Xie, T -- Corey, D P -- Clapham, D E -- 5R01 DC000304/DC/NIDCD NIH HHS/ -- P30-HD 18655/HD/NICHD NIH HHS/ -- R01 DC000304/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 31;531(7596):656-60. doi: 10.1038/nature17426. Epub 2016 Mar 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cardiology, Howard Hughes Medical Institute, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Image and Data Analysis Core (IDAC), Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27007841" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2016 Apr 14;532(7598):162-4. doi: 10.1038/532162a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27075078" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2016 Mar 17;531(7594):294-7. doi: 10.1038/531294a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26983522" target="_blank"〉PubMed〈/a〉

Description: Medulloblastoma is a highly malignant paediatric brain tumour, often inflicting devastating consequences on the developing child. Genomic studies have revealed four distinct molecular subgroups with divergent biology and clinical behaviour. An understanding of the regulatory circuitry governing the transcriptional landscapes of medulloblastoma subgroups, and how this relates to their respective developmental origins, is lacking. Here, using H3K27ac and BRD4 chromatin immunoprecipitation followed by sequencing (ChIP-seq) coupled with tissue-matched DNA methylation and transcriptome data, we describe the active cis-regulatory landscape across 28 primary medulloblastoma specimens. Analysis of differentially regulated enhancers and super-enhancers reinforced inter-subgroup heterogeneity and revealed novel, clinically relevant insights into medulloblastoma biology. Computational reconstruction of core regulatory circuitry identified a master set of transcription factors, validated by ChIP-seq, that is responsible for subgroup divergence, and implicates candidate cells of origin for Group 4. Our integrated analysis of enhancer elements in a large series of primary tumour samples reveals insights into cis-regulatory architecture, unrecognized dependencies, and cellular origins.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lin, Charles Y -- Erkek, Serap -- Tong, Yiai -- Yin, Linlin -- Federation, Alexander J -- Zapatka, Marc -- Haldipur, Parthiv -- Kawauchi, Daisuke -- Risch, Thomas -- Warnatz, Hans-Jorg -- Worst, Barbara C -- Ju, Bensheng -- Orr, Brent A -- Zeid, Rhamy -- Polaski, Donald R -- Segura-Wang, Maia -- Waszak, Sebastian M -- Jones, David T W -- Kool, Marcel -- Hovestadt, Volker -- Buchhalter, Ivo -- Sieber, Laura -- Johann, Pascal -- Chavez, Lukas -- Groschel, Stefan -- Ryzhova, Marina -- Korshunov, Andrey -- Chen, Wenbiao -- Chizhikov, Victor V -- Millen, Kathleen J -- Amstislavskiy, Vyacheslav -- Lehrach, Hans -- Yaspo, Marie-Laure -- Eils, Roland -- Lichter, Peter -- Korbel, Jan O -- Pfister, Stefan M -- Bradner, James E -- Northcott, Paul A -- England -- Nature. 2016 Feb 4;530(7588):57-62. doi: 10.1038/nature16546. Epub 2016 Jan 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Medical Oncology, Dana Farber Cancer Institute (DFCI), Boston, Massachusetts 02215, USA. ; Genome Biology Unit, European Molecular Biology Laboratory (EMBL), 69117 Heidelberg, Germany. ; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Molecular Physiology &Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37212, USA. ; Division of Molecular Genetics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, Washington 98105, USA. ; Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Bone Marrow Transplantation &Cellular Therapy, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Translational Oncology, NCT Heidelberg, 69120 Heidelberg, Germany. ; Department of Neuropathology, NN Burdenko Neurosurgical Institute, 125047 Moscow, Russia. ; Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), and Department of Neuropathology University Hospital, 69120 Heidelberg, Germany. ; Department of Anatomy and Neurobiology, University of Tennessee Health Sciences Center, Memphis, Tennessee 38163, USA. ; Department of Pediatrics, Genetics Division, University of Washington, Seattle, Washington 98195, USA. ; Institute of Pharmacy and Molecular Biotechnology and BioQuant, University of Heidelberg, 69117 Heidelberg, Germany. ; Department of Pediatrics, University of Heidelberg, 69117 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26814967" target="_blank"〉PubMed〈/a〉

Description: Mutations disabling the TP53 tumour suppressor gene represent the most frequent events in human cancer and typically occur through a two-hit mechanism involving a missense mutation in one allele and a 'loss of heterozygosity' deletion encompassing the other. While TP53 missense mutations can also contribute gain-of-function activities that impact tumour progression, it remains unclear whether the deletion event, which frequently includes many genes, impacts tumorigenesis beyond TP53 loss alone. Here we show that somatic heterozygous deletion of mouse chromosome 11B3, a 4-megabase region syntenic to human 17p13.1, produces a greater effect on lymphoma and leukaemia development than Trp53 deletion. Mechanistically, the effect of 11B3 loss on tumorigenesis involves co-deleted genes such as Eif5a and Alox15b (also known as Alox8), the suppression of which cooperates with Trp53 loss to produce more aggressive disease. Our results imply that the selective advantage produced by human chromosome 17p deletion reflects the combined impact of TP53 loss and the reduced dosage of linked tumour suppressor genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836395/" 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/PMC4836395/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Yu -- Chen, Chong -- Xu, Zhengmin -- Scuoppo, Claudio -- Rillahan, Cory D -- Gao, Jianjiong -- Spitzer, Barbara -- Bosbach, Benedikt -- Kastenhuber, Edward R -- Baslan, Timour -- Ackermann, Sarah -- Cheng, Lihua -- Wang, Qingguo -- Niu, Ting -- Schultz, Nikolaus -- Levine, Ross L -- Mills, Alea A -- Lowe, Scott W -- P30 CA008748/CA/NCI NIH HHS/ -- P30 CA016042/CA/NCI NIH HHS/ -- R01 CA190261/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 24;531(7595):471-5. doi: 10.1038/nature17157. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology and Department of Liver Surgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China. ; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Institute for Cancer Genetics, Columbia University Medical Center, New York, New York 10032, USA. ; Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Human Oncology &Pathogenesis Program and Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hematology &Research Laboratory of Hematology, West China Hospital, Sichuan University, Chengdu 610041, China. ; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. ; Howard Hughes Medical Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982726" target="_blank"〉PubMed〈/a〉

Description: The gut is home to trillions of microorganisms that have fundamental roles in many aspects of human biology, including immune function and metabolism. The reduced diversity of the gut microbiota in Western populations compared to that in populations living traditional lifestyles presents the question of which factors have driven microbiota change during modernization. Microbiota-accessible carbohydrates (MACs) found in dietary fibre have a crucial involvement in shaping this microbial ecosystem, and are notably reduced in the Western diet (high in fat and simple carbohydrates, low in fibre) compared with a more traditional diet. Here we show that changes in the microbiota of mice consuming a low-MAC diet and harbouring a human microbiota are largely reversible within a single generation. However, over several generations, a low-MAC diet results in a progressive loss of diversity, which is not recoverable after the reintroduction of dietary MACs. To restore the microbiota to its original state requires the administration of missing taxa in combination with dietary MAC consumption. Our data illustrate that taxa driven to low abundance when dietary MACs are scarce are inefficiently transferred to the next generation, and are at increased risk of becoming extinct within an isolated population. As more diseases are linked to the Western microbiota and the microbiota is targeted therapeutically, microbiota reprogramming may need to involve strategies that incorporate dietary MACs as well as taxa not currently present in the Western gut.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sonnenburg, Erica D -- Smits, Samuel A -- Tikhonov, Mikhail -- Higginbottom, Steven K -- Wingreen, Ned S -- Sonnenburg, Justin L -- R01-DK085025/DK/NIDDK NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):212-5. doi: 10.1038/nature16504.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305, USA. ; Harvard John A. Paulson School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts 02138, USA. ; Kavli Institute for Bionano Science and Technology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA. ; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762459" target="_blank"〉PubMed〈/a〉

Description: Haematopoietic stem cells (HSCs), which sustain production of all blood cell lineages, rely on glycolysis for ATP production, yet little attention has been paid to the role of mitochondria. Here we show in mice that the short isoform of a critical regulator of HSCs, Prdm16 (refs 4, 5), induces mitofusin 2 (Mfn2), a protein involved in mitochondrial fusion and in tethering of mitochondria to the endoplasmic reticulum. Overexpression and deletion studies, including single-cell transplantation assays, revealed that Mfn2 is specifically required for the maintenance of HSCs with extensive lymphoid potential, but not, or less so, for the maintenance of myeloid-dominant HSCs. Mfn2 increased buffering of intracellular Ca(2+), an effect mediated through its endoplasmic reticulum-mitochondria tethering activity, thereby negatively regulating nuclear translocation and transcriptional activity of nuclear factor of activated T cells (Nfat). Nfat inhibition rescued the effects of Mfn2 deletion in HSCs, demonstrating that negative regulation of Nfat is the prime downstream mechanism of Mfn2 in the maintenance of HSCs with extensive lymphoid potential. Mitochondria therefore have an important role in HSCs. These findings provide a mechanism underlying clonal heterogeneity among HSCs and may lead to the design of approaches to bias HSC differentiation into desired lineages after transplantation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Luchsinger, Larry L -- de Almeida, Mariana Justino -- Corrigan, David J -- Mumau, Melanie -- Snoeck, Hans-Willem -- 1S10OD020056-01/OD/NIH HHS/ -- 1S10RR027050-01/RR/NCRR NIH HHS/ -- F31 CA196045/CA/NCI NIH HHS/ -- R01 AG029262/AG/NIA NIH HHS/ -- R01 CA167286/CA/NCI NIH HHS/ -- England -- Nature. 2016 Jan 28;529(7587):528-31. doi: 10.1038/nature16500. Epub 2016 Jan 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Columbia Center for Translational Immunology, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Microbiology and Immunology, 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/26789249" target="_blank"〉PubMed〈/a〉

Description: During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garcia-Prat, Laura -- Martinez-Vicente, Marta -- Perdiguero, Eusebio -- Ortet, Laura -- Rodriguez-Ubreva, Javier -- Rebollo, Elena -- Ruiz-Bonilla, Vanessa -- Gutarra, Susana -- Ballestar, Esteban -- Serrano, Antonio L -- Sandri, Marco -- Munoz-Canoves, Pura -- England -- Nature. 2016 Jan 7;529(7584):37-42. doi: 10.1038/nature16187.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University (UPF), CIBER on Neurodegenerative diseases (CIBERNED), E-08003 Barcelona, Spain. ; Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-CIBERNED, E-08035 Barcelona, Spain. ; Chromatin and Disease Group, Cancer Epigenetics and Biology Programme (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, E-08907 Barcelona, Spain. ; Advanced Fluorescence Microscopy Unit, Molecular Biology Institute of Barcelona (IBMB-CSIC), E-08028 Barcelona, Spain. ; Department of Biomedical Science, University of Padova, 35100 Padova, Italy. ; Telethon Institute of Genetics and Medicine (TIGEM), 80131 Napoli, Italy. ; ICREA, E-08908 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26738589" target="_blank"〉PubMed〈/a〉

Description: Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Non-alcoholic fatty liver disease (NAFLD) affects a large proportion of the US population and is considered to be a metabolic predisposition to liver cancer. However, the role of adaptive immune responses in NAFLD-promoted HCC is largely unknown. Here we show, in mouse models and human samples, that dysregulation of lipid metabolism in NAFLD causes a selective loss of intrahepatic CD4(+) but not CD8(+) T lymphocytes, leading to accelerated hepatocarcinogenesis. We also demonstrate that CD4(+) T lymphocytes have greater mitochondrial mass than CD8(+) T lymphocytes and generate higher levels of mitochondrially derived reactive oxygen species (ROS). Disruption of mitochondrial function by linoleic acid, a fatty acid accumulated in NAFLD, causes more oxidative damage than other free fatty acids such as palmitic acid, and mediates selective loss of intrahepatic CD4(+) T lymphocytes. In vivo blockade of ROS reversed NAFLD-induced hepatic CD4(+) T lymphocyte decrease and delayed NAFLD-promoted HCC. Our results provide an unexpected link between lipid dysregulation and impaired anti-tumour surveillance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786464/" 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/PMC4786464/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ma, Chi -- Kesarwala, Aparna H -- Eggert, Tobias -- Medina-Echeverz, Jose -- Kleiner, David E -- Jin, Ping -- Stroncek, David F -- Terabe, Masaki -- Kapoor, Veena -- ElGindi, Mei -- Han, Miaojun -- Thornton, Angela M -- Zhang, Haibo -- Egger, Michele -- Luo, Ji -- Felsher, Dean W -- McVicar, Daniel W -- Weber, Achim -- Heikenwalder, Mathias -- Greten, Tim F -- ZIA BC011345-06/Intramural NIH HHS/ -- ZIABC011303/PHS HHS/ -- England -- Nature. 2016 Mar 10;531(7593):253-7. doi: 10.1038/nature16969. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Cell Processing Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Laboratory of Cancer Biology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Institute of Surgical Pathology, University and University Hospital Zurich, Zurich 8091, Switzerland. ; Division of Oncology, Department of Medicine and Pathology, Stanford University, California 94305, USA. ; Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland 21702, USA. ; Institute of Virology, Technische Universitat Munchen/Helmholtz Zentrum Munchen, Munich 81675, Germany. ; Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934227" target="_blank"〉PubMed〈/a〉

Description: Cellular senescence, a stress-induced irreversible growth arrest often characterized by expression of p16(Ink4a) (encoded by the Ink4a/Arf locus, also known as Cdkn2a) and a distinctive secretory phenotype, prevents the proliferation of preneoplastic cells and has beneficial roles in tissue remodelling during embryogenesis and wound healing. Senescent cells accumulate in various tissues and organs over time, and have been speculated to have a role in ageing. To explore the physiological relevance and consequences of naturally occurring senescent cells, here we use a previously established transgene, INK-ATTAC, to induce apoptosis in p16(Ink4a)-expressing cells of wild-type mice by injection of AP20187 twice a week starting at one year of age. We show that compared to vehicle alone, AP20187 treatment extended median lifespan in both male and female mice of two distinct genetic backgrounds. The clearance of p16(Ink4a)-positive cells delayed tumorigenesis and attenuated age-related deterioration of several organs without apparent side effects, including kidney, heart and fat, where clearance preserved the functionality of glomeruli, cardio-protective KATP channels and adipocytes, respectively. Thus, p16(Ink4a)-positive cells that accumulate during adulthood negatively influence lifespan and promote age-dependent changes in several organs, and their therapeutic removal may be an attractive approach to extend healthy lifespan.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Darren J -- Childs, Bennett G -- Durik, Matej -- Wijers, Melinde E -- Sieben, Cynthia J -- Zhong, Jian -- Saltness, Rachel A -- Jeganathan, Karthik B -- Verzosa, Grace Casaclang -- Pezeshki, Abdulmohammad -- Khazaie, Khashayarsha -- Miller, Jordan D -- van Deursen, Jan M -- AG041122/AG/NIA NIH HHS/ -- HL111121/HL/NHLBI NIH HHS/ -- P01 AG041122/AG/NIA NIH HHS/ -- R01 CA096985/CA/NCI NIH HHS/ -- R01CA96985/CA/NCI NIH HHS/ -- England -- Nature. 2016 Feb 11;530(7589):184-9. doi: 10.1038/nature16932. Epub 2016 Feb 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Division of Cardiovascular Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. ; Department of Immunology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26840489" target="_blank"〉PubMed〈/a〉

Description: The vertebrate brain is highly complex, but its evolutionary origin remains elusive. Because of the absence of certain developmental domains generally marked by the expression of regulatory genes, the embryonic brain of the lamprey, a jawless vertebrate, had been regarded as representing a less complex, ancestral state of the vertebrate brain. Specifically, the absence of a Hedgehog- and Nkx2.1-positive domain in the lamprey subpallium was thought to be similar to mouse mutants in which the suppression of Nkx2-1 leads to a loss of the medial ganglionic eminence. Here we show that the brain of the inshore hagfish (Eptatretus burgeri), another cyclostome group, develops domains equivalent to the medial ganglionic eminence and rhombic lip, resembling the gnathostome brain. Moreover, further investigation of lamprey larvae revealed that these domains are also present, ruling out the possibility of convergent evolution between hagfish and gnathostomes. Thus, brain regionalization as seen in crown gnathostomes is not an evolutionary innovation of this group, but dates back to the latest vertebrate ancestor before the divergence of cyclostomes and gnathostomes more than 500 million years ago.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sugahara, Fumiaki -- Pascual-Anaya, Juan -- Oisi, Yasuhiro -- Kuraku, Shigehiro -- Aota, Shin-ichi -- Adachi, Noritaka -- Takagi, Wataru -- Hirai, Tamami -- Sato, Noboru -- Murakami, Yasunori -- Kuratani, Shigeru -- England -- Nature. 2016 Mar 3;531(7592):97-100. doi: 10.1038/nature16518. Epub 2016 Feb 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Evolutionary Morphology Laboratory, RIKEN, Kobe 650-0047, Japan. ; Division of Biology, Hyogo College of Medicine, Nishinomiya 663-8501, Japan. ; Development and Function of Inhibitory Neural Circuits, Max Planck Florida Institute for Neuroscience, Jupiter, Florida 33458, USA. ; Phyloinformatics Unit, RIKEN Center for Life Science Technologies, Kobe 650-0047, Japan. ; Department of Organismal Biology and Anatomy, University of Chicago, Chicago, Illinois 60637, USA. ; Division of Gross Anatomy and Morphogenesis, Niigata University Graduate School of Medical and Dental Sciences, Niigata 950-8510, Japan. ; Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26878236" target="_blank"〉PubMed〈/a〉

Description: Identifying key molecules that launch regeneration has been a long-sought goal. Multiple regenerative animals show an initial wound-associated proliferative response that transits into sustained proliferation if a considerable portion of the body part has been removed. In the axolotl, appendage amputation initiates a round of wound-associated cell cycle induction followed by continued proliferation that is dependent on nerve-derived signals. A wound-associated molecule that triggers the initial proliferative response to launch regeneration has remained obscure. Here, using an expression cloning strategy followed by in vivo gain- and loss-of-function assays, we identified axolotl MARCKS-like protein (MLP) as an extracellularly released factor that induces the initial cell cycle response during axolotl appendage regeneration. The identification of a regeneration-initiating molecule opens the possibility of understanding how to elicit regeneration in other animals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4795554/" 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/PMC4795554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sugiura, Takuji -- Wang, Heng -- Barsacchi, Rico -- Simon, Andras -- Tanaka, Elly M -- England -- Nature. 2016 Mar 10;531(7593):237-40. doi: 10.1038/nature16974.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉DFG Research Center for Regenerative Therapies (CRTD), Technische Universitat Dresden, Fetscherstrasse 105, 01307 Dresden, Germany. ; Max Planck Institute for Molecular Cell Biology and Genetics, Pfotenhauerstrasse 108, 01307 Dresden, Germany. ; Karolinska Institute, Department of Cell and Molecular Biology, Centre of Developmental Biology for Regenerative Medicine, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934225" target="_blank"〉PubMed〈/a〉

Description: Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Ralpha-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Ralpha signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gerbe, Francois -- Sidot, Emmanuelle -- Smyth, Danielle J -- Ohmoto, Makoto -- Matsumoto, Ichiro -- Dardalhon, Valerie -- Cesses, Pierre -- Garnier, Laure -- Pouzolles, Marie -- Brulin, Benedicte -- Bruschi, Marco -- Harcus, Yvonne -- Zimmermann, Valerie S -- Taylor, Naomi -- Maizels, Rick M -- Jay, Philippe -- 106122/Wellcome Trust/United Kingdom -- P30DC011735/DC/NIDCD NIH HHS/ -- England -- Nature. 2016 Jan 14;529(7585):226-30. doi: 10.1038/nature16527.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, UMR-5203, Institut de Genomique Fonctionnelle, F-34094 Montpellier, France. ; INSERM, U1191, F-34094 Montpellier, France. ; Universite de Montpellier, F-34000 Montpellier, France. ; Institute of Immunology and Infection Research, School of Biological Sciences and Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh EH9 3JT, UK. ; Monell Chemical Senses Center, 3500 Market Street, Philadelphia, Pennsylvania 19104, USA. ; Institut de Genetique Moleculaire de Montpellier, CNRS, UMR5535, F-34293 Montpellier, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26762460" target="_blank"〉PubMed〈/a〉

Description: Defects in clearance of dying cells have been proposed to underlie the pathogenesis of systemic lupus erythematosus (SLE). Mice lacking molecules associated with dying cell clearance develop SLE-like disease, and phagocytes from patients with SLE often display defective clearance and increased inflammatory cytokine production when exposed to dying cells in vitro. Previously, we and others described a form of noncanonical autophagy known as LC3-associated phagocytosis (LAP), in which phagosomes containing engulfed particles, including dying cells, recruit elements of the autophagy pathway to facilitate maturation of phagosomes and digestion of their contents. Genome-wide association studies have identified polymorphisms in the Atg5 (ref. 8) and possibly Atg7 (ref. 9) genes, involved in both canonical autophagy and LAP, as markers of a predisposition for SLE. Here we describe the consequences of defective LAP in vivo. Mice lacking any of several components of the LAP pathway show increased serum levels of inflammatory cytokines and autoantibodies, glomerular immune complex deposition, and evidence of kidney damage. When dying cells are injected into LAP-deficient mice, they are engulfed but not efficiently degraded and trigger acute elevation of pro-inflammatory cytokines but not anti-inflammatory interleukin (IL)-10. Repeated injection of dying cells into LAP-deficient, but not LAP-sufficient, mice accelerated the development of SLE-like disease, including increased serum levels of autoantibodies. By contrast, mice deficient in genes required for canonical autophagy but not LAP do not display defective dying cell clearance, inflammatory cytokine production, or SLE-like disease, and, like wild-type mice, produce IL-10 in response to dying cells. Therefore, defects in LAP, rather than canonical autophagy, can cause SLE-like phenomena, and may contribute to the pathogenesis of SLE.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860026/" 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/PMC4860026/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martinez, Jennifer -- Cunha, Larissa D -- Park, Sunmin -- Yang, Mao -- Lu, Qun -- Orchard, Robert -- Li, Quan-Zhen -- Yan, Mei -- Janke, Laura -- Guy, Cliff -- Linkermann, Andreas -- Virgin, Herbert W -- Green, Douglas R -- 1ZIAES10328601/PHS HHS/ -- R01 AI040646/AI/NIAID NIH HHS/ -- R01 AI40646/AI/NIAID NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- ZIA ES103286-01/Intramural NIH HHS/ -- England -- Nature. 2016 May 5;533(7601):115-9. doi: 10.1038/nature17950. Epub 2016 Apr 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Immunity, Inflammation, and Disease Laboratory, National Institute of Environmental Health Sciences, 111 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Division of Nephrology and Hypertension, Christian-Albrechts-University, Kiel 24105, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27096368" target="_blank"〉PubMed〈/a〉

Description: Author: Jake Yeston

Description: Author: Jake Yeston

Description: Piezo proteins are evolutionarily conserved and functionally diverse mechanosensitive cation channels. However, the overall structural architecture and gating mechanisms of Piezo channels have remained unknown. Here we determine the cryo-electron microscopy structure of the full-length (2,547 amino acids) mouse Piezo1 (Piezo1) at a resolution of 4.8 A. Piezo1 forms a trimeric propeller-like structure (about 900 kilodalton), with the extracellular domains resembling three distal blades and a central cap. The transmembrane region has 14 apparently resolved segments per subunit. These segments form three peripheral wings and a central pore module that encloses a potential ion-conducting pore. The rather flexible extracellular blade domains are connected to the central intracellular domain by three long beam-like structures. This trimeric architecture suggests that Piezo1 may use its peripheral regions as force sensors to gate the central ion-conducting pore.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ge, Jingpeng -- Li, Wanqiu -- Zhao, Qiancheng -- Li, Ningning -- Chen, Maofei -- Zhi, Peng -- Li, Ruochong -- Gao, Ning -- Xiao, Bailong -- Yang, Maojun -- England -- Nature. 2015 Nov 5;527(7576):64-9. doi: 10.1038/nature15247. Epub 2015 Sep 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences or Medicine, Tsinghua University, Beijing 100084, China. ; Ministry of Education, Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China. ; Department of Pharmacology and Pharmaceutical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China. ; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26390154" target="_blank"〉PubMed〈/a〉

Description: Epithelial regeneration is critical for barrier maintenance and organ function after intestinal injury. The intestinal stem cell (ISC) niche provides Wnt, Notch and epidermal growth factor (EGF) signals supporting Lgr5(+) crypt base columnar ISCs for normal epithelial maintenance. However, little is known about the regulation of the ISC compartment after tissue damage. Using ex vivo organoid cultures, here we show that innate lymphoid cells (ILCs), potent producers of interleukin-22 (IL-22) after intestinal injury, increase the growth of mouse small intestine organoids in an IL-22-dependent fashion. Recombinant IL-22 directly targeted ISCs, augmenting the growth of both mouse and human intestinal organoids, increasing proliferation and promoting ISC expansion. IL-22 induced STAT3 phosphorylation in Lgr5(+) ISCs, and STAT3 was crucial for both organoid formation and IL-22-mediated regeneration. Treatment with IL-22 in vivo after mouse allogeneic bone marrow transplantation enhanced the recovery of ISCs, increased epithelial regeneration and reduced intestinal pathology and mortality from graft-versus-host disease. ATOH1-deficient organoid culture demonstrated that IL-22 induced epithelial regeneration independently of the Paneth cell niche. Our findings reveal a fundamental mechanism by which the immune system is able to support the intestinal epithelium, activating ISCs to promote regeneration.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4720437/" 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/PMC4720437/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lindemans, Caroline A -- Calafiore, Marco -- Mertelsmann, Anna M -- O'Connor, Margaret H -- Dudakov, Jarrod A -- Jenq, Robert R -- Velardi, Enrico -- Young, Lauren F -- Smith, Odette M -- Lawrence, Gillian -- Ivanov, Juliet A -- Fu, Ya-Yuan -- Takashima, Shuichiro -- Hua, Guoqiang -- Martin, Maria L -- O'Rourke, Kevin P -- Lo, Yuan-Hung -- Mokry, Michal -- Romera-Hernandez, Monica -- Cupedo, Tom -- Dow, Lukas E -- Nieuwenhuis, Edward E -- Shroyer, Noah F -- Liu, Chen -- Kolesnick, Richard -- van den Brink, Marcel R M -- Hanash, Alan M -- HHSN272200900059C/PHS HHS/ -- K08 HL115355/HL/NHLBI NIH HHS/ -- K08-HL115355/HL/NHLBI NIH HHS/ -- K99 CA176376/CA/NCI NIH HHS/ -- K99-CA176376/CA/NCI NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P01-CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- P30-CA008748/CA/NCI NIH HHS/ -- R01 AI080455/AI/NIAID NIH HHS/ -- R01 AI100288/AI/NIAID NIH HHS/ -- R01 AI101406/AI/NIAID NIH HHS/ -- R01 HL069929/HL/NHLBI NIH HHS/ -- R01 HL125571/HL/NHLBI NIH HHS/ -- R01-AI080455/AI/NIAID NIH HHS/ -- R01-AI100288/AI/NIAID NIH HHS/ -- R01-AI101406/AI/NIAID NIH HHS/ -- R01-HL069929/HL/NHLBI NIH HHS/ -- R01-HL125571/HL/NHLBI NIH HHS/ -- U19 AI116497/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):560-4. doi: 10.1038/nature16460. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pediatrics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands. ; Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Anatomy and Developmental Biology, Monash University, Clayton 3800, Australia. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Cancer Biology &Genetics, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Baylor College of Medicine, Houston, Texas 77030, USA. ; Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands. ; Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, Gainesville, Florida 32610, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649819" target="_blank"〉PubMed〈/a〉

Description: Thirst is the basic instinct to drink water. Previously, it was shown that neurons in several circumventricular organs of the hypothalamus are activated by thirst-inducing conditions. Here we identify two distinct, genetically separable neural populations in the subfornical organ that trigger or suppress thirst. We show that optogenetic activation of subfornical organ excitatory neurons, marked by the expression of the transcription factor ETV-1, evokes intense drinking behaviour, and does so even in fully water-satiated animals. The light-induced response is highly specific for water, immediate and strictly locked to the laser stimulus. In contrast, activation of a second population of subfornical organ neurons, marked by expression of the vesicular GABA transporter VGAT, drastically suppresses drinking, even in water-craving thirsty animals. These results reveal an innate brain circuit that can turn an animal's water-drinking behaviour on and off, and probably functions as a centre for thirst control in the mammalian brain.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401619/" 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/PMC4401619/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oka, Yuki -- Ye, Mingyu -- Zuker, Charles S -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 16;520(7547):349-52. doi: 10.1038/nature14108. Epub 2015 Jan 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA [2] Department of Neuroscience, Columbia College of Physicians and Surgeons, Howard Hughes Medical Institute, Columbia University, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25624099" target="_blank"〉PubMed〈/a〉

Description: The regulated release of anorexigenic alpha-melanocyte stimulating hormone (alpha-MSH) and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the central nervous system has a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data show that alpha-MSH is an agonist that couples the receptor to the Galphas signalling pathway, while AgRP binds competitively to block alpha-MSH binding and blocks the constitutive activity mediated by the ligand-mimetic amino-terminal domain of the receptor. Here we show that, in mice, regulation of firing activity of neurons from the paraventricular nucleus of the hypothalamus (PVN) by alpha-MSH and AgRP can be mediated independently of Galphas signalling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Furthermore, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of alpha-MSH binding. Consequently, Kir7.1 signalling appears to be central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signalling, including the gene dosage effect of MC4R and the sustained effects of AgRP on food intake.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383680/" 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/PMC4383680/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ghamari-Langroudi, Masoud -- Digby, Gregory J -- Sebag, Julien A -- Millhauser, Glenn L -- Palomino, Rafael -- Matthews, Robert -- Gillyard, Taneisha -- Panaro, Brandon L -- Tough, Iain R -- Cox, Helen M -- Denton, Jerod S -- Cone, Roger D -- 5R01 DK082884-03/DK/NIDDK NIH HHS/ -- DK020593/DK/NIDDK NIH HHS/ -- F31 DK102343/DK/NIDDK NIH HHS/ -- P30 DK020593/DK/NIDDK NIH HHS/ -- R01 DK064265/DK/NIDDK NIH HHS/ -- R01 DK070332/DK/NIDDK NIH HHS/ -- R01DK064265/DK/NIDDK NIH HHS/ -- R01DK070332/DK/NIDDK NIH HHS/ -- R25 GM059994/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):94-8. doi: 10.1038/nature14051. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. ; Department of Chemistry &Biochemistry, University of California, Santa Cruz, California 95064, USA. ; 1] Department of Molecular Physiology &Biophysics, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Meharry Medical College, Nashville, Tennessee 37208, USA. ; King's College London, Wolfson Centre for Age-Related Diseases, Guy's Campus, London SE1 1UL, UK. ; 1] Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA [2] Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600267" target="_blank"〉PubMed〈/a〉

Description: Alzheimer's disease (AD) is a severe age-related neurodegenerative disorder characterized by accumulation of amyloid-beta plaques and neurofibrillary tangles, synaptic and neuronal loss, and cognitive decline. Several genes have been implicated in AD, but chromatin state alterations during neurodegeneration remain uncharacterized. Here we profile transcriptional and chromatin state dynamics across early and late pathology in the hippocampus of an inducible mouse model of AD-like neurodegeneration. We find a coordinated downregulation of synaptic plasticity genes and regulatory regions, and upregulation of immune response genes and regulatory regions, which are targeted by factors that belong to the ETS family of transcriptional regulators, including PU.1. Human regions orthologous to increasing-level enhancers show immune-cell-specific enhancer signatures as well as immune cell expression quantitative trait loci, while decreasing-level enhancer orthologues show fetal-brain-specific enhancer activity. Notably, AD-associated genetic variants are specifically enriched in increasing-level enhancer orthologues, implicating immune processes in AD predisposition. Indeed, increasing enhancers overlap known AD loci lacking protein-altering variants, and implicate additional loci that do not reach genome-wide significance. Our results reveal new insights into the mechanisms of neurodegeneration and establish the mouse as a useful model for functional studies of AD regulatory regions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530583/" 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/PMC4530583/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gjoneska, Elizabeta -- Pfenning, Andreas R -- Mathys, Hansruedi -- Quon, Gerald -- Kundaje, Anshul -- Tsai, Li-Huei -- Kellis, Manolis -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 NS078839/NS/NINDS NIH HHS/ -- R01HG004037-07/HG/NHGRI NIH HHS/ -- R01NS078839/NS/NINDS NIH HHS/ -- RC1 HG005334/HG/NHGRI NIH HHS/ -- RC1HG005334/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Feb 19;518(7539):365-9. doi: 10.1038/nature14252.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Genetics, Department of Computer Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25693568" target="_blank"〉PubMed〈/a〉

Description: Intracellular energy distribution has attracted much interest and has been proposed to occur in skeletal muscle via metabolite-facilitated diffusion; however, genetic evidence suggests that facilitated diffusion is not critical for normal function. We hypothesized that mitochondrial structure minimizes metabolite diffusion distances in skeletal muscle. Here we demonstrate a mitochondrial reticulum providing a conductive pathway for energy distribution, in the form of the proton-motive force, throughout the mouse skeletal muscle cell. Within this reticulum, we find proteins associated with mitochondrial proton-motive force production preferentially in the cell periphery and proteins that use the proton-motive force for ATP production in the cell interior near contractile and transport ATPases. Furthermore, we show a rapid, coordinated depolarization of the membrane potential component of the proton-motive force throughout the cell in response to spatially controlled uncoupling of the cell interior. We propose that membrane potential conduction via the mitochondrial reticulum is the dominant pathway for skeletal muscle energy distribution.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Glancy, Brian -- Hartnell, Lisa M -- Malide, Daniela -- Yu, Zu-Xi -- Combs, Christian A -- Connelly, Patricia S -- Subramaniam, Sriram -- Balaban, Robert S -- Intramural NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):617-20. doi: 10.1038/nature14614.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26223627" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Delude, Cathryn M -- England -- Nature. 2015 Nov 5;527(7576):S14-5. doi: 10.1038/527S14a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536218" target="_blank"〉PubMed〈/a〉

Description: FOXP3(+) regulatory T cells (Treg cells) prevent autoimmunity by limiting the effector activity of T cells that have escaped thymic negative selection or peripheral inactivation. Despite the information available about molecular factors mediating the suppressive function of Treg cells, the relevant cellular events in intact tissues remain largely unexplored, and whether Treg cells prevent activation of self-specific T cells or primarily limit damage from such cells has not been determined. Here we use multiplex, quantitative imaging in mice to show that, within secondary lymphoid tissues, highly suppressive Treg cells expressing phosphorylated STAT5 exist in discrete clusters with rare IL-2-positive T cells that are activated by self-antigens. This local IL-2 induction of STAT5 phosphorylation in Treg cells is part of a feedback circuit that limits further autoimmune responses. Inducible ablation of T cell receptor expression by Treg cells reduces their regulatory capacity and disrupts their localization in clusters, resulting in uncontrolled effector T cell responses. Our data thus reveal that autoreactive T cells are activated to cytokine production on a regular basis, with physically co-clustering T cell receptor-stimulated Treg cells responding in a negative feedback manner to suppress incipient autoimmunity and maintain immune homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702500/" 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/PMC4702500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Zhiduo -- Gerner, Michael Y -- Van Panhuys, Nicholas -- Levine, Andrew G -- Rudensky, Alexander Y -- Germain, Ronald N -- R37 AI034206/AI/NIAID NIH HHS/ -- R37AI034206/AI/NIAID NIH HHS/ -- T32GM007739/GM/NIGMS NIH HHS/ -- Z01 AI000403-25/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 10;528(7581):225-30. doi: 10.1038/nature16169. Epub 2015 Nov 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Biology Section, Laboratory of Systems Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1892, USA. ; Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26605524" target="_blank"〉PubMed〈/a〉

Description: Stem cells integrate inputs from multiple sources. Stem cell niches provide signals that promote stem cell maintenance, while differentiated daughter cells are known to provide feedback signals to regulate stem cell replication and differentiation. Recently, stem cells have been shown to regulate themselves using an autocrine mechanism. The existence of a 'stem cell niche' was first postulated by Schofield in 1978 to define local environments necessary for the maintenance of haematopoietic stem cells. Since then, an increasing body of work has focused on defining stem cell niches. Yet little is known about how progenitor cell and differentiated cell numbers and proportions are maintained. In the airway epithelium, basal cells function as stem/progenitor cells that can both self-renew and produce differentiated secretory cells and ciliated cells. Secretory cells also act as transit-amplifying cells that eventually differentiate into post-mitotic ciliated cells . Here we describe a mode of cell regulation in which adult mammalian stem/progenitor cells relay a forward signal to their own progeny. Surprisingly, this forward signal is shown to be necessary for daughter cell maintenance. Using a combination of cell ablation, lineage tracing and signalling pathway modulation, we show that airway basal stem/progenitor cells continuously supply a Notch ligand to their daughter secretory cells. Without these forward signals, the secretory progenitor cell pool fails to be maintained and secretory cells execute a terminal differentiation program and convert into ciliated cells. Thus, a parent stem/progenitor cell can serve as a functional daughter cell niche.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521991/" 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/PMC4521991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pardo-Saganta, Ana -- Tata, Purushothama Rao -- Law, Brandon M -- Saez, Borja -- Chow, Ryan Dz-Wei -- Prabhu, Mythili -- Gridley, Thomas -- Rajagopal, Jayaraj -- 5P30HL101287-02/HL/NHLBI NIH HHS/ -- R01 HL118185/HL/NHLBI NIH HHS/ -- R01HL118185/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 30;523(7562):597-601. doi: 10.1038/nature14553. Epub 2015 Jul 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Departments of Internal Medicine and Pediatrics, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA. ; 1] Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Stem Cell and Regenerative Biology Department, Harvard University, Cambridge, Massachusetts 02138, USA. ; Center for Molecular Medicine, Maine Medical Center Research Institute, 81 Research Drive, Scarborough, Maine 04074, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26147083" target="_blank"〉PubMed〈/a〉

Description: Autism is a multifactorial neurodevelopmental disorder affecting more males than females; consequently, under a multifactorial genetic hypothesis, females are affected only when they cross a higher biological threshold. We hypothesize that deleterious variants at conserved residues are enriched in severely affected patients arising from female-enriched multiplex families with severe disease, enhancing the detection of key autism genes in modest numbers of cases. Here we show the use of this strategy by identifying missense and dosage sequence variants in the gene encoding the adhesive junction-associated delta-catenin protein (CTNND2) in female-enriched multiplex families and demonstrating their loss-of-function effect by functional analyses in zebrafish embryos and cultured hippocampal neurons from wild-type and Ctnnd2 null mouse embryos. Finally, through gene expression and network analyses, we highlight a critical role for CTNND2 in neuronal development and an intimate connection to chromatin biology. Our data contribute to the understanding of the genetic architecture of autism and suggest that genetic analyses of phenotypic extremes, such as female-enriched multiplex families, are of innate value in multifactorial disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4383723/" 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/PMC4383723/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Turner, Tychele N -- Sharma, Kamal -- Oh, Edwin C -- Liu, Yangfan P -- Collins, Ryan L -- Sosa, Maria X -- Auer, Dallas R -- Brand, Harrison -- Sanders, Stephan J -- Moreno-De-Luca, Daniel -- Pihur, Vasyl -- Plona, Teri -- Pike, Kristen -- Soppet, Daniel R -- Smith, Michael W -- Cheung, Sau Wai -- Martin, Christa Lese -- State, Matthew W -- Talkowski, Michael E -- Cook, Edwin -- Huganir, Richard -- Katsanis, Nicholas -- Chakravarti, Aravinda -- 1U24MH081810/MH/NIMH NIH HHS/ -- 5R25MH071584-07/MH/NIMH NIH HHS/ -- MH095867/MH/NIMH NIH HHS/ -- MH19961-14/MH/NIMH NIH HHS/ -- R00 MH095867/MH/NIMH NIH HHS/ -- R01 DK075972/DK/NIDDK NIH HHS/ -- R01 MH060007/MH/NIMH NIH HHS/ -- R01 MH074090/MH/NIMH NIH HHS/ -- R01MH074090/MH/NIMH NIH HHS/ -- R01MH081754/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):51-6. doi: 10.1038/nature14186. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Predoctoral Training Program in Human Genetics and Molecular Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [3] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Center for Human Disease Modeling, Duke University, Durham, North Carolina 27710, USA. ; Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Center for Complex Disease Genomics, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA. ; 1] Center for Human Genetic Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114 USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, University of California, San Francisco, San Francisco, California 94158, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Department of Psychiatry, Yale University, New Haven, Connecticut 06511, USA. ; Leidos Biomedical Research, Inc., Frederick, Maryland 21702, USA. ; National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] National Institute of Mental Health (NIMH) Autism Centers of Excellence (ACE) Genetics Consortium at the University of California, Los Angeles, Los Angeles, California 90095, USA [2] Autism &Developmental Medicine Institute, Geisinger Health System, Lewisburg, Pennsylvania 17837, USA. ; University of Illinois at Chicago, Chicago, Illinois 60608, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807484" target="_blank"〉PubMed〈/a〉

Description: Immune checkpoint inhibitors result in impressive clinical responses, but optimal results will require combination with each other and other therapies. This raises fundamental questions about mechanisms of non-redundancy and resistance. Here we report major tumour regressions in a subset of patients with metastatic melanoma treated with an anti-CTLA4 antibody (anti-CTLA4) and radiation, and reproduced this effect in mouse models. Although combined treatment improved responses in irradiated and unirradiated tumours, resistance was common. Unbiased analyses of mice revealed that resistance was due to upregulation of PD-L1 on melanoma cells and associated with T-cell exhaustion. Accordingly, optimal response in melanoma and other cancer types requires radiation, anti-CTLA4 and anti-PD-L1/PD-1. Anti-CTLA4 predominantly inhibits T-regulatory cells (Treg cells), thereby increasing the CD8 T-cell to Treg (CD8/Treg) ratio. Radiation enhances the diversity of the T-cell receptor (TCR) repertoire of intratumoral T cells. Together, anti-CTLA4 promotes expansion of T cells, while radiation shapes the TCR repertoire of the expanded peripheral clones. Addition of PD-L1 blockade reverses T-cell exhaustion to mitigate depression in the CD8/Treg ratio and further encourages oligoclonal T-cell expansion. Similarly to results from mice, patients on our clinical trial with melanoma showing high PD-L1 did not respond to radiation plus anti-CTLA4, demonstrated persistent T-cell exhaustion, and rapidly progressed. Thus, PD-L1 on melanoma cells allows tumours to escape anti-CTLA4-based therapy, and the combination of radiation, anti-CTLA4 and anti-PD-L1 promotes response and immunity through distinct mechanisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4401634/" 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/PMC4401634/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Twyman-Saint Victor, Christina -- Rech, Andrew J -- Maity, Amit -- Rengan, Ramesh -- Pauken, Kristen E -- Stelekati, Erietta -- Benci, Joseph L -- Xu, Bihui -- Dada, Hannah -- Odorizzi, Pamela M -- Herati, Ramin S -- Mansfield, Kathleen D -- Patsch, Dana -- Amaravadi, Ravi K -- Schuchter, Lynn M -- Ishwaran, Hemant -- Mick, Rosemarie -- Pryma, Daniel A -- Xu, Xiaowei -- Feldman, Michael D -- Gangadhar, Tara C -- Hahn, Stephen M -- Wherry, E John -- Vonderheide, Robert H -- Minn, Andy J -- KL2TR000139/TR/NCATS NIH HHS/ -- P01AI112521/AI/NIAID NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- P30CA016520/CA/NCI NIH HHS/ -- P50 CA174523/CA/NCI NIH HHS/ -- P50CA174523/CA/NCI NIH HHS/ -- R01 AI105343/AI/NIAID NIH HHS/ -- R01 CA158186/CA/NCI NIH HHS/ -- R01 CA163739/CA/NCI NIH HHS/ -- R01AI105343/AI/NIAID NIH HHS/ -- R01CA158186/CA/NCI NIH HHS/ -- R01CA163739/CA/NCI NIH HHS/ -- R01CA172651/CA/NCI NIH HHS/ -- T32DK007066/DK/NIDDK NIH HHS/ -- U01AI095608/AI/NIAID NIH HHS/ -- U19 AI082630/AI/NIAID NIH HHS/ -- U19AI082630/AI/NIAID NIH HHS/ -- UL1RR024134/RR/NCRR NIH HHS/ -- England -- Nature. 2015 Apr 16;520(7547):373-7. doi: 10.1038/nature14292. Epub 2015 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Division of Biostatistics, Department of Public Health Sciences, University of Miami, Miami, Florida 33136, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [2] Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [3] Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA [4] Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25754329" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bourzac, Katherine -- England -- Nature. 2015 Dec 17;528(7582):S134-6. doi: 10.1038/528S134a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26672788" target="_blank"〉PubMed〈/a〉

Description: Oncogenic activation of BRAF fuels cancer growth by constitutively promoting RAS-independent mitogen-activated protein kinase (MAPK) pathway signalling. Accordingly, RAF inhibitors have brought substantially improved personalized treatment of metastatic melanoma. However, these targeted agents have also revealed an unexpected consequence: stimulated growth of certain cancers. Structurally diverse ATP-competitive RAF inhibitors can either inhibit or paradoxically activate the MAPK pathway, depending whether activation is by BRAF mutation or by an upstream event, such as RAS mutation or receptor tyrosine kinase activation. Here we have identified next-generation RAF inhibitors (dubbed 'paradox breakers') that suppress mutant BRAF cells without activating the MAPK pathway in cells bearing upstream activation. In cells that express the same HRAS mutation prevalent in squamous tumours from patients treated with RAF inhibitors, the first-generation RAF inhibitor vemurafenib stimulated in vitro and in vivo growth and induced expression of MAPK pathway response genes; by contrast the paradox breakers PLX7904 and PLX8394 had no effect. Paradox breakers also overcame several known mechanisms of resistance to first-generation RAF inhibitors. Dissociating MAPK pathway inhibition from paradoxical activation might yield both improved safety and more durable efficacy than first-generation RAF inhibitors, a concept currently undergoing human clinical evaluation with PLX8394.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chao -- Spevak, Wayne -- Zhang, Ying -- Burton, Elizabeth A -- Ma, Yan -- Habets, Gaston -- Zhang, Jiazhong -- Lin, Jack -- Ewing, Todd -- Matusow, Bernice -- Tsang, Garson -- Marimuthu, Adhirai -- Cho, Hanna -- Wu, Guoxian -- Wang, Weiru -- Fong, Daniel -- Nguyen, Hoa -- Shi, Songyuan -- Womack, Patrick -- Nespi, Marika -- Shellooe, Rafe -- Carias, Heidi -- Powell, Ben -- Light, Emily -- Sanftner, Laura -- Walters, Jason -- Tsai, James -- West, Brian L -- Visor, Gary -- Rezaei, Hamid -- Lin, Paul S -- Nolop, Keith -- Ibrahim, Prabha N -- Hirth, Peter -- Bollag, Gideon -- England -- Nature. 2015 Oct 22;526(7574):583-6. doi: 10.1038/nature14982. Epub 2015 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26466569" target="_blank"〉PubMed〈/a〉

Description: The endoplasmic reticulum (ER) is the largest intracellular endomembrane system, enabling protein and lipid synthesis, ion homeostasis, quality control of newly synthesized proteins and organelle communication. Constant ER turnover and modulation is needed to meet different cellular requirements and autophagy has an important role in this process. However, its underlying regulatory mechanisms remain unexplained. Here we show that members of the FAM134 reticulon protein family are ER-resident receptors that bind to autophagy modifiers LC3 and GABARAP, and facilitate ER degradation by autophagy ('ER-phagy'). Downregulation of FAM134B protein in human cells causes an expansion of the ER, while FAM134B overexpression results in ER fragmentation and lysosomal degradation. Mutant FAM134B proteins that cause sensory neuropathy in humans are unable to act as ER-phagy receptors. Consistently, disruption of Fam134b in mice causes expansion of the ER, inhibits ER turnover, sensitizes cells to stress-induced apoptotic cell death and leads to degeneration of sensory neurons. Therefore, selective ER-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khaminets, Aliaksandr -- Heinrich, Theresa -- Mari, Muriel -- Grumati, Paolo -- Huebner, Antje K -- Akutsu, Masato -- Liebmann, Lutz -- Stolz, Alexandra -- Nietzsche, Sandor -- Koch, Nicole -- Mauthe, Mario -- Katona, Istvan -- Qualmann, Britta -- Weis, Joachim -- Reggiori, Fulvio -- Kurth, Ingo -- Hubner, Christian A -- Dikic, Ivan -- England -- Nature. 2015 Jun 18;522(7556):354-8. doi: 10.1038/nature14498. Epub 2015 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. ; Institute of Human Genetics, Jena University Hospital, Friedrich-Schiller-University Jena, Kollegiengasse 10, 07743 Jena, Germany. ; 1] Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands [2] Department of Cell Biology, University Medical Center Utrecht, University of Groningen, Antonious Deusinglaan 1, 3713 AV Groningen, The Netherlands. ; Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany. ; Electron Microscopy Center, Jena University Hospital, Friedrich-Schiller-University Jena, Ziegelmuhlenweg 1, 07743 Jena, Germany. ; Institute for Biochemistry I, Jena University Hospital, Friedrich-Schiller-University Jena, 07743 Jena, Germany. ; Institute of Neuropathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. ; 1] Institute of Biochemistry II, Goethe University School of Medicine, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany [2] Buchmann Institute for Molecular Life Sciences, Goethe University Frankfurt, Riedberg Campus, Max-von-Laue-Strasse 15, 60438 Frankfurt am Main, Germany [3] Institute of Immunology, School of Medicine University of Split, Mestrovicevo setaliste bb, 21 000 Split, Croatia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26040720" target="_blank"〉PubMed〈/a〉

Description: Blood polymorphonuclear neutrophils provide immune protection against pathogens, but may also promote tissue injury in inflammatory diseases. Although neutrophils are generally considered to be a relatively homogeneous population, evidence for heterogeneity is emerging. Under steady-state conditions, neutrophil heterogeneity may arise from ageing and replenishment by newly released neutrophils from the bone marrow. Aged neutrophils upregulate CXCR4, a receptor allowing their clearance in the bone marrow, with feedback inhibition of neutrophil production via the IL-17/G-CSF axis, and rhythmic modulation of the haematopoietic stem-cell niche. The aged subset also expresses low levels of L-selectin. Previous studies have suggested that in vitro-aged neutrophils exhibit impaired migration and reduced pro-inflammatory properties. Here, using in vivo ageing analyses in mice, we show that neutrophil pro-inflammatory activity correlates positively with their ageing whilst in circulation. Aged neutrophils represent an overly active subset exhibiting enhanced alphaMbeta2 integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Neutrophil ageing is driven by the microbiota via Toll-like receptor and myeloid differentiation factor 88-mediated signalling pathways. Depletion of the microbiota significantly reduces the number of circulating aged neutrophils and dramatically improves the pathogenesis and inflammation-related organ damage in models of sickle-cell disease or endotoxin-induced septic shock. These results identify a role for the microbiota in regulating a disease-promoting neutrophil subset.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712631/" 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/PMC4712631/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Dachuan -- Chen, Grace -- Manwani, Deepa -- Mortha, Arthur -- Xu, Chunliang -- Faith, Jeremiah J -- Burk, Robert D -- Kunisaki, Yuya -- Jang, Jung-Eun -- Scheiermann, Christoph -- Merad, Miriam -- Frenette, Paul S -- R01 CA154947/CA/NCI NIH HHS/ -- R01 CA173861/CA/NCI NIH HHS/ -- R01 CA190400/CA/NCI NIH HHS/ -- R01 DK056638/DK/NIDDK NIH HHS/ -- R01 HL069438/HL/NHLBI NIH HHS/ -- R01 HL116340/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Sep 24;525(7570):528-32. doi: 10.1038/nature15367. Epub 2015 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA. ; Department of Oncological Sciences, Mount Sinai School of Medicine, New York, New York 10029, USA. ; The Immunology Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. ; The Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York 10029, USA. ; Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26374999" target="_blank"〉PubMed〈/a〉

Description: Despite antiretroviral therapy (ART), human immunodeficiency virus (HIV)-1 persists in a stable latent reservoir, primarily in resting memory CD4(+) T cells. This reservoir presents a major barrier to the cure of HIV-1 infection. To purge the reservoir, pharmacological reactivation of latent HIV-1 has been proposed and tested both in vitro and in vivo. A key remaining question is whether virus-specific immune mechanisms, including cytotoxic T lymphocytes (CTLs), can clear infected cells in ART-treated patients after latency is reversed. Here we show that there is a striking all or none pattern for CTL escape mutations in HIV-1 Gag epitopes. Unless ART is started early, the vast majority (〉98%) of latent viruses carry CTL escape mutations that render infected cells insensitive to CTLs directed at common epitopes. To solve this problem, we identified CTLs that could recognize epitopes from latent HIV-1 that were unmutated in every chronically infected patient tested. Upon stimulation, these CTLs eliminated target cells infected with autologous virus derived from the latent reservoir, both in vitro and in patient-derived humanized mice. The predominance of CTL-resistant viruses in the latent reservoir poses a major challenge to viral eradication. Our results demonstrate that chronically infected patients retain a broad-spectrum viral-specific CTL response and that appropriate boosting of this response may be required for the elimination of the latent reservoir.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4406054/" 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/PMC4406054/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Kai -- Pertea, Mihaela -- Rongvaux, Anthony -- Wang, Leyao -- Durand, Christine M -- Ghiaur, Gabriel -- Lai, Jun -- McHugh, Holly L -- Hao, Haiping -- Zhang, Hao -- Margolick, Joseph B -- Gurer, Cagan -- Murphy, Andrew J -- Valenzuela, David M -- Yancopoulos, George D -- Deeks, Steven G -- Strowig, Till -- Kumar, Priti -- Siliciano, Janet D -- Salzberg, Steven L -- Flavell, Richard A -- Shan, Liang -- Siliciano, Robert F -- 1U19AI096109/AI/NIAID NIH HHS/ -- AI096113/AI/NIAID NIH HHS/ -- K08 HL127269/HL/NHLBI NIH HHS/ -- P30 AI094189/AI/NIAID NIH HHS/ -- P30AI094189/AI/NIAID NIH HHS/ -- R01 AI043222/AI/NIAID NIH HHS/ -- R01 AI051178/AI/NIAID NIH HHS/ -- T32 AI007019/AI/NIAID NIH HHS/ -- T32 AI07019/AI/NIAID NIH HHS/ -- T32 HL007525/HL/NHLBI NIH HHS/ -- U19 AI096109/AI/NIAID NIH HHS/ -- U19 AI096113/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jan 15;517(7534):381-5. doi: 10.1038/nature14053. Epub 2015 Jan 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut 06510, USA. ; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Deep Sequencing and Microarray Core, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA. ; Regeneron Pharmaceuticals Inc., Tarrytown, New York 10591, USA. ; Department of Medicine, University of California, San Francisco, San Francisco, California 94110, USA. ; Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; 1] Center for Computational Biology, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. ; 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA [2] Howard Hughes Medical Institute, New Haven, Connecticut 06510, USA. ; 1] Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA [2] Howard Hughes Medical Institute, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25561180" target="_blank"〉PubMed〈/a〉

Description: Enhancers regulate spatiotemporal gene expression and impart cell-specific transcriptional outputs that drive cell identity. Super-enhancers (SEs), also known as stretch-enhancers, are a subset of enhancers especially important for genes associated with cell identity and genetic risk of disease. CD4(+) T cells are critical for host defence and autoimmunity. Here we analysed maps of mouse T-cell SEs as a non-biased means of identifying key regulatory nodes involved in cell specification. We found that cytokines and cytokine receptors were the dominant class of genes exhibiting SE architecture in T cells. Nonetheless, the locus encoding Bach2, a key negative regulator of effector differentiation, emerged as the most prominent T-cell SE, revealing a network in which SE-associated genes critical for T-cell biology are repressed by BACH2. Disease-associated single-nucleotide polymorphisms for immune-mediated disorders, including rheumatoid arthritis, were highly enriched for T-cell SEs versus typical enhancers or SEs in other cell lineages. Intriguingly, treatment of T cells with the Janus kinase (JAK) inhibitor tofacitinib disproportionately altered the expression of rheumatoid arthritis risk genes with SE structures. Together, these results indicate that genes with SE architecture in T cells encompass a variety of cytokines and cytokine receptors but are controlled by a 'guardian' transcription factor, itself endowed with an SE. Thus, enumeration of SEs allows the unbiased determination of key regulatory nodes in T cells, which are preferentially modulated by pharmacological intervention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409450/" 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/PMC4409450/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vahedi, Golnaz -- Kanno, Yuka -- Furumoto, Yasuko -- Jiang, Kan -- Parker, Stephen C J -- Erdos, Michael R -- Davis, Sean R -- Roychoudhuri, Rahul -- Restifo, Nicholas P -- Gadina, Massimo -- Tang, Zhonghui -- Ruan, Yijun -- Collins, Francis S -- Sartorelli, Vittorio -- O'Shea, John J -- 105663/Z/14/Z/Wellcome Trust/United Kingdom -- R01 CA186714/CA/NCI NIH HHS/ -- ZIA AR041159-07/Intramural NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):558-62. doi: 10.1038/nature14154. Epub 2015 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Cell Biology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; Translational Immunology Section, NIAMS, NIH, Bethesda, Maryland 20892, USA. ; Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland 20892, USA. ; Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA. ; The Jackson Laboratory for Genomic Medicine and Department of Genetic and Development Biology, University of Connecticut, Farmington, Connecticut 06030, USA. ; Laboratory of Muscle Stem Cells and Gene Regulation, NIAMS, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686607" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmidt, Charles -- England -- Nature. 2015 Feb 26;518(7540):S12-5. doi: 10.1038/518S13a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25715275" target="_blank"〉PubMed〈/a〉

Description: Cancer cells adapt their metabolic processes to support rapid proliferation, but less is known about how cancer cells alter metabolism to promote cell survival in a poorly vascularized tumour microenvironment. Here we identify a key role for serine and glycine metabolism in the survival of brain cancer cells within the ischaemic zones of gliomas. In human glioblastoma multiforme, mitochondrial serine hydroxymethyltransferase (SHMT2) and glycine decarboxylase (GLDC) are highly expressed in the pseudopalisading cells that surround necrotic foci. We find that SHMT2 activity limits that of pyruvate kinase (PKM2) and reduces oxygen consumption, eliciting a metabolic state that confers a profound survival advantage to cells in poorly vascularized tumour regions. GLDC inhibition impairs cells with high SHMT2 levels as the excess glycine not metabolized by GLDC can be converted to the toxic molecules aminoacetone and methylglyoxal. Thus, SHMT2 is required for cancer cells to adapt to the tumour environment, but also renders these cells sensitive to glycine cleavage system inhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533874/" 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/PMC4533874/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Dohoon -- Fiske, Brian P -- Birsoy, Kivanc -- Freinkman, Elizaveta -- Kami, Kenjiro -- Possemato, Richard L -- Chudnovsky, Yakov -- Pacold, Michael E -- Chen, Walter W -- Cantor, Jason R -- Shelton, Laura M -- Gui, Dan Y -- Kwon, Manjae -- Ramkissoon, Shakti H -- Ligon, Keith L -- Kang, Seong Woo -- Snuderl, Matija -- Vander Heiden, Matthew G -- Sabatini, David M -- 5P30CA14051/CA/NCI NIH HHS/ -- AI07389/AI/NIAID NIH HHS/ -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- K08 NS087118/NS/NINDS NIH HHS/ -- K08-NS087118/NS/NINDS NIH HHS/ -- K99 CA168940/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- R01 CA103866/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA168653/CA/NCI NIH HHS/ -- R01CA168653/CA/NCI NIH HHS/ -- R37 AI047389/AI/NIAID NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 16;520(7547):363-7. doi: 10.1038/nature14363. Epub 2015 Apr 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA. ; Human Metabolome Technologies, Inc., Tsuruoka 997-0052, Japan. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [4] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [5] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [6] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA. ; Human Metabolome Technologies America, Inc., Boston, Massachusetts 02134, USA. ; 1] Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA [3] Department of Pathology, Boston Children's Hospital, Boston, Massachusetts 02115, USA. ; Department of Pathology, NYU Langone Medical Center and Medical School, New York, New York 10016, USA. ; 1] The David H. Koch Institute for Integrative Cancer Research at MIT, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA [2] Department of Biology, Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02139, USA [3] Broad Institute of Harvard and MIT, Seven Cambridge Center, Cambridge, Massachusetts 02142, USA [4] Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25855294" target="_blank"〉PubMed〈/a〉

Description: The development of life-threatening cancer metastases at distant organs requires disseminated tumour cells' adaptation to, and co-evolution with, the drastically different microenvironments of metastatic sites. Cancer cells of common origin manifest distinct gene expression patterns after metastasizing to different organs. Clearly, the dynamic interaction between metastatic tumour cells and extrinsic signals at individual metastatic organ sites critically effects the subsequent metastatic outgrowth. Yet, it is unclear when and how disseminated tumour cells acquire the essential traits from the microenvironment of metastatic organs that prime their subsequent outgrowth. Here we show that both human and mouse tumour cells with normal expression of PTEN, an important tumour suppressor, lose PTEN expression after dissemination to the brain, but not to other organs. The PTEN level in PTEN-loss brain metastatic tumour cells is restored after leaving the brain microenvironment. This brain microenvironment-dependent, reversible PTEN messenger RNA and protein downregulation is epigenetically regulated by microRNAs from brain astrocytes. Mechanistically, astrocyte-derived exosomes mediate an intercellular transfer of PTEN-targeting microRNAs to metastatic tumour cells, while astrocyte-specific depletion of PTEN-targeting microRNAs or blockade of astrocyte exosome secretion rescues the PTEN loss and suppresses brain metastasis in vivo. Furthermore, this adaptive PTEN loss in brain metastatic tumour cells leads to an increased secretion of the chemokine CCL2, which recruits IBA1-expressing myeloid cells that reciprocally enhance the outgrowth of brain metastatic tumour cells via enhanced proliferation and reduced apoptosis. Our findings demonstrate a remarkable plasticity of PTEN expression in metastatic tumour cells in response to different organ microenvironments, underpinning an essential role of co-evolution between the metastatic cells and their microenvironment during the adaptive metastatic outgrowth. Our findings signify the dynamic and reciprocal cross-talk between tumour cells and the metastatic niche; importantly, they provide new opportunities for effective anti-metastasis therapies, especially of consequence for brain metastasis patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Lin -- Zhang, Siyuan -- Yao, Jun -- Lowery, Frank J -- Zhang, Qingling -- Huang, Wen-Chien -- Li, Ping -- Li, Min -- Wang, Xiao -- Zhang, Chenyu -- Wang, Hai -- Ellis, Kenneth -- Cheerathodi, Mujeeburahiman -- McCarty, Joseph H -- Palmieri, Diane -- Saunus, Jodi -- Lakhani, Sunil -- Huang, Suyun -- Sahin, Aysegul A -- Aldape, Kenneth D -- Steeg, Patricia S -- Yu, Dihua -- 5R00CA158066-05/CA/NCI NIH HHS/ -- P01-CA099031/CA/NCI NIH HHS/ -- P30 CA016672/CA/NCI NIH HHS/ -- R00 CA158066/CA/NCI NIH HHS/ -- R01 CA194697/CA/NCI NIH HHS/ -- R01-CA112567-06/CA/NCI NIH HHS/ -- R01CA184836/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 5;527(7576):100-4. doi: 10.1038/nature15376. Epub 2015 Oct 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Cancer Biology Program, Graduate School of Biomedical Sciences, Houston, Texas 77030, USA. ; Department of Biological Sciences, University of Notre Dame, Notre Dame, Indiana 46556, USA. ; Department of Neurosurgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Woman's Malignancies Branch, National Cancer Institute, Bethesda, Maryland 20892, USA. ; The University of Queensland Centre for Clinical Research, Brisbane, Queensland 4029, Australia. ; The School of Medicine and Pathology Queensland, Brisbane, Queensland 4029, Australia. ; The Royal Brisbane and Women's Hospital, Brisbane, Queensland 4029, Australia. ; Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA. ; Center for Molecular Medicine, China Medical University, Taichung 40402, Taiwan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26479035" target="_blank"〉PubMed〈/a〉

Description: The gut microbiota plays a crucial role in the maturation of the intestinal mucosal immune system of its host. Within the thousand bacterial species present in the intestine, the symbiont segmented filamentous bacterium (SFB) is unique in its ability to potently stimulate the post-natal maturation of the B- and T-cell compartments and induce a striking increase in the small-intestinal Th17 responses. Unlike other commensals, SFB intimately attaches to absorptive epithelial cells in the ileum and cells overlying Peyer's patches. This colonization does not result in pathology; rather, it protects the host from pathogens. Yet, little is known about the SFB-host interaction that underlies the important immunostimulatory properties of SFB, because SFB have resisted in vitro culturing for more than 50 years. Here we grow mouse SFB outside their host in an SFB-host cell co-culturing system. Single-celled SFB isolated from monocolonized mice undergo filamentation, segmentation, and differentiation to release viable infectious particles, the intracellular offspring, which can colonize mice to induce signature immune responses. In vitro, intracellular offspring can attach to mouse and human host cells and recruit actin. In addition, SFB can potently stimulate the upregulation of host innate defence genes, inflammatory cytokines, and chemokines. In vitro culturing thereby mimics the in vivo niche, provides new insights into SFB growth requirements and their immunostimulatory potential, and makes possible the investigation of the complex developmental stages of SFB and the detailed dissection of the unique SFB-host interaction at the cellular and molecular levels.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnupf, Pamela -- Gaboriau-Routhiau, Valerie -- Gros, Marine -- Friedman, Robin -- Moya-Nilges, Maryse -- Nigro, Giulia -- Cerf-Bensussan, Nadine -- Sansonetti, Philippe J -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 2;520(7545):99-103. doi: 10.1038/nature14027. Epub 2015 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Institut national de la recherche agronomique (INRA) Micalis UMR1319, 78350 Jouy-en-Josas, France [3] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France [2] Ecole Normale Superieure de Lyon, Department of Biology, 69007 Lyon, France. ; Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; Imagopole, Ultrastructural Microscopy Platform, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France. ; 1] INSERM, UMR1163, Laboratory of Intestinal Immunity, Institut Imagine, 24, Boulevard du Montparnasse, 75015 Paris, France [2] Universite Paris Descartes-Sorbonne Paris Cite and Institut Imagine, 75015 Paris, France. ; 1] Unite de Pathogenie Microbienne Moleculaire and Institut national de la sante et de la recherche medicale (INSERM) unit U786, Institut Pasteur, 25-28 Rue du Dr Roux, 75724 Paris Cedex 15, France [2] Microbiologie et Maladies Infectieuses, College de France, 11 Marcelin Berthelot Square, 75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25600271" target="_blank"〉PubMed〈/a〉

Description: Breast cancer is the most frequent cancer in women and consists of heterogeneous types of tumours that are classified into different histological and molecular subtypes. PIK3CA and P53 (also known as TP53) are the two most frequently mutated genes and are associated with different types of human breast cancers. The cellular origin and the mechanisms leading to PIK3CA-induced tumour heterogeneity remain unknown. Here we used a genetic approach in mice to define the cellular origin of Pik3ca-derived tumours and the impact of mutations in this gene on tumour heterogeneity. Surprisingly, oncogenic Pik3ca(H1047R) mutant expression at physiological levels in basal cells using keratin (K)5-CreER(T2) mice induced the formation of luminal oestrogen receptor (ER)-positive/progesterone receptor (PR)-positive tumours, while its expression in luminal cells using K8-CReER(T2) mice gave rise to luminal ER(+)PR(+) tumours or basal-like ER(-)PR(-) tumours. Concomitant deletion of p53 and expression of Pik3ca(H1047R) accelerated tumour development and induced more aggressive mammary tumours. Interestingly, expression of Pik3ca(H1047R) in unipotent basal cells gave rise to luminal-like cells, while its expression in unipotent luminal cells gave rise to basal-like cells before progressing into invasive tumours. Transcriptional profiling of cells that underwent cell fate transition upon Pik3ca(H1047R) expression in unipotent progenitors demonstrated a profound oncogene-induced reprogramming of these newly formed cells and identified gene signatures characteristic of the different cell fate switches that occur upon Pik3ca(H1047R) expression in basal and luminal cells, which correlated with the cell of origin, tumour type and different clinical outcomes. Altogether our study identifies the cellular origin of Pik3ca-induced tumours and reveals that oncogenic Pik3ca(H1047R) activates a multipotent genetic program in normally lineage-restricted populations at the early stage of tumour initiation, setting the stage for future intratumoural heterogeneity. These results have important implications for our understanding of the mechanisms controlling tumour heterogeneity and the development of new strategies to block PIK3CA breast cancer initiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Keymeulen, Alexandra -- Lee, May Yin -- Ousset, Marielle -- Brohee, Sylvain -- Rorive, Sandrine -- Giraddi, Rajshekhar R -- Wuidart, Aline -- Bouvencourt, Gaelle -- Dubois, Christine -- Salmon, Isabelle -- Sotiriou, Christos -- Phillips, Wayne A -- Blanpain, Cedric -- England -- Nature. 2015 Sep 3;525(7567):119-23. doi: 10.1038/nature14665. Epub 2015 Aug 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium. ; Institut Jules Bordet, Universite Libre de Bruxelles, Brussels B-1000, Belgium. ; Department of Pathology, Erasme Hospital, Universite Libre de Bruxelles, Brussels B-1070, Belgium. ; DIAPATH - Center for Microscopy and Molecular Imaging (CMMI), Gosselies B-6041, Belgium. ; Surgical Oncology Research Laboratory, Peter MacCallum Cancer Centre, Melbourne 3002, Australia. ; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville 3002, Australia. ; WELBIO, Universite Libre de Bruxelles, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26266985" target="_blank"〉PubMed〈/a〉

Description: Epigenetic modifiers have fundamental roles in defining unique cellular identity through the establishment and maintenance of lineage-specific chromatin and methylation status. Several DNA modifications such as 5-hydroxymethylcytosine (5hmC) are catalysed by the ten eleven translocation (Tet) methylcytosine dioxygenase family members, and the roles of Tet proteins in regulating chromatin architecture and gene transcription independently of DNA methylation have been gradually uncovered. However, the regulation of immunity and inflammation by Tet proteins independent of their role in modulating DNA methylation remains largely unknown. Here we show that Tet2 selectively mediates active repression of interleukin-6 (IL-6) transcription during inflammation resolution in innate myeloid cells, including dendritic cells and macrophages. Loss of Tet2 resulted in the upregulation of several inflammatory mediators, including IL-6, at late phase during the response to lipopolysaccharide challenge. Tet2-deficient mice were more susceptible to endotoxin shock and dextran-sulfate-sodium-induced colitis, displaying a more severe inflammatory phenotype and increased IL-6 production compared to wild-type mice. IkappaBzeta, an IL-6-specific transcription factor, mediated specific targeting of Tet2 to the Il6 promoter, further indicating opposite regulatory roles of IkappaBzeta at initial and resolution phases of inflammation. For the repression mechanism, independent of DNA methylation and hydroxymethylation, Tet2 recruited Hdac2 and repressed transcription of Il6 via histone deacetylation. We provide mechanistic evidence for the gene-specific transcription repression activity of Tet2 via histone deacetylation and for the prevention of constant transcription activation at the chromatin level for resolving inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697747/" 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/PMC4697747/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Qian -- Zhao, Kai -- Shen, Qicong -- Han, Yanmei -- Gu, Yan -- Li, Xia -- Zhao, Dezhi -- Liu, Yiqi -- Wang, Chunmei -- Zhang, Xiang -- Su, Xiaoping -- Liu, Juan -- Ge, Wei -- Levine, Ross L -- Li, Nan -- Cao, Xuetao -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA173636/CA/NCI NIH HHS/ -- England -- Nature. 2015 Sep 17;525(7569):389-93. doi: 10.1038/nature15252. Epub 2015 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Key Laboratory of Medical Molecular Biology &Department of Immunology, Institute of Basic Medical Sciences, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100005, China. ; National Key Laboratory of Medical Immunology &Institute of Immunology, Second Military Medical University, Shanghai 200433, China. ; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan-Kettering Cancer, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26287468" target="_blank"〉PubMed〈/a〉

Description: V(D)J recombination in the vertebrate immune system generates a highly diverse population of immunoglobulins and T-cell receptors by combinatorial joining of segments of coding DNA. The RAG1-RAG2 protein complex initiates this site-specific recombination by cutting DNA at specific sites flanking the coding segments. Here we report the crystal structure of the mouse RAG1-RAG2 complex at 3.2 A resolution. The 230-kilodalton RAG1-RAG2 heterotetramer is 'Y-shaped', with the amino-terminal domains of the two RAG1 chains forming an intertwined stalk. Each RAG1-RAG2 heterodimer composes one arm of the 'Y', with the active site in the middle and RAG2 at its tip. The RAG1-RAG2 structure rationalizes more than 60 mutations identified in immunodeficient patients, as well as a large body of genetic and biochemical data. The architectural similarity between RAG1 and the hairpin-forming transposases Hermes and Tn5 suggests the evolutionary conservation of these DNA rearrangements.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342785/" 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/PMC4342785/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Min-Sung -- Lapkouski, Mikalai -- Yang, Wei -- Gellert, Martin -- Z01 DK036147-01/Intramural NIH HHS/ -- Z01 DK036147-02/Intramural NIH HHS/ -- Z01 DK036167-01/Intramural NIH HHS/ -- Z01 DK036167-02/Intramural NIH HHS/ -- ZIA DK036147-03/Intramural NIH HHS/ -- ZIA DK036147-04/Intramural NIH HHS/ -- ZIA DK036147-05/Intramural NIH HHS/ -- ZIA DK036147-06/Intramural NIH HHS/ -- ZIA DK036147-07/Intramural NIH HHS/ -- ZIA DK036147-08/Intramural NIH HHS/ -- ZIA DK036167-03/Intramural NIH HHS/ -- ZIA DK036167-04/Intramural NIH HHS/ -- ZIA DK036167-05/Intramural NIH HHS/ -- ZIA DK036167-06/Intramural NIH HHS/ -- ZIA DK036167-07/Intramural NIH HHS/ -- England -- Nature. 2015 Feb 26;518(7540):507-11. doi: 10.1038/nature14174. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Biology, NIDDK, NIH, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707801" target="_blank"〉PubMed〈/a〉

Description: Mycobacterium tuberculosis, a major global health threat, replicates in macrophages in part by inhibiting phagosome-lysosome fusion, until interferon-gamma (IFNgamma) activates the macrophage to traffic M. tuberculosis to the lysosome. How IFNgamma elicits this effect is unknown, but many studies suggest a role for macroautophagy (herein termed autophagy), a process by which cytoplasmic contents are targeted for lysosomal degradation. The involvement of autophagy has been defined based on studies in cultured cells where M. tuberculosis co-localizes with autophagy factors ATG5, ATG12, ATG16L1, p62, NDP52, BECN1 and LC3 (refs 2-6), stimulation of autophagy increases bacterial killing, and inhibition of autophagy increases bacterial survival. Notably, these studies reveal modest (~1.5-3-fold change) effects on M. tuberculosis replication. By contrast, mice lacking ATG5 in monocyte-derived cells and neutrophils (polymorponuclear cells, PMNs) succumb to M. tuberculosis within 30 days, an extremely severe phenotype similar to mice lacking IFNgamma signalling. Importantly, ATG5 is the only autophagy factor that has been studied during M. tuberculosis infection in vivo and autophagy-independent functions of ATG5 have been described. For this reason, we used a genetic approach to elucidate the role for multiple autophagy-related genes and the requirement for autophagy in resistance to M. tuberculosis infection in vivo. Here we show that, contrary to expectation, autophagic capacity does not correlate with the outcome of M. tuberculosis infection. Instead, ATG5 plays a unique role in protection against M. tuberculosis by preventing PMN-mediated immunopathology. Furthermore, while Atg5 is dispensable in alveolar macrophages during M. tuberculosis infection, loss of Atg5 in PMNs can sensitize mice to M. tuberculosis. These findings shift our understanding of the role of ATG5 during M. tuberculosis infection, reveal new outcomes of ATG5 activity, and shed light on early events in innate immunity that are required to regulate disease pathology and bacterial replication.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimmey, Jacqueline M -- Huynh, Jeremy P -- Weiss, Leslie A -- Park, Sunmin -- Kambal, Amal -- Debnath, Jayanta -- Virgin, Herbert W -- Stallings, Christina L -- GM007067/GM/NIGMS NIH HHS/ -- U19 AI109725/AI/NIAID NIH HHS/ -- England -- Nature. 2015 Dec 24;528(7583):565-9. doi: 10.1038/nature16451. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Microbiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649827" target="_blank"〉PubMed〈/a〉

Description: Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation. Chromosomal marking, viral integration and barcoding of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie2(+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or approximately 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polyclonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligoclonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Busch, Katrin -- Klapproth, Kay -- Barile, Melania -- Flossdorf, Michael -- Holland-Letz, Tim -- Schlenner, Susan M -- Reth, Michael -- Hofer, Thomas -- Rodewald, Hans-Reimer -- England -- Nature. 2015 Feb 26;518(7540):542-6. doi: 10.1038/nature14242. Epub 2015 Feb 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. ; 1] Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium [2] Autoimmune Genetics Laboratory, VIB, B-3000 Leuven, Belgium. ; 1] BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Schanzlestrasse 18, D-79104 Freiburg, Germany [2] Department of Molecular Immunology, BioIII, Faculty of Biology, University of Freiburg, and Max-Planck Institute of Immunobiology and Epigenetics, Stubeweg 51, D-79108 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25686605" target="_blank"〉PubMed〈/a〉

Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeWeerdt, Sarah -- England -- Nature. 2015 May 14;521(7551):S10-1. doi: 10.1038/521S10a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970451" target="_blank"〉PubMed〈/a〉

Description: Although the adult mammalian heart is incapable of meaningful functional recovery following substantial cardiomyocyte loss, it is now clear that modest cardiomyocyte turnover occurs in adult mouse and human hearts, mediated primarily by proliferation of pre-existing cardiomyocytes. However, fate mapping of these cycling cardiomyocytes has not been possible thus far owing to the lack of identifiable genetic markers. In several organs, stem or progenitor cells reside in relatively hypoxic microenvironments where the stabilization of the hypoxia-inducible factor 1 alpha (Hif-1alpha) subunit is critical for their maintenance and function. Here we report fate mapping of hypoxic cells and their progenies by generating a transgenic mouse expressing a chimaeric protein in which the oxygen-dependent degradation (ODD) domain of Hif-1alpha is fused to the tamoxifen-inducible CreERT2 recombinase. In mice bearing the creERT2-ODD transgene driven by either the ubiquitous CAG promoter or the cardiomyocyte-specific alpha myosin heavy chain promoter, we identify a rare population of hypoxic cardiomyocytes that display characteristics of proliferative neonatal cardiomyocytes, such as smaller size, mononucleation and lower oxidative DNA damage. Notably, these hypoxic cardiomyocytes contributed widely to new cardiomyocyte formation in the adult heart. These results indicate that hypoxia signalling is an important hallmark of cycling cardiomyocytes, and suggest that hypoxia fate mapping can be a powerful tool for identifying cycling cells in adult mammals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kimura, Wataru -- Xiao, Feng -- Canseco, Diana C -- Muralidhar, Shalini -- Thet, SuWannee -- Zhang, Helen M -- Abderrahman, Yezan -- Chen, Rui -- Garcia, Joseph A -- Shelton, John M -- Richardson, James A -- Ashour, Abdelrahman M -- Asaithamby, Aroumougame -- Liang, Hanquan -- Xing, Chao -- Lu, Zhigang -- Zhang, Cheng Cheng -- Sadek, Hesham A -- I01 BX000446/BX/BLRD VA/ -- R01 HL108104/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Jul 9;523(7559):226-30. doi: 10.1038/nature14582. Epub 2015 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8577, Japan. ; Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Departments of Physiology and Developmental Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Medicine, VA North Texas Health Care System, 4600 South Lancaster Road, Dallas, Texas 75216, USA. ; 1] Department of Molecular Biology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Department of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Radiation Oncology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; McDermott Center for Human Growth and Development, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; 1] Department of Internal Medicine, Division of Cardiology, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA [2] Hamon Center for Regenerative Science and Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26098368" target="_blank"〉PubMed〈/a〉

Description: The metabolism of endothelial cells during vessel sprouting remains poorly studied. Here we report that endothelial loss of CPT1A, a rate-limiting enzyme of fatty acid oxidation (FAO), causes vascular sprouting defects due to impaired proliferation, not migration, of human and murine endothelial cells. Reduction of FAO in endothelial cells did not cause energy depletion or disturb redox homeostasis, but impaired de novo nucleotide synthesis for DNA replication. Isotope labelling studies in control endothelial cells showed that fatty acid carbons substantially replenished the Krebs cycle, and were incorporated into aspartate (a nucleotide precursor), uridine monophosphate (a precursor of pyrimidine nucleoside triphosphates) and DNA. CPT1A silencing reduced these processes and depleted endothelial cell stores of aspartate and deoxyribonucleoside triphosphates. Acetate (metabolized to acetyl-CoA, thereby substituting for the depleted FAO-derived acetyl-CoA) or a nucleoside mix rescued the phenotype of CPT1A-silenced endothelial cells. Finally, CPT1 blockade inhibited pathological ocular angiogenesis in mice, suggesting a novel strategy for blocking angiogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4413024/" 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/PMC4413024/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schoors, Sandra -- Bruning, Ulrike -- Missiaen, Rindert -- Queiroz, Karla C S -- Borgers, Gitte -- Elia, Ilaria -- Zecchin, Annalisa -- Cantelmo, Anna Rita -- Christen, Stefan -- Goveia, Jermaine -- Heggermont, Ward -- Godde, Lucica -- Vinckier, Stefan -- Van Veldhoven, Paul P -- Eelen, Guy -- Schoonjans, Luc -- Gerhardt, Holger -- Dewerchin, Mieke -- Baes, Myriam -- De Bock, Katrien -- Ghesquiere, Bart -- Lunt, Sophia Y -- Fendt, Sarah-Maria -- Carmeliet, Peter -- 269073/European Research Council/International -- England -- Nature. 2015 Apr 9;520(7546):192-7. doi: 10.1038/nature14362. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium. ; 1] Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, B-3000 Leuven, Belgium. ; Center for Molecular &Vascular Biology, Department of Cardiovascular Research, KU Leuven; Division of Clinical Cardiology, UZ Leuven, B-3000 Leuven, Belgium. ; Laboratory of Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium. ; 1] Vascular Patterning Laboratory, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Vascular Patterning Laboratory, Vesalius Research Center, VIB, B-3000 Leuven, Belgium [3] Integrative Vascular Biology Laboratory, Max Delbruck Center for Molecular Medicine, 13125 Berlin, Germany. ; Laboratory of Cell Metabolism, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, B-3000 Leuven, Belgium. ; 1] Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, KU Leuven, B-3000 Leuven, Belgium [2] Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, B-3000 Leuven, Belgium [3] Exercise Physiology Research Group, Department of Kinesiology, KU Leuven, B-3001 Leuven, Belgium. ; Department of Biochemistry and Molecular Biology, Michigan State University, East Lansing, Michigan 48824, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830893" target="_blank"〉PubMed〈/a〉

Description: Epigenetic silencing including histone modifications and DNA methylation is an important tumorigenic mechanism. However, its role in cancer immunopathology and immunotherapy is poorly understood. Using human ovarian cancers as our model, here we show that enhancer of zeste homologue 2 (EZH2)-mediated histone H3 lysine 27 trimethylation (H3K27me3) and DNA methyltransferase 1 (DNMT1)-mediated DNA methylation repress the tumour production of T helper 1 (TH1)-type chemokines CXCL9 and CXCL10, and subsequently determine effector T-cell trafficking to the tumour microenvironment. Treatment with epigenetic modulators removes the repression and increases effector T-cell tumour infiltration, slows down tumour progression, and improves the therapeutic efficacy of programmed death-ligand 1 (PD-L1; also known as B7-H1) checkpoint blockade and adoptive T-cell transfusion in tumour-bearing mice. Moreover, tumour EZH2 and DNMT1 are negatively associated with tumour-infiltrating CD8(+) T cells and patient outcome. Thus, epigenetic silencing of TH1-type chemokines is a novel immune-evasion mechanism of tumours. Selective epigenetic reprogramming alters the T-cell landscape in cancer and may enhance the clinical efficacy of cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779053/" 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/PMC4779053/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Dongjun -- Kryczek, Ilona -- Nagarsheth, Nisha -- Zhao, Lili -- Wei, Shuang -- Wang, Weimin -- Sun, Yuqing -- Zhao, Ende -- Vatan, Linda -- Szeliga, Wojciech -- Kotarski, Jan -- Tarkowski, Rafal -- Dou, Yali -- Cho, Kathleen -- Hensley-Alford, Sharon -- Munkarah, Adnan -- Liu, Rebecca -- Zou, Weiping -- 5P30CA46592/CA/NCI NIH HHS/ -- CA099985/CA/NCI NIH HHS/ -- CA123088/CA/NCI NIH HHS/ -- CA152470/CA/NCI NIH HHS/ -- CA156685/CA/NCI NIH HHS/ -- CA171306/CA/NCI NIH HHS/ -- CA190176/CA/NCI NIH HHS/ -- CA193136/CA/NCI NIH HHS/ -- R01 CA099985/CA/NCI NIH HHS/ -- R01 CA123088/CA/NCI NIH HHS/ -- R01 CA152470/CA/NCI NIH HHS/ -- R01 CA156685/CA/NCI NIH HHS/ -- R01 CA171306/CA/NCI NIH HHS/ -- R01 CA190176/CA/NCI NIH HHS/ -- R01 CA193136/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 12;527(7577):249-53. doi: 10.1038/nature15520. Epub 2015 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Surgery, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Immunology, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Biostatistics, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; The First Department of Gynecologic Oncology and Gynecology, Medical University in Lublin, Lublin 20-081, Poland. ; The University of Michigan Comprehensive Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Women's Health Services, Henry Ford Health System, Detroit, Michigan 48202, USA. ; Department of Obstetrics and Gynecology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA. ; Graduate Program in Tumor Biology, University of Michigan, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26503055" target="_blank"〉PubMed〈/a〉

Description: Oxytocin is important for social interactions and maternal behaviour. However, little is known about when, where and how oxytocin modulates neural circuits to improve social cognition. Here we show how oxytocin enables pup retrieval behaviour in female mice by enhancing auditory cortical pup call responses. Retrieval behaviour required the left but not right auditory cortex, was accelerated by oxytocin in the left auditory cortex, and oxytocin receptors were preferentially expressed in the left auditory cortex. Neural responses to pup calls were lateralized, with co-tuned and temporally precise excitatory and inhibitory responses in the left cortex of maternal but not pup-naive adults. Finally, pairing calls with oxytocin enhanced responses by balancing the magnitude and timing of inhibition with excitation. Our results describe fundamental synaptic mechanisms by which oxytocin increases the salience of acoustic social stimuli. Furthermore, oxytocin-induced plasticity provides a biological basis for lateralization of auditory cortical processing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409554/" 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/PMC4409554/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Marlin, Bianca J -- Mitre, Mariela -- D'amour, James A -- Chao, Moses V -- Froemke, Robert C -- DC009635/DC/NIDCD NIH HHS/ -- DC12557/DC/NIDCD NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R00 DC009635/DC/NIDCD NIH HHS/ -- R01 DC012557/DC/NIDCD NIH HHS/ -- T32 MH019524/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Apr 23;520(7548):499-504. doi: 10.1038/nature14402. Epub 2015 Apr 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [6] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA [5] Department of Psychiatry, New York University School of Medicine, New York, New York 10016, USA [6] Center for Neural Science, New York University, New York, New York 10003, USA. ; 1] Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York 10016, USA [2] Neuroscience Institute, New York University School of Medicine, New York, New York 10016, USA [3] Department of Otolaryngology, New York University School of Medicine, New York, New York 10016, USA [4] Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York 10016, USA [5] Center for Neural Science, New York University, New York, New York 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25874674" target="_blank"〉PubMed〈/a〉

Description: Postnatal tissue quiescence is thought to be a default state in the absence of a proliferative stimulus such as injury. Although previous studies have demonstrated that certain embryonic developmental programs are reactivated aberrantly in adult organs to drive repair and regeneration, it is not well understood how quiescence is maintained in organs such as the lung, which displays a remarkably low level of cellular turnover. Here we demonstrate that quiescence in the adult lung is an actively maintained state and is regulated by hedgehog signalling. Epithelial-specific deletion of sonic hedgehog (Shh) during postnatal homeostasis in the murine lung results in a proliferative expansion of the adjacent lung mesenchyme. Hedgehog signalling is initially downregulated during the acute phase of epithelial injury as the mesenchyme proliferates in response, but returns to baseline during injury resolution as quiescence is restored. Activation of hedgehog during acute epithelial injury attenuates the proliferative expansion of the lung mesenchyme, whereas inactivation of hedgehog signalling prevents the restoration of quiescence during injury resolution. Finally, we show that hedgehog also regulates epithelial quiescence and regeneration in response to injury via a mesenchymal feedback mechanism. These results demonstrate that epithelial-mesenchymal interactions coordinated by hedgehog actively maintain postnatal tissue homeostasis, and deregulation of hedgehog during injury leads to aberrant repair and regeneration in the lung.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4713039/" 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/PMC4713039/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Tien -- Frank, David B -- Kadzik, Rachel S -- Morley, Michael P -- Rathi, Komal S -- Wang, Tao -- Zhou, Su -- Cheng, Lan -- Lu, Min Min -- Morrisey, Edward E -- HL087825/HL/NHLBI NIH HHS/ -- HL100405/HL/NHLBI NIH HHS/ -- HL110942/HL/NHLBI NIH HHS/ -- K08-HL121146/HL/NHLBI NIH HHS/ -- R01 HL087825/HL/NHLBI NIH HHS/ -- T32 HL007915/HL/NHLBI NIH HHS/ -- U01 HL100405/HL/NHLBI NIH HHS/ -- U01 HL110942/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Oct 22;526(7574):578-82. doi: 10.1038/nature14984. Epub 2015 Oct 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Pediatrics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Center for Pulmonary Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Cardiovascular Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Penn Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26436454" target="_blank"〉PubMed〈/a〉

Description: Maternal age is a risk factor for congenital heart disease even in the absence of any chromosomal abnormality in the newborn. Whether the basis of this risk resides with the mother or oocyte is unknown. The impact of maternal age on congenital heart disease can be modelled in mouse pups that harbour a mutation of the cardiac transcription factor gene Nkx2-5 (ref. 8). Here, reciprocal ovarian transplants between young and old mothers establish a maternal basis for the age-associated risk in mice. A high-fat diet does not accelerate the effect of maternal ageing, so hyperglycaemia and obesity do not simply explain the mechanism. The age-associated risk varies with the mother's strain background, making it a quantitative genetic trait. Most remarkably, voluntary exercise, whether begun by mothers at a young age or later in life, can mitigate the risk when they are older. Thus, even when the offspring carry a causal mutation, an intervention aimed at the mother can meaningfully reduce their risk of congenital heart disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393370/" 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/PMC4393370/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schulkey, Claire E -- Regmi, Suk D -- Magnan, Rachel A -- Danzo, Megan T -- Luther, Herman -- Hutchinson, Alayna K -- Panzer, Adam A -- Grady, Mary M -- Wilson, David B -- Jay, Patrick Y -- P30 DK020579/DK/NIDDK NIH HHS/ -- P30 DK052574/DK/NIDDK NIH HHS/ -- P30 DK52574/DK/NIDDK NIH HHS/ -- R01 HL105857/HL/NHLBI NIH HHS/ -- T32 HL007873/HL/NHLBI NIH HHS/ -- T32HL007873/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Apr 9;520(7546):230-3. doi: 10.1038/nature14361. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. ; 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Developmental Biology, Washington University School of Medicine, St Louis, Missouri 63110 USA. ; 1] Department of Pediatrics, Washington University School of Medicine, St Louis, Missouri 63110 USA. [2] Department of Genetics, Washington University School of Medicine, St Louis, Missouri 63110 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830876" target="_blank"〉PubMed〈/a〉

Description: Taste is responsible for evaluating the nutritious content of food, guiding essential appetitive behaviours, preventing the ingestion of toxic substances, and helping to ensure the maintenance of a healthy diet. Sweet and bitter are two of the most salient sensory percepts for humans and other animals; sweet taste allows the identification of energy-rich nutrients whereas bitter warns against the intake of potentially noxious chemicals. In mammals, information from taste receptor cells in the tongue is transmitted through multiple neural stations to the primary gustatory cortex in the brain. Recent imaging studies have shown that sweet and bitter are represented in the primary gustatory cortex by neurons organized in a spatial map, with each taste quality encoded by distinct cortical fields. Here we demonstrate that by manipulating the brain fields representing sweet and bitter taste we directly control an animal's internal representation, sensory perception, and behavioural actions. These results substantiate the segregation of taste qualities in the cortex, expose the innate nature of appetitive and aversive taste responses, and illustrate the ability of gustatory cortex to recapitulate complex behaviours in the absence of sensory input.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712381/" 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/PMC4712381/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peng, Yueqing -- Gillis-Smith, Sarah -- Jin, Hao -- Trankner, Dimitri -- Ryba, Nicholas J P -- Zuker, Charles S -- DA035025/DA/NIDA NIH HHS/ -- R01 DA035025/DA/NIDA NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Nov 26;527(7579):512-5. doi: 10.1038/nature15763. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Departments of Biochemistry and Molecular Biophysics, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; Department of Neuroscience, Columbia College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA. ; HHMI/Janelia Farm Research Campus, 19700 Helix Drive, Ashburn, Virginia 20147, USA. ; National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580015" target="_blank"〉PubMed〈/a〉

Description: The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF 〈/= 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 x 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 x 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 x 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4755714/" 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/PMC4755714/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Hou-Feng -- Forgetta, Vincenzo -- Hsu, Yi-Hsiang -- Estrada, Karol -- Rosello-Diez, Alberto -- Leo, Paul J -- Dahia, Chitra L -- Park-Min, Kyung Hyun -- Tobias, Jonathan H -- Kooperberg, Charles -- Kleinman, Aaron -- Styrkarsdottir, Unnur -- Liu, Ching-Ti -- Uggla, Charlotta -- Evans, Daniel S -- Nielson, Carrie M -- Walter, Klaudia -- Pettersson-Kymmer, Ulrika -- McCarthy, Shane -- Eriksson, Joel -- Kwan, Tony -- Jhamai, Mila -- Trajanoska, Katerina -- Memari, Yasin -- Min, Josine -- Huang, Jie -- Danecek, Petr -- Wilmot, Beth -- Li, Rui -- Chou, Wen-Chi -- Mokry, Lauren E -- Moayyeri, Alireza -- Claussnitzer, Melina -- Cheng, Chia-Ho -- Cheung, Warren -- Medina-Gomez, Carolina -- Ge, Bing -- Chen, Shu-Huang -- Choi, Kwangbom -- Oei, Ling -- Fraser, James -- Kraaij, Robert -- Hibbs, Matthew A -- Gregson, Celia L -- Paquette, Denis -- Hofman, Albert -- Wibom, Carl -- Tranah, Gregory J -- Marshall, Mhairi -- Gardiner, Brooke B -- Cremin, Katie -- Auer, Paul -- Hsu, Li -- Ring, Sue -- Tung, Joyce Y -- Thorleifsson, Gudmar -- Enneman, Anke W -- van Schoor, Natasja M -- de Groot, Lisette C P G M -- van der Velde, Nathalie -- Melin, Beatrice -- Kemp, John P -- Christiansen, Claus -- Sayers, Adrian -- Zhou, Yanhua -- Calderari, Sophie -- van Rooij, Jeroen -- Carlson, Chris -- Peters, Ulrike -- Berlivet, Soizik -- Dostie, Josee -- Uitterlinden, Andre G -- Williams, Stephen R -- Farber, Charles -- Grinberg, Daniel -- LaCroix, Andrea Z -- Haessler, Jeff -- Chasman, Daniel I -- Giulianini, Franco -- Rose, Lynda M -- Ridker, Paul M -- Eisman, John A -- Nguyen, Tuan V -- Center, Jacqueline R -- Nogues, Xavier -- Garcia-Giralt, Natalia -- Launer, Lenore L -- Gudnason, Vilmunder -- Mellstrom, Dan -- Vandenput, Liesbeth -- Amin, Najaf -- van Duijn, Cornelia M -- Karlsson, Magnus K -- Ljunggren, Osten -- Svensson, Olle -- Hallmans, Goran -- Rousseau, Francois -- Giroux, Sylvie -- Bussiere, Johanne -- Arp, Pascal P -- Koromani, Fjorda -- Prince, Richard L -- Lewis, Joshua R -- Langdahl, Bente L -- Hermann, A Pernille -- Jensen, Jens-Erik B -- Kaptoge, Stephen -- Khaw, Kay-Tee -- Reeve, Jonathan -- Formosa, Melissa M -- Xuereb-Anastasi, Angela -- Akesson, Kristina -- McGuigan, Fiona E -- Garg, Gaurav -- Olmos, Jose M -- Zarrabeitia, Maria T -- Riancho, Jose A -- Ralston, Stuart H -- Alonso, Nerea -- Jiang, Xi -- Goltzman, David -- Pastinen, Tomi -- Grundberg, Elin -- Gauguier, Dominique -- Orwoll, Eric S -- Karasik, David -- Davey-Smith, George -- AOGC Consortium -- Smith, Albert V -- Siggeirsdottir, Kristin -- Harris, Tamara B -- Zillikens, M Carola -- van Meurs, Joyce B J -- Thorsteinsdottir, Unnur -- Maurano, Matthew T -- Timpson, Nicholas J -- Soranzo, Nicole -- Durbin, Richard -- Wilson, Scott G -- Ntzani, Evangelia E -- Brown, Matthew A -- Stefansson, Kari -- Hinds, David A -- Spector, Tim -- Cupples, L Adrienne -- Ohlsson, Claes -- Greenwood, Celia M T -- UK10K Consortium -- Jackson, Rebecca D -- Rowe, David W -- Loomis, Cynthia A -- Evans, David M -- Ackert-Bicknell, Cheryl L -- Joyner, Alexandra L -- Duncan, Emma L -- Kiel, Douglas P -- Rivadeneira, Fernando -- Richards, J Brent -- G1000143/Medical Research Council/United Kingdom -- K01 AR062655/AR/NIAMS NIH HHS/ -- MC_UU_12013/3/Medical Research Council/United Kingdom -- R01 AG005394/AG/NIA NIH HHS/ -- R01 AG005407/AG/NIA NIH HHS/ -- R01 AG027574/AG/NIA NIH HHS/ -- R01 AG027576/AG/NIA NIH HHS/ -- R01 AR035582/AR/NIAMS NIH HHS/ -- R01 AR035583/AR/NIAMS NIH HHS/ -- RC2 AR058973/AR/NIAMS NIH HHS/ -- U01 AG018197/AG/NIA NIH HHS/ -- U01 AG042140/AG/NIA NIH HHS/ -- U01 AG042143/AG/NIA NIH HHS/ -- U01 AR045580/AR/NIAMS NIH HHS/ -- U01 AR045583/AR/NIAMS NIH HHS/ -- U01 AR045614/AR/NIAMS NIH HHS/ -- U01 AR045632/AR/NIAMS NIH HHS/ -- U01 AR045647/AR/NIAMS NIH HHS/ -- U01 AR045654/AR/NIAMS NIH HHS/ -- U01 AR066160/AR/NIAMS NIH HHS/ -- England -- Nature. 2015 Oct 1;526(7571):112-7. doi: 10.1038/nature14878. Epub 2015 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Departments of Medicine, Human Genetics, Epidemiology and Biostatistics, McGill University, Montreal H3A 1A2, Canada. ; Department of Medicine, Lady Davis Institute for Medical Research, Jewish General Hospital, McGill University, Montreal H3T 1E2, Canada. ; Institute for Aging Research, Hebrew SeniorLife, Boston, Massachusetts 02131, USA. ; Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Broad Institute of MIT and Harvard, Boston, Massachusetts 02115, USA. ; Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Developmental Biology Program, Sloan Kettering Institute, New York, New York 10065, USA. ; The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane 4102, Australia. ; Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, New York 10065, USA. ; Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York 10021, USA. ; Rheumatology Divison, Hospital for Special Surgery New York, New York 10021, USA. ; School of Clinical Science, University of Bristol, Bristol BS10 5NB, UK. ; MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Department of Research, 23andMe, Mountain View, California 94041, USA. ; Department of Population Genomics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA. ; Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; California Pacific Medical Center Research Institute, San Francisco, California 94158, USA. ; Department of Public Health and Preventive Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Bone &Mineral Unit, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SA, UK. ; Departments of Pharmacology and Clinical Neurosciences, Umea University, Umea S-901 87, Sweden. ; Department of Public Health and Clinical Medicine, Umea University, Umea SE-901 87, Sweden. ; Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg S-413 45, Sweden. ; McGill University and Genome Quebec Innovation Centre, Montreal H3A 0G1, Canada. ; Department of Epidemiology, Erasmus Medical Center, Rotterdam 3015GE, The Netherlands. ; Oregon Clinical and Translational Research Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Department of Medical and Clinical Informatics, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Farr Institute of Health Informatics Research, University College London, London NW1 2DA, UK. ; Department of Twin Research and Genetic Epidemiology, King's College London, London SE1 7EH, UK. ; Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA. ; Department of Human Genetics, McGill University, Montreal H3A 1B1, Canada. ; Netherlands Genomics Initiative (NGI)-sponsored Netherlands Consortium for Healthy Aging (NCHA), Leiden 2300RC, The Netherlands. ; Center for Musculoskeletal Research, University of Rochester, Rochester, New York 14642, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal H3G 1Y6, Canada. ; Department of Computer Science, Trinity University, San Antonio, Texas 78212, USA. ; Musculoskeletal Research Unit, University of Bristol, Bristol BS10 5NB, UK. ; Department of Radiation Sciences, Umea University, Umea S-901 87, Sweden. ; School of Public Health, University of Wisconsin, Milwaukee, Wisconsin 53726, USA. ; School of Social and Community Medicine, University of Bristol, Bristol BS8 2BN, UK. ; Department of Statistics, deCODE Genetics, Reykjavik IS-101, Iceland. ; Department of Epidemiology and Biostatistics and the EMGO Institute for Health and Care Research, VU University Medical Center, Amsterdam 1007 MB, The Netherlands. ; Department of Human Nutrition, Wageningen University, Wageningen 6700 EV, The Netherlands. ; Department of Internal Medicine, Section Geriatrics, Academic Medical Center, Amsterdam 1105, The Netherlands. ; Nordic Bioscience, Herlev 2730, Denmark. ; Cordeliers Research Centre, INSERM UMRS 1138, Paris 75006, France. ; Institute of Cardiometabolism and Nutrition, University Pierre &Marie Curie, Paris 75013, France. ; Departments of Medicine (Cardiovascular Medicine), Centre for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Genetics, University of Barcelona, Barcelona 08028, Spain. ; U-720, Centre for Biomedical Network Research on Rare Diseases (CIBERER), Barcelona 28029, Spain. ; Department of Human Molecular Genetics, The Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. ; Women's Health Center of Excellence Family Medicine and Public Health, University of California - San Diego, San Diego, California 92093, USA. ; Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02215, USA. ; Osteoporosis &Bone Biology Program, Garvan Institute of Medical Research, Sydney 2010, Australia. ; School of Medicine Sydney, University of Notre Dame Australia, Sydney 6959, Australia. ; St. Vincent's Hospital &Clinical School, NSW University, Sydney 2010, Australia. ; Musculoskeletal Research Group, Institut Hospital del Mar d'Investigacions Mediques, Barcelona 08003, Spain. ; Cooperative Research Network on Aging and Fragility (RETICEF), Institute of Health Carlos III, 28029, Spain. ; Department of Internal Medicine, Hospital del Mar, Universitat Autonoma de Barcelona, Barcelona 08193, Spain. ; Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Icelandic Heart Association, Kopavogur IS-201, Iceland. ; Faculty of Medicine, University of Iceland, Reykjavik IS-101, Iceland. ; Genetic epidemiology unit, Department of Epidemiology, Erasmus MC, Rotterdam 3000CA, The Netherlands. ; Department of Orthopaedics, Skane University Hospital Malmo 205 02, Sweden. ; Department of Medical Sciences, University of Uppsala, Uppsala 751 85, Sweden. ; Department of Surgical and Perioperative Sciences, Umea Unviersity, Umea 901 85, Sweden. ; Department of Molecular Biology, Medical Biochemistry and Pathology, Universite Laval, Quebec City G1V 0A6, Canada. ; Axe Sante des Populations et Pratiques Optimales en Sante, Centre de recherche du CHU de Quebec, Quebec City G1V 4G2, Canada. ; Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands 6009, Australia. ; Department of Medicine, University of Western Australia, Perth 6009, Australia. ; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus C 8000, Denmark. ; Department of Endocrinology, Odense University Hospital, Odense C 5000, Denmark. ; Department of Endocrinology, Hvidovre University Hospital, Hvidovre 2650, Denmark. ; Clinical Gerontology Unit, University of Cambridge, Cambridge CB2 2QQ, UK. ; Medicine and Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. ; Institute of Musculoskeletal Sciences, The Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK. ; Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida MSD 2080, Malta. ; Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences Malmo, Lund University, 205 02, Sweden. ; Department of Medicine and Psychiatry, University of Cantabria, Santander 39011, Spain. ; Department of Internal Medicine, Hospital U.M. Valdecilla- IDIVAL, Santander 39008, Spain. ; Department of Legal Medicine, University of Cantabria, Santander 39011, Spain. ; Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK. ; Department of Reconstructive Sciences, College of Dental Medicine, University of Connecticut Health Center, Farmington, Connecticut 06030, USA. ; Department of Medicine and Physiology, McGill University, Montreal H4A 3J1, Canada. ; Department of Medicine, Oregon Health &Science University, Portland, Oregon 97239, USA. ; Faculty of Medicine in the Galilee, Bar-Ilan University, Safed 13010, Israel. ; Laboratory of Epidemiology, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA. ; School of Medicine and Pharmacology, University of Western Australia, Crawley 6009, Australia. ; Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina 45110, Greece. ; Department of Health Services, Policy and Practice, Brown University School of Public Health, Providence, Rhode Island 02903, USA. ; deCODE Genetics, Reykjavik IS-101, Iceland. ; Framingham Heart Study, Framingham, Massachusetts 01702, USA. ; Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal H3A 1A2, Canada. ; Department of Oncology, Gerald Bronfman Centre, McGill University, Montreal H2W 1S6, Canada. ; Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, Ohio 43210, USA. ; The Ronald O. Perelman Department of Dermatology and Department of Cell Biology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Diabetes and Endocrinology, Royal Brisbane and Women's Hospital, Brisbane 4029, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26367794" target="_blank"〉PubMed〈/a〉