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  • Mice, Inbred C57BL  (470)
  • Nature Publishing Group (NPG)  (470)
  • 1
    Publication Date: 2016-01-07
    Description: Endothelial cells (ECs) are plastic cells that can switch between growth states with different bioenergetic and biosynthetic requirements. Although quiescent in most healthy tissues, ECs divide and migrate rapidly upon proangiogenic stimulation. Adjusting endothelial metabolism to the growth state is central to normal vessel growth and function, yet it is poorly understood at the molecular level. Here we report that the forkhead box O (FOXO) transcription factor FOXO1 is an essential regulator of vascular growth that couples metabolic and proliferative activities in ECs. Endothelial-restricted deletion of FOXO1 in mice induces a profound increase in EC proliferation that interferes with coordinated sprouting, thereby causing hyperplasia and vessel enlargement. Conversely, forced expression of FOXO1 restricts vascular expansion and leads to vessel thinning and hypobranching. We find that FOXO1 acts as a gatekeeper of endothelial quiescence, which decelerates metabolic activity by reducing glycolysis and mitochondrial respiration. Mechanistically, FOXO1 suppresses signalling by MYC (also known as c-MYC), a powerful driver of anabolic metabolism and growth. MYC ablation impairs glycolysis, mitochondrial function and proliferation of ECs while its EC-specific overexpression fuels these processes. Moreover, restoration of MYC signalling in FOXO1-overexpressing endothelium normalizes metabolic activity and branching behaviour. Our findings identify FOXO1 as a critical rheostat of vascular expansion and define the FOXO1-MYC transcriptional network as a novel metabolic checkpoint during endothelial growth and proliferation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wilhelm, Kerstin -- Happel, Katharina -- Eelen, Guy -- Schoors, Sandra -- Oellerich, Mark F -- Lim, Radiance -- Zimmermann, Barbara -- Aspalter, Irene M -- Franco, Claudio A -- Boettger, Thomas -- Braun, Thomas -- Fruttiger, Marcus -- Rajewsky, Klaus -- Keller, Charles -- Bruning, Jens C -- Gerhardt, Holger -- Carmeliet, Peter -- Potente, Michael -- K08CA090438/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2016 Jan 14;529(7585):216-20. doi: 10.1038/nature16498. Epub 2016 Jan 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Angiogenesis &Metabolism Laboratory, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany. ; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, Department of Oncology, University of Leuven, Leuven 3000, Belgium. ; Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven 3000, Belgium. ; Vascular Biology Laboratory, London Research Institute, Cancer Research UK, London WC2A 3LY, UK. ; Vascular Morphogenesis Laboratory, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon 1649-028, Portugal. ; Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, D-61231 Bad Nauheim, Germany. ; UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK. ; Max Delbruck Center for Molecular Medicine (MDC), D-13125 Berlin, Germany. ; Children's Cancer Therapy Development Institute, Beaverton, Oregon 97005, USA. ; Max Planck Institute for Metabolism Research, Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University of Cologne, D-50931 Cologne, Germany. ; Vascular Patterning Laboratory, Vesalius Research Center, VIB and University of Leuven, Leuven 3000, Belgium. ; DZHK (German Center for Cardiovascular Research), partner site Berlin, D-13347 Berlin, Germany. ; Berlin Institute of Health (BIH), D-10117 Berlin, Germany. ; International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland. ; DZHK (German Center for Cardiovascular Research), partner site Frankfurt Rhine-Main, D-13347 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26735015" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Proliferation ; Cell Respiration ; Endothelium, Vascular/cytology/*growth & development/*metabolism ; Female ; Forkhead Transcription Factors/deficiency/genetics/*metabolism ; Glycolysis ; Human Umbilical Vein Endothelial Cells/cytology/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-myc/deficiency/genetics/metabolism ; Signal Transduction
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  • 2
    Publication Date: 2016-04-14
    Description: Bone marrow endothelial cells (BMECs) form a network of blood vessels that regulate both leukocyte trafficking and haematopoietic stem and progenitor cell (HSPC) maintenance. However, it is not clear how BMECs balance these dual roles, and whether these events occur at the same vascular site. We found that mammalian bone marrow stem cell maintenance and leukocyte trafficking are regulated by distinct blood vessel types with different permeability properties. Less permeable arterial blood vessels maintain haematopoietic stem cells in a low reactive oxygen species (ROS) state, whereas the more permeable sinusoids promote HSPC activation and are the exclusive site for immature and mature leukocyte trafficking to and from the bone marrow. A functional consequence of high permeability of blood vessels is that exposure to blood plasma increases bone marrow HSPC ROS levels, augmenting their migration and differentiation, while compromising their long-term repopulation and survival. These findings may have relevance for clinical haematopoietic stem cell transplantation and mobilization protocols.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itkin, Tomer -- Gur-Cohen, Shiri -- Spencer, Joel A -- Schajnovitz, Amir -- Ramasamy, Saravana K -- Kusumbe, Anjali P -- Ledergor, Guy -- Jung, Yookyung -- Milo, Idan -- Poulos, Michael G -- Kalinkovich, Alexander -- Ludin, Aya -- Kollet, Orit -- Shakhar, Guy -- Butler, Jason M -- Rafii, Shahin -- Adams, Ralf H -- Scadden, David T -- Lin, Charles P -- Lapidot, Tsvee -- EB017274/EB/NIBIB NIH HHS/ -- HL100402/HL/NHLBI NIH HHS/ -- R01 EB017274/EB/NIBIB NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):323-8. doi: 10.1038/nature17624. Epub 2016 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. ; Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; Harvard Stem Cell Institute, Cambridge, Massachusetts 02114, USA. ; Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA. ; Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis and Faculty of Medicine, University of Munster, D-48149 Munster, Germany. ; Internal Medicine Department, Tel-Aviv Sourasky Medical Center, Tel-Aviv 64239, Israel. ; Department of Genetic Medicine, Weill Cornell Medical College, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27074509" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Ly/metabolism ; Arteries/cytology/physiology ; Blood Vessels/*cytology/*physiology ; Bone Marrow/*blood supply ; Bone Marrow Cells/cytology ; Cell Differentiation ; Cell Movement ; Cell Self Renewal ; Cell Survival ; Chemokine CXCL12/metabolism ; Endothelial Cells/physiology ; Female ; *Hematopoiesis ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/cytology ; Leukocytes/cytology ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Nestin/metabolism ; Pericytes/physiology ; Permeability ; Plasma/metabolism ; Reactive Oxygen Species/metabolism ; Receptors, CXCR4/metabolism
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  • 3
    Publication Date: 2016-03-17
    Description: The energetic burden of continuously concentrating solutes against gradients along the tubule may render the kidney especially vulnerable to ischaemia. Acute kidney injury (AKI) affects 3% of all hospitalized patients. Here we show that the mitochondrial biogenesis regulator, PGC1alpha, is a pivotal determinant of renal recovery from injury by regulating nicotinamide adenine dinucleotide (NAD) biosynthesis. Following renal ischaemia, Pgc1alpha(-/-) (also known as Ppargc1a(-/-)) mice develop local deficiency of the NAD precursor niacinamide (NAM, also known as nicotinamide), marked fat accumulation, and failure to re-establish normal function. Notably, exogenous NAM improves local NAD levels, fat accumulation, and renal function in post-ischaemic Pgc1alpha(-/-) mice. Inducible tubular transgenic mice (iNephPGC1alpha) recapitulate the effects of NAM supplementation, including more local NAD and less fat accumulation with better renal function after ischaemia. PGC1alpha coordinately upregulates the enzymes that synthesize NAD de novo from amino acids whereas PGC1alpha deficiency or AKI attenuates the de novo pathway. NAM enhances NAD via the enzyme NAMPT and augments production of the fat breakdown product beta-hydroxybutyrate, leading to increased production of prostaglandin PGE2 (ref. 5), a secreted autacoid that maintains renal function. NAM treatment reverses established ischaemic AKI and also prevented AKI in an unrelated toxic model. Inhibition of beta-hydroxybutyrate signalling or prostaglandin production similarly abolishes PGC1alpha-dependent renoprotection. Given the importance of mitochondrial health in ageing and the function of metabolically active organs, the results implicate NAM and NAD as key effectors for achieving PGC1alpha-dependent stress resistance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, Mei T -- Zsengeller, Zsuzsanna K -- Berg, Anders H -- Khankin, Eliyahu V -- Bhasin, Manoj K -- Kim, Wondong -- Clish, Clary B -- Stillman, Isaac E -- Karumanchi, S Ananth -- Rhee, Eugene P -- Parikh, Samir M -- K08-DK090142/DK/NIDDK NIH HHS/ -- K08-DK101560/DK/NIDDK NIH HHS/ -- P30-DK079337/DK/NIDDK NIH HHS/ -- R01 DK095072/DK/NIDDK NIH HHS/ -- R01-DK095072/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Mar 24;531(7595):528-32. doi: 10.1038/nature17184. Epub 2016 Mar 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Division of Clinical Chemistry, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Bioinformatics and Systems Biology Core, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Nephrology and Endocrine Divisions, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02139, USA. ; Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26982719" target="_blank"〉PubMed〈/a〉
    Keywords: 3-Hydroxybutyric Acid/metabolism ; Acute Kidney Injury/drug therapy/*metabolism ; Adipose Tissue/drug effects/metabolism ; Amino Acids/metabolism ; Animals ; Cytokines/metabolism ; Dinoprostone/biosynthesis/metabolism ; Humans ; Ischemia/drug therapy/metabolism ; Kidney/drug effects/*metabolism/physiology/physiopathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism ; NAD/*biosynthesis ; Niacinamide/deficiency/pharmacology/therapeutic use ; Nicotinamide Phosphoribosyltransferase/metabolism ; Oxidation-Reduction ; Signal Transduction/drug effects ; Stress, Physiological ; Transcription Factors/deficiency/*metabolism
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  • 4
    Publication Date: 2016-03-29
    Description: Circuits in the cerebral cortex consist of thousands of neurons connected by millions of synapses. A precise understanding of these local networks requires relating circuit activity with the underlying network structure. For pyramidal cells in superficial mouse visual cortex (V1), a consensus is emerging that neurons with similar visual response properties excite each other, but the anatomical basis of this recurrent synaptic network is unknown. Here we combined physiological imaging and large-scale electron microscopy to study an excitatory network in V1. We found that layer 2/3 neurons organized into subnetworks defined by anatomical connectivity, with more connections within than between groups. More specifically, we found that pyramidal neurons with similar orientation selectivity preferentially formed synapses with each other, despite the fact that axons and dendrites of all orientation selectivities pass near (〈5 mum) each other with roughly equal probability. Therefore, we predict that mechanisms of functionally specific connectivity take place at the length scale of spines. Neurons with similar orientation tuning formed larger synapses, potentially enhancing the net effect of synaptic specificity. With the ability to study thousands of connections in a single circuit, functional connectomics is proving a powerful method to uncover the organizational logic of cortical networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4844839/" 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/PMC4844839/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Wei-Chung Allen -- Bonin, Vincent -- Reed, Michael -- Graham, Brett J -- Hood, Greg -- Glattfelder, Katie -- Reid, R Clay -- P30 EY012196/EY/NEI NIH HHS/ -- P30 EY12196/EY/NEI NIH HHS/ -- P41 GM103712/GM/NIGMS NIH HHS/ -- P41 RR006009/RR/NCRR NIH HHS/ -- P41 RR06009/RR/NCRR NIH HHS/ -- R01 EY010115/EY/NEI NIH HHS/ -- R01 EY10115/EY/NEI NIH HHS/ -- R01 NS075436/NS/NINDS NIH HHS/ -- R21 NS085320/NS/NINDS NIH HHS/ -- England -- Nature. 2016 Apr 21;532(7599):370-4. doi: 10.1038/nature17192. Epub 2016 Mar 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Neuro-Electronics Research Flanders, a research initiative by imec, Vlaams Instituut voor Biotechnologie (VIB) and Katholieke Universiteit (KU) Leuven, 3001 Leuven, Belgium. ; Biomedical Applications Group, Pittsburgh Supercomputing Center, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213, USA. ; Allen Institute for Brain Science, Seattle, Washington 98103, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27018655" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/physiology ; Calcium/analysis ; Dendrites/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Photons ; Pyramidal Cells/cytology/physiology ; Synapses/metabolism ; Visual Cortex/*anatomy & histology/cytology/*physiology/ultrastructure ; Visual Pathways/anatomy & histology/*cytology/*physiology/ultrastructure
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  • 5
    Publication Date: 2016-04-07
    Description: Neoplastic pancreatic epithelial cells are believed to die through caspase 8-dependent apoptotic cell death, and chemotherapy is thought to promote tumour apoptosis. Conversely, cancer cells often disrupt apoptosis to survive. Another type of programmed cell death is necroptosis (programmed necrosis), but its role in pancreatic ductal adenocarcinoma (PDA) is unclear. There are many potential inducers of necroptosis in PDA, including ligation of tumour necrosis factor receptor 1 (TNFR1), CD95, TNF-related apoptosis-inducing ligand (TRAIL) receptors, Toll-like receptors, reactive oxygen species, and chemotherapeutic drugs. Here we report that the principal components of the necrosome, receptor-interacting protein (RIP)1 and RIP3, are highly expressed in PDA and are further upregulated by the chemotherapy drug gemcitabine. Blockade of the necrosome in vitro promoted cancer cell proliferation and induced an aggressive oncogenic phenotype. By contrast, in vivo deletion of RIP3 or inhibition of RIP1 protected against oncogenic progression in mice and was associated with the development of a highly immunogenic myeloid and T cell infiltrate. The immune-suppressive tumour microenvironment associated with intact RIP1/RIP3 signalling depended in part on necroptosis-induced expression of the chemokine attractant CXCL1, and CXCL1 blockade protected against PDA. Moreover, cytoplasmic SAP130 (a subunit of the histone deacetylase complex) was expressed in PDA in a RIP1/RIP3-dependent manner, and Mincle--its cognate receptor--was upregulated in tumour-infiltrating myeloid cells. Ligation of Mincle by SAP130 promoted oncogenesis, whereas deletion of Mincle protected against oncogenesis and phenocopied the immunogenic reprogramming of the tumour microenvironment that was induced by RIP3 deletion. Cellular depletion suggested that whereas inhibitory macrophages promote tumorigenesis in PDA, they lose their immune-suppressive effects when RIP3 or Mincle is deleted. Accordingly, T cells, which are not protective against PDA progression in mice with intact RIP3 or Mincle signalling, are reprogrammed into indispensable mediators of anti-tumour immunity in the absence of RIP3 or Mincle. Our work describes parallel networks of necroptosis-induced CXCL1 and Mincle signalling that promote macrophage-induced adaptive immune suppression and thereby enable PDA progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833566/" 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/PMC4833566/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seifert, Lena -- Werba, Gregor -- Tiwari, Shaun -- Giao Ly, Nancy Ngoc -- Alothman, Sara -- Alqunaibit, Dalia -- Avanzi, Antonina -- Barilla, Rocky -- Daley, Donnele -- Greco, Stephanie H -- Torres-Hernandez, Alejandro -- Pergamo, Matthew -- Ochi, Atsuo -- Zambirinis, Constantinos P -- Pansari, Mridul -- Rendon, Mauricio -- Tippens, Daniel -- Hundeyin, Mautin -- Mani, Vishnu R -- Hajdu, Cristina -- Engle, Dannielle -- Miller, George -- CA155649/CA/NCI NIH HHS/ -- CA168611/CA/NCI NIH HHS/ -- CA193111/CA/NCI NIH HHS/ -- P30CA016087/CA/NCI NIH HHS/ -- R01 CA168611/CA/NCI NIH HHS/ -- T32 CA193111/CA/NCI NIH HHS/ -- UL1 TR000038/TR/NCATS NIH HHS/ -- England -- Nature. 2016 Apr 14;532(7598):245-9. doi: 10.1038/nature17403. Epub 2016 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. ; Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. ; Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. ; Cold Spring Harbor Laboratories, Cold Spring Harbor, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27049944" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/immunology/metabolism/pathology ; Animals ; Apoptosis/drug effects ; *Carcinogenesis/drug effects ; Carcinoma, Pancreatic Ductal/immunology/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Chemokine CXCL1/antagonists & inhibitors/*metabolism ; Deoxycytidine/analogs & derivatives/pharmacology ; Disease Progression ; Female ; GTPase-Activating Proteins/metabolism ; Gene Expression Regulation, Neoplastic ; Humans ; *Immune Tolerance ; Lectins, C-Type/immunology/*metabolism ; Male ; Membrane Proteins/immunology/*metabolism ; Mice ; Mice, Inbred C57BL ; *Necrosis ; Pancreatic Neoplasms/*immunology/metabolism/*pathology ; Receptor-Interacting Protein Serine-Threonine Kinases/metabolism ; Signal Transduction ; Up-Regulation
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  • 6
    Publication Date: 2016-02-09
    Description: Sighs are long, deep breaths expressing sadness, relief or exhaustion. Sighs also occur spontaneously every few minutes to reinflate alveoli, and sighing increases under hypoxia, stress, and certain psychiatric conditions. Here we use molecular, genetic, and pharmacologic approaches to identify a peptidergic sigh control circuit in murine brain. Small neural subpopulations in a key breathing control centre, the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG), express bombesin-like neuropeptide genes neuromedin B (Nmb) or gastrin-releasing peptide (Grp). These project to the preBotzinger Complex (preBotC), the respiratory rhythm generator, which expresses NMB and GRP receptors in overlapping subsets of ~200 neurons. Introducing either neuropeptide into preBotC or onto preBotC slices, induced sighing or in vitro sigh activity, whereas elimination or inhibition of either receptor reduced basal sighing, and inhibition of both abolished it. Ablating receptor-expressing neurons eliminated basal and hypoxia-induced sighing, but left breathing otherwise intact initially. We propose that these overlapping peptidergic pathways comprise the core of a sigh control circuit that integrates physiological and perhaps emotional input to transform normal breaths into sighs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Peng -- Janczewski, Wiktor A -- Yackle, Kevin -- Kam, Kaiwen -- Pagliardini, Silvia -- Krasnow, Mark A -- Feldman, Jack L -- HL40959/HL/NHLBI NIH HHS/ -- HL70029/HL/NHLBI NIH HHS/ -- NS72211/NS/NINDS NIH HHS/ -- R01 HL040959/HL/NHLBI NIH HHS/ -- R01 HL070029/HL/NHLBI NIH HHS/ -- R01 NS072211/NS/NINDS NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2016 Feb 18;530(7590):293-7. doi: 10.1038/nature16964. Epub 2016 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry and Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. ; Systems Neurobiology Laboratory, Department of Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26855425" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bombesin/pharmacology ; Emotions/physiology ; Female ; Gastrin-Releasing Peptide/deficiency/genetics/*metabolism ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Neurokinin B/*analogs & derivatives/deficiency/genetics/metabolism/pharmacology ; Neurons/drug effects/*physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Bombesin/*metabolism ; *Respiration/drug effects ; Respiratory Center/cytology/drug effects/physiology ; Ribosome Inactivating Proteins, Type 1/pharmacology ; Signal Transduction/drug effects/*physiology
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  • 7
    Publication Date: 2016-03-10
    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〉
    Keywords: Animals ; Female ; Insulin-Like Growth Factor I/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; *Neural Inhibition ; Neural Pathways ; Neuronal Plasticity ; Neurons/cytology/*metabolism/secretion ; Pyramidal Cells/metabolism ; Synapses/metabolism ; Vasoactive Intestinal Peptide/*metabolism ; Vision, Ocular/physiology ; Visual Cortex/*cytology/*physiology
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  • 8
    Publication Date: 2016-02-13
    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〉
    Keywords: Animals ; Antigens, CD/metabolism ; Biomarkers/analysis ; Bone Marrow/metabolism ; Cadherins/metabolism ; Cell Self Renewal ; Gene Expression Regulation ; Genes, Reporter/genetics ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/*metabolism ; Homeodomain Proteins/genetics/*metabolism ; Immunophenotyping ; Male ; Mice ; Mice, Inbred C57BL ; *Stem Cell Niche
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  • 9
    Publication Date: 2016-03-24
    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〉
    Keywords: Animals ; Bacterial Outer Membrane Proteins/metabolism ; Brucella abortus/immunology/pathogenicity ; Cell Line ; Dithiothreitol/pharmacology ; Endoplasmic Reticulum/drug effects/pathology ; *Endoplasmic Reticulum Stress/drug effects ; Endoribonucleases/antagonists & inhibitors ; Female ; Humans ; Immunity, Innate ; Inflammation/chemically induced/*metabolism ; Interleukin-6/biosynthesis ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; Nod1 Signaling Adaptor Protein/immunology/*metabolism ; Nod2 Signaling Adaptor Protein/immunology/*metabolism ; Protein-Serine-Threonine Kinases/antagonists & inhibitors ; Receptors, Pattern Recognition/metabolism ; *Signal Transduction/drug effects ; TNF Receptor-Associated Factor 2/metabolism ; Taurochenodeoxycholic Acid/pharmacology ; Thapsigargin/pharmacology ; Unfolded Protein Response/drug effects
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  • 10
    Publication Date: 2016-03-31
    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〉
    Keywords: Adipose Tissue, Brown/chemistry/cytology/metabolism ; Animals ; Cell Respiration ; Cysteine/*chemistry/genetics/metabolism ; *Energy Metabolism/drug effects ; Female ; Humans ; Ion Channels/*chemistry/deficiency/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/*metabolism ; Mitochondrial Proteins/*chemistry/deficiency/genetics/*metabolism ; Mutant Proteins/chemistry/genetics/metabolism ; Oxidation-Reduction ; Reactive Oxygen Species/*metabolism ; Sulfhydryl Compounds/metabolism ; *Thermogenesis/drug effects
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  • 11
    Publication Date: 2016-02-04
    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〉
    Keywords: Animals ; Avoidance Learning ; Disease Models, Animal ; Long-Term Synaptic Depression ; Male ; Mice ; Mice, Inbred C57BL ; Morphine/administration & dosage/pharmacology ; *Neural Pathways/drug effects ; Neuronal Plasticity ; Neurons/drug effects/metabolism ; Nucleus Accumbens/drug effects/*physiopathology ; Opioid-Related Disorders/*physiopathology/therapy ; Optogenetics ; Rats, Sprague-Dawley ; Receptors, AMPA/metabolism ; Receptors, Dopamine D2/metabolism ; Reward ; Substance Withdrawal Syndrome/*physiopathology/therapy ; Synaptic Transmission/drug effects ; Thalamus/drug effects/pathology/*physiopathology
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  • 12
    Publication Date: 2016-01-28
    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〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics/metabolism ; Biocatalysis ; Carrier Proteins/chemistry/genetics/*metabolism ; Caspase 1/metabolism ; Catalytic Domain ; Cells, Cultured ; Cryopyrin-Associated Periodic Syndromes/genetics ; Enzyme Activation ; HEK293 Cells ; Humans ; Inflammasomes/*chemistry/*metabolism ; Interleukin-1beta/secretion ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; Potassium/*metabolism ; Protein Binding ; Protein Multimerization ; Protein-Serine-Threonine Kinases/chemistry/deficiency/genetics/*metabolism
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  • 13
    Publication Date: 2016-02-04
    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〉
    Keywords: Alleles ; Animals ; Binding Sites ; Chromosome Pairing/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA Breaks, Double-Stranded ; Female ; *Genetic Speciation ; Histone-Lysine N-Methyltransferase/*chemistry/genetics/*metabolism ; Humans ; Hybridization, Genetic/*genetics ; Infertility/*genetics ; Male ; Meiosis/genetics ; Mice ; Mice, Inbred C57BL ; Protein Binding ; *Protein Engineering ; Protein Structure, Tertiary/genetics ; Recombination, Genetic/genetics ; Zinc Fingers/*genetics
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  • 14
    Publication Date: 2016-03-05
    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〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/immunology/metabolism/*pathology ; CD8-Positive T-Lymphocytes/immunology/pathology ; *Carcinogenesis/immunology/pathology ; Carcinoma, Hepatocellular/*immunology/metabolism/*pathology ; Case-Control Studies ; Choline/metabolism ; Diet ; Disease Models, Animal ; Genes, myc ; Hepatocytes/metabolism/pathology ; Humans ; Linoleic Acid/metabolism ; Lipid Metabolism ; Liver/immunology/pathology ; Liver Neoplasms/*immunology/metabolism/*pathology ; Male ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/pathology ; Non-alcoholic Fatty Liver Disease/*immunology/metabolism/pathology ; Oxidative Stress ; Reactive Oxygen Species/metabolism
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  • 15
    Publication Date: 2015-08-01
    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〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/biosynthesis/metabolism ; Animals ; Diffusion ; *Energy Metabolism ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Mitochondria, Muscle/*metabolism ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/*cytology/*metabolism ; Proton-Motive Force
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  • 16
    Publication Date: 2015-11-26
    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〉
    Keywords: Animals ; Cell Movement ; Dendritic Cells/cytology/immunology ; Female ; Gene Expression Regulation ; Homeostasis/*immunology ; Mice ; Mice, Inbred C57BL ; Phenotype ; Protein Transport ; STAT5 Transcription Factor/metabolism ; T-Lymphocytes, Regulatory/*immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 17
    Publication Date: 2015-03-11
    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〉
    Keywords: Animals ; Antigens, CD274/*antagonists & inhibitors/metabolism ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/*drug effects ; Female ; Humans ; Melanoma/*drug therapy/*immunology/pathology/*radiotherapy ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell/drug effects/immunology/metabolism ; T-Lymphocytes/cytology/*drug effects/immunology/*radiation effects ; T-Lymphocytes, Regulatory/drug effects/immunology/radiation effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 18
    Publication Date: 2015-02-18
    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〉
    Keywords: Animals ; Arthritis, Rheumatoid/*genetics/immunology/pathology ; Basic-Leucine Zipper Transcription Factors/metabolism ; Cell Differentiation/genetics ; Cell Lineage/genetics ; Enhancer Elements, Genetic/*genetics ; Gene Expression Regulation/genetics ; Genetic Predisposition to Disease/genetics ; Janus Kinase 3/antagonists & inhibitors ; Mice ; Mice, Inbred C57BL ; Piperidines/pharmacology ; Pyrimidines/pharmacology ; Pyrroles/pharmacology ; RNA, Untranslated/genetics ; T-Lymphocytes, Helper-Inducer/immunology/*metabolism/*pathology ; Transcription, Genetic/genetics ; p300-CBP Transcription Factors/metabolism
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  • 19
    Publication Date: 2015-08-20
    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〉
    Keywords: Acetylation ; Animals ; Chromatin/chemistry/genetics/metabolism ; Colitis/enzymology/immunology/metabolism ; DNA Methylation ; DNA-Binding Proteins/deficiency/*metabolism ; Dendritic Cells/cytology/metabolism ; Down-Regulation/genetics ; Epigenesis, Genetic ; Female ; HEK293 Cells ; Histone Deacetylase 2/*metabolism ; Histones/chemistry/metabolism ; Humans ; I-kappa B Proteins/metabolism ; Inflammation/enzymology/immunology/*metabolism ; Interleukin-6/*antagonists & inhibitors/*biosynthesis/genetics/immunology ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins/deficiency/*metabolism ; Transcription, Genetic
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  • 20
    Publication Date: 2015-04-16
    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〉
    Keywords: Acoustic Stimulation ; Animals ; Animals, Newborn ; Auditory Cortex/cytology/*physiology ; Auditory Perception/physiology ; Evoked Potentials, Auditory ; Female ; Male ; Maternal Behavior/*physiology ; Mice ; Mice, Inbred C57BL ; Neural Inhibition/*physiology ; Neuronal Plasticity ; Oxytocin/*metabolism ; Receptors, Oxytocin/metabolism ; Sexual Abstinence ; Vocalization, Animal
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  • 21
    Publication Date: 2015-11-19
    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〉
    Keywords: Animals ; Appetitive Behavior/*physiology/radiation effects ; Avoidance Learning/*physiology/radiation effects ; Brain Mapping ; Cerebral Cortex/*cytology/*physiology/radiation effects ; Discrimination (Psychology)/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Optogenetics ; Stereotaxic Techniques ; Taste/*physiology ; Taste Perception/*physiology/radiation effects ; Wakefulness/*physiology
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  • 22
    Publication Date: 2015-05-21
    Description: The lymphatic vasculature is a blind-ended network crucial for tissue-fluid homeostasis, immune surveillance and lipid absorption from the gut. Recent evidence has proposed an entirely venous-derived mammalian lymphatic system. By contrast, here we show that cardiac lymphatic vessels in mice have a heterogeneous cellular origin, whereby formation of at least part of the cardiac lymphatic network is independent of sprouting from veins. Multiple Cre-lox-based lineage tracing revealed a potential contribution from the putative haemogenic endothelium during development, and discrete lymphatic endothelial progenitor populations were confirmed by conditional knockout of Prox1 in Tie2+ and Vav1+ compartments. In the adult heart, myocardial infarction promoted a significant lymphangiogenic response, which was augmented by treatment with VEGF-C, resulting in improved cardiac function. These data prompt the re-evaluation of a century-long debate on the origin of lymphatic vessels and suggest that lymphangiogenesis may represent a therapeutic target to promote cardiac repair following injury.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4458138/" 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/PMC4458138/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klotz, Linda -- Norman, Sophie -- Vieira, Joaquim Miguel -- Masters, Megan -- Rohling, Mala -- Dube, Karina N -- Bollini, Sveva -- Matsuzaki, Fumio -- Carr, Carolyn A -- Riley, Paul R -- CH/11/1/28798/British Heart Foundation/United Kingdom -- PG/13/34/30216/British Heart Foundation/United Kingdom -- RG/08/003/25264/British Heart Foundation/United Kingdom -- RM/13/3/30159/British Heart Foundation/United Kingdom -- British Heart Foundation/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2015 Jun 4;522(7554):62-7.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25992544" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Endothelial Cells/cytology/metabolism ; Female ; Heart/physiology/physiopathology ; Homeodomain Proteins/metabolism ; *Lymphangiogenesis ; Lymphatic Vessels/*cytology/*injuries/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Myocardial Infarction/metabolism/physiopathology ; Myocardium/*cytology/metabolism ; Proto-Oncogene Proteins c-vav/metabolism ; Receptor, Macrophage Colony-Stimulating Factor/metabolism ; Receptor, Platelet-Derived Growth Factor beta/metabolism ; Receptor, TIE-2/metabolism ; Spatio-Temporal Analysis ; Tumor Suppressor Proteins/deficiency/metabolism ; Vascular Endothelial Growth Factor C/metabolism ; Veins/cytology ; Yolk Sac/cytology
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    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 23
    Publication Date: 2015-02-25
    Description: Hypothalamic pro-opiomelanocortin (POMC) neurons promote satiety. Cannabinoid receptor 1 (CB1R) is critical for the central regulation of food intake. Here we test whether CB1R-controlled feeding in sated mice is paralleled by decreased activity of POMC neurons. We show that chemical promotion of CB1R activity increases feeding, and notably, CB1R activation also promotes neuronal activity of POMC cells. This paradoxical increase in POMC activity was crucial for CB1R-induced feeding, because designer-receptors-exclusively-activated-by-designer-drugs (DREADD)-mediated inhibition of POMC neurons diminishes, whereas DREADD-mediated activation of POMC neurons enhances CB1R-driven feeding. The Pomc gene encodes both the anorexigenic peptide alpha-melanocyte-stimulating hormone, and the opioid peptide beta-endorphin. CB1R activation selectively increases beta-endorphin but not alpha-melanocyte-stimulating hormone release in the hypothalamus, and systemic or hypothalamic administration of the opioid receptor antagonist naloxone blocks acute CB1R-induced feeding. These processes involve mitochondrial adaptations that, when blocked, abolish CB1R-induced cellular responses and feeding. Together, these results uncover a previously unsuspected role of POMC neurons in the promotion of feeding by cannabinoids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496586/" 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/PMC4496586/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koch, Marco -- Varela, Luis -- Kim, Jae Geun -- Kim, Jung Dae -- Hernandez-Nuno, Francisco -- Simonds, Stephanie E -- Castorena, Carlos M -- Vianna, Claudia R -- Elmquist, Joel K -- Morozov, Yury M -- Rakic, Pasko -- Bechmann, Ingo -- Cowley, Michael A -- Szigeti-Buck, Klara -- Dietrich, Marcelo O -- Gao, Xiao-Bing -- Diano, Sabrina -- Horvath, Tamas L -- DP1 DK098058/DK/NIDDK NIH HHS/ -- DP1DK098058/DK/NIDDK NIH HHS/ -- P01 NS062686/NS/NINDS NIH HHS/ -- R01 AG040236/AG/NIA NIH HHS/ -- R01 DA023999/DA/NIDA NIH HHS/ -- R01AG040236/AG/NIA NIH HHS/ -- R01DK097566/DK/NIDDK NIH HHS/ -- R37 DK053301/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Mar 5;519(7541):45-50. doi: 10.1038/nature14260. Epub 2015 Feb 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany. ; Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Obesity &Diabetes Institute, Department of Physiology, Monash University, Clayton, Victoria 3800, Australia. ; Division of Endocrinology &Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; Institute of Anatomy, University of Leipzig, 04103 Leipzig, Germany. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. ; 1] Program in Integrative Cell Signaling and Neurobiology of Metabolism, Section of Comparative Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA [2] Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut 06520, USA [3] Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA [4] Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25707796" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cannabinoids/*pharmacology ; Eating/*drug effects/*physiology ; Energy Metabolism/drug effects ; Hypothalamus/*cytology/drug effects/physiology ; Ion Channels/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/drug effects/metabolism ; Mitochondrial Proteins/metabolism ; Naloxone/pharmacology ; Neurons/*drug effects/*metabolism ; Pro-Opiomelanocortin/*metabolism ; Receptor, Cannabinoid, CB1/agonists/metabolism ; Satiety Response/drug effects/physiology ; alpha-MSH/secretion ; beta-Endorphin/metabolism
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  • 24
    Publication Date: 2015-09-30
    Description: Haematopoietic stem cells (HSCs) reside in a perivascular niche but the specific location of this niche remains controversial. HSCs are rare and few can be found in thin tissue sections or upon live imaging, making it difficult to comprehensively localize dividing and non-dividing HSCs. Here, using a green fluorescent protein (GFP) knock-in for the gene Ctnnal1 in mice (hereafter denoted as alpha-catulin(GFP)), we discover that alpha-catulin(GFP) is expressed by only 0.02% of bone marrow haematopoietic cells, including almost all HSCs. We find that approximately 30% of alpha-catulin-GFP(+)c-kit(+) cells give long-term multilineage reconstitution of irradiated mice, indicating that alpha-catulin-GFP(+)c-kit(+) cells are comparable in HSC purity to cells obtained using the best markers currently available. We optically cleared the bone marrow to perform deep confocal imaging, allowing us to image thousands of alpha-catulin-GFP(+)c-kit(+) cells and to digitally reconstruct large segments of bone marrow. The distribution of alpha-catulin-GFP(+)c-kit(+) cells indicated that HSCs were more common in central marrow than near bone surfaces, and in the diaphysis relative to the metaphysis. Nearly all HSCs contacted leptin receptor positive (Lepr(+)) and Cxcl12(high) niche cells, and approximately 85% of HSCs were within 10 mum of a sinusoidal blood vessel. Most HSCs, both dividing (Ki-67(+)) and non-dividing (Ki-67(-)), were distant from arterioles, transition zone vessels, and bone surfaces. Dividing and non-dividing HSCs thus reside mainly in perisinusoidal niches with Lepr(+)Cxcl12(high) cells throughout the bone marrow.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Acar, Melih -- Kocherlakota, Kiranmai S -- Murphy, Malea M -- Peyer, James G -- Oguro, Hideyuki -- Inra, Christopher N -- Jaiyeola, Christabel -- Zhao, Zhiyu -- Luby-Phelps, Katherine -- Morrison, Sean J -- HL097760/HL/NHLBI NIH HHS/ -- R01 DK100848/DK/NIDDK NIH HHS/ -- S10 RR029731/RR/NCRR NIH HHS/ -- S10RR029731/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Oct 1;526(7571):126-30. doi: 10.1038/nature15250. Epub 2015 Sep 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Research Institute and the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA. ; Department of Cell Biology, 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/26416744" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/metabolism ; Biomarkers/analysis/metabolism ; Bone Marrow/*anatomy & histology ; Cell Division ; Cell Lineage ; Chemokine CXCL12/metabolism ; Diaphyses/cytology/metabolism ; Female ; Hematopoietic Stem Cells/cytology/*metabolism ; Image Processing, Computer-Assisted ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; *Molecular Imaging ; Proto-Oncogene Proteins c-kit/metabolism ; Receptors, Leptin/metabolism ; Stem Cell Niche ; Tibia/anatomy & histology/blood supply/cytology ; alpha Catenin/analysis/metabolism
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  • 25
    Publication Date: 2015-11-05
    Description: Anxiety-related conditions are among the most difficult neuropsychiatric diseases to treat pharmacologically, but respond to cognitive therapies. There has therefore been interest in identifying relevant top-down pathways from cognitive control regions in medial prefrontal cortex (mPFC). Identification of such pathways could contribute to our understanding of the cognitive regulation of affect, and provide pathways for intervention. Previous studies have suggested that dorsal and ventral mPFC subregions exert opposing effects on fear, as do subregions of other structures. However, precise causal targets for top-down connections among these diverse possibilities have not been established. Here we show that the basomedial amygdala (BMA) represents the major target of ventral mPFC in amygdala in mice. Moreover, BMA neurons differentiate safe and aversive environments, and BMA activation decreases fear-related freezing and high-anxiety states. Lastly, we show that the ventral mPFC-BMA projection implements top-down control of anxiety state and learned freezing, both at baseline and in stress-induced anxiety, defining a broadly relevant new top-down behavioural regulation pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adhikari, Avishek -- Lerner, Talia N -- Finkelstein, Joel -- Pak, Sally -- Jennings, Joshua H -- Davidson, Thomas J -- Ferenczi, Emily -- Gunaydin, Lisa A -- Mirzabekov, Julie J -- Ye, Li -- Kim, Sung-Yon -- Lei, Anna -- Deisseroth, Karl -- 1F32MH105053-01/MH/NIMH NIH HHS/ -- K99 MH106649/MH/NIMH NIH HHS/ -- K99MH106649/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Nov 12;527(7577):179-85. doi: 10.1038/nature15698. Epub 2015 Nov 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioengineering, Stanford University, Stanford, California 94305, USA. ; CNC Program, Stanford University, Stanford, California 94304, USA. ; Neurosciences Program, Stanford University, Stanford, California 94305, USA. ; Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California 94305, USA. ; Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26536109" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/cytology/*physiology ; Animals ; Anxiety/*physiopathology/psychology ; Extinction, Psychological/physiology ; Fear/*physiology/psychology ; Female ; Freezing Reaction, Cataleptic/physiology ; Learning/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Neural Pathways/*physiology ; Prefrontal Cortex/cytology/physiology ; Stress, Psychological/physiopathology
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  • 26
    Publication Date: 2015-06-19
    Description: Stress is considered a potent environmental risk factor for many behavioural abnormalities, including anxiety and mood disorders. Animal models can exhibit limited but quantifiable behavioural impairments resulting from chronic stress, including deficits in motivation, abnormal responses to behavioural challenges, and anhedonia. The hippocampus is thought to negatively regulate the stress response and to mediate various cognitive and mnemonic aspects of stress-induced impairments, although the neuronal underpinnings sufficient to support behavioural improvements are largely unknown. Here we acutely rescue stress-induced depression-related behaviours in mice by optogenetically reactivating dentate gyrus cells that were previously active during a positive experience. A brain-wide histological investigation, coupled with pharmacological and projection-specific optogenetic blockade experiments, identified glutamatergic activity in the hippocampus-amygdala-nucleus-accumbens pathway as a candidate circuit supporting the acute rescue. Finally, chronically reactivating hippocampal cells associated with a positive memory resulted in the rescue of stress-induced behavioural impairments and neurogenesis at time points beyond the light stimulation. Together, our data suggest that activating positive memories artificially is sufficient to suppress depression-like behaviours and point to dentate gyrus engram cells as potential therapeutic nodes for intervening with maladaptive behavioural states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramirez, Steve -- Liu, Xu -- MacDonald, Christopher J -- Moffa, Anthony -- Zhou, Joanne -- Redondo, Roger L -- Tonegawa, Susumu -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Jun 18;522(7556):335-9. doi: 10.1038/nature14514.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26085274" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/cytology/metabolism/physiology ; Animals ; Behavior, Animal ; Depression/*psychology/*therapy ; Female ; Hippocampus/cytology/physiology ; Male ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Neural Pathways ; Nucleus Accumbens/cytology/metabolism/physiology ; Optogenetics ; Pleasure/*physiology ; Proto-Oncogene Proteins c-fos/metabolism ; Stress, Psychological/psychology ; Time Factors
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  • 27
    Publication Date: 2015-12-10
    Description: Inactivation of the TNFAIP3 gene, encoding the A20 protein, is associated with critical inflammatory diseases including multiple sclerosis, rheumatoid arthritis and Crohn's disease. However, the role of A20 in attenuating inflammatory signalling is unclear owing to paradoxical in vitro and in vivo findings. Here we utilize genetically engineered mice bearing mutations in the A20 ovarian tumour (OTU)-type deubiquitinase domain or in the zinc finger-4 (ZnF4) ubiquitin-binding motif to investigate these discrepancies. We find that phosphorylation of A20 promotes cleavage of Lys63-linked polyubiquitin chains by the OTU domain and enhances ZnF4-mediated substrate ubiquitination. Additionally, levels of linear ubiquitination dictate whether A20-deficient cells die in response to tumour necrosis factor. Mechanistically, linear ubiquitin chains preserve the architecture of the TNFR1 signalling complex by blocking A20-mediated disassembly of Lys63-linked polyubiquitin scaffolds. Collectively, our studies reveal molecular mechanisms whereby A20 deubiquitinase activity and ubiquitin binding, linear ubiquitination, and cellular kinases cooperate to regulate inflammation and cell death.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wertz, Ingrid E -- Newton, Kim -- Seshasayee, Dhaya -- Kusam, Saritha -- Lam, Cynthia -- Zhang, Juan -- Popovych, Nataliya -- Helgason, Elizabeth -- Schoeffler, Allyn -- Jeet, Surinder -- Ramamoorthi, Nandhini -- Kategaya, Lorna -- Newman, Robert J -- Horikawa, Keisuke -- Dugger, Debra -- Sandoval, Wendy -- Mukund, Susmith -- Zindal, Anuradha -- Martin, Flavius -- Quan, Clifford -- Tom, Jeffrey -- Fairbrother, Wayne J -- Townsend, Michael -- Warming, Soren -- DeVoss, Jason -- Liu, Jinfeng -- Dueber, Erin -- Caplazi, Patrick -- Lee, Wyne P -- Goodnow, Christopher C -- Balazs, Mercedesz -- Yu, Kebing -- Kolumam, Ganesh -- Dixit, Vishva M -- England -- Nature. 2015 Dec 17;528(7582):370-5. doi: 10.1038/nature16165. Epub 2015 Dec 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Discovery Oncology, Genentech, South San Francisco, California 94080, USA. ; Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA. ; Physiological Chemistry, Genentech, South San Francisco, California 94080, USA. ; Immunology, Genentech, South San Francisco, California 94080, USA. ; Molecular Biology, Genentech, South San Francisco, California 94080, USA. ; Department of Cancer Biology and Therapeutics, The John Curtin School of Medical Research, The Australian National University, Canberra, Australian Capital Territory 2601, Australia. ; Protein Chemistry, Genentech, South San Francisco, California 94080, USA. ; Structural Biology, Genentech, South San Francisco, California 94080, USA. ; Bioinformatics, Genentech, South San Francisco, California 94080, USA. ; Pathology, Genentech, South San Francisco, California 94080, USA. ; Immunogenomics Laboratory, Immunology Division, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, New South Wales 2010, Sydney, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26649818" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Death ; Cysteine Endopeptidases/chemistry/genetics/*metabolism ; Female ; Inflammation/genetics/*metabolism/pathology ; Intracellular Signaling Peptides and Proteins/chemistry/genetics/*metabolism ; Lysine/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mutation ; Phosphorylation ; Polyubiquitin/chemistry/metabolism ; Protein Binding ; Protein Kinases/metabolism ; Signal Transduction ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitin/*chemistry/*metabolism ; Ubiquitination
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  • 28
    Publication Date: 2015-11-03
    Description: Ever since Stephen Paget's 1889 hypothesis, metastatic organotropism has remained one of cancer's greatest mysteries. Here we demonstrate that exosomes from mouse and human lung-, liver- and brain-tropic tumour cells fuse preferentially with resident cells at their predicted destination, namely lung fibroblasts and epithelial cells, liver Kupffer cells and brain endothelial cells. We show that tumour-derived exosomes uptaken by organ-specific cells prepare the pre-metastatic niche. Treatment with exosomes from lung-tropic models redirected the metastasis of bone-tropic tumour cells. Exosome proteomics revealed distinct integrin expression patterns, in which the exosomal integrins alpha6beta4 and alpha6beta1 were associated with lung metastasis, while exosomal integrin alphavbeta5 was linked to liver metastasis. Targeting the integrins alpha6beta4 and alphavbeta5 decreased exosome uptake, as well as lung and liver metastasis, respectively. We demonstrate that exosome integrin uptake by resident cells activates Src phosphorylation and pro-inflammatory S100 gene expression. Finally, our clinical data indicate that exosomal integrins could be used to predict organ-specific metastasis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoshino, Ayuko -- Costa-Silva, Bruno -- Shen, Tang-Long -- Rodrigues, Goncalo -- Hashimoto, Ayako -- Tesic Mark, Milica -- Molina, Henrik -- Kohsaka, Shinji -- Di Giannatale, Angela -- Ceder, Sophia -- Singh, Swarnima -- Williams, Caitlin -- Soplop, Nadine -- Uryu, Kunihiro -- Pharmer, Lindsay -- King, Tari -- Bojmar, Linda -- Davies, Alexander E -- Ararso, Yonathan -- Zhang, Tuo -- Zhang, Haiying -- Hernandez, Jonathan -- Weiss, Joshua M -- Dumont-Cole, Vanessa D -- Kramer, Kimberly -- Wexler, Leonard H -- Narendran, Aru -- Schwartz, Gary K -- Healey, John H -- Sandstrom, Per -- Labori, Knut Jorgen -- Kure, Elin H -- Grandgenett, Paul M -- Hollingsworth, Michael A -- de Sousa, Maria -- Kaur, Sukhwinder -- Jain, Maneesh -- Mallya, Kavita -- Batra, Surinder K -- Jarnagin, William R -- Brady, Mary S -- Fodstad, Oystein -- Muller, Volkmar -- Pantel, Klaus -- Minn, Andy J -- Bissell, Mina J -- Garcia, Benjamin A -- Kang, Yibin -- Rajasekhar, Vinagolu K -- Ghajar, Cyrus M -- Matei, Irina -- Peinado, Hector -- Bromberg, Jacqueline -- Lyden, David -- R01 CA169416/CA/NCI NIH HHS/ -- R01-CA169416/CA/NCI NIH HHS/ -- U01 CA169538/CA/NCI NIH HHS/ -- U01-CA169538/CA/NCI NIH HHS/ -- England -- Nature. 2015 Nov 19;527(7578):329-35. doi: 10.1038/nature15756. Epub 2015 Oct 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Plant Pathology and Microbiology and Center for Biotechnology, National Taiwan University, Taipei 10617, Taiwan. ; Graduate Program in Areas of Basic and Applied Biology, Abel Salazar Biomedical Sciences Institute, University of Porto, 4099-003 Porto, Portugal. ; Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. ; Proteomics Resource Center, The Rockefeller University, New York, New York 10065, USA. ; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Oncology and Pathology, Karolinska Institutet, 17176 Stockholm, Sweden. ; Electron Microscopy Resource Center (EMRC), Rockefeller University, New York, New York 10065, USA. ; Breast Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, 10065, USA. ; Department of Surgery, County Council of Ostergotland, and Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linkoping University, 58185 Linkoping, Sweden. ; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720, USA. ; Genomics Resources Core Facility, Weill Cornell Medicine, New York, New York 10021, USA. ; Department of Surgery, 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. ; Division of Pediatric Oncology, Alberta Children's Hospital, Calgary, Alberta T3B 6A8, Canada. ; Division of Hematology/Oncology, Columbia University School of Medicine, New York, New York 10032, USA. ; Orthopaedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. ; Gastric and Mixed Tumor Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Tumor Biology, Norwegian Radium Hospital, Oslo University Hospital, Nydalen, Oslo 0424, Norway. ; Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Blindern, Oslo 0318, Norway. ; Department of Gynecology, University Medical Center, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. ; Department of Radiation Oncology, Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA. ; Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA. ; Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. ; Microenvironment and Metastasis Laboratory, Department of Molecular Oncology, Spanish National Cancer Research Center (CNIO), Madrid 28029, Spain. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Department of Medicine, Weill Cornell Medicine, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26524530" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers/metabolism ; Brain/cytology/*metabolism ; Cell Line, Tumor ; Endothelial Cells/cytology/metabolism ; Epithelial Cells/cytology/metabolism ; Exosomes/*metabolism ; Female ; Fibroblasts/cytology/metabolism ; Genes, src ; Humans ; Integrin alpha6beta1/metabolism ; Integrin alpha6beta4/antagonists & inhibitors/metabolism ; Integrin beta Chains/metabolism ; Integrin beta4/metabolism ; Integrins/antagonists & inhibitors/*metabolism ; Kupffer Cells/cytology/metabolism ; Liver/cytology/*metabolism ; Lung/cytology/*metabolism ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/*pathology/*prevention & control ; Organ Specificity ; Phosphorylation ; Receptors, Vitronectin/antagonists & inhibitors/metabolism ; S100 Proteins/genetics ; *Tropism
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  • 29
    Publication Date: 2015-05-01
    Description: The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4418228/" 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/PMC4418228/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Namburi, Praneeth -- Beyeler, Anna -- Yorozu, Suzuko -- Calhoon, Gwendolyn G -- Halbert, Sarah A -- Wichmann, Romy -- Holden, Stephanie S -- Mertens, Kim L -- Anahtar, Melodi -- Felix-Ortiz, Ada C -- Wickersham, Ian R -- Gray, Jesse M -- Tye, Kay M -- DP2 DK102256/DK/NIDDK NIH HHS/ -- DP2-DK-102256-01/DK/NIDDK NIH HHS/ -- R01 MH101528/MH/NIMH NIH HHS/ -- R01 MH102441/MH/NIMH NIH HHS/ -- R01-MH101528-01/MH/NIMH NIH HHS/ -- R01-MH102441-01/MH/NIMH NIH HHS/ -- U01 MH106018/MH/NIMH NIH HHS/ -- U01-MH106018/MH/NIMH NIH HHS/ -- U01-NS090473/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Apr 30;520(7549):675-8. doi: 10.1038/nature14366.〈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] Neuroscience Graduate Program, 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. ; Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, NRB 356, Boston, Massachusetts 02115, USA. ; 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Undergraduate Program in Neuroscience, Wellesley College, Wellesley, Massachusetts 02481, USA. ; 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Undergraduate Program in Neuroscience, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] The Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Master's Program in Biomedical Sciences, University of Amsterdam, Amsterdam 1098 XH, The Netherlands. ; McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25925480" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/*cytology/*physiology ; Animals ; Conditioning, Classical ; Fear/*physiology/psychology ; Gene Expression Profiling ; Long-Term Potentiation ; Male ; Mice ; Mice, Inbred C57BL ; Motivation ; *Neural Pathways ; Neurons/*physiology ; Nucleus Accumbens/cytology/physiology/radiation effects ; Reinforcement (Psychology) ; *Reward ; Transcription, Genetic
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  • 30
    Publication Date: 2015-12-18
    Description: T helper 17 (TH17) lymphocytes protect mucosal barriers from infections, but also contribute to multiple chronic inflammatory diseases. Their differentiation is controlled by RORgammat, a ligand-regulated nuclear receptor. Here we identify the RNA helicase DEAD-box protein 5 (DDX5) as a RORgammat partner that coordinates transcription of selective TH17 genes, and is required for TH17-mediated inflammatory pathologies. Surprisingly, the ability of DDX5 to interact with RORgammat and coactivate its targets depends on intrinsic RNA helicase activity and binding of a conserved nuclear long noncoding RNA (lncRNA), Rmrp, which is mutated in patients with cartilage-hair hypoplasia. A targeted Rmrp gene mutation in mice, corresponding to a gene mutation in cartilage-hair hypoplasia patients, altered lncRNA chromatin occupancy, and reduced the DDX5-RORgammat interaction and RORgammat target gene transcription. Elucidation of the link between Rmrp and the DDX5-RORgammat complex reveals a role for RNA helicases and lncRNAs in tissue-specific transcriptional regulation, and provides new opportunities for therapeutic intervention in TH17-dependent diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4762670/" 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/PMC4762670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Wendy -- Thomas, Benjamin -- Flynn, Ryan A -- Gavzy, Samuel J -- Wu, Lin -- Kim, Sangwon V -- Hall, Jason A -- Miraldi, Emily R -- Ng, Charles P -- Rigo, Frank W -- Meadows, Sarah -- Montoya, Nina R -- Herrera, Natalia G -- Domingos, Ana I -- Rastinejad, Fraydoon -- Myers, Richard M -- Fuller-Pace, Frances V -- Bonneau, Richard -- Chang, Howard Y -- Acuto, Oreste -- Littman, Dan R -- 1F30CA189514-01/CA/NCI NIH HHS/ -- F30 CA189514/CA/NCI NIH HHS/ -- P50 HG007735/HG/NHGRI NIH HHS/ -- P50-HG007735/HG/NHGRI NIH HHS/ -- R01 AI080885/AI/NIAID NIH HHS/ -- R01 AI121436/AI/NIAID NIH HHS/ -- R01 DK103358/DK/NIDDK NIH HHS/ -- R01 HG004361/HG/NHGRI NIH HHS/ -- R01AI080885/AI/NIAID NIH HHS/ -- R01DK103358/DK/NIDDK NIH HHS/ -- R01HG004361/HG/NHGRI NIH HHS/ -- T32 AI100853/AI/NIAID NIH HHS/ -- T32 CA009161/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Dec 24;528(7583):517-22. doi: 10.1038/nature16193. Epub 2015 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA. ; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, UK. ; Center for Personal Dynamic Regulomes, Stanford University, Stanford, California 94305, USA. ; Center for Genomics and Systems Biology, Department of Biology, New York University, New York, New York 10003, USA. ; Courant Institute of Mathematical Sciences, Computer Science Department, New York University, New York, New York 10012, USA. ; Simons Center for Data Analysis, Simons Foundation, New York, New York 10010, USA. ; Isis Pharmaceuticals, Carlsbad, California 92010, USA. ; HudsonAlpha Institute for Biotechnology, Huntsville, Alabama 35806, USA. ; Instituto Gulbenkian de Ciencia, Oeiras 2780-156, Portugal. ; Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, Florida 32827, USA. ; Division of Cancer Research, University of Dundee, Dundee DD1 9SY, UK. ; Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26675721" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromatin/genetics/metabolism ; DEAD-box RNA Helicases/genetics/*metabolism ; Female ; Gene Expression Regulation/genetics ; Hair/abnormalities ; Hirschsprung Disease/genetics ; Humans ; Immunologic Deficiency Syndromes/genetics ; Inflammation/immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Organ Specificity ; Osteochondrodysplasias/congenital/genetics ; Protein Binding ; RNA, Long Noncoding/genetics/*metabolism ; Th17 Cells/*immunology/*metabolism ; Transcription, Genetic/genetics
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  • 31
    Publication Date: 2015-03-13
    Description: After stimulation, dendritic cells (DCs) mature and migrate to draining lymph nodes to induce immune responses. As such, autologous DCs generated ex vivo have been pulsed with tumour antigens and injected back into patients as immunotherapy. While DC vaccines have shown limited promise in the treatment of patients with advanced cancers including glioblastoma, the factors dictating DC vaccine efficacy remain poorly understood. Here we show that pre-conditioning the vaccine site with a potent recall antigen such as tetanus/diphtheria (Td) toxoid can significantly improve the lymph node homing and efficacy of tumour-antigen-specific DCs. To assess the effect of vaccine site pre-conditioning in humans, we randomized patients with glioblastoma to pre-conditioning with either mature DCs or Td unilaterally before bilateral vaccination with DCs pulsed with Cytomegalovirus phosphoprotein 65 (pp65) RNA. We and other laboratories have shown that pp65 is expressed in more than 90% of glioblastoma specimens but not in surrounding normal brain, providing an unparalleled opportunity to subvert this viral protein as a tumour-specific target. Patients given Td had enhanced DC migration bilaterally and significantly improved survival. In mice, Td pre-conditioning also enhanced bilateral DC migration and suppressed tumour growth in a manner dependent on the chemokine CCL3. Our clinical studies and corroborating investigations in mice suggest that pre-conditioning with a potent recall antigen may represent a viable strategy to improve anti-tumour immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4510871/" 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/PMC4510871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitchell, Duane A -- Batich, Kristen A -- Gunn, Michael D -- Huang, Min-Nung -- Sanchez-Perez, Luis -- Nair, Smita K -- Congdon, Kendra L -- Reap, Elizabeth A -- Archer, Gary E -- Desjardins, Annick -- Friedman, Allan H -- Friedman, Henry S -- Herndon, James E 2nd -- Coan, April -- McLendon, Roger E -- Reardon, David A -- Vredenburgh, James J -- Bigner, Darell D -- Sampson, John H -- 1UL2 RR024128-01/RR/NCRR NIH HHS/ -- P01 CA154291/CA/NCI NIH HHS/ -- P01-CA154291-01A1/CA/NCI NIH HHS/ -- P50 CA108786/CA/NCI NIH HHS/ -- P50 NS020023/NS/NINDS NIH HHS/ -- P50-CA108786/CA/NCI NIH HHS/ -- P50-NS20023/NS/NINDS NIH HHS/ -- R01 CA134844/CA/NCI NIH HHS/ -- R01 CA177476/CA/NCI NIH HHS/ -- R01 NS067037/NS/NINDS NIH HHS/ -- R01-CA134844/CA/NCI NIH HHS/ -- R01-CA177476-01/CA/NCI NIH HHS/ -- R01-NS067037/NS/NINDS NIH HHS/ -- T32 AI052077/AI/NIAID NIH HHS/ -- T32 GM007171/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Mar 19;519(7543):366-9. doi: 10.1038/nature14320. Epub 2015 Mar 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Division of Cardiology, Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Division of Surgical Sciences, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ; Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. ; 1] Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina 27710, USA [2] Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA [3] Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA [4] Department of Immunology, Duke University Medical Center, Durham, North Carolina 27710, USA [5] Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25762141" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/immunology ; CD4-Positive T-Lymphocytes/drug effects/immunology ; Cancer Vaccines/administration & dosage/*immunology/therapeutic use ; Cell Movement/drug effects ; Chemokine CCL3/*immunology ; Dendritic Cells/cytology/*drug effects/immunology ; Female ; Glioblastoma/drug therapy/*immunology/pathology/*therapy ; Humans ; Immunotherapy/methods ; Lymph Nodes/cytology/drug effects/immunology ; Mice ; Mice, Inbred C57BL ; Phosphoproteins/chemistry/genetics/immunology ; Substrate Specificity ; Survival Rate ; Tetanus Toxoid/*administration & dosage/*pharmacology/therapeutic use ; Treatment Outcome ; Viral Matrix Proteins/chemistry/genetics/immunology
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  • 32
    Publication Date: 2015-03-25
    Description: Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4376609/" 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/PMC4376609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Dong I -- Zhu, Guangshuo -- Sasaki, Takashi -- Cho, Gun-Sik -- Hamdani, Nazha -- Holewinski, Ronald -- Jo, Su-Hyun -- Danner, Thomas -- Zhang, Manling -- Rainer, Peter P -- Bedja, Djahida -- Kirk, Jonathan A -- Ranek, Mark J -- Dostmann, Wolfgang R -- Kwon, Chulan -- Margulies, Kenneth B -- Van Eyk, Jennifer E -- Paulus, Walter J -- Takimoto, Eiki -- Kass, David A -- HHSN268201000032C/HL/NHLBI NIH HHS/ -- HL-07227/HL/NHLBI NIH HHS/ -- HL-089297/HL/NHLBI NIH HHS/ -- HL-093432/HL/NHLBI NIH HHS/ -- HL-119012/HL/NHLBI NIH HHS/ -- HL089847/HL/NHLBI NIH HHS/ -- HL105993/HL/NHLBI NIH HHS/ -- HL68891/HL/NHLBI NIH HHS/ -- N01HV28180/HL/NHLBI NIH HHS/ -- P01 HL107153/HL/NHLBI NIH HHS/ -- R01 HL089297/HL/NHLBI NIH HHS/ -- R01 HL089847/HL/NHLBI NIH HHS/ -- R01 HL093432/HL/NHLBI NIH HHS/ -- R01 HL105993/HL/NHLBI NIH HHS/ -- R01 HL111198/HL/NHLBI NIH HHS/ -- R01 HL119012/HL/NHLBI NIH HHS/ -- T32 HL007227/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 Mar 26;519(7544):472-6. doi: 10.1038/nature14332. Epub 2015 Mar 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA. ; Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Kanagawa 227-0033, Japan. ; Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. ; 1] Division of Cardiology, Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205, USA [2] Heart Institute and Advanced Clinical Biosystems Research Institute, Cedar Sinai Medical Center, 8700 Beverly Blvd, AHSP A9229 Los Angeles, California 90048, USA. ; Department of Physiology, Institute of Bioscience and Biotechnology, BK21 plus Graduate Program, Kangwon National University College of Medicine, Chuncheon 200-701, Korea. ; Department of Pharmacology, University of Vermont, Burlington, Vermont 05405, USA. ; Department of Medicine, Division of Cardiovascular Medicine, Cardiovascular Institute, 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/25799991" target="_blank"〉PubMed〈/a〉
    Keywords: 3',5'-Cyclic-AMP Phosphodiesterases/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Animals ; Aortic Valve Stenosis/complications ; Cardiomegaly/drug therapy/*enzymology/etiology/*metabolism ; Cyclic GMP/*metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Cells/enzymology ; Myocardium/enzymology ; Natriuretic Peptides/metabolism ; *Nitric Oxide/metabolism ; Nitric Oxide Synthase ; Phosphodiesterase Inhibitors/pharmacology/therapeutic use ; Pressure ; Signal Transduction/drug effects ; Stress, Physiological ; Up-Regulation
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  • 33
    Publication Date: 2015-09-01
    Description: Dopamine neurons are thought to facilitate learning by comparing actual and expected reward. Despite two decades of investigation, little is known about how this comparison is made. To determine how dopamine neurons calculate prediction error, we combined optogenetic manipulations with extracellular recordings in the ventral tegmental area while mice engaged in classical conditioning. Here we demonstrate, by manipulating the temporal expectation of reward, that dopamine neurons perform subtraction, a computation that is ideal for reinforcement learning but rarely observed in the brain. Furthermore, selectively exciting and inhibiting neighbouring GABA (gamma-aminobutyric acid) neurons in the ventral tegmental area reveals that these neurons are a source of subtraction: they inhibit dopamine neurons when reward is expected, causally contributing to prediction-error calculations. Finally, bilaterally stimulating ventral tegmental area GABA neurons dramatically reduces anticipatory licking to conditioned odours, consistent with an important role for these neurons in reinforcement learning. Together, our results uncover the arithmetic and local circuitry underlying dopamine prediction errors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4567485/" 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/PMC4567485/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eshel, Neir -- Bukwich, Michael -- Rao, Vinod -- Hemmelder, Vivian -- Tian, Ju -- Uchida, Naoshige -- F30 MH100729/MH/NIMH NIH HHS/ -- F30MH100729/MH/NIMH NIH HHS/ -- R01 MH095953/MH/NIMH NIH HHS/ -- R01 MH101207/MH/NIMH NIH HHS/ -- R01MH095953/MH/NIMH NIH HHS/ -- R01MH101207/MH/NIMH NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2015 Sep 10;525(7568):243-6. doi: 10.1038/nature14855. Epub 2015 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26322583" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Conditioning, Classical ; Dopamine/*metabolism ; Dopaminergic Neurons/*metabolism ; GABAergic Neurons/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; *Models, Neurological ; Neural Pathways/*physiology ; Odors/analysis ; Optogenetics ; Reinforcement (Psychology) ; Reward ; Time Factors ; Ventral Tegmental Area/*cytology/*physiology ; gamma-Aminobutyric Acid/metabolism
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  • 34
    Publication Date: 2015-04-02
    Description: The RNA-guided endonuclease Cas9 has emerged as a versatile genome-editing platform. However, the size of the commonly used Cas9 from Streptococcus pyogenes (SpCas9) limits its utility for basic research and therapeutic applications that use the highly versatile adeno-associated virus (AAV) delivery vehicle. Here, we characterize six smaller Cas9 orthologues and show that Cas9 from Staphylococcus aureus (SaCas9) can edit the genome with efficiencies similar to those of SpCas9, while being more than 1 kilobase shorter. We packaged SaCas9 and its single guide RNA expression cassette into a single AAV vector and targeted the cholesterol regulatory gene Pcsk9 in the mouse liver. Within one week of injection, we observed 〉40% gene modification, accompanied by significant reductions in serum Pcsk9 and total cholesterol levels. We further assess the genome-wide targeting specificity of SaCas9 and SpCas9 using BLESS, and demonstrate that SaCas9-mediated in vivo genome editing has the potential to be efficient and specific.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4393360/" 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/PMC4393360/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ran, F Ann -- Cong, Le -- Yan, Winston X -- Scott, David A -- Gootenberg, Jonathan S -- Kriz, Andrea J -- Zetsche, Bernd -- Shalem, Ophir -- Wu, Xuebing -- Makarova, Kira S -- Koonin, Eugene V -- Sharp, Phillip A -- Zhang, Feng -- 5DP1-MH100706/DP/NCCDPHP CDC HHS/ -- 5P30EY012196-17/EY/NEI NIH HHS/ -- 5R01DK097768-03/DK/NIDDK NIH HHS/ -- DP1 MH100706/MH/NIMH NIH HHS/ -- P01-CA42063/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 EY024259/EY/NEI NIH HHS/ -- R01-CA133404/CA/NCI NIH HHS/ -- R01-GM34277/GM/NIGMS NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- T32 GM008313/GM/NIGMS NIH HHS/ -- T32GM007753/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Apr 9;520(7546):186-91. doi: 10.1038/nature14299. Epub 2015 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Society of Fellows, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Graduate Program in Biophysics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA. ; 1] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25830891" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; CRISPR-Associated Proteins/genetics/*metabolism ; Cholesterol/blood/metabolism ; Gene Targeting ; Genetic Engineering/*methods ; Genome/*genetics ; Liver/metabolism/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Proprotein Convertases/biosynthesis/blood/deficiency/genetics ; Serine Endopeptidases/biosynthesis/blood/deficiency/genetics ; Staphylococcus aureus/*enzymology/genetics ; Substrate Specificity
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 35
    Publication Date: 2015-05-15
    Description: The tumour microenvironment may contribute to tumorigenesis owing to mechanical forces such as fibrotic stiffness or mechanical pressure caused by the expansion of hyper-proliferative cells. Here we explore the contribution of the mechanical pressure exerted by tumour growth onto non-tumorous adjacent epithelium. In the early stage of mouse colon tumour development in the Notch(+)Apc(+/1638N) mouse model, we observed mechanistic pressure stress in the non-tumorous epithelial cells caused by hyper-proliferative adjacent crypts overexpressing active Notch, which is associated with increased Ret and beta-catenin signalling. We thus developed a method that allows the delivery of a defined mechanical pressure in vivo, by subcutaneously inserting a magnet close to the mouse colon. The implanted magnet generated a magnetic force on ultra-magnetic liposomes, stabilized in the mesenchymal cells of the connective tissue surrounding colonic crypts after intravenous injection. The magnetically induced pressure quantitatively mimicked the endogenous early tumour growth stress in the order of 1,200 Pa, without affecting tissue stiffness, as monitored by ultrasound strain imaging and shear wave elastography. The exertion of pressure mimicking that of tumour growth led to rapid Ret activation and downstream phosphorylation of beta-catenin on Tyr654, imparing its interaction with the E-cadherin in adherens junctions, and which was followed by beta-catenin nuclear translocation after 15 days. As a consequence, increased expression of beta-catenin-target genes was observed at 1 month, together with crypt enlargement accompanying the formation of early tumorous aberrant crypt foci. Mechanical activation of the tumorigenic beta-catenin pathway suggests unexplored modes of tumour propagation based on mechanical signalling pathways in healthy epithelial cells surrounding the tumour, which may contribute to tumour heterogeneity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fernandez-Sanchez, Maria Elena -- Barbier, Sandrine -- Whitehead, Joanne -- Bealle, Gaelle -- Michel, Aude -- Latorre-Ossa, Heldmuth -- Rey, Colette -- Fouassier, Laura -- Claperon, Audrey -- Brulle, Laura -- Girard, Elodie -- Servant, Nicolas -- Rio-Frio, Thomas -- Marie, Helene -- Lesieur, Sylviane -- Housset, Chantal -- Gennisson, Jean-Luc -- Tanter, Mickael -- Menager, Christine -- Fre, Silvia -- Robine, Sylvie -- Farge, Emmanuel -- England -- Nature. 2015 Jul 2;523(7558):92-5. doi: 10.1038/nature14329. Epub 2015 May 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie, Centre de Recherche, PSL Research University, CNRS UMR 168, Physicochimie Curie Mechanics and Genetics of Embryonic and Tumour Development, INSERM, Fondation Pierre-Gilles de Gennes, F-75005 Paris, France. ; UPMC, Sorbonne Universites, Laboratoire PHENIX Physico-chimie des Electrolytes et Nanosystemes Interfaciaux, CNRS UMR 8234, F-75005 Paris, France. ; Langevin Institut, Waves and Images ESPCI ParisTech, PSL Research University, CNRS UMR7587, Inserm U979. F-75005 Paris, France. ; Sorbonne Universites, UPMC and INSERM, UMR-S 938, CDR Saint-Antoine, F-75012 Paris, France. ; CNRS UMR3666/INSERM U1143, Endocytic Trafficking and Therapeutic Delivery, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; Bioinformatic platform, U900, Institut Curie, MINES ParisTech, F-75005 Paris, France. ; Next-generation sequencing platform, Institut Curie, F-75005 Paris, France. ; CNRS UMR 8612, Laboratoire Physico-Chimie des Systemes Polyphases, Institut Galien Paris-Sud, LabEx LERMIT, Faculte de Pharmacie, Universite Paris-Sud, 92 296 Chatenay-Malabry, France. ; CNRS UMR 3215/INSERM U934, Unite de Genetique et Biologie du Developpement, Notch Signaling in Stem Cells and Tumors, Institut Curie, Centre de Recherche, F-75005 Paris, France. ; CNRS UMR144, Compartimentation et dynamique cellulaires, Morphogenesis and Cell Signalling Institut Curie, Centre de Recherche, F-75005 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25970250" target="_blank"〉PubMed〈/a〉
    Keywords: Active Transport, Cell Nucleus ; Animals ; Carcinogenesis/*pathology ; Colonic Neoplasms/*physiopathology ; Epithelial Cells/cytology/pathology ; Female ; Gene Expression Regulation, Neoplastic ; Magnets ; Male ; Metal Nanoparticles ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; *Pressure ; Proto-Oncogene Proteins c-ret/metabolism ; Receptors, Notch/genetics/metabolism ; Signal Transduction ; *Tumor Microenvironment ; beta Catenin/*genetics/metabolism
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  • 36
    Publication Date: 2015-11-19
    Description: Prevailing dogma holds that cell-cell communication through Notch ligands and receptors determines binary cell fate decisions during progenitor cell divisions, with differentiated lineages remaining fixed. Mucociliary clearance in mammalian respiratory airways depends on secretory cells (club and goblet) and ciliated cells to produce and transport mucus. During development or repair, the closely related Jagged ligands (JAG1 and JAG2) induce Notch signalling to determine the fate of these lineages as they descend from a common proliferating progenitor. In contrast to such situations in which cell fate decisions are made in rapidly dividing populations, cells of the homeostatic adult airway epithelium are long-lived, and little is known about the role of active Notch signalling under such conditions. To disrupt Jagged signalling acutely in adult mammals, here we generate antibody antagonists that selectively target each Jagged paralogue, and determine a crystal structure that explains selectivity. We show that acute Jagged blockade induces a rapid and near-complete loss of club cells, with a concomitant gain in ciliated cells, under homeostatic conditions without increased cell death or division. Fate analyses demonstrate a direct conversion of club cells to ciliated cells without proliferation, meeting a conservative definition of direct transdifferentiation. Jagged inhibition also reversed goblet cell metaplasia in a preclinical asthma model, providing a therapeutic foundation. Our discovery that Jagged antagonism relieves a blockade of cell-to-cell conversion unveils unexpected plasticity, and establishes a model for Notch regulation of transdifferentiation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lafkas, Daniel -- Shelton, Amy -- Chiu, Cecilia -- de Leon Boenig, Gladys -- Chen, Yongmei -- Stawicki, Scott S -- Siltanen, Christian -- Reichelt, Mike -- Zhou, Meijuan -- Wu, Xiumin -- Eastham-Anderson, Jeffrey -- Moore, Heather -- Roose-Girma, Meron -- Chinn, Yvonne -- Hang, Julie Q -- Warming, Soren -- Egen, Jackson -- Lee, Wyne P -- Austin, Cary -- Wu, Yan -- Payandeh, Jian -- Lowe, John B -- Siebel, Christian W -- England -- Nature. 2015 Dec 3;528(7580):127-31. doi: 10.1038/nature15715. Epub 2015 Nov 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Discovery Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Antibody Engineering, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Structural Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Translational Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Discovery Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Departments of Protein Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26580007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/pharmacology/*therapeutic use ; Asthma/drug therapy/metabolism/pathology ; Calcium-Binding Proteins/antagonists & inhibitors/immunology/metabolism ; Cell Death/drug effects ; Cell Division/drug effects ; Cell Lineage/drug effects ; Cell Tracking ; *Cell Transdifferentiation/drug effects ; Cilia/metabolism ; Disease Models, Animal ; Female ; Goblet Cells/cytology/drug effects/pathology ; Homeostasis/drug effects ; Humans ; Intercellular Signaling Peptides and Proteins/immunology/metabolism ; Ligands ; Lung/*cytology/drug effects/*metabolism ; Male ; Membrane Proteins/antagonists & inhibitors/immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Receptors, Notch/*metabolism ; Signal Transduction/drug effects
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  • 37
    Publication Date: 2015-06-02
    Description: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506234/" 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/PMC4506234/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Louveau, Antoine -- Smirnov, Igor -- Keyes, Timothy J -- Eccles, Jacob D -- Rouhani, Sherin J -- Peske, J David -- Derecki, Noel C -- Castle, David -- Mandell, James W -- Lee, Kevin S -- Harris, Tajie H -- Kipnis, Jonathan -- P30 CA044579/CA/NCI NIH HHS/ -- R01 AG034113/AG/NIA NIH HHS/ -- R01 NS061973/NS/NINDS NIH HHS/ -- R01AG034113/AG/NIA NIH HHS/ -- R01NS061973/NS/NINDS NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):337-41. doi: 10.1038/nature14432. Epub 2015 Jun 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Medicine (Division of Allergy), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; Department of Pathology (Neuropathology), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA [3] Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26030524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Central Nervous System/*anatomy & histology/cytology/*immunology ; Cranial Sinuses/anatomy & histology ; Female ; Humans ; Immune Tolerance/immunology ; Immunologic Surveillance/immunology ; Lymphatic Vessels/*anatomy & histology/cytology/*immunology ; Male ; Meninges/anatomy & histology/cytology/immunology ; Mice, Inbred C57BL ; T-Lymphocytes/cytology/immunology
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  • 38
    Publication Date: 2015-06-09
    Description: Lipid mediators influence immunity in myriad ways. For example, circulating sphingosine-1-phosphate (S1P) is a key regulator of lymphocyte egress. Although the majority of plasma S1P is bound to apolipoprotein M (ApoM) in the high-density lipoprotein (HDL) particle, the immunological functions of the ApoM-S1P complex are unknown. Here we show that ApoM-S1P is dispensable for lymphocyte trafficking yet restrains lymphopoiesis by activating the S1P1 receptor on bone marrow lymphocyte progenitors. Mice that lacked ApoM (Apom(-/-)) had increased proliferation of Lin(-) Sca-1(+) cKit(+) haematopoietic progenitor cells (LSKs) and common lymphoid progenitors (CLPs) in bone marrow. Pharmacological activation or genetic overexpression of S1P1 suppressed LSK and CLP cell proliferation in vivo. ApoM was stably associated with bone marrow CLPs, which showed active S1P1 signalling in vivo. Moreover, ApoM-bound S1P, but not albumin-bound S1P, inhibited lymphopoiesis in vitro. Upon immune stimulation, Apom(-/-) mice developed more severe experimental autoimmune encephalomyelitis, characterized by increased lymphocytes in the central nervous system and breakdown of the blood-brain barrier. Thus, the ApoM-S1P-S1P1 signalling axis restrains the lymphocyte compartment and, subsequently, adaptive immune responses. Unique biological functions imparted by specific S1P chaperones could be exploited for novel therapeutic opportunities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506268/" 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/PMC4506268/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Blaho, Victoria A -- Galvani, Sylvain -- Engelbrecht, Eric -- Liu, Catherine -- Swendeman, Steven L -- Kono, Mari -- Proia, Richard L -- Steinman, Lawrence -- Han, May H -- Hla, Timothy -- F32 CA14211/CA/NCI NIH HHS/ -- F32 CA142117/CA/NCI NIH HHS/ -- HL67330/HL/NHLBI NIH HHS/ -- HL70694/HL/NHLBI NIH HHS/ -- HL89934/HL/NHLBI NIH HHS/ -- P01 HL070694/HL/NHLBI NIH HHS/ -- P20 RR017677/RR/NCRR NIH HHS/ -- P30 CA138313/CA/NCI NIH HHS/ -- R01 HL089934/HL/NHLBI NIH HHS/ -- R37 HL067330/HL/NHLBI NIH HHS/ -- Z01 DK056014-02/Intramural NIH HHS/ -- Z01 DK056015-01/Intramural NIH HHS/ -- England -- Nature. 2015 Jul 16;523(7560):342-6. doi: 10.1038/nature14462. Epub 2015 Jun 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA [2] Brain and Mind Research Institute, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, New York 10065, USA. ; Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892, USA. ; Department of Neurology and Neurological Sciences, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26053123" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins/deficiency/genetics/*metabolism ; Blood-Brain Barrier/pathology ; Cell Movement ; Cell Proliferation/genetics ; Central Nervous System/immunology/metabolism/*pathology ; Encephalomyelitis, Autoimmune, ; Experimental/genetics/immunology/metabolism/pathology ; Female ; Fingolimod Hydrochloride/pharmacology ; Hematopoietic Stem Cells/cytology/metabolism ; Inflammation/immunology/metabolism/pathology ; Lipoproteins, HDL/*metabolism ; Lymphocytes/*cytology/immunology/*metabolism ; Lymphoid Progenitor Cells/cytology/metabolism ; *Lymphopoiesis ; Lysophospholipids/agonists/blood/genetics/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Receptors, Lysosphingolipid/metabolism ; Signal Transduction ; Sphingosine/agonists/*analogs & derivatives/blood/genetics/metabolism
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  • 39
    Publication Date: 2015-06-13
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636083/" 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/PMC4636083/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lloyd, Kent -- Franklin, Craig -- Lutz, Cat -- Magnuson, Terry -- U24 DK092993/DK/NIDDK NIH HHS/ -- U42 OD010921/OD/NIH HHS/ -- U42 OD011175/OD/NIH HHS/ -- U42 OD012210/OD/NIH HHS/ -- U42 RR033193/RR/NCRR NIH HHS/ -- U54 HG006364/HG/NHGRI NIH HHS/ -- England -- Nature. 2015 Jun 11;522(7555):151-3. doi: 10.1038/522151a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mutant Mouse Resource and Research Center (MMRRC) at the University of California, Davis, California, USA. ; MMRRC at the University of Missouri, Columbia, Missouri, USA. ; MMRRC at the Jackson Laboratory in Bar Harbor, Maine, USA. ; MMRRC at the University of North Carolina at Chapel Hill, North Carolina, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26062496" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Specimen Banks/*standards/*utilization ; DNA Mutational Analysis ; Disease Models, Animal ; Genetic Testing ; Genome/genetics ; Humans ; *Mice/classification/genetics/microbiology ; Mice, Inbred C57BL ; Microbiota/genetics ; Mutation/genetics ; Quality Control ; Reproducibility of Results
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  • 40
    Publication Date: 2015-03-26
    Description: Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and 〉8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617540/" 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/PMC4617540/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, You -- Klena, Nikolai T -- Gabriel, George C -- Liu, Xiaoqin -- Kim, Andrew J -- Lemke, Kristi -- Chen, Yu -- Chatterjee, Bishwanath -- Devine, William -- Damerla, Rama Rao -- Chang, Chienfu -- Yagi, Hisato -- San Agustin, Jovenal T -- Thahir, Mohamed -- Anderton, Shane -- Lawhead, Caroline -- Vescovi, Anita -- Pratt, Herbert -- Morgan, Judy -- Haynes, Leslie -- Smith, Cynthia L -- Eppig, Janan T -- Reinholdt, Laura -- Francis, Richard -- Leatherbury, Linda -- Ganapathiraju, Madhavi K -- Tobita, Kimimasa -- Pazour, Gregory J -- Lo, Cecilia W -- HG000330/HG/NHGRI NIH HHS/ -- R01 GM060992/GM/NIGMS NIH HHS/ -- R01MH094564/MH/NIMH NIH HHS/ -- U01 HL098180/HL/NHLBI NIH HHS/ -- U01HL098180/HL/NHLBI NIH HHS/ -- U01HL098188/HL/NHLBI NIH HHS/ -- England -- Nature. 2015 May 28;521(7553):520-4. doi: 10.1038/nature14269. Epub 2015 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15201, USA. ; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA. ; 1] Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15206, USA [2] Intelligent Systems Program, School of Arts and Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 16260, USA. ; The Jackson Laboratory, Bar Harbor, Maine 04609, USA. ; The Heart Center, Children's National Medical Center, Washington DC 20010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25807483" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cilia/genetics/*pathology/physiology/ultrasonography ; DNA Mutational Analysis ; Electrocardiography ; Exome/genetics ; Genes, Recessive ; Genetic Testing ; Heart Defects, Congenital/*genetics/*pathology/ultrasonography ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Signal Transduction
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  • 41
    Publication Date: 2015-02-06
    Description: The strength of synaptic connections fundamentally determines how neurons influence each other's firing. Excitatory connection amplitudes between pairs of cortical neurons vary over two orders of magnitude, comprising only very few strong connections among many weaker ones. Although this highly skewed distribution of connection strengths is observed in diverse cortical areas, its functional significance remains unknown: it is not clear how connection strength relates to neuronal response properties, nor how strong and weak inputs contribute to information processing in local microcircuits. Here we reveal that the strength of connections between layer 2/3 (L2/3) pyramidal neurons in mouse primary visual cortex (V1) obeys a simple rule--the few strong connections occur between neurons with most correlated responses, while only weak connections link neurons with uncorrelated responses. Moreover, we show that strong and reciprocal connections occur between cells with similar spatial receptive field structure. Although weak connections far outnumber strong connections, each neuron receives the majority of its local excitation from a small number of strong inputs provided by the few neurons with similar responses to visual features. By dominating recurrent excitation, these infrequent yet powerful inputs disproportionately contribute to feature preference and selectivity. Therefore, our results show that the apparently complex organization of excitatory connection strength reflects the similarity of neuronal responses, and suggest that rare, strong connections mediate stimulus-specific response amplification in cortical microcircuits.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cossell, Lee -- Iacaruso, Maria Florencia -- Muir, Dylan R -- Houlton, Rachael -- Sader, Elie N -- Ko, Ho -- Hofer, Sonja B -- Mrsic-Flogel, Thomas D -- 095074/Wellcome Trust/United Kingdom -- England -- Nature. 2015 Feb 19;518(7539):399-403. doi: 10.1038/nature14182. Epub 2015 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK [2] Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH - 4056 Basel, Switzerland. ; Biozentrum, University of Basel, Klingelbergstrasse 50/70, CH - 4056 Basel, Switzerland. ; Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK. ; 1] Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK [2] Lui Che Woo Institute of Innovative Medicine and Chow Yuk Ho Technology Center for Innovative Medicine, Faculty of Medicine, the Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25652823" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Excitatory Postsynaptic Potentials/*physiology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neural Pathways ; Photic Stimulation ; Pyramidal Cells/cytology/physiology ; Synapses/*physiology ; Visual Cortex/*cytology/*physiology
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  • 42
    Publication Date: 2014-08-28
    Description: Sensory regions of the brain integrate environmental cues with copies of motor-related signals important for imminent and ongoing movements. In mammals, signals propagating from the motor cortex to the auditory cortex are thought to have a critical role in normal hearing and behaviour, yet the synaptic and circuit mechanisms by which these motor-related signals influence auditory cortical activity remain poorly understood. Using in vivo intracellular recordings in behaving mice, we find that excitatory neurons in the auditory cortex are suppressed before and during movement, owing in part to increased activity of local parvalbumin-positive interneurons. Electrophysiology and optogenetic gain- and loss-of-function experiments reveal that motor-related changes in auditory cortical dynamics are driven by a subset of neurons in the secondary motor cortex that innervate the auditory cortex and are active during movement. These findings provide a synaptic and circuit basis for the motor-related corollary discharge hypothesized to facilitate hearing and auditory-guided behaviours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4248668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schneider, David M -- Nelson, Anders -- Mooney, Richard -- NS079929/NS/NINDS NIH HHS/ -- R01 DC013826/DC/NIDCD NIH HHS/ -- R21 NS079929/NS/NINDS NIH HHS/ -- T32 GM008441/GM/NIGMS NIH HHS/ -- England -- Nature. 2014 Sep 11;513(7517):189-94. doi: 10.1038/nature13724. Epub 2014 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA [2]. ; Department of Neurobiology, Duke University School of Medicine, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25162524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Auditory Cortex/*physiology ; Electrical Synapses/*physiology ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/*physiology ; Optogenetics ; Sensory Receptor Cells/metabolism
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  • 43
    Publication Date: 2014-12-04
    Description: T-helper type 17 (TH17) cells that produce the cytokines interleukin-17A (IL-17A) and IL-17F are implicated in the pathogenesis of several autoimmune diseases. The differentiation of TH17 cells is regulated by transcription factors such as RORgammat, but post-translational mechanisms preventing the rampant production of pro-inflammatory IL-17A have received less attention. Here we show that the deubiquitylating enzyme DUBA is a negative regulator of IL-17A production in T cells. Mice with DUBA-deficient T cells developed exacerbated inflammation in the small intestine after challenge with anti-CD3 antibodies. DUBA interacted with the ubiquitin ligase UBR5, which suppressed DUBA abundance in naive T cells. DUBA accumulated in activated T cells and stabilized UBR5, which then ubiquitylated RORgammat in response to TGF-beta signalling. Our data identify DUBA as a cell-intrinsic suppressor of IL-17 production.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rutz, Sascha -- Kayagaki, Nobuhiko -- Phung, Qui T -- Eidenschenk, Celine -- Noubade, Rajkumar -- Wang, Xiaoting -- Lesch, Justin -- Lu, Rongze -- Newton, Kim -- Huang, Oscar W -- Cochran, Andrea G -- Vasser, Mark -- Fauber, Benjamin P -- DeVoss, Jason -- Webster, Joshua -- Diehl, Lauri -- Modrusan, Zora -- Kirkpatrick, Donald S -- Lill, Jennie R -- Ouyang, Wenjun -- Dixit, Vishva M -- England -- Nature. 2015 Feb 19;518(7539):417-21. doi: 10.1038/nature13979. Epub 2014 Dec 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Physiological Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Protein Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Early Discovery Biochemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25470037" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Enzyme Stability ; Female ; Inflammation/genetics/pathology ; Interleukin-17/*biosynthesis ; Intestine, Small/metabolism/pathology ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism ; Proteasome Endopeptidase Complex/metabolism ; Protein Binding ; *Protein Biosynthesis ; Signal Transduction ; Substrate Specificity ; Th17 Cells/*metabolism ; Transforming Growth Factor beta/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitin-Specific Proteases/biosynthesis/deficiency/genetics/*metabolism ; Ubiquitination
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  • 44
    Publication Date: 2014-10-23
    Description: The gastrointestinal tracts of mammals are colonized by hundreds of microbial species that contribute to health, including colonization resistance against intestinal pathogens. Many antibiotics destroy intestinal microbial communities and increase susceptibility to intestinal pathogens. Among these, Clostridium difficile, a major cause of antibiotic-induced diarrhoea, greatly increases morbidity and mortality in hospitalized patients. Which intestinal bacteria provide resistance to C. difficile infection and their in vivo inhibitory mechanisms remain unclear. Here we correlate loss of specific bacterial taxa with development of infection, by treating mice with different antibiotics that result in distinct microbiota changes and lead to varied susceptibility to C. difficile. Mathematical modelling augmented by analyses of the microbiota of hospitalized patients identifies resistance-associated bacteria common to mice and humans. Using these platforms, we determine that Clostridium scindens, a bile acid 7alpha-dehydroxylating intestinal bacterium, is associated with resistance to C. difficile infection and, upon administration, enhances resistance to infection in a secondary bile acid dependent fashion. Using a workflow involving mouse models, clinical studies, metagenomic analyses, and mathematical modelling, we identify a probiotic candidate that corrects a clinically relevant microbiome deficiency. These findings have implications for the rational design of targeted antimicrobials as well as microbiome-based diagnostics and therapeutics for individuals at risk of C. difficile infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4354891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buffie, Charlie G -- Bucci, Vanni -- Stein, Richard R -- McKenney, Peter T -- Ling, Lilan -- Gobourne, Asia -- No, Daniel -- Liu, Hui -- Kinnebrew, Melissa -- Viale, Agnes -- Littmann, Eric -- van den Brink, Marcel R M -- Jenq, Robert R -- Taur, Ying -- Sander, Chris -- Cross, Justin R -- Toussaint, Nora C -- Xavier, Joao B -- Pamer, Eric G -- AI95706/AI/NIAID NIH HHS/ -- DP2 OD008440/OD/NIH HHS/ -- DP2OD008440/OD/NIH HHS/ -- K23 AI095398/AI/NIAID NIH HHS/ -- P01 CA023766/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01 AI042135/AI/NIAID NIH HHS/ -- R01 AI095706/AI/NIAID NIH HHS/ -- R01 AI42135/AI/NIAID NIH HHS/ -- T32 CA009149/CA/NCI NIH HHS/ -- T32 GM007739/GM/NIGMS NIH HHS/ -- T32GM07739/GM/NIGMS NIH HHS/ -- U54 CA148967/CA/NCI NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):205-8. doi: 10.1038/nature13828. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA [2] Department of Biology, University of Massachusetts Dartmouth, North Dartmouth, Massachusetts 02747, USA. ; Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; Donald B. and Catherine C. Marron Cancer Metabolism Center, Sloan-Kettering Institute, New York, New York 10065, USA. ; Genomics Core Laboratory, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. ; 1] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Computational Biology Program, Sloan-Kettering Institute, New York, New York 10065, USA. ; 1] Infectious Diseases Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [2] Lucille Castori Center for Microbes, Inflammation and Cancer, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA [3] Immunology Program, Sloan-Kettering Institute, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Bile Acids and Salts/*metabolism ; Biological Evolution ; Clostridium/metabolism ; Clostridium difficile/drug effects/*physiology ; Colitis/metabolism/microbiology/prevention & control/therapy ; Disease Susceptibility/*microbiology ; Feces/microbiology ; Female ; Humans ; Intestines/drug effects/*metabolism/*microbiology ; Metagenome/genetics ; Mice ; Mice, Inbred C57BL ; Microbiota/drug effects/genetics/*physiology ; Symbiosis
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  • 45
    Publication Date: 2014-11-05
    Description: Establishing the hippocampal cellular ensemble that represents an animal's environment involves the emergence and disappearance of place fields in specific CA1 pyramidal neurons, and the acquisition of different spatial firing properties across the active population. While such firing flexibility and diversity have been linked to spatial memory, attention and task performance, the cellular and network origin of these place cell features is unknown. Basic integrate-and-fire models of place firing propose that such features result solely from varying inputs to place cells, but recent studies suggest instead that place cells themselves may play an active role through regenerative dendritic events. However, owing to the difficulty of performing functional recordings from place cell dendrites, no direct evidence of regenerative dendritic events exists, leaving any possible connection to place coding unknown. Using multi-plane two-photon calcium imaging of CA1 place cell somata, axons and dendrites in mice navigating a virtual environment, here we show that regenerative dendritic events do exist in place cells of behaving mice, and, surprisingly, their prevalence throughout the arbour is highly spatiotemporally variable. Furthermore, we show that the prevalence of such events predicts the spatial precision and persistence or disappearance of place fields. This suggests that the dynamics of spiking throughout the dendritic arbour may play a key role in forming the hippocampal representation of space.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289090/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289090/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sheffield, Mark E J -- Dombeck, Daniel A -- 1R01MH101297/MH/NIMH NIH HHS/ -- R01 MH101297/MH/NIMH NIH HHS/ -- England -- Nature. 2015 Jan 8;517(7533):200-4. doi: 10.1038/nature13871. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Northwestern University, Evanston, Illinois 60208, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363782" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Axons/metabolism ; Calcium/*metabolism ; *Calcium Signaling ; Dendrites/*metabolism ; Hippocampus/*cytology/*physiology ; Male ; Memory, Long-Term/physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity/physiology ; Space Perception/*physiology ; Time Factors
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  • 46
    Publication Date: 2014-05-16
    Description: During development, thalamocortical (TC) input has a critical role in the spatial delineation and patterning of cortical areas, yet the underlying cellular and molecular mechanisms that drive cortical neuron differentiation are poorly understood. In the primary (S1) and secondary (S2) somatosensory cortex, layer 4 (L4) neurons receive mutually exclusive input originating from two thalamic nuclei: the ventrobasalis (VB), which conveys tactile input, and the posterior nucleus (Po), which conveys modulatory and nociceptive input. Recently, we have shown that L4 neuron identity is not fully committed postnatally, implying a capacity for TC input to influence differentiation during cortical circuit assembly. Here we investigate whether the cell-type-specific molecular and functional identity of L4 neurons is instructed by the origin of their TC input. Genetic ablation of the VB at birth resulted in an anatomical and functional rewiring of Po projections onto L4 neurons in S1. This induced acquisition of Po input led to a respecification of postsynaptic L4 neurons, which developed functional molecular features of Po-target neurons while repressing VB-target traits. Respecified L4 neurons were able to respond both to touch and to noxious stimuli, in sharp contrast to the normal segregation of these sensory modalities in distinct cortical circuits. These findings reveal a behaviourally relevant TC-input-type-specific control over the molecular and functional differentiation of postsynaptic L4 neurons and cognate intracortical circuits, which instructs the development of modality-specific neuronal and circuit properties during corticogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pouchelon, Gabrielle -- Gambino, Frederic -- Bellone, Camilla -- Telley, Ludovic -- Vitali, Ilaria -- Luscher, Christian -- Holtmaat, Anthony -- Jabaudon, Denis -- England -- Nature. 2014 Jul 24;511(7510):471-4. doi: 10.1038/nature13390. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland. ; 1] Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland [2] Interdisciplinary Institute for NeuroScience, CNRS UMR 5297, 33077 Bordeaux, France. ; 1] Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland [2] Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland [3] Institute of Genetics & Genomics in Geneva (iGE3), University of Geneva, CH-1211 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/drug effects/physiology ; Capsaicin/pharmacology ; *Cell Differentiation/drug effects ; Female ; Male ; Mice, Inbred C57BL ; Neural Pathways/drug effects/*physiology ; Neurons/*cytology/drug effects/*physiology ; Noxae/pharmacology ; Optogenetics ; Post-Synaptic Density/drug effects/*physiology ; Somatosensory Cortex/cytology/drug effects/*physiology ; Synaptic Potentials/drug effects ; Thalamic Nuclei/cytology/drug effects/*physiology ; Touch/physiology ; Vibrissae/drug effects/physiology
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  • 47
    Publication Date: 2014-06-12
    Description: Cutaneous melanoma is epidemiologically linked to ultraviolet radiation (UVR), but the molecular mechanisms by which UVR drives melanomagenesis remain unclear. The most common somatic mutation in melanoma is a V600E substitution in BRAF, which is an early event. To investigate how UVR accelerates oncogenic BRAF-driven melanomagenesis, we used a BRAF(V600E) mouse model. In mice expressing BRAF(V600E) in their melanocytes, a single dose of UVR that mimicked mild sunburn in humans induced clonal expansion of the melanocytes, and repeated doses of UVR increased melanoma burden. Here we show that sunscreen (UVA superior, UVB sun protection factor (SPF) 50) delayed the onset of UVR-driven melanoma, but only provided partial protection. The UVR-exposed tumours showed increased numbers of single nucleotide variants and we observed mutations (H39Y, S124F, R245C, R270C, C272G) in the Trp53 tumour suppressor in approximately 40% of cases. TP53 is an accepted UVR target in human non-melanoma skin cancer, but is not thought to have a major role in melanoma. However, we show that, in mice, mutant Trp53 accelerated BRAF(V600E)-driven melanomagenesis, and that TP53 mutations are linked to evidence of UVR-induced DNA damage in human melanoma. Thus, we provide mechanistic insight into epidemiological data linking UVR to acquired naevi in humans. Furthermore, we identify TP53/Trp53 as a UVR-target gene that cooperates with BRAF(V600E) to induce melanoma, providing molecular insight into how UVR accelerates melanomagenesis. Our study validates public health campaigns that promote sunscreen protection for individuals at risk of melanoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112218/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Viros, Amaya -- Sanchez-Laorden, Berta -- Pedersen, Malin -- Furney, Simon J -- Rae, Joel -- Hogan, Kate -- Ejiama, Sarah -- Girotti, Maria Romina -- Cook, Martin -- Dhomen, Nathalie -- Marais, Richard -- A12738/Cancer Research UK/United Kingdom -- A13540/Cancer Research UK/United Kingdom -- A17240/Cancer Research UK/United Kingdom -- A7091/Cancer Research UK/United Kingdom -- A7192/Cancer Research UK/United Kingdom -- C107/A10433/Cancer Research UK/United Kingdom -- C5759/A12328/Cancer Research UK/United Kingdom -- England -- Nature. 2014 Jul 24;511(7510):478-82. doi: 10.1038/nature13298. Epub 2014 Jun 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2]. ; 1] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK [2]. ; Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. ; Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Histopathology, Royal Surrey County Hospital, Egerton Road, Guildford GU2 7XX, UK. ; 1] Molecular Oncology Group, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK [2] Signal Transduction Team, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24919155" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Transformation, Neoplastic/*genetics/*radiation effects ; DNA Damage/genetics ; Disease Models, Animal ; Female ; Humans ; Melanocytes/metabolism/pathology/radiation effects ; Melanoma/etiology/*genetics/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mutagenesis/genetics/*radiation effects ; Mutation/genetics/radiation effects ; Nevus/etiology/genetics/metabolism/pathology ; Proto-Oncogene Proteins B-raf/*genetics/metabolism ; Skin Neoplasms/etiology/genetics/metabolism/pathology ; Sunburn/complications/etiology/genetics ; Sunscreening Agents/pharmacology ; Tumor Suppressor Protein p53/*genetics/metabolism ; Ultraviolet Rays/*adverse effects
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  • 48
    Publication Date: 2014-01-28
    Description: The tissue-resident macrophages of barrier organs constitute the first line of defence against pathogens at the systemic interface with the ambient environment. In the lung, resident alveolar macrophages (AMs) provide a sentinel function against inhaled pathogens. Bacterial constituents ligate Toll-like receptors (TLRs) on AMs, causing AMs to secrete proinflammatory cytokines that activate alveolar epithelial receptors, leading to recruitment of neutrophils that engulf pathogens. Because the AM-induced response could itself cause tissue injury, it is unclear how AMs modulate the response to prevent injury. Here, using real-time alveolar imaging in situ, we show that a subset of AMs attached to the alveolar wall form connexin 43 (Cx43)-containing gap junction channels with the epithelium. During lipopolysaccharide-induced inflammation, the AMs remained sessile and attached to the alveoli, and they established intercommunication through synchronized Ca(2+) waves, using the epithelium as the conducting pathway. The intercommunication was immunosuppressive, involving Ca(2+)-dependent activation of Akt, because AM-specific knockout of Cx43 enhanced alveolar neutrophil recruitment and secretion of proinflammatory cytokines in the bronchoalveolar lavage. A picture emerges of a novel immunomodulatory process in which a subset of alveolus-attached AMs intercommunicates immunosuppressive signals to reduce endotoxin-induced lung inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117212/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4117212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Westphalen, Kristin -- Gusarova, Galina A -- Islam, Mohammad N -- Subramanian, Manikandan -- Cohen, Taylor S -- Prince, Alice S -- Bhattacharya, Jahar -- HL57556/HL/NHLBI NIH HHS/ -- HL64896/HL/NHLBI NIH HHS/ -- HL73989/HL/NHLBI NIH HHS/ -- HL78645/HL/NHLBI NIH HHS/ -- R01 HL057556/HL/NHLBI NIH HHS/ -- R01 HL064896/HL/NHLBI NIH HHS/ -- R01 HL073989/HL/NHLBI NIH HHS/ -- R01 HL078645/HL/NHLBI NIH HHS/ -- R01 HL079395/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):503-6. doi: 10.1038/nature12902. Epub 2014 Jan 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Medicine, Division of Molecular Medicine, Columbia University Medical Center, New York, New York 10032, USA. ; Department of Pediatrics, Columbia University Medical Center, New York, New York 10032, USA. ; 1] Lung Biology Laboratory, Department of Medicine, Division of Pulmonary, Allergy and Critical Care, Columbia University Medical Center, New York, New York 10032, USA [2] Department of Physiology & Cellular Biophysics, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24463523" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bronchoalveolar Lavage Fluid/immunology ; Calcium/metabolism ; Cell Adhesion ; *Cell Communication ; Connexin 43/deficiency/genetics/metabolism ; Cytokines/immunology/secretion ; Female ; Gap Junctions/metabolism ; Lipopolysaccharides/pharmacology ; Macrophages, Alveolar/*cytology/*immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophil Infiltration ; Neutrophils/immunology ; Pneumonia/chemically induced/immunology/pathology ; Pulmonary Alveoli/*cytology/*immunology ; Respiratory Mucosa/*cytology/*immunology
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  • 49
    Publication Date: 2014-11-20
    Description: Intestinal microbial communities have profound effects on host physiology. Whereas the symbiotic contribution of commensal bacteria is well established, the role of eukaryotic viruses that are present in the gastrointestinal tract under homeostatic conditions is undefined. Here we demonstrate that a common enteric RNA virus can replace the beneficial function of commensal bacteria in the intestine. Murine norovirus (MNV) infection of germ-free or antibiotic-treated mice restored intestinal morphology and lymphocyte function without inducing overt inflammation and disease. The presence of MNV also suppressed an expansion of group 2 innate lymphoid cells observed in the absence of bacteria, and induced transcriptional changes in the intestine associated with immune development and type I interferon (IFN) signalling. Consistent with this observation, the IFN-alpha receptor was essential for the ability of MNV to compensate for bacterial depletion. Importantly, MNV infection offset the deleterious effect of treatment with antibiotics in models of intestinal injury and pathogenic bacterial infection. These data indicate that eukaryotic viruses have the capacity to support intestinal homeostasis and shape mucosal immunity, similarly to commensal bacteria.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257755/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257755/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kernbauer, Elisabeth -- Ding, Yi -- Cadwell, Ken -- J 3435/Austrian Science Fund FWF/Austria -- P30CA016087/CA/NCI NIH HHS/ -- R01 DK093668/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):94-8. doi: 10.1038/nature13960. Epub 2014 Nov 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA [2] Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA. ; 1] New York Presbyterian Hospital, New York, New York 10065, USA [2] Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409145" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Bacterial Physiological Phenomena/*immunology ; Citrobacter rodentium/physiology ; Enterobacteriaceae Infections/immunology ; Enterovirus/immunology/*physiology ; Female ; Gene Expression Profiling ; Gene Expression Regulation/immunology ; Immunity, Innate/immunology ; Immunity, Mucosal/*immunology ; Interferon Type I/immunology ; Intestinal Mucosa/cytology/drug effects/*immunology/*virology ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Norovirus/immunology/physiology ; Signal Transduction/immunology ; Specific Pathogen-Free Organisms
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  • 50
    Publication Date: 2014-08-28
    Description: The valence of memories is malleable because of their intrinsic reconstructive property. This property of memory has been used clinically to treat maladaptive behaviours. However, the neuronal mechanisms and brain circuits that enable the switching of the valence of memories remain largely unknown. Here we investigated these mechanisms by applying the recently developed memory engram cell- manipulation technique. We labelled with channelrhodopsin-2 (ChR2) a population of cells in either the dorsal dentate gyrus (DG) of the hippocampus or the basolateral complex of the amygdala (BLA) that were specifically activated during contextual fear or reward conditioning. Both groups of fear-conditioned mice displayed aversive light-dependent responses in an optogenetic place avoidance test, whereas both DG- and BLA-labelled mice that underwent reward conditioning exhibited an appetitive response in an optogenetic place preference test. Next, in an attempt to reverse the valence of memory within a subject, mice whose DG or BLA engram had initially been labelled by contextual fear or reward conditioning were subjected to a second conditioning of the opposite valence while their original DG or BLA engram was reactivated by blue light. Subsequent optogenetic place avoidance and preference tests revealed that although the DG-engram group displayed a response indicating a switch of the memory valence, the BLA-engram group did not. This switch was also evident at the cellular level by a change in functional connectivity between DG engram-bearing cells and BLA engram-bearing cells. Thus, we found that in the DG, the neurons carrying the memory engram of a given neutral context have plasticity such that the valence of a conditioned response evoked by their reactivation can be reversed by re-associating this contextual memory engram with a new unconditioned stimulus of an opposite valence. Our present work provides new insight into the functional neural circuits underlying the malleability of emotional memory.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169316/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4169316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Redondo, Roger L -- Kim, Joshua -- Arons, Autumn L -- Ramirez, Steve -- Liu, Xu -- Tonegawa, Susumu -- P50 MH058880/MH/NIMH NIH HHS/ -- R01 MH078821/MH/NIMH NIH HHS/ -- T32GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 18;513(7518):426-30. doi: 10.1038/nature13725. Epub 2014 Aug 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3]. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2]. ; 1] RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory, Department of Biology and Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25162525" target="_blank"〉PubMed〈/a〉
    Keywords: Affect ; Amygdala/physiology ; Animals ; Avoidance Learning ; Conditioning, Classical/physiology ; Cues ; Dentate Gyrus/physiology ; Fear ; Female ; Hippocampus/*physiology ; Male ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Neuronal Plasticity/physiology ; Optogenetics ; Reward
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  • 51
    Publication Date: 2014-07-06
    Description: Tuberculosis remains second only to HIV/AIDS as the leading cause of mortality worldwide due to a single infectious agent. Despite chemotherapy, the global tuberculosis epidemic has intensified because of HIV co-infection, the lack of an effective vaccine and the emergence of multi-drug-resistant bacteria. Alternative host-directed strategies could be exploited to improve treatment efficacy and outcome, contain drug-resistant strains and reduce disease severity and mortality. The innate inflammatory response elicited by Mycobacterium tuberculosis (Mtb) represents a logical host target. Here we demonstrate that interleukin-1 (IL-1) confers host resistance through the induction of eicosanoids that limit excessive type I interferon (IFN) production and foster bacterial containment. We further show that, in infected mice and patients, reduced IL-1 responses and/or excessive type I IFN induction are linked to an eicosanoid imbalance associated with disease exacerbation. Host-directed immunotherapy with clinically approved drugs that augment prostaglandin E2 levels in these settings prevented acute mortality of Mtb-infected mice. Thus, IL-1 and type I IFNs represent two major counter-regulatory classes of inflammatory cytokines that control the outcome of Mtb infection and are functionally linked via eicosanoids. Our findings establish proof of concept for host-directed treatment strategies that manipulate the host eicosanoid network and represent feasible alternatives to conventional chemotherapy.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mayer-Barber, Katrin D -- Andrade, Bruno B -- Oland, Sandra D -- Amaral, Eduardo P -- Barber, Daniel L -- Gonzales, Jacqueline -- Derrick, Steven C -- Shi, Ruiru -- Kumar, Nathella Pavan -- Wei, Wang -- Yuan, Xing -- Zhang, Guolong -- Cai, Ying -- Babu, Subash -- Catalfamo, Marta -- Salazar, Andres M -- Via, Laura E -- Barry, Clifton E 3rd -- Sher, Alan -- Intramural NIH HHS/ -- England -- Nature. 2014 Jul 3;511(7507):99-103. doi: 10.1038/nature13489. Epub 2014 Jun 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; 1] Immunobiology Section, Laboratory of Parasitic Diseases (LPD), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Department of Immunology, Biomedical Sciences Institutes, University of Sao Paulo, 05508-900 Sao Paulo, Brazil. ; T Lymphocyte Biology Unit, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, Maryland 20892, USA. ; Henan Chest Hospital, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] National Institute for Research in Tuberculosis (NIRT), 600 031 Chennai, India. ; Sino-US International Research Center for Tuberculosis, and Henan Public Health Center, 450003 Zhengzhou, China. ; 1] NIH, International Center for Excellence in Research, 600 031 Chennai, India [2] Helminth Immunology Section, LPD, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Clinical and Molecular Retrovirology Section, Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland 20892, USA. ; Oncovir Inc., Washington, Washington DC 20008, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24990750" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dinoprostone/antagonists & inhibitors/biosynthesis/metabolism ; Disease Models, Animal ; Female ; Humans ; Immunity, Innate/immunology ; *Immunotherapy ; Interferon Type I/antagonists & inhibitors/biosynthesis/*immunology ; Interleukin-1/*immunology ; Male ; Mice ; Mice, Inbred C57BL ; Mycobacterium tuberculosis/*immunology ; Tuberculosis, Pulmonary/*immunology/microbiology/*therapy
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  • 52
    Publication Date: 2014-09-19
    Description: Non-caloric artificial sweeteners (NAS) are among the most widely used food additives worldwide, regularly consumed by lean and obese individuals alike. NAS consumption is considered safe and beneficial owing to their low caloric content, yet supporting scientific data remain sparse and controversial. Here we demonstrate that consumption of commonly used NAS formulations drives the development of glucose intolerance through induction of compositional and functional alterations to the intestinal microbiota. These NAS-mediated deleterious metabolic effects are abrogated by antibiotic treatment, and are fully transferrable to germ-free mice upon faecal transplantation of microbiota configurations from NAS-consuming mice, or of microbiota anaerobically incubated in the presence of NAS. We identify NAS-altered microbial metabolic pathways that are linked to host susceptibility to metabolic disease, and demonstrate similar NAS-induced dysbiosis and glucose intolerance in healthy human subjects. Collectively, our results link NAS consumption, dysbiosis and metabolic abnormalities, thereby calling for a reassessment of massive NAS usage.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suez, Jotham -- Korem, Tal -- Zeevi, David -- Zilberman-Schapira, Gili -- Thaiss, Christoph A -- Maza, Ori -- Israeli, David -- Zmora, Niv -- Gilad, Shlomit -- Weinberger, Adina -- Kuperman, Yael -- Harmelin, Alon -- Kolodkin-Gal, Ilana -- Shapiro, Hagit -- Halpern, Zamir -- Segal, Eran -- Elinav, Eran -- England -- Nature. 2014 Oct 9;514(7521):181-6. doi: 10.1038/nature13793. Epub 2014 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel. ; 1] Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel [2]. ; 1] Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel [2]. ; Day Care Unit and the Laboratory of Imaging and Brain Stimulation, Kfar Shaul hospital, Jerusalem Center for Mental Health, Jerusalem 91060, Israel. ; 1] Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel [2] Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel [3] Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. ; The Nancy and Stephen Grand Israel National Center for Personalized Medicine (INCPM), Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Veterinary Resources, Weizmann Institute of Science, Rehovot 76100, Israel. ; Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel. ; 1] Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel [2] Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv 64239, Israel.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231862" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Aspartame/adverse effects ; Body Weight/drug effects ; Diet, High-Fat ; Dietary Fats/pharmacology ; Feces/microbiology ; Female ; Gastrointestinal Tract/*drug effects/*microbiology ; Germ-Free Life ; Glucose/metabolism ; Glucose Intolerance/*chemically induced/metabolism/*microbiology ; Humans ; Male ; Metabolic Syndrome X/chemically induced/metabolism/microbiology ; Mice ; Mice, Inbred C57BL ; Microbiota/*drug effects ; Saccharin/administration & dosage/adverse effects ; Sucrose/adverse effects/analogs & derivatives ; Sweetening Agents/*adverse effects ; Waist-Hip Ratio
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  • 53
    Publication Date: 2014-08-15
    Description: The connection between an altered gut microbiota and metabolic disorders such as obesity, diabetes, and cardiovascular disease is well established. Defects in preserving the integrity of the mucosal barriers can result in systemic endotoxaemia that contributes to chronic low-grade inflammation, which further promotes the development of metabolic syndrome. Interleukin (IL)-22 exerts essential roles in eliciting antimicrobial immunity and maintaining mucosal barrier integrity within the intestine. Here we investigate the connection between IL-22 and metabolic disorders. We find that the induction of IL-22 from innate lymphoid cells and CD4(+) T cells is impaired in obese mice under various immune challenges, especially in the colon during infection with Citrobacter rodentium. While innate lymphoid cell populations are largely intact in obese mice, the upregulation of IL-23, a cytokine upstream of IL-22, is compromised during the infection. Consequently, these mice are susceptible to C. rodentium infection, and both exogenous IL-22 and IL-23 are able to restore the mucosal host defence. Importantly, we further unveil unexpected functions of IL-22 in regulating metabolism. Mice deficient in IL-22 receptor and fed with high-fat diet are prone to developing metabolic disorders. Strikingly, administration of exogenous IL-22 in genetically obese leptin-receptor-deficient (db/db) mice and mice fed with high-fat diet reverses many of the metabolic symptoms, including hyperglycaemia and insulin resistance. IL-22 shows diverse metabolic benefits, as it improves insulin sensitivity, preserves gut mucosal barrier and endocrine functions, decreases endotoxaemia and chronic inflammation, and regulates lipid metabolism in liver and adipose tissues. In summary, we identify the IL-22 pathway as a novel target for therapeutic intervention in metabolic diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Xiaoting -- Ota, Naruhisa -- Manzanillo, Paolo -- Kates, Lance -- Zavala-Solorio, Jose -- Eidenschenk, Celine -- Zhang, Juan -- Lesch, Justin -- Lee, Wyne P -- Ross, Jed -- Diehl, Lauri -- van Bruggen, Nicholas -- Kolumam, Ganesh -- Ouyang, Wenjun -- England -- Nature. 2014 Oct 9;514(7521):237-41. doi: 10.1038/nature13564. Epub 2014 Aug 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Immunology, Genentech, South San Francisco, California 94080, USA [2]. ; Department of Immunology, Genentech, South San Francisco, California 94080, USA. ; Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, South San Francisco, California 94080, USA. ; 1] Department of Biomedical Imaging, Genentech, South San Francisco, California 94080, USA [2].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25119041" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, White/drug effects/metabolism ; Animals ; CD4-Positive T-Lymphocytes/immunology/secretion ; Chronic Disease ; Citrobacter rodentium/drug effects/immunology/physiology ; Colon/drug effects/immunology/microbiology ; Diabetes Mellitus/*immunology/*metabolism/pathology ; Diet, High-Fat ; Female ; Hyperglycemia/diet therapy/drug therapy/metabolism ; *Immunity, Mucosal/drug effects ; Inflammation/drug therapy/metabolism/pathology ; Insulin/metabolism ; Insulin Resistance ; Interleukin-23/immunology/metabolism/pharmacology ; Interleukins/*immunology/*metabolism/pharmacology/therapeutic use ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Male ; Metabolic Diseases/diet therapy/drug therapy/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/metabolism ; Receptors, Interleukin/deficiency/metabolism ; Receptors, Leptin/deficiency/metabolism
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  • 54
    Publication Date: 2014-08-01
    Description: In mammals, cytosine methylation is predominantly restricted to CpG dinucleotides and stably distributed across the genome, with local, cell-type-specific regulation directed by DNA binding factors. This comparatively static landscape is in marked contrast with the events of fertilization, during which the paternal genome is globally reprogrammed. Paternal genome demethylation includes the majority of CpGs, although methylation remains detectable at several notable features. These dynamics have been extensively characterized in the mouse, with only limited observations available in other mammals, and direct measurements are required to understand the extent to which early embryonic landscapes are conserved. We present genome-scale DNA methylation maps of human preimplantation development and embryonic stem cell derivation, confirming a transient state of global hypomethylation that includes most CpGs, while sites of residual maintenance are primarily restricted to gene bodies. Although most features share similar dynamics to those in mouse, maternally contributed methylation is divergently targeted to species-specific sets of CpG island promoters that extend beyond known imprint control regions. Retrotransposon regulation is also highly diverse, and transitions from maternally to embryonically expressed elements. Together, our data confirm that paternal genome demethylation is a general attribute of early mammalian development that is characterized by distinct modes of epigenetic regulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178976/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4178976/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smith, Zachary D -- Chan, Michelle M -- Humm, Kathryn C -- Karnik, Rahul -- Mekhoubad, Shila -- Regev, Aviv -- Eggan, Kevin -- Meissner, Alexander -- 1P50HG006193-01/HG/NHGRI NIH HHS/ -- 5DP1OD003958/OD/NIH HHS/ -- P01 GM099117/GM/NIGMS NIH HHS/ -- P01GM099117/GM/NIGMS NIH HHS/ -- P50 HG006193/HG/NHGRI NIH HHS/ -- U01 ES017155/ES/NIEHS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Jul 31;511(7511):611-5. doi: 10.1038/nature13581. Epub 2014 Jul 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [4] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA [5]. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Computational and Systems Biology Program, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3]. ; 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Division of Reproductive Endocrinology &Infertility, Department of Obstetrics &Gynecology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA [3] Obstetrics, Gynecology, and Reproductive Biology, Harvard Medical School, Boston, Massachusetts 02215, USA [4] Boston IVF, Waltham, Massachusetts 02451, USA [5] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [6]. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [2] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [4] Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA [5] Howard Hughes Medical Institute, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079558" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blastocyst/*metabolism ; Cell Line ; CpG Islands/physiology ; DNA/metabolism ; *DNA Methylation ; Embryonic Stem Cells ; Female ; Gene Expression Regulation, Developmental ; Humans ; Male ; Mice ; Mice, Inbred C57BL
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  • 55
    Publication Date: 2014-11-11
    Description: Autophagy is an evolutionarily conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis. Its acute regulation by nutrient-sensing signalling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors peroxisome proliferator-activated receptor-alpha (PPARalpha) and farnesoid X receptor (FXR) are activated in the fasted and fed liver, respectively. Here we show that both PPARalpha and FXR regulate hepatic autophagy in mice. Pharmacological activation of PPARalpha reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARalpha knockout (Ppara(-/-), also known as Nr1c1(-/-)) mice, which are partially defective in the induction of autophagy by fasting. Pharmacological activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (Fxr(-/-), also known as Nr1h4(-/-)) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARalpha and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267857/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lee, Jae Man -- Wagner, Martin -- Xiao, Rui -- Kim, Kang Ho -- Feng, Dan -- Lazar, Mitchell A -- Moore, David D -- DK43806/DK/NIDDK NIH HHS/ -- P30 DK019525/DK/NIDDK NIH HHS/ -- P30DX56338-05A2/PHS HHS/ -- P39CA125123-04/CA/NCI NIH HHS/ -- R01 DK049780/DK/NIDDK NIH HHS/ -- R01 DK49780/DK/NIDDK NIH HHS/ -- R37 DK043806/DK/NIDDK NIH HHS/ -- S10RR027783-01A1/RR/NCRR NIH HHS/ -- U54HD-07495-39/HD/NICHD NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):112-5. doi: 10.1038/nature13961. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; Division of Endocrinology, Diabetes, and Metabolism and the Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383539" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/genetics/*physiology ; Cell Line ; Cells, Cultured ; Fasting/physiology ; Gene Expression Regulation ; Hepatocytes/metabolism ; Liver/cytology/*metabolism/ultrastructure ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Microtubule-Associated Proteins/genetics/metabolism ; PPAR alpha ; Receptors, Cytoplasmic and Nuclear/genetics/*metabolism
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  • 56
    Publication Date: 2014-03-22
    Description: The mammalian skeletal system harbours a hierarchical system of mesenchymal stem cells, osteoprogenitors and osteoblasts sustaining lifelong bone formation. Osteogenesis is indispensable for the homeostatic renewal of bone as well as regenerative fracture healing, but these processes frequently decline in ageing organisms, leading to loss of bone mass and increased fracture incidence. Evidence indicates that the growth of blood vessels in bone and osteogenesis are coupled, but relatively little is known about the underlying cellular and molecular mechanisms. Here we identify a new capillary subtype in the murine skeletal system with distinct morphological, molecular and functional properties. These vessels are found in specific locations, mediate growth of the bone vasculature, generate distinct metabolic and molecular microenvironments, maintain perivascular osteoprogenitors and couple angiogenesis to osteogenesis. The abundance of these vessels and associated osteoprogenitors was strongly reduced in bone from aged animals, and pharmacological reversal of this decline allowed the restoration of bone mass.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kusumbe, Anjali P -- Ramasamy, Saravana K -- Adams, Ralf H -- England -- Nature. 2014 Mar 20;507(7492):323-8. doi: 10.1038/nature13145. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2]. ; 1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2] University of Munster, Faculty of Medicine, D-48149 Munster, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24646994" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/metabolism/pathology ; Animals ; Blood Vessels/anatomy & histology/cytology/growth & development/*physiology ; Bone and Bones/*blood supply/cytology ; Endothelial Cells/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/*physiology ; Osteoblasts/cytology/metabolism ; Osteogenesis/*physiology ; Oxygen/metabolism ; Stem Cells/cytology/metabolism
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  • 57
    Publication Date: 2014-03-29
    Description: Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976267/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3976267/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hall, Catherine N -- Reynell, Clare -- Gesslein, Bodil -- Hamilton, Nicola B -- Mishra, Anusha -- Sutherland, Brad A -- O'Farrell, Fergus M -- Buchan, Alastair M -- Lauritzen, Martin -- Attwell, David -- 075232/Wellcome Trust/United Kingdom -- G0500495/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Apr 3;508(7494):55-60. doi: 10.1038/nature13165. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK [2]. ; 1] Department of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen N, Denmark [2]. ; Acute Stroke Programme, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK. ; Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London, WC1E 6BT, UK. ; 1] Department of Neuroscience and Pharmacology and Center for Healthy Aging, University of Copenhagen, DK-2200 Copenhagen N, Denmark [2] Department of Clinical Neurophysiology, Glostrup University Hospital, DK-2600 Glostrup, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670647" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arterioles/physiology ; Blood-Brain Barrier/pathology/physiopathology ; Brain Ischemia/pathology ; Capillaries/*cytology/drug effects ; Cell Death ; Cerebellum/blood supply ; Cerebral Cortex/blood supply/cytology ; Cerebrovascular Circulation/drug effects/*physiology ; Dinoprostone/metabolism ; Excitatory Amino Acid Antagonists/pharmacology ; Female ; Functional Neuroimaging ; Glutamic Acid/pharmacology ; Hydroxyeicosatetraenoic Acids/biosynthesis ; In Vitro Techniques ; Male ; Mice ; Mice, Inbred C57BL ; Nitric Oxide/metabolism ; Pericytes/cytology/drug effects/pathology/*physiology ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar ; Receptors, Glutamate/metabolism ; Signal Transduction/drug effects ; Stroke/pathology ; Vasoconstriction ; Vasodilation/drug effects
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  • 58
    Publication Date: 2014-02-14
    Description: Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16(INK4a) (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16(INK4a) silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sousa-Victor, Pedro -- Gutarra, Susana -- Garcia-Prat, Laura -- Rodriguez-Ubreva, Javier -- Ortet, Laura -- Ruiz-Bonilla, Vanessa -- Jardi, Merce -- Ballestar, Esteban -- Gonzalez, Susana -- Serrano, Antonio L -- Perdiguero, Eusebio -- Munoz-Canoves, Pura -- England -- Nature. 2014 Feb 20;506(7488):316-21. doi: 10.1038/nature13013. Epub 2014 Feb 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2] Buck Institute for Research on Aging, Novato, California 94945, USA. ; 1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2]. ; Chromatin and Disease Group, Cancer Epigenetics and Biology Programme, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, E-08907 Barcelona, Spain. ; Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain. ; Stem Cell Aging Group, Centro Nacional de Investigaciones Cardiovasculares, E-28029 Madrid, Spain. ; 1] Cell Biology Group, Department of Experimental and Health Sciences, Pompeu Fabra University, CIBER on Neurodegenerative diseases, E-08003 Barcelona, Spain [2] Institucio Catalana de Recerca i Estudis Avancats, E-08010 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24522534" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aging/*metabolism ; Animals ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/*metabolism ; E2F1 Transcription Factor/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Progeria/metabolism/pathology ; Regeneration ; Rejuvenation ; Retinoblastoma Protein/metabolism ; Satellite Cells, Skeletal Muscle/*cytology/*metabolism ; Young Adult
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  • 59
    Publication Date: 2014-02-21
    Description: Crohn's disease is a debilitating inflammatory bowel disease (IBD) that can involve the entire digestive tract. A single-nucleotide polymorphism (SNP) encoding a missense variant in the autophagy gene ATG16L1 (rs2241880, Thr300Ala) is strongly associated with the incidence of Crohn's disease. Numerous studies have demonstrated the effect of ATG16L1 deletion or deficiency; however, the molecular consequences of the Thr300Ala (T300A) variant remains unknown. Here we show that amino acids 296-299 constitute a caspase cleavage motif in ATG16L1 and that the T300A variant (T316A in mice) significantly increases ATG16L1 sensitization to caspase-3-mediated processing. We observed that death-receptor activation or starvation-induced metabolic stress in human and murine macrophages increased degradation of the T300A or T316A variants of ATG16L1, respectively, resulting in diminished autophagy. Knock-in mice harbouring the T316A variant showed defective clearance of the ileal pathogen Yersinia enterocolitica and an elevated inflammatory cytokine response. In turn, deletion of the caspase-3-encoding gene, Casp3, or elimination of the caspase cleavage site by site-directed mutagenesis rescued starvation-induced autophagy and pathogen clearance, respectively. These findings demonstrate that caspase 3 activation in the presence of a common risk allele leads to accelerated degradation of ATG16L1, placing cellular stress, apoptotic stimuli and impaired autophagy in a unified pathway that predisposes to Crohn's disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Murthy, Aditya -- Li, Yun -- Peng, Ivan -- Reichelt, Mike -- Katakam, Anand Kumar -- Noubade, Rajkumar -- Roose-Girma, Merone -- DeVoss, Jason -- Diehl, Lauri -- Graham, Robert R -- van Lookeren Campagne, Menno -- England -- Nature. 2014 Feb 27;506(7489):456-62. doi: 10.1038/nature13044. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. ; ITGR Human Genetics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553140" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; Autophagy/genetics ; Carrier Proteins/chemistry/*genetics/*metabolism ; Caspase 3/deficiency/genetics/*metabolism ; Cell Line ; Cells, Cultured ; Crohn Disease/*genetics/pathology ; Cytokines/immunology ; Enzyme Activation ; Female ; Food Deprivation ; Humans ; Macrophages/immunology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mutagenesis, Site-Directed ; Polymorphism, Single Nucleotide/*genetics ; *Proteolysis ; Stress, Physiological ; Yersinia enterocolitica/immunology
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  • 60
    Publication Date: 2014-02-28
    Description: The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when. Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output. Genetic lesions of EC (ref. 3) and hippocampal dentate gyrus (ref. 4), CA3 (ref. 5) and CA1 (ref. 6) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output. Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory--the ability of an animal to remember a conspecific--with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000264/" 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/PMC4000264/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hitti, Frederick L -- Siegelbaum, Steven A -- F30 MH098633/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 3;508(7494):88-92. doi: 10.1038/nature13028. Epub 2014 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Kavli Institute, College of Physicians and Surgeons, Columbia University 1051 Riverside Drive, New York, New York 10032, USA. ; 1] Department of Neuroscience, Kavli Institute, College of Physicians and Surgeons, Columbia University 1051 Riverside Drive, New York, New York 10032, USA [2] Department of Pharmacology, Howard Hughes Medical Institute, College of Physicians and Surgeons, Columbia University 1051 Riverside Drive, New York, New York 10032, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572357" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/physiopathology ; CA2 Region, Hippocampal/cytology/*physiology ; Electrophysiology ; Female ; Integrases/genetics/metabolism ; Male ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Pyramidal Cells/physiology ; Schizophrenia/physiopathology ; *Social Behavior ; Space Perception/physiology ; Synapses/metabolism
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  • 61
    Publication Date: 2014-09-19
    Description: Gain-of-function mutations in the fibroblast growth factor receptor 3 gene (FGFR3) result in skeletal dysplasias, such as thanatophoric dysplasia and achondroplasia (ACH). The lack of disease models using human cells has hampered the identification of a clinically effective treatment for these diseases. Here we show that statin treatment can rescue patient-specific induced pluripotent stem cell (iPSC) models and a mouse model of FGFR3 skeletal dysplasia. We converted fibroblasts from thanatophoric dysplasia type I (TD1) and ACH patients into iPSCs. The chondrogenic differentiation of TD1 iPSCs and ACH iPSCs resulted in the formation of degraded cartilage. We found that statins could correct the degraded cartilage in both chondrogenically differentiated TD1 and ACH iPSCs. Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggest that statins could represent a medical treatment for infants and children with TD1 and ACH.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamashita, Akihiro -- Morioka, Miho -- Kishi, Hiromi -- Kimura, Takeshi -- Yahara, Yasuhito -- Okada, Minoru -- Fujita, Kaori -- Sawai, Hideaki -- Ikegawa, Shiro -- Tsumaki, Noriyuki -- England -- Nature. 2014 Sep 25;513(7519):507-11. doi: 10.1038/nature13775. Epub 2014 Sep 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. ; Department of Obstetrics and Gynecology, Hyogo College of Medicine, Hyogo 663-8501, Japan. ; Laboratory of Bone and Joint Diseases, Center for Integrated Medical Sciences, RIKEN, Tokyo 108-8639, Japan. ; 1] Cell Induction and Regulation Field, Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto 606-8507, Japan [2] Japan Science and Technology Agency, CREST, Tokyo 102-0075, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25231866" target="_blank"〉PubMed〈/a〉
    Keywords: Achondroplasia/*drug therapy/genetics/*pathology ; Animals ; Bone Development/drug effects ; Cartilage/cytology/drug effects/pathology ; Cell Differentiation ; Chondrocytes/cytology/pathology ; Disease Models, Animal ; Female ; Fluorobenzenes/administration & dosage/pharmacology/therapeutic use ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & ; dosage/pharmacology/*therapeutic use ; Induced Pluripotent Stem Cells/cytology/pathology ; Lovastatin/pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Pyrimidines/administration & dosage/pharmacology/therapeutic use ; Receptor, Fibroblast Growth Factor, Type 3/*deficiency/*genetics ; Rosuvastatin Calcium ; Sulfonamides/administration & dosage/pharmacology/therapeutic use ; Thanatophoric Dysplasia/*drug therapy/genetics/*pathology
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  • 62
    Publication Date: 2014-10-23
    Description: Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras(G12D)-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras(G12D) combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292871/" 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/PMC4292871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanchez-Rivera, Francisco J -- Papagiannakopoulos, Thales -- Romero, Rodrigo -- Tammela, Tuomas -- Bauer, Matthew R -- Bhutkar, Arjun -- Joshi, Nikhil S -- Subbaraj, Lakshmipriya -- Bronson, Roderick T -- Xue, Wen -- Jacks, Tyler -- K99 CA169512/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 CA169512/CA/NCI NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):428-31. doi: 10.1038/nature13906. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Tufts University, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337879" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*genetics/pathology ; Animals ; *Caspase 9 ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Disease Models, Animal ; Genes, Tumor Suppressor ; *Genetic Engineering ; Genome/*genetics ; Humans ; Lentivirus/genetics ; Lung Neoplasms/*genetics/pathology ; Mice ; Mice, Inbred C57BL ; Models, Genetic ; Mutation/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 63
    Publication Date: 2014-02-28
    Description: Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bald, Tobias -- Quast, Thomas -- Landsberg, Jennifer -- Rogava, Meri -- Glodde, Nicole -- Lopez-Ramos, Dorys -- Kohlmeyer, Judith -- Riesenberg, Stefanie -- van den Boorn-Konijnenberg, Debby -- Homig-Holzel, Cornelia -- Reuten, Raphael -- Schadow, Benjamin -- Weighardt, Heike -- Wenzel, Daniela -- Helfrich, Iris -- Schadendorf, Dirk -- Bloch, Wilhelm -- Bianchi, Marco E -- Lugassy, Claire -- Barnhill, Raymond L -- Koch, Manuel -- Fleischmann, Bernd K -- Forster, Irmgard -- Kastenmuller, Wolfgang -- Kolanus, Waldemar -- Holzel, Michael -- Gaffal, Evelyn -- Tuting, Thomas -- England -- Nature. 2014 Mar 6;507(7490):109-13. doi: 10.1038/nature13111. Epub 2014 Feb 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53115 Bonn, Germany. ; Molecular Immunology and Cell Biology, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. ; Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany. ; Institute for Dental Research and Oral Musculoskeletal Biology, Center for Biochemistry, Medical Faculty, University of Cologne, D-50931 Cologne, Germany. ; Immunology and Environment, Life and Medical Sciences Institute, University of Bonn, 53115 Bonn, Germany. ; Institute for Physiology I, Life & Brain Center, University of Bonn, 53105 Bonn, Germany. ; Department of Dermatology, University Hospital Essen, 45122 Essen, Germany. ; Institute of Cardiovascular Research and Sport Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, 50933 Cologne, Germany. ; Division of Genetics and Cell Biology, San Raffaele University and Scientific Institute, 20132 Milan, Italy. ; Department of Pathology and Laboratory Medicine, Jonsson Comprehensive Cancer Center, University of California Los Angeles (UCLA) Medical Center, Los Angeles, California 90095, USA. ; Institutes of Molecular Medicine and Experimental Immunology, University of Bonn, 53105 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24572365" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Movement/radiation effects ; Cell Transformation, Neoplastic/radiation effects ; Disease Models, Animal ; Disease Progression ; Female ; HMGB1 Protein/metabolism ; Immunity, Innate/radiation effects ; Inflammation/*etiology ; Keratinocytes/metabolism/pathology/radiation effects ; Lung Neoplasms/blood supply/etiology/*secondary ; Male ; Melanocytes/pathology/radiation effects ; Melanoma/*blood supply/etiology/*pathology ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/etiology ; Neutrophils/immunology/metabolism ; Skin Neoplasms/blood supply/etiology/*pathology ; Sunburn/complications/*etiology ; Toll-Like Receptor 4/metabolism ; *Ultraviolet Rays
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  • 64
    Publication Date: 2014-05-16
    Description: Cell competition is an emerging principle underlying selection for cellular fitness during development and disease. Competition may be relevant for cancer, but an experimental link between defects in competition and tumorigenesis is elusive. In the thymus, T lymphocytes develop from precursors that are constantly replaced by bone-marrow-derived progenitors. Here we show that in mice this turnover is regulated by natural cell competition between 'young' bone-marrow-derived and 'old' thymus-resident progenitors that, although genetically identical, execute differential gene expression programs. Disruption of cell competition leads to progenitor self-renewal, upregulation of Hmga1, transformation, and T-cell acute lymphoblastic leukaemia (T-ALL) resembling the human disease in pathology, genomic lesions, leukaemia-associated transcripts, and activating mutations in Notch1. Hence, cell competition is a tumour suppressor mechanism in the thymus. Failure to select fit progenitors through cell competition may explain leukaemia in X-linked severe combined immune deficiency patients who showed thymus-autonomous T-cell development after therapy with gene-corrected autologous progenitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Martins, Vera C -- Busch, Katrin -- Juraeva, Dilafruz -- Blum, Carmen -- Ludwig, Carolin -- Rasche, Volker -- Lasitschka, Felix -- Mastitsky, Sergey E -- Brors, Benedikt -- Hielscher, Thomas -- Fehling, Hans Joerg -- Rodewald, Hans-Reimer -- England -- Nature. 2014 May 22;509(7501):465-70. doi: 10.1038/nature13317. Epub 2014 May 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany [2] Institute of Immunology, University of Ulm, D-89081 Ulm, Germany. ; Division of Cellular Immunology, German Cancer Research Center, D-69120 Heidelberg, Germany. ; Division of Theoretical Bioinformatics, German Cancer Research Center, D-69120 Heidelberg, Germany. ; Institute of Immunology, University of Ulm, D-89081 Ulm, Germany. ; Core Facility Small Animal MRI, University of Ulm, D-89081 Ulm, Germany. ; Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany. ; Division of Biostatistics, German Cancer Research Center, D-69120 Heidelberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24828041" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cell Movement ; *Cell Transformation, Neoplastic/genetics ; Disease Progression ; Female ; Gene Expression Regulation, Neoplastic ; HMGA Proteins/genetics ; Hematopoietic Stem Cells/*cytology/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics/*pathology ; Receptor, Notch1/genetics ; T-Lymphocytes/cytology/metabolism/pathology ; Thymus Gland/*cytology/pathology ; Transcriptome/genetics
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  • 65
    Publication Date: 2014-07-22
    Description: Macrophages have an important role in the maintenance of tissue homeostasis. To perform this function, macrophages must have the capacity to monitor the functional states of their 'client cells': namely, the parenchymal cells in the various tissues in which macrophages reside. Tumours exhibit many features of abnormally developed organs, including tissue architecture and cellular composition. Similarly to macrophages in normal tissues and organs, macrophages in tumours (tumour-associated macrophages) perform some key homeostatic functions that allow tumour maintenance and growth. However, the signals involved in communication between tumours and macrophages are poorly defined. Here we show that lactic acid produced by tumour cells, as a by-product of aerobic or anaerobic glycolysis, has a critical function in signalling, through inducing the expression of vascular endothelial growth factor and the M2-like polarization of tumour-associated macrophages. Furthermore, we demonstrate that this effect of lactic acid is mediated by hypoxia-inducible factor 1alpha (HIF1alpha). Finally, we show that the lactate-induced expression of arginase 1 by macrophages has an important role in tumour growth. Collectively, these findings identify a mechanism of communication between macrophages and their client cells, including tumour cells. This communication most probably evolved to promote homeostasis in normal tissues but can also be engaged in tumours to promote their growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4301845/" 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/PMC4301845/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Colegio, Oscar R -- Chu, Ngoc-Quynh -- Szabo, Alison L -- Chu, Thach -- Rhebergen, Anne Marie -- Jairam, Vikram -- Cyrus, Nika -- Brokowski, Carolyn E -- Eisenbarth, Stephanie C -- Phillips, Gillian M -- Cline, Gary W -- Phillips, Andrew J -- Medzhitov, Ruslan -- 1 P50 CA121974/CA/NCI NIH HHS/ -- 1K08CA172580-01/CA/NCI NIH HHS/ -- 5KL2RR024138/RR/NCRR NIH HHS/ -- AI046688/AI/NIAID NIH HHS/ -- AI089771/AI/NIAID NIH HHS/ -- CA157461/CA/NCI NIH HHS/ -- K08 CA172580/CA/NCI NIH HHS/ -- P30 CA016359/CA/NCI NIH HHS/ -- R01 AI089771/AI/NIAID NIH HHS/ -- R01 CA157461/CA/NCI NIH HHS/ -- R37 AI046688/AI/NIAID NIH HHS/ -- UL1 TR000142/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 25;513(7519):559-63. doi: 10.1038/nature13490. Epub 2014 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06520-8059, USA [3] Yale-New Haven Transplantation Center, Yale University School of Medicine, New Haven, Connecticut 06519-1369, USA [4] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA. ; Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA. ; 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Department of Laboratory Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8035, USA. ; Department of Chemistry, Yale University School of Medicine, New Haven, Connecticut 06520-8107, USA. ; Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA. ; 1] Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06519-1612, USA [2] Yale Cancer Center, Yale University School of Medicine, New Haven, Connecticut 06520-8028, USA [3] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815-6789, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043024" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arginase/genetics/metabolism ; Carcinoma, Lewis Lung/pathology ; Cell Communication/drug effects ; Cell Division/drug effects ; Culture Media, Conditioned/chemistry/pharmacology ; Female ; Glycolysis ; Homeostasis ; Hypoxia-Inducible Factor 1, alpha Subunit/metabolism ; Lactic Acid/*metabolism/pharmacology ; Macrophages/*metabolism/*pathology ; Male ; Melanoma, Experimental/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neoplasms/*metabolism/*pathology ; RNA, Messenger/analysis/genetics ; Solubility ; Up-Regulation/drug effects ; Vascular Endothelial Growth Factor A/genetics/metabolism
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  • 66
    Publication Date: 2014-07-22
    Description: Eukaryotic cells coordinately control anabolic and catabolic processes to maintain cell and tissue homeostasis. Mechanistic target of rapamycin complex 1 (mTORC1) promotes nutrient-consuming anabolic processes, such as protein synthesis. Here we show that as well as increasing protein synthesis, mTORC1 activation in mouse and human cells also promotes an increased capacity for protein degradation. Cells with activated mTORC1 exhibited elevated levels of intact and active proteasomes through a global increase in the expression of genes encoding proteasome subunits. The increase in proteasome gene expression, cellular proteasome content, and rates of protein turnover downstream of mTORC1 were all dependent on induction of the transcription factor nuclear factor erythroid-derived 2-related factor 1 (NRF1; also known as NFE2L1). Genetic activation of mTORC1 through loss of the tuberous sclerosis complex tumour suppressors, TSC1 or TSC2, or physiological activation of mTORC1 in response to growth factors or feeding resulted in increased NRF1 expression in cells and tissues. We find that this NRF1-dependent elevation in proteasome levels serves to increase the intracellular pool of amino acids, which thereby influences rates of new protein synthesis. Therefore, mTORC1 signalling increases the efficiency of proteasome-mediated protein degradation for both quality control and as a mechanism to supply substrate for sustained protein synthesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4402229/" 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/PMC4402229/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Yinan -- Nicholatos, Justin -- Dreier, John R -- Ricoult, Stephane J H -- Widenmaier, Scott B -- Hotamisligil, Gokhan S -- Kwiatkowski, David J -- Manning, Brendan D -- CA120964/CA/NCI NIH HHS/ -- CA122617/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- R01 CA122617/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Sep 18;513(7518):440-3. doi: 10.1038/nature13492. Epub 2014 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA. ; Translational Medicine Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043031" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/metabolism ; Animals ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/*metabolism ; Nuclear Respiratory Factor 1/genetics/metabolism ; Proteasome Endopeptidase Complex/genetics/metabolism ; *Protein Biosynthesis ; Proteins/chemistry/*metabolism ; *Proteolysis ; Signal Transduction ; Sterol Regulatory Element Binding Protein 1/metabolism ; TOR Serine-Threonine Kinases/*metabolism ; Transcription, Genetic
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  • 67
    Publication Date: 2014-07-22
    Description: 'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767149/" 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/PMC4767149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tseng, Yuen-Yi -- Moriarity, Branden S -- Gong, Wuming -- Akiyama, Ryutaro -- Tiwari, Ashutosh -- Kawakami, Hiroko -- Ronning, Peter -- Reuland, Brian -- Guenther, Kacey -- Beadnell, Thomas C -- Essig, Jaclyn -- Otto, George M -- O'Sullivan, M Gerard -- Largaespada, David A -- Schwertfeger, Kathryn L -- Marahrens, York -- Kawakami, Yasuhiko -- Bagchi, Anindya -- P30 CA077598/CA/NCI NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):82-6. doi: 10.1038/nature13311. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India. ; Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043044" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Transformation, Neoplastic ; Chromosomes, Human, Pair 8/genetics ; DNA Copy Number Variations/*genetics ; Disease Models, Animal ; Gene Amplification/*genetics ; Gene Dosage/*genetics ; Genes, myc/*genetics ; HCT116 Cells ; Humans ; Mice ; Mice, Inbred C57BL ; Oncogene Protein p55(v-myc)/*genetics/metabolism ; Phenotype ; RNA, Long Noncoding/*genetics
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  • 68
    Publication Date: 2014-09-02
    Description: Long-term synaptic potentiation (LTP) is thought to be a key process in cortical synaptic network plasticity and memory formation. Hebbian forms of LTP depend on strong postsynaptic depolarization, which in many models is generated by action potentials that propagate back from the soma into dendrites. However, local dendritic depolarization has been shown to mediate these forms of LTP as well. As pyramidal cells in supragranular layers of the somatosensory cortex spike infrequently, it is unclear which of the two mechanisms prevails for those cells in vivo. Using whole-cell recordings in the mouse somatosensory cortex in vivo, we demonstrate that rhythmic sensory whisker stimulation efficiently induces synaptic LTP in layer 2/3 (L2/3) pyramidal cells in the absence of somatic spikes. The induction of LTP depended on the occurrence of NMDAR (N-methyl-d-aspartate receptor)-mediated long-lasting depolarizations, which bear similarities to dendritic plateau potentials. In addition, we show that whisker stimuli recruit synaptic networks that originate from the posteromedial complex of the thalamus (POm). Photostimulation of channelrhodopsin-2 expressing POm neurons generated NMDAR-mediated plateau potentials, whereas the inhibition of POm activity during rhythmic whisker stimulation suppressed the generation of those potentials and prevented whisker-evoked LTP. Taken together, our data provide evidence for sensory-driven synaptic LTP in vivo, in the absence of somatic spiking. Instead, LTP is mediated by plateau potentials that are generated through the cooperative activity of lemniscal and paralemniscal synaptic circuitry.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gambino, Frederic -- Pages, Stephane -- Kehayas, Vassilis -- Baptista, Daniela -- Tatti, Roberta -- Carleton, Alan -- Holtmaat, Anthony -- England -- Nature. 2014 Nov 6;515(7525):116-9. doi: 10.1038/nature13664. Epub 2014 Aug 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Basic Neurosciences and the Center for Neuroscience, CMU, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland [2] [3] Institute for Interdisciplinary Neuroscience (IINS), UMR 5297 CNRS and University of Bordeaux, 146 rue Leo-Saignat, 33077 Bordeaux, France. ; 1] Department of Basic Neurosciences and the Center for Neuroscience, CMU, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland [2]. ; 1] Department of Basic Neurosciences and the Center for Neuroscience, CMU, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland [2] Lemanic Neuroscience Doctoral School, 1 rue Michel Servet, 1211 Geneva, Switzerland. ; Department of Basic Neurosciences and the Center for Neuroscience, CMU, University of Geneva, 1 rue Michel Servet, 1211 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25174710" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Dendrites/*physiology ; *Long-Term Potentiation ; Male ; Mice ; Mice, Inbred C57BL ; Physical Stimulation ; Receptors, N-Methyl-D-Aspartate/metabolism ; Rhodopsin/metabolism ; Somatosensory Cortex/*cytology/*physiology ; Thalamus/cytology/physiology ; Vibrissae/physiology
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  • 69
    Publication Date: 2014-12-30
    Description: The skin represents the primary interface between the host and the environment. This organ is also home to trillions of microorganisms that play an important role in tissue homeostasis and local immunity. Skin microbial communities are highly diverse and can be remodelled over time or in response to environmental challenges. How, in the context of this complexity, individual commensal microorganisms may differentially modulate skin immunity and the consequences of these responses for tissue physiology remains unclear. Here we show that defined commensals dominantly affect skin immunity and identify the cellular mediators involved in this specification. In particular, colonization with Staphylococcus epidermidis induces IL-17A(+) CD8(+) T cells that home to the epidermis, enhance innate barrier immunity and limit pathogen invasion. Commensal-specific T-cell responses result from the coordinated action of skin-resident dendritic cell subsets and are not associated with inflammation, revealing that tissue-resident cells are poised to sense and respond to alterations in microbial communities. This interaction may represent an evolutionary means by which the skin immune system uses fluctuating commensal signals to calibrate barrier immunity and provide heterologous protection against invasive pathogens. These findings reveal that the skin immune landscape is a highly dynamic environment that can be rapidly and specifically remodelled by encounters with defined commensals, findings that have profound implications for our understanding of tissue-specific immunity and pathologies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667810/" 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/PMC4667810/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naik, Shruti -- Bouladoux, Nicolas -- Linehan, Jonathan L -- Han, Seong-Ji -- Harrison, Oliver J -- Wilhelm, Christoph -- Conlan, Sean -- Himmelfarb, Sarah -- Byrd, Allyson L -- Deming, Clayton -- Quinones, Mariam -- Brenchley, Jason M -- Kong, Heidi H -- Tussiwand, Roxanne -- Murphy, Kenneth M -- Merad, Miriam -- Segre, Julia A -- Belkaid, Yasmine -- R01 CA173861/CA/NCI NIH HHS/ -- R01 CA190400/CA/NCI NIH HHS/ -- U01 AI095611/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2015 Apr 2;520(7545):104-8. doi: 10.1038/nature14052. Epub 2015 Jan 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA. ; Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; 1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, Maryland 20892, USA [3] Translational and Functional Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA. ; Bioinformatics and Computational Bioscience Branch, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland 20892, USA. ; 1] Immunity at Barrier Sites Initiative, National Institute of Allergy and Infectious Diseases, NIH, Bethesda 20892, USA [2] Immunopathogenesis Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, NIH Bethesda, Maryland 20892, USA. ; Dermatology Branch, National Cancer Institute, NIH Bethesda, Maryland 20892, USA. ; Howard Hughes Medical Institute, Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri 63110, USA. ; Department of Oncological Sciences, Tisch Cancer Institute and Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25539086" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Bacterial/immunology ; CD8-Positive T-Lymphocytes/cytology/*immunology ; Dendritic Cells/cytology/*immunology ; Humans ; Immunity, Innate/immunology ; Interleukin-17/immunology ; Langerhans Cells/cytology/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Primates ; Skin/cytology/*immunology/*microbiology ; Staphylococcus epidermidis/immunology ; Symbiosis/*immunology
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  • 70
    Publication Date: 2014-12-19
    Description: Naturally occurring variations of Polycomb repressive complex 1 (PRC1) comprise a core assembly of Polycomb group proteins and additional factors that include, surprisingly, autism susceptibility candidate 2 (AUTS2). Although AUTS2 is often disrupted in patients with neuronal disorders, the mechanism underlying the pathogenesis is unclear. We investigated the role of AUTS2 as part of a previously identified PRC1 complex (PRC1-AUTS2), and in the context of neurodevelopment. In contrast to the canonical role of PRC1 in gene repression, PRC1-AUTS2 activates transcription. Biochemical studies demonstrate that the CK2 component of PRC1-AUTS2 neutralizes PRC1 repressive activity, whereas AUTS2-mediated recruitment of P300 leads to gene activation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrated that AUTS2 regulates neuronal gene expression through promoter association. Conditional targeting of Auts2 in the mouse central nervous system (CNS) leads to various developmental defects. These findings reveal a natural means of subverting PRC1 activity, linking key epigenetic modulators with neuronal functions and diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4323097/" 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/PMC4323097/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gao, Zhonghua -- Lee, Pedro -- Stafford, James M -- von Schimmelmann, Melanie -- Schaefer, Anne -- Reinberg, Danny -- 1DP2MH100012-01/DP/NCCDPHP CDC HHS/ -- 1F32GM105275/GM/NIGMS NIH HHS/ -- 5T32CA160002/CA/NCI NIH HHS/ -- DP2 MH100012/MH/NIMH NIH HHS/ -- F32AA022842/AA/NIAAA NIH HHS/ -- GM-64844/GM/NIGMS NIH HHS/ -- P30 CA016087/CA/NCI NIH HHS/ -- R01 GM064844/GM/NIGMS NIH HHS/ -- T32 CA160002/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):349-54. doi: 10.1038/nature13921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, New York University Langone School of Medicine, Department of Biochemistry and Molecular Pharmacology, New York, New York 10016, USA. ; Friedman Brain Institute, Department of Neuroscience, Mount Sinai School of Medicine, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25519132" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/physiology ; Cell Cycle Proteins/genetics/*metabolism ; Central Nervous System/*metabolism ; Female ; Gene Expression Profiling ; Gene Expression Regulation/*genetics ; Gene Knockout Techniques ; Genotype ; HEK293 Cells ; Histones/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Phosphorylation ; Proteins/genetics/*metabolism ; Ubiquitination
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  • 71
    Publication Date: 2014-01-15
    Description: Cells differentiate when transcription factors bind accessible cis-regulatory elements to establish specific gene expression programs. In differentiating embryonic stem cells, chromatin at lineage-restricted genes becomes sequentially accessible, probably by means of 'pioneer' transcription factor activity, but tissues may use other strategies in vivo. Lateral inhibition is a pervasive process in which one cell forces a different identity on its neighbours, and it is unclear how chromatin in equipotent progenitors undergoing lateral inhibition quickly enables distinct, transiently reversible cell fates. Here we report the chromatin and transcriptional underpinnings of differentiation in mouse small intestine crypts, where notch signalling mediates lateral inhibition to assign progenitor cells into absorptive or secretory lineages. Transcript profiles in isolated LGR5(+) intestinal stem cells and secretory and absorptive progenitors indicated that each cell population was distinct and the progenitors specified. Nevertheless, secretory and absorptive progenitors showed comparable levels of H3K4me2 and H3K27ac histone marks and DNase I hypersensitivity--signifying accessible, permissive chromatin-at most of the same cis-elements. Enhancers acting uniquely in progenitors were well demarcated in LGR5(+) intestinal stem cells, revealing early priming of chromatin for divergent transcriptional programs, and retained active marks well after lineages were specified. On this chromatin background, ATOH1, a secretory-specific transcription factor, controls lateral inhibition through delta-like notch ligand genes and also drives the expression of numerous secretory lineage genes. Depletion of ATOH1 from specified secretory cells converted them into functional enterocytes, indicating prolonged responsiveness of marked enhancers to the presence or absence of a key transcription factor. Thus, lateral inhibition and intestinal crypt lineage plasticity involve interaction of a lineage-restricted transcription factor with broadly permissive chromatin established in multipotent stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151315/" 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/PMC4151315/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Tae-Hee -- Li, Fugen -- Ferreiro-Neira, Isabel -- Ho, Li-Lun -- Luyten, Annouck -- Nalapareddy, Kodandaramireddy -- Long, Henry -- Verzi, Michael -- Shivdasani, Ramesh A -- K01 DK088868/DK/NIDDK NIH HHS/ -- K01DK088868/DK/NIDDK NIH HHS/ -- K99 DK095983/DK/NIDDK NIH HHS/ -- K99DK095983/DK/NIDDK NIH HHS/ -- P50 CA127003/CA/NCI NIH HHS/ -- P50CA127003/CA/NCI NIH HHS/ -- R01 DK081113/DK/NIDDK NIH HHS/ -- R01 DK082889/DK/NIDDK NIH HHS/ -- R01DK081113/DK/NIDDK NIH HHS/ -- R01DK082889/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Feb 27;506(7489):511-5. doi: 10.1038/nature12903. Epub 2014 Jan 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02215, USA. ; Department of Medical Oncology and Center for Functional Cancer Epigenetics, 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/24413398" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/deficiency/metabolism ; Cell Differentiation/*genetics ; Cell Lineage/genetics ; Chromatin/*genetics/*metabolism ; Deoxyribonuclease I/metabolism ; Enhancer Elements, Genetic/genetics ; Enterocytes/cytology/metabolism ; Female ; *Gene Expression Regulation ; Histones/metabolism ; Intestine, Small/cytology/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Notch/metabolism ; Stem Cells/cytology/metabolism ; Transcription, Genetic
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  • 72
    Publication Date: 2014-07-22
    Description: Mutations that deregulate Notch1 and Ras/phosphoinositide 3 kinase (PI3K)/Akt signalling are prevalent in T-cell acute lymphoblastic leukaemia (T-ALL), and often coexist. Here we show that the PI3K inhibitor GDC-0941 is active against primary T-ALLs from wild-type and Kras(G12D) mice, and addition of the MEK inhibitor PD0325901 increases its efficacy. Mice invariably relapsed after treatment with drug-resistant clones, most of which unexpectedly had reduced levels of activated Notch1 protein, downregulated many Notch1 target genes, and exhibited cross-resistance to gamma-secretase inhibitors. Multiple resistant primary T-ALLs that emerged in vivo did not contain somatic Notch1 mutations present in the parental leukaemia. Importantly, resistant clones upregulated PI3K signalling. Consistent with these data, inhibiting Notch1 activated the PI3K pathway, providing a likely mechanism for selection against oncogenic Notch1 signalling. These studies validate PI3K as a therapeutic target in T-ALL and raise the unexpected possibility that dual inhibition of PI3K and Notch1 signalling could promote drug resistance in T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4213126/" 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/PMC4213126/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dail, Monique -- Wong, Jason -- Lawrence, Jessica -- O'Connor, Daniel -- Nakitandwe, Joy -- Chen, Shann-Ching -- Xu, Jin -- Lee, Leslie B -- Akagi, Keiko -- Li, Qing -- Aster, Jon C -- Pear, Warren S -- Downing, James R -- Sampath, Deepak -- Shannon, Kevin -- K08 CA134649/CA/NCI NIH HHS/ -- K99 CA157950/CA/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P30 CA021765/CA/NCI NIH HHS/ -- R01 CA180037/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 25;513(7519):512-6. doi: 10.1038/nature13495. Epub 2014 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics and Benniof Children's Hospital, University of California, San Francisco, California 94143, USA. ; Department of Pathology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA. ; Department of Translational Oncology, Genentech Inc., South San Francisco, California 94080, USA. ; Department of Molecular Virology, Immunology and Medical Genetics, Ohio State University, Columbus, Ohio 43210, USA. ; Division of Haematology/Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan 48109, USA. ; Department of Pathology, Brigham &Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Abramson Family Cancer Research Institute and the Department of Pathology and Laboratory Medicine, 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/25043004" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology/therapeutic use ; Clone Cells/drug effects/metabolism/pathology ; Diphenylamine/analogs & derivatives/pharmacology/therapeutic use ; Down-Regulation/drug effects ; *Drug Resistance, Neoplasm/drug effects/genetics ; Drug Synergism ; Genes, ras/genetics ; Indazoles/*pharmacology/therapeutic use ; Male ; Mice ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Phosphatidylinositol 3-Kinases/*antagonists & inhibitors ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/*drug ; therapy/*genetics/metabolism/pathology ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Protein Structure, Tertiary ; Proto-Oncogene Proteins c-akt/metabolism ; Receptor, Notch1/chemistry/deficiency/genetics/*metabolism ; Signal Transduction/drug effects ; Sulfonamides/*pharmacology/therapeutic use
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  • 73
    Publication Date: 2014-04-11
    Description: In obesity and type 2 diabetes, Glut4 glucose transporter expression is decreased selectively in adipocytes. Adipose-specific knockout or overexpression of Glut4 alters systemic insulin sensitivity. Here we show, using DNA array analyses, that nicotinamide N-methyltransferase (Nnmt) is the most strongly reciprocally regulated gene when comparing gene expression in white adipose tissue (WAT) from adipose-specific Glut4-knockout or adipose-specific Glut4-overexpressing mice with their respective controls. NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor of NAD(+), an important cofactor linking cellular redox states with energy metabolism. SAM provides propylamine for polyamine biosynthesis and donates a methyl group for histone methylation. Polyamine flux including synthesis, catabolism and excretion, is controlled by the rate-limiting enzymes ornithine decarboxylase (ODC) and spermidine-spermine N(1)-acetyltransferase (SSAT; encoded by Sat1) and by polyamine oxidase (PAO), and has a major role in energy metabolism. We report that NNMT expression is increased in WAT and liver of obese and diabetic mice. Nnmt knockdown in WAT and liver protects against diet-induced obesity by augmenting cellular energy expenditure. NNMT inhibition increases adipose SAM and NAD(+) levels and upregulates ODC and SSAT activity as well as expression, owing to the effects of NNMT on histone H3 lysine 4 methylation in adipose tissue. Direct evidence for increased polyamine flux resulting from NNMT inhibition includes elevated urinary excretion and adipocyte secretion of diacetylspermine, a product of polyamine metabolism. NNMT inhibition in adipocytes increases oxygen consumption in an ODC-, SSAT- and PAO-dependent manner. Thus, NNMT is a novel regulator of histone methylation, polyamine flux and NAD(+)-dependent SIRT1 signalling, and is a unique and attractive target for treating obesity and type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4107212/" 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/PMC4107212/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kraus, Daniel -- Yang, Qin -- Kong, Dong -- Banks, Alexander S -- Zhang, Lin -- Rodgers, Joseph T -- Pirinen, Eija -- Pulinilkunnil, Thomas C -- Gong, Fengying -- Wang, Ya-chin -- Cen, Yana -- Sauve, Anthony A -- Asara, John M -- Peroni, Odile D -- Monia, Brett P -- Bhanot, Sanjay -- Alhonen, Leena -- Puigserver, Pere -- Kahn, Barbara B -- K01 DK094943/DK/NIDDK NIH HHS/ -- K08 DK090149/DK/NIDDK NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01CA120964/CA/NCI NIH HHS/ -- P30 DK040561/DK/NIDDK NIH HHS/ -- P30 DK0460200/DK/NIDDK NIH HHS/ -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P30 DK57521/DK/NIDDK NIH HHS/ -- P30CA006516-46/CA/NCI NIH HHS/ -- R01 DK069966/DK/NIDDK NIH HHS/ -- R01 DK100385/DK/NIDDK NIH HHS/ -- R01 DK69966/DK/NIDDK NIH HHS/ -- R37 DK043051/DK/NIDDK NIH HHS/ -- R37 DK43051/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):258-62. doi: 10.1038/nature13198.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] [3] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. ; Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Biotechnology and Molecular Medicine, A.I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, Kuopio Campus, PO Box 1627, FI-70211 Kuopio, Finland [2] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; 1] Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA [2] Division of Nephrology, Department of Internal Medicine I, Wurzburg University Hospital, Oberdurrbacher Strasse 6, 97080 Wurzburg, Germany (D.K.); Department of Medicine, Physiology and Biophysics, Center for Diabetes Research and Treatment, and Center for Epigenetics and Metabolism, University of California, Irvine, California 92697, USA (Q.Y.); Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, 00290, Helsinki, Finland (E.P.); Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie Medicine New Brunswick, Dalhousie University, Saint John, New Brunswick E2L4L5, USA (T.C.P.); Department of Endocrinology, Key Laboratory of Endocrinology of Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China (F.G.); School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland (L.A.). ; Department of Pharmacology, Weill Medical College of Cornell University, 1300 York Avenue, New York, New York 10065, USA. ; Division of Signal Transduction, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Ave, Boston, Massachusetts 02215, USA. ; Isis Pharmaceuticals, 1896 Rutherford Road, Carlsbad, California 92008-7326, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24717514" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyltransferases/metabolism ; Adipocytes/metabolism/secretion ; Adipose Tissue/enzymology/metabolism ; Adipose Tissue, White/enzymology/metabolism ; Animals ; Diabetes Mellitus, Type 2/enzymology/metabolism ; *Diet ; Energy Metabolism ; Fatty Liver ; Gene Knockdown Techniques ; Glucose Intolerance ; Glucose Transporter Type 4/deficiency/genetics/metabolism ; Insulin Resistance ; Liver/enzymology ; Male ; Mice ; Mice, Inbred C57BL ; NAD/metabolism ; Niacinamide/metabolism ; Nicotinamide N-Methyltransferase/*deficiency/genetics/*metabolism ; Obesity/*enzymology/etiology/genetics/*prevention & control ; Ornithine Decarboxylase/metabolism ; Oxidoreductases Acting on CH-NH Group Donors/metabolism ; S-Adenosylmethionine/metabolism ; Sirtuin 1/metabolism ; Spermine/analogs & derivatives/metabolism ; Thinness/enzymology/metabolism
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  • 74
    Publication Date: 2014-03-22
    Description: Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ramasamy, Saravana K -- Kusumbe, Anjali P -- Wang, Lin -- Adams, Ralf H -- England -- Nature. 2014 Mar 20;507(7492):376-80. doi: 10.1038/nature13146. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2]. ; Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany. ; 1] Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, D-48149 Munster, Germany [2] University of Munster, Faculty of Medicine, D-48149 Munster, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24647000" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Blood Vessels/growth & development ; Bone Development/drug effects ; Bone and Bones/*blood supply/cytology/drug effects/*metabolism ; Calcification, Physiologic/drug effects ; Carrier Proteins/administration & dosage/metabolism/pharmacology ; Cell Proliferation ; Chondrocytes/cytology/drug effects ; Endothelium, Vascular/cytology/*metabolism ; Female ; Male ; Mice ; Mice, Inbred C57BL ; *Neovascularization, Physiologic ; *Osteogenesis/drug effects ; Receptors, Notch/*metabolism ; Signal Transduction/genetics
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  • 75
    Publication Date: 2014-07-22
    Description: Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4184286/" 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/PMC4184286/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Suh, Jae Myoung -- Jonker, Johan W -- Ahmadian, Maryam -- Goetz, Regina -- Lackey, Denise -- Osborn, Olivia -- Huang, Zhifeng -- Liu, Weilin -- Yoshihara, Eiji -- van Dijk, Theo H -- Havinga, Rick -- Fan, Weiwei -- Yin, Yun-Qiang -- Yu, Ruth T -- Liddle, Christopher -- Atkins, Annette R -- Olefsky, Jerrold M -- Mohammadi, Moosa -- Downes, Michael -- Evans, Ronald M -- DE13686/DE/NIDCR NIH HHS/ -- DK-033651/DK/NIDDK NIH HHS/ -- DK-063491/DK/NIDDK NIH HHS/ -- DK-074868/DK/NIDDK NIH HHS/ -- DK057978/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- ES010337/ES/NIEHS NIH HHS/ -- HL088093/HL/NHLBI NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P01 DK054441/DK/NIDDK NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P01 HL088093/HL/NHLBI NIH HHS/ -- P01-DK054441-14A1/DK/NIDDK NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- P42 ES010337/ES/NIEHS NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R37 DK033651/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- T32 DK007494/DK/NIDDK NIH HHS/ -- T32-DK-007494/DK/NIDDK NIH HHS/ -- U54 HD012303/HD/NICHD NIH HHS/ -- U54-HD-012303-25/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Sep 18;513(7518):436-9. doi: 10.1038/nature13540. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA [2]. ; 1] Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands [2]. ; Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA. ; Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA. ; Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, California 92093, USA. ; 1] Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, New York 10016, USA [2] School of Pharmacy, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China. ; Center for Liver, Digestive and Metabolic Diseases, Departments of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. ; The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia. ; 1] Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA [2] Howard Hughes Medical Institute, 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/25043058" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Glucose/metabolism ; Body Weight/drug effects ; Diabetes Mellitus, Experimental/drug therapy/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Diet, High-Fat ; Dose-Response Relationship, Drug ; Fibroblast Growth Factor 1/administration & dosage/adverse effects/*pharmacology ; Glucose/*metabolism ; Glucose Tolerance Test ; Humans ; Insulin/*metabolism ; Insulin Resistance ; Liver/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Mitogens/pharmacology ; Muscle, Skeletal/drug effects/metabolism ; Receptor, Fibroblast Growth Factor, Type 1/metabolism
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  • 76
    Publication Date: 2014-08-01
    Description: Haematopoietic stem cells (HSCs) self-renew for life, thereby making them one of the few blood cells that truly age. Paradoxically, although HSCs numerically expand with age, their functional activity declines over time, resulting in degraded blood production and impaired engraftment following transplantation. While many drivers of HSC ageing have been proposed, the reason why HSC function degrades with age remains unknown. Here we show that cycling old HSCs in mice have heightened levels of replication stress associated with cell cycle defects and chromosome gaps or breaks, which are due to decreased expression of mini-chromosome maintenance (MCM) helicase components and altered dynamics of DNA replication forks. Nonetheless, old HSCs survive replication unless confronted with a strong replication challenge, such as transplantation. Moreover, once old HSCs re-establish quiescence, residual replication stress on ribosomal DNA (rDNA) genes leads to the formation of nucleolar-associated gammaH2AX signals, which persist owing to ineffective H2AX dephosphorylation by mislocalized PP4c phosphatase rather than ongoing DNA damage. Persistent nucleolar gammaH2AX also acts as a histone modification marking the transcriptional silencing of rDNA genes and decreased ribosome biogenesis in quiescent old HSCs. Our results identify replication stress as a potent driver of functional decline in old HSCs, and highlight the MCM DNA helicase as a potential molecular target for rejuvenation therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456040/" 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/PMC4456040/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Flach, Johanna -- Bakker, Sietske T -- Mohrin, Mary -- Conroy, Pauline C -- Pietras, Eric M -- Reynaud, Damien -- Alvarez, Silvia -- Diolaiti, Morgan E -- Ugarte, Fernando -- Forsberg, E Camilla -- Le Beau, Michelle M -- Stohr, Bradley A -- Mendez, Juan -- Morrison, Ciaran G -- Passegue, Emmanuelle -- F32 HL106989/HL/NHLBI NIH HHS/ -- R01 CA184014/CA/NCI NIH HHS/ -- R01 HL092471/HL/NHLBI NIH HHS/ -- R01 HL115158/HL/NHLBI NIH HHS/ -- T32 AI007334/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Aug 14;512(7513):198-202. doi: 10.1038/nature13619. Epub 2014 Jul 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA [2] Institute of Experimental Cancer Research, Comprehensive Cancer Center, 89081 Ulm, Germany. ; The Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Medicine, Hem/Onc Division, University of California San Francisco, San Francisco, California 94143, USA. ; Center for Chromosome Biology, School of Natural Sciences, National University of Ireland Galway, Galway, Ireland. ; Spanish National Cancer Research Centre (CNIO), E-28049 Madrid, Spain. ; Department of Pathology, University of California San Francisco, San Francisco, California 94143, USA. ; Institute for the Biology of Stem Cells, Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, California 95064, USA. ; Section of Hematology/Oncology and the Comprehensive Cancer Center, University of Chicago, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079315" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging/genetics/*physiology ; Cell Proliferation ; DNA Damage/genetics ; DNA Replication/*physiology ; DNA, Ribosomal/genetics ; Female ; Gene Expression Regulation ; Hematopoietic Stem Cells/cytology/*pathology ; Histones/genetics/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Minichromosome Maintenance Proteins/genetics ; *Stress, Physiological
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  • 77
    Publication Date: 2014-10-03
    Description: Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Galpha12 and Galpha13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Galpha13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor's Akt and migration inhibitory functions. Galpha13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Galpha13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Galpha13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Galpha13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Galpha13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt's lymphoma, also represses germinal centre B-cell growth and promotes confinement via Galpha13. These findings identify a Galpha13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4267955/" 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/PMC4267955/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Muppidi, Jagan R -- Schmitz, Roland -- Green, Jesse A -- Xiao, Wenming -- Larsen, Adrien B -- Braun, Sterling E -- An, Jinping -- Xu, Ying -- Rosenwald, Andreas -- Ott, German -- Gascoyne, Randy D -- Rimsza, Lisa M -- Campo, Elias -- Jaffe, Elaine S -- Delabie, Jan -- Smeland, Erlend B -- Braziel, Rita M -- Tubbs, Raymond R -- Cook, J R -- Weisenburger, Dennis D -- Chan, Wing C -- Vaidehi, Nagarajan -- Staudt, Louis M -- Cyster, Jason G -- AI45073/AI/NIAID NIH HHS/ -- GM097261/GM/NIGMS NIH HHS/ -- R01 AI045073/AI/NIAID NIH HHS/ -- R01 GM097261/GM/NIGMS NIH HHS/ -- T32 CA128583/CA/NCI NIH HHS/ -- T32 CA1285835/CA/NCI NIH HHS/ -- T32 DK007636/DK/NIDDK NIH HHS/ -- UL1 TR000439/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2014 Dec 11;516(7530):254-8. doi: 10.1038/nature13765. Epub 2014 Sep 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Department of Medicine, University of California, San Francisco, California 94143, USA [3] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA. ; Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA [3] Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Division of Immunology, Beckman Research Institute of the City of Hope, Duarte, California 91010, USA. ; 1] Department of Microbiology and Immunology, University of California, San Francisco, California, 94143, USA [2] Howard Hughes Medical Institute, University of California, San Francisco, California 94143, USA. ; Department of Pathology, University of Wurzburg, 97080 Wurzburg, Germany. ; 1] Department of Clinical Pathology, Robert-Bosch-Krankenhaus, Auerbachstrasse 110, 70376 Stuttgart, Germany [2] Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, 70376 Stuttgart, Germany. ; British Columbia Cancer Agency, Vancouver, British Columbia V5Z 1L3, Canada. ; Department of Pathology, University of Arizona, Tucson, Arizona 85724, USA. ; Hospital Clinic, University of Barcelona, 08036 Barcelona, Spain. ; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. ; Pathology Clinic, Rikshospitalet University Hospital, 0372 Oslo, Norway. ; 1] Institute for Cancer Research, Rikshospitalet University Hospital, University of Oslo, 0310 Oslo, Norway [2] Center for Cancer Biomedicine, Faculty Division of the Norwegian Radium Hospital, University of Oslo, 0310 Oslo, Norway. ; Oregon Health and Science University, Portland, Oregon 97239, USA. ; Cleveland Clinic Pathology and Laboratory Medicine Institute, Cleveland, Ohio 44195, USA. ; Department of Pathology, City of Hope National Medical Center, Duarte, California 91010, USA. ; 1] Department of Pathology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA [2] Department of Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25274307" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*metabolism/*pathology ; Blood/immunology ; Burkitt Lymphoma/metabolism/pathology ; Cell Line, Tumor ; Cell Movement/genetics ; GTP-Binding Protein alpha Subunits, G12-G13/*metabolism ; Germinal Center/*pathology ; Humans ; Lymph/cytology ; Lymphoma, Large B-Cell, Diffuse/genetics/*metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Oncogene Protein v-akt/genetics/metabolism ; Receptors, Lysosphingolipid/deficiency/genetics/metabolism ; Receptors, Purinergic P2Y/genetics/metabolism ; Rho Guanine Nucleotide Exchange Factors/deficiency/genetics ; *Signal Transduction
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  • 78
    Publication Date: 2014-03-29
    Description: Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are at present the most effective therapy for the treatment of obesity, and are associated with considerable improvements in co-morbidities, including type-2 diabetes mellitus. The underlying molecular mechanisms contributing to these benefits remain largely undetermined, despite offering the potential to reveal new targets for therapeutic intervention. Substantial changes in circulating total bile acids are known to occur after VSG. Moreover, bile acids are known to regulate metabolism by binding to the nuclear receptor FXR (farsenoid-X receptor, also known as NR1H4). We therefore examined the results of VSG surgery applied to mice with diet-induced obesity and targeted genetic disruption of FXR. Here we demonstrate that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach. Rather, VSG is associated with increased circulating bile acids, and associated changes to gut microbial communities. Moreover, in the absence of FXR, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. These results point to bile acids and FXR signalling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016120/" 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/PMC4016120/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ryan, Karen K -- Tremaroli, Valentina -- Clemmensen, Christoffer -- Kovatcheva-Datchary, Petia -- Myronovych, Andriy -- Karns, Rebekah -- Wilson-Perez, Hilary E -- Sandoval, Darleen A -- Kohli, Rohit -- Backhed, Fredrik -- Seeley, Randy J -- DK078392/DK/NIDDK NIH HHS/ -- DK082173/DK/NIDDK NIH HHS/ -- DK093848/DK/NIDDK NIH HHS/ -- HL111319/HL/NHLBI NIH HHS/ -- K08 DK084310/DK/NIDDK NIH HHS/ -- K99 HL111319/HL/NHLBI NIH HHS/ -- P30 DK078392/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 May 8;509(7499):183-8. doi: 10.1038/nature13135. Epub 2014 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA. ; Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, S-413 45 Gothenburg, Sweden. ; 1] Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Cincinnati, Cincinnati, Ohio 45237, USA [2] Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. ; Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; Divison of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA. ; 1] Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, S-413 45 Gothenburg, Sweden [2] Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, DK-2200, Denmark.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24670636" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Bariatric Surgery ; Bile Acids and Salts/blood ; Body Composition ; Cecum/microbiology ; Feeding Behavior ; *Gastrectomy ; Glucose Intolerance/surgery ; Glucose Tolerance Test ; Male ; Mice ; Mice, Inbred C57BL ; Obesity/etiology/surgery ; Receptors, Cytoplasmic and Nuclear/deficiency/genetics/*metabolism ; Signal Transduction ; Stomach/metabolism/surgery ; Weight Loss
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  • 79
    Publication Date: 2014-02-04
    Description: The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230338/" 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/PMC4230338/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Azim, Eiman -- Jiang, Juan -- Alstermark, Bror -- Jessell, Thomas M -- NS033245/NS/NINDS NIH HHS/ -- R01 NS033245/NS/NINDS NIH HHS/ -- R01 NS080932/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Apr 17;508(7496):357-63. doi: 10.1038/nature13021. Epub 2014 Feb 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Kavli Institute for Brain Science, Mortimer B. Zuckerman Mind Brain Behavior Institute, Departments of Neuroscience and Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA. ; Department of Integrative Medical Biology, Section of Physiology, Umea University, Umea, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24487617" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cerebellum/physiology ; Feedback, Physiological ; Female ; Forelimb/*innervation/*physiology ; Interneurons/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Motor Neurons/*physiology ; Motor Skills/*physiology ; Movement/*physiology ; *Neural Pathways ; Optogenetics ; Psychomotor Performance/physiology ; Spinal Cord/*cytology
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  • 80
    Publication Date: 2014-08-01
    Description: The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492470/" 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/PMC4492470/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolfe, Andrew L -- Singh, Kamini -- Zhong, Yi -- Drewe, Philipp -- Rajasekhar, Vinagolu K -- Sanghvi, Viraj R -- Mavrakis, Konstantinos J -- Jiang, Man -- Roderick, Justine E -- Van der Meulen, Joni -- Schatz, Jonathan H -- Rodrigo, Christina M -- Zhao, Chunying -- Rondou, Pieter -- de Stanchina, Elisa -- Teruya-Feldstein, Julie -- Kelliher, Michelle A -- Speleman, Frank -- Porco, John A Jr -- Pelletier, Jerry -- Ratsch, Gunnar -- Wendel, Hans-Guido -- GM-067041/GM/NIGMS NIH HHS/ -- GM-073855/GM/NIGMS NIH HHS/ -- MOP-10653/Canadian Institutes of Health Research/Canada -- P30 CA008748/CA/NCI NIH HHS/ -- R01 CA142798/CA/NCI NIH HHS/ -- R01-CA142798-01/CA/NCI NIH HHS/ -- England -- Nature. 2014 Sep 4;513(7516):65-70. doi: 10.1038/nature13485. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3]. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2]. ; Computational Biology Department, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Stem Cell Center and Developmental Biology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.). ; Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts 01605 USA. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. ; 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [3] Novartis, Cambridge, Massachusetts 02139, USA (K.J.M.); The University of Arizona Cancer Center, Tucson, Arizona 85719, USA (J.H.S.). ; Department of Chemistry, Center for Chemical Methodology and Library Development, Boston University, Boston, Massachusetts 02215, USA. ; Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, B-9000 Ghent, Belgium. ; Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. ; 1] Department of Biochemistry, McGill University, Montreal, Quebec H3G 1Y6, Canada [2] Department of Oncology, McGill University, Montreal, Quebec H3G 1Y6, Canada [3] The Rosalind and Morris Goodman Cancer Research Center, McGill University, Montreal, Quebec H3G 1Y6, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079319" target="_blank"〉PubMed〈/a〉
    Keywords: 5' Untranslated Regions/*genetics ; Animals ; Antineoplastic Agents, Phytogenic/pharmacology/therapeutic use ; Base Sequence ; Cell Line, Tumor ; Epigenesis, Genetic ; Eukaryotic Initiation Factor-4A/*metabolism ; Female ; *G-Quadruplexes ; Humans ; Mice ; Mice, Inbred C57BL ; Nucleotide Motifs ; Oncogene Proteins/*biosynthesis/*genetics ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug ; therapy/genetics/*metabolism ; *Protein Biosynthesis/drug effects ; Ribosomes/metabolism ; Transcription Factors/metabolism ; Transcription, Genetic/drug effects/genetics ; Triterpenes/pharmacology
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  • 81
    Publication Date: 2014-04-18
    Description: The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145853/" 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/PMC4145853/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Treutlein, Barbara -- Brownfield, Doug G -- Wu, Angela R -- Neff, Norma F -- Mantalas, Gary L -- Espinoza, F Hernan -- Desai, Tushar J -- Krasnow, Mark A -- Quake, Stephen R -- 5K08HL084095/HL/NHLBI NIH HHS/ -- K08 HL084095/HL/NHLBI NIH HHS/ -- T32 HD007249/HD/NICHD NIH HHS/ -- T32HD007249/HD/NICHD NIH HHS/ -- U01 HL099995/HL/NHLBI NIH HHS/ -- U01 HL099999/HL/NHLBI NIH HHS/ -- U01HL099995/HL/NHLBI NIH HHS/ -- U01HL099999/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 May 15;509(7500):371-5. doi: 10.1038/nature13173. Epub 2014 Apr 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Departments of Bioengineering and Applied Physics, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA [2]. ; 1] Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA [2]. ; Departments of Bioengineering and Applied Physics, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305, USA. ; Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24739965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bronchi/cytology ; Cell Differentiation/genetics ; Cell Lineage/*genetics ; Epithelial Cells/classification/*cytology/*metabolism ; Female ; Genetic Markers ; Genome/genetics ; Genomics ; Lung/*cytology/embryology ; Mice ; Mice, Inbred C57BL ; Pulmonary Alveoli/cytology ; Pulmonary Gas Exchange ; Sequence Analysis, RNA/*methods ; Single-Cell Analysis/*methods ; Stem Cells/cytology ; Transcriptome/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 82
    Publication Date: 2014-11-11
    Description: Inactivation of APC is a strongly predisposing event in the development of colorectal cancer, prompting the search for vulnerabilities specific to cells that have lost APC function. Signalling through the mTOR pathway is known to be required for epithelial cell proliferation and tumour growth, and the current paradigm suggests that a critical function of mTOR activity is to upregulate translational initiation through phosphorylation of 4EBP1 (refs 6, 7). This model predicts that the mTOR inhibitor rapamycin, which does not efficiently inhibit 4EBP1 (ref. 8), would be ineffective in limiting cancer progression in APC-deficient lesions. Here we show in mice that mTOR complex 1 (mTORC1) activity is absolutely required for the proliferation of Apc-deficient (but not wild-type) enterocytes, revealing an unexpected opportunity for therapeutic intervention. Although APC-deficient cells show the expected increases in protein synthesis, our study reveals that it is translation elongation, and not initiation, which is the rate-limiting component. Mechanistically, mTORC1-mediated inhibition of eEF2 kinase is required for the proliferation of APC-deficient cells. Importantly, treatment of established APC-deficient adenomas with rapamycin (which can target eEF2 through the mTORC1-S6K-eEF2K axis) causes tumour cells to undergo growth arrest and differentiation. Taken together, our data suggest that inhibition of translation elongation using existing, clinically approved drugs, such as the rapalogs, would provide clear therapeutic benefit for patients at high risk of developing colorectal cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304784/" 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/PMC4304784/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Faller, William J -- Jackson, Thomas J -- Knight, John R P -- Ridgway, Rachel A -- Jamieson, Thomas -- Karim, Saadia A -- Jones, Carolyn -- Radulescu, Sorina -- Huels, David J -- Myant, Kevin B -- Dudek, Kate M -- Casey, Helen A -- Scopelliti, Alessandro -- Cordero, Julia B -- Vidal, Marcos -- Pende, Mario -- Ryazanov, Alexey G -- Sonenberg, Nahum -- Meyuhas, Oded -- Hall, Michael N -- Bushell, Martin -- Willis, Anne E -- Sansom, Owen J -- 311301/European Research Council/International -- A7130/Cancer Research UK/United Kingdom -- G1000078/1/National Centre for the Replacement, Refinement and Reduction of Animals in Research/United Kingdom -- MC_UP_A600_1023/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2015 Jan 22;517(7535):497-500. doi: 10.1038/nature13896. Epub 2014 Nov 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Beatson Institute, Glasgow G61 1BD, UK. ; Medical Research Council Toxicology Unit, Leicester LE1 9HN, UK. ; Institut Necker-Enfants Malades, CS 61431, Paris, France Institut National de la Sante et de la Recherche Medicale, U1151, F-75014 Paris, France Universite Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France. ; Department of Pharmacology, Rutgers The State University of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA. ; Department of Biochemistry and Goodman Cancer Research Center, McGill University, Montreal, Quebec H3A 1A3, Canada. ; Department of Biochemistry and Molecular Biology, IMRIC, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel. ; Biozentrum, University of Basel, CH-4056 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383520" target="_blank"〉PubMed〈/a〉
    Keywords: Adenomatous Polyposis Coli Protein/deficiency/genetics ; Animals ; Cell Proliferation ; Cell Transformation, Neoplastic/metabolism/*pathology ; Elongation Factor 2 Kinase/deficiency/genetics/metabolism ; Enzyme Activation ; Genes, APC ; Intestinal Neoplasms/genetics/*metabolism/*pathology ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/*metabolism ; Oncogene Protein p55(v-myc)/metabolism ; *Peptide Chain Elongation, Translational ; Peptide Elongation Factor 2/metabolism ; Ribosomal Protein S6 Kinases/metabolism ; Signal Transduction ; TOR Serine-Threonine Kinases/*metabolism ; Wnt Proteins/metabolism
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  • 83
    Publication Date: 2014-01-31
    Description: Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4052214/" 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/PMC4052214/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Penghui -- Shaffer, Donald R -- Alvarez Arias, Diana A -- Nakazaki, Yukoh -- Pos, Wouter -- Torres, Alexis J -- Cremasco, Viviana -- Dougan, Stephanie K -- Cowley, Glenn S -- Elpek, Kutlu -- Brogdon, Jennifer -- Lamb, John -- Turley, Shannon J -- Ploegh, Hidde L -- Root, David E -- Love, J Christopher -- Dranoff, Glenn -- Hacohen, Nir -- Cantor, Harvey -- Wucherpfennig, Kai W -- 1R01CA173750/CA/NCI NIH HHS/ -- DP3 DK097681/DK/NIDDK NIH HHS/ -- P01 AI045757/AI/NIAID NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 CA173750/CA/NCI NIH HHS/ -- T32 AI007386/AI/NIAID NIH HHS/ -- T32 AI07386/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Feb 6;506(7486):52-7. doi: 10.1038/nature12988. Epub 2014 Jan 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2]. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] [3] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. ; 1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA. ; Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA. ; Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24476824" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/immunology ; Apoptosis/immunology ; CD4-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/cytology/immunology/secretion ; Cell Proliferation ; Cytokines/immunology/secretion ; Female ; Gene Knockdown Techniques ; High-Throughput Nucleotide Sequencing ; *Immunotherapy/methods ; Lymphocytes, Tumor-Infiltrating/cytology/immunology/metabolism/secretion ; Melanoma, Experimental/immunology ; Mice ; Mice, Inbred C57BL ; *Molecular Targeted Therapy ; Protein Phosphatase 2/deficiency/genetics/*metabolism ; RNA, Small Interfering/genetics ; Reproducibility of Results ; Tumor Microenvironment/*immunology
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  • 84
    Publication Date: 2014-11-05
    Description: T-cell immunoglobulin domain and mucin domain-3 (TIM-3, also known as HAVCR2) is an activation-induced inhibitory molecule involved in tolerance and shown to induce T-cell exhaustion in chronic viral infection and cancers. Under some conditions, TIM-3 expression has also been shown to be stimulatory. Considering that TIM-3, like cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), is being targeted for cancer immunotherapy, it is important to identify the circumstances under which TIM-3 can inhibit and activate T-cell responses. Here we show that TIM-3 is co-expressed and forms a heterodimer with carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1), another well-known molecule expressed on activated T cells and involved in T-cell inhibition. Biochemical, biophysical and X-ray crystallography studies show that the membrane-distal immunoglobulin-variable (IgV)-like amino-terminal domain of each is crucial to these interactions. The presence of CEACAM1 endows TIM-3 with inhibitory function. CEACAM1 facilitates the maturation and cell surface expression of TIM-3 by forming a heterodimeric interaction in cis through the highly related membrane-distal N-terminal domains of each molecule. CEACAM1 and TIM-3 also bind in trans through their N-terminal domains. Both cis and trans interactions between CEACAM1 and TIM-3 determine the tolerance-inducing function of TIM-3. In a mouse adoptive transfer colitis model, CEACAM1-deficient T cells are hyper-inflammatory with reduced cell surface expression of TIM-3 and regulatory cytokines, and this is restored by T-cell-specific CEACAM1 expression. During chronic viral infection and in a tumour environment, CEACAM1 and TIM-3 mark exhausted T cells. Co-blockade of CEACAM1 and TIM-3 leads to enhancement of anti-tumour immune responses with improved elimination of tumours in mouse colorectal cancer models. Thus, CEACAM1 serves as a heterophilic ligand for TIM-3 that is required for its ability to mediate T-cell inhibition, and this interaction has a crucial role in regulating autoimmunity and anti-tumour immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297519/" 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/PMC4297519/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Yu-Hwa -- Zhu, Chen -- Kondo, Yasuyuki -- Anderson, Ana C -- Gandhi, Amit -- Russell, Andrew -- Dougan, Stephanie K -- Petersen, Britt-Sabina -- Melum, Espen -- Pertel, Thomas -- Clayton, Kiera L -- Raab, Monika -- Chen, Qiang -- Beauchemin, Nicole -- Yazaki, Paul J -- Pyzik, Michal -- Ostrowski, Mario A -- Glickman, Jonathan N -- Rudd, Christopher E -- Ploegh, Hidde L -- Franke, Andre -- Petsko, Gregory A -- Kuchroo, Vijay K -- Blumberg, Richard S -- AI039671/AI/NIAID NIH HHS/ -- AI056299/AI/NIAID NIH HHS/ -- AI073748/AI/NIAID NIH HHS/ -- DK0034854/DK/NIDDK NIH HHS/ -- DK044319/DK/NIDDK NIH HHS/ -- DK051362/DK/NIDDK NIH HHS/ -- DK053056/DK/NIDDK NIH HHS/ -- DK088199/DK/NIDDK NIH HHS/ -- GM32415/GM/NIGMS NIH HHS/ -- MOP-93787/Canadian Institutes of Health Research/Canada -- NS045937/NS/NINDS NIH HHS/ -- P01 AI039671/AI/NIAID NIH HHS/ -- P01 AI056299/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P30 DK034854/DK/NIDDK NIH HHS/ -- P41 GM111244/GM/NIGMS NIH HHS/ -- R01 DK051362/DK/NIDDK NIH HHS/ -- R01 GM026788/GM/NIGMS NIH HHS/ -- R01 NS045937/NS/NINDS NIH HHS/ -- T32 GM007122/GM/NIGMS NIH HHS/ -- UL1 TR001102/TR/NCATS NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):386-90. doi: 10.1038/nature13848. Epub 2014 Oct 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA. ; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Harvard Institutes of Medicine, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. ; Rosenstiel Basic Medical Sciences Research Center, Brandeis University, 415 South Street, Waltham, Massachusetts 02454, USA. ; Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel 24105, Germany. ; 1] Division of Gastroenterology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts 02115, USA [2] Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Oslo 0424, Norway. ; Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada. ; Cell Signalling Section, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, UK. ; State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China. ; Goodman Cancer Research Centre, McGill University, Montreal H3G 1Y6, Canada. ; Beckman Institute, City of Hope, Duarte, California 91010, USA. ; 1] Department of Immunology, University of Toronto, Toronto, Ontario M5S1A8, Canada [2] Keenan Research Centre of St. Michael's Hospital, Toronto, Ontario M5S1A8, Canada. ; GI Pathology, Miraca Life Sciences, Newton, Massachusetts 02464, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25363763" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/immunology/*metabolism ; Autoimmunity/immunology ; Cell Adhesion Molecules/chemistry/immunology/*metabolism ; Cell Line ; Colorectal Neoplasms/immunology ; Disease Models, Animal ; Female ; Humans ; Immune Tolerance/*immunology ; Inflammation/immunology/pathology ; Ligands ; Male ; Membrane Proteins/chemistry/immunology/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Models, Molecular ; Mucous Membrane/immunology/pathology ; Protein Conformation ; Protein Multimerization ; Receptors, Virus/chemistry/immunology/*metabolism ; T-Lymphocytes/*immunology/*metabolism
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  • 85
    Publication Date: 2014-10-16
    Description: Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies. Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of beta-adrenergic receptors. Because BAT therapies based on cold exposure or beta-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A2A receptors or injection of lentiviral vectors expressing the A2A receptor into white fat induces brown-like cells-so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine-A2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gnad, Thorsten -- Scheibler, Saskia -- von Kugelgen, Ivar -- Scheele, Camilla -- Kilic, Ana -- Glode, Anja -- Hoffmann, Linda S -- Reverte-Salisa, Laia -- Horn, Philipp -- Mutlu, Samet -- El-Tayeb, Ali -- Kranz, Mathias -- Deuther-Conrad, Winnie -- Brust, Peter -- Lidell, Martin E -- Betz, Matthias J -- Enerback, Sven -- Schrader, Jurgen -- Yegutkin, Gennady G -- Muller, Christa E -- Pfeifer, Alexander -- England -- Nature. 2014 Dec 18;516(7531):395-9. doi: 10.1038/nature13816. Epub 2014 Oct 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany. ; 1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Research Training Group 1873, University of Bonn, 53127 Bonn, Germany. ; The Centre of Inflammation and Metabolism and the Centre for Physical Activity Research, Department of Infectious Diseases, Rigshospitalet, 2100 Copenhagen, Denmark. ; Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany. ; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiopharmaceutical Cancer Research, Research Site Leipzig, 04318 Leipzig, Germany. ; Department of Medical and Clinical Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, 413 90 Gothenburg, Sweden. ; Department for Molecular Cardiology, University of Dusseldorf, 40225 Dusseldorf, Germany. ; Medicity Research Laboratory, University of Turku, 20520 Turku, Finland. ; 1] Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, 53121 Bonn, Germany [2] Pharma Center, University of Bonn, 53127 Bonn, Germany. ; 1] Institute of Pharmacology and Toxicology, University Hospital, University of Bonn, 53127 Bonn, Germany [2] Pharma Center, University of Bonn, 53127 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25317558" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine/analogs & derivatives/*metabolism/pharmacology ; Adenosine A2 Receptor Agonists/pharmacology ; Adipocytes/*metabolism ; Adipose Tissue, Brown/drug effects/*metabolism ; Animals ; Cells, Cultured ; Cricetinae ; Diet ; Humans ; Male ; Mesocricetus ; Mice ; Mice, Inbred C57BL ; Phenethylamines/pharmacology ; Receptor, Adenosine A2A/*metabolism
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  • 86
    Publication Date: 2014-11-11
    Description: beta-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice beta-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide beta-catenin enrichment mapping, we identify Dicer1-important in small RNA (for example, microRNA) biogenesis--as a beta-catenin target gene that mediates resilience. Small RNA profiling after excising beta-catenin from nucleus accumbens in the context of chronic stress reveals beta-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish beta-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257892/" 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/PMC4257892/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dias, Caroline -- Feng, Jian -- Sun, Haosheng -- Shao, Ning Yi -- Mazei-Robison, Michelle S -- Damez-Werno, Diane -- Scobie, Kimberly -- Bagot, Rosemary -- LaBonte, Benoit -- Ribeiro, Efrain -- Liu, XiaoChuan -- Kennedy, Pamela -- Vialou, Vincent -- Ferguson, Deveroux -- Pena, Catherine -- Calipari, Erin S -- Koo, Ja Wook -- Mouzon, Ezekiell -- Ghose, Subroto -- Tamminga, Carol -- Neve, Rachael -- Shen, Li -- Nestler, Eric J -- P50 MH096890/MH/NIMH NIH HHS/ -- R00 MH094405/MH/NIMH NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):51-5. doi: 10.1038/nature13976. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA. ; Department of Psychiatry, University of Texas Southwestern, Dallas, Texas 75390, USA. ; Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383518" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/genetics ; Animals ; DEAD-box RNA Helicases/*genetics/metabolism ; Depression/physiopathology ; Gene Expression Profiling ; *Gene Expression Regulation ; Genome-Wide Association Study ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*genetics/metabolism ; Neurons/metabolism ; *Resilience, Psychological ; Ribonuclease III/*genetics/metabolism ; Signal Transduction ; Stress, Physiological/*genetics ; beta Catenin/genetics/*metabolism
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  • 87
    Publication Date: 2014-11-11
    Description: Lysosomal degradation of cytoplasmic components by autophagy is essential for cellular survival and homeostasis under nutrient-deprived conditions. Acute regulation of autophagy by nutrient-sensing kinases is well defined, but longer-term transcriptional regulation is relatively unknown. Here we show that the fed-state sensing nuclear receptor farnesoid X receptor (FXR) and the fasting transcriptional activator cAMP response element-binding protein (CREB) coordinately regulate the hepatic autophagy gene network. Pharmacological activation of FXR repressed many autophagy genes and inhibited autophagy even in fasted mice, and feeding-mediated inhibition of macroautophagy was attenuated in FXR-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, FXR and CREB binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. CREB promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and FXR inhibited this response. Mechanistically, CREB upregulated autophagy genes, including Atg7, Ulk1 and Tfeb, by recruiting the coactivator CRTC2. After feeding or pharmacological activation, FXR trans-repressed these genes by disrupting the functional CREB-CRTC2 complex. This study identifies the new FXR-CREB axis as a key physiological switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257899/" 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/PMC4257899/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Seok, Sunmi -- Fu, Ting -- Choi, Sung-E -- Li, Yang -- Zhu, Rong -- Kumar, Subodh -- Sun, Xiaoxiao -- Yoon, Gyesoon -- Kang, Yup -- Zhong, Wenxuan -- Ma, Jian -- Kemper, Byron -- Kemper, Jongsook Kim -- DK62777/DK/NIDDK NIH HHS/ -- DK95842/DK/NIDDK NIH HHS/ -- R01 DK062777/DK/NIDDK NIH HHS/ -- R01 DK095842/DK/NIDDK NIH HHS/ -- England -- Nature. 2014 Dec 4;516(7529):108-11. doi: 10.1038/nature13949. Epub 2014 Nov 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; 1] Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA [2] Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea. ; Department of Bioengineering and the Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA. ; Department of Statistics, University of Georgia, Athens, Gerogia 30602, USA. ; Institute for Medical Science, Ajou University School of Medicine, Suwon 442-749, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25383523" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/*genetics ; Cyclic AMP Response Element-Binding Protein/*metabolism ; Fasting/physiology ; *Gene Expression Regulation/drug effects ; Isoxazoles/pharmacology ; Liver/cytology/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Protein Binding ; Receptors, Cytoplasmic and Nuclear/agonists/*metabolism
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  • 88
    Publication Date: 2014-03-22
    Description: Plasma membrane pannexin 1 channels (PANX1) release nucleotide find-me signals from apoptotic cells to attract phagocytes. Here we show that the quinolone antibiotic trovafloxacin is a novel PANX1 inhibitor, by using a small-molecule screen. Although quinolones are widely used to treat bacterial infections, some quinolones have unexplained side effects, including deaths among children. PANX1 is a direct target of trovafloxacin at drug concentrations seen in human plasma, and its inhibition led to dysregulated fragmentation of apoptotic cells. Genetic loss of PANX1 phenocopied trovafloxacin effects, revealing a non-redundant role for pannexin channels in regulating cellular disassembly during apoptosis. Increase in drug-resistant bacteria worldwide and the dearth of new antibiotics is a major human health challenge. Comparing different quinolone antibiotics suggests that certain structural features may contribute to PANX1 blockade. These data identify a novel linkage between an antibiotic, pannexin channels and cellular integrity, and suggest that re-engineering certain quinolones might help develop newer antibacterials.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4078991/" 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/PMC4078991/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Poon, Ivan K H -- Chiu, Yu-Hsin -- Armstrong, Allison J -- Kinchen, Jason M -- Juncadella, Ignacio J -- Bayliss, Douglas A -- Ravichandran, Kodi S -- 107848/PHS HHS/ -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 GM107848/GM/NIGMS NIH HHS/ -- T32 AI007496/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Mar 20;507(7492):329-34. doi: 10.1038/nature13147. Epub 2014 Mar 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA [3] Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA [4] La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia. ; Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA. ; 1] The Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA [2] Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA [3] Beirne B. Carter Center for Immunology Research, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24646995" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/*adverse effects/blood/*pharmacology ; Apoptosis/*drug effects ; Connexins/*antagonists & inhibitors/deficiency/genetics/metabolism ; Drug Discovery/methods ; Female ; Fluoroquinolones/*adverse effects/blood/*pharmacology ; Humans ; Jurkat Cells ; Male ; Mice ; Mice, Inbred C57BL ; Naphthyridines/*adverse effects/blood/*pharmacology ; Nerve Tissue Proteins/*antagonists & inhibitors/deficiency/genetics/metabolism ; Thymocytes/cytology/drug effects/metabolism
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  • 89
    Publication Date: 2014-04-25
    Description: The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and interleukin (IL)-17-producing gammadelta T (gammadeltaT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal gammadeltaT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4127885/" 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/PMC4127885/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Riol-Blanco, Lorena -- Ordovas-Montanes, Jose -- Perro, Mario -- Naval, Elena -- Thiriot, Aude -- Alvarez, David -- Paust, Silke -- Wood, John N -- von Andrian, Ulrich H -- 101054/Wellcome Trust/United Kingdom -- 5F31AR063546-02/AR/NIAMS NIH HHS/ -- AI069259/AI/NIAID NIH HHS/ -- AI078897/AI/NIAID NIH HHS/ -- AI095261/AI/NIAID NIH HHS/ -- AI111595/AI/NIAID NIH HHS/ -- F31 AR063546/AR/NIAMS NIH HHS/ -- G0901905/Medical Research Council/United Kingdom -- P01 AI078897/AI/NIAID NIH HHS/ -- P01 AI112521/AI/NIAID NIH HHS/ -- R01 AI069259/AI/NIAID NIH HHS/ -- R01 AI111595/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jun 5;510(7503):157-61. doi: 10.1038/nature13199. Epub 2014 Apr 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2]. ; Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA. ; Institute for Biomedical Research, University College London, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24759321" target="_blank"〉PubMed〈/a〉
    Keywords: Aminoquinolines ; Animals ; Disease Models, Animal ; Female ; Inflammation/chemically induced/immunology/pathology ; Interleukin-17/biosynthesis/immunology ; Interleukin-23/biosynthesis/*immunology ; Interleukins/biosynthesis/immunology ; Langerhans Cells/immunology/metabolism ; Lymph Nodes/immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; NAV1.8 Voltage-Gated Sodium Channel/metabolism ; Nociceptors/drug effects/*metabolism ; Psoriasis/chemically induced/*immunology/*pathology ; Sensory Receptor Cells/drug effects/*metabolism ; Skin/cytology/immunology/*innervation/*pathology ; T-Lymphocytes/immunology/metabolism ; TRPV Cation Channels/metabolism
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  • 90
    Publication Date: 2014-08-01
    Description: Haematopoiesis is a developmental cascade that generates all blood cell lineages in health and disease. This process relies on quiescent haematopoietic stem cells capable of differentiating, self renewing and expanding upon physiological demand. However, the mechanisms that regulate haematopoietic stem cell homeostasis and function remain largely unknown. Here we show that the neurotrophic factor receptor RET (rearranged during transfection) drives haematopoietic stem cell survival, expansion and function. We find that haematopoietic stem cells express RET and that its neurotrophic factor partners are produced in the haematopoietic stem cell environment. Ablation of Ret leads to impaired survival and reduced numbers of haematopoietic stem cells with normal differentiation potential, but loss of cell-autonomous stress response and reconstitution potential. Strikingly, RET signals provide haematopoietic stem cells with critical Bcl2 and Bcl2l1 surviving cues, downstream of p38 mitogen-activated protein (MAP) kinase and cyclic-AMP-response element binding protein (CREB) activation. Accordingly, enforced expression of RET downstream targets, Bcl2 or Bcl2l1, is sufficient to restore the activity of Ret null progenitors in vivo. Activation of RET results in improved haematopoietic stem cell survival, expansion and in vivo transplantation efficiency. Remarkably, human cord-blood progenitor expansion and transplantation is also improved by neurotrophic factors, opening the way for exploration of RET agonists in human haematopoietic stem cell transplantation. Our work shows that neurotrophic factors are novel components of the haematopoietic stem cell microenvironment, revealing that haematopoietic stem cells and neurons are regulated by similar signals.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fonseca-Pereira, Diogo -- Arroz-Madeira, Silvia -- Rodrigues-Campos, Mariana -- Barbosa, Ines A M -- Domingues, Rita G -- Bento, Teresa -- Almeida, Afonso R M -- Ribeiro, Helder -- Potocnik, Alexandre J -- Enomoto, Hideki -- Veiga-Fernandes, Henrique -- England -- Nature. 2014 Oct 2;514(7520):98-101. doi: 10.1038/nature13498. Epub 2014 Jul 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Avenida Professor Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal [2]. ; Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Avenida Professor Egas Moniz, Edificio Egas Moniz, 1649-028 Lisboa, Portugal. ; 1] Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK [2] Institute of Immunology and Infection Research, University of Edinburgh, West Mains Road, Edinburgh EH9 3JT, UK. ; 1] Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan [2] Graduate School of Medicine, Kobe University7-5-1 Kusunoki-cho, Chuo-ku, Kobe City, Hyogo 650-0017, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25079320" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Survival ; Cyclic AMP Response Element-Binding Protein/metabolism ; Enzyme Activation ; Female ; Hematopoiesis ; Hematopoietic Stem Cell Transplantation ; Hematopoietic Stem Cells/*cytology/*metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Growth Factors/*metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Proto-Oncogene Proteins c-ret/deficiency/genetics/*metabolism ; Signal Transduction ; Stem Cell Niche ; bcl-X Protein/metabolism ; p38 Mitogen-Activated Protein Kinases/metabolism
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  • 91
    Publication Date: 2014-02-18
    Description: In cancer patients, visual identification of sentinel lymph nodes (LNs) is achieved by the injection of dyes that bind avidly to endogenous albumin, targeting these compounds to LNs, where they are efficiently filtered by resident phagocytes. Here we translate this 'albumin hitchhiking' approach to molecular vaccines, through the synthesis of amphiphiles (amph-vaccines) comprising an antigen or adjuvant cargo linked to a lipophilic albumin-binding tail by a solubility-promoting polar polymer chain. Administration of structurally optimized CpG-DNA/peptide amph-vaccines in mice resulted in marked increases in LN accumulation and decreased systemic dissemination relative to their parent compounds, leading to 30-fold increases in T-cell priming and enhanced anti-tumour efficacy while greatly reducing systemic toxicity. Amph-vaccines provide a simple, broadly applicable strategy to simultaneously increase the potency and safety of subunit vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069155/" 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/PMC4069155/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Liu, Haipeng -- Moynihan, Kelly D -- Zheng, Yiran -- Szeto, Gregory L -- Li, Adrienne V -- Huang, Bonnie -- Van Egeren, Debra S -- Park, Clara -- Irvine, Darrell J -- AI091693/AI/NIAID NIH HHS/ -- AI095109/AI/NIAID NIH HHS/ -- AI104715/AI/NIAID NIH HHS/ -- F32 CA180586/CA/NCI NIH HHS/ -- P01 AI104715/AI/NIAID NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R01 AI095109/AI/NIAID NIH HHS/ -- U19 AI091693/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Mar 27;507(7493):519-22. doi: 10.1038/nature12978. Epub 2014 Feb 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA. ; 1] Department of Materials Science and Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [3] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [4] Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard, Cambridge, Massachusetts 02139, USA [5] Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24531764" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; CpG Islands/genetics/immunology ; Female ; Lymph Nodes/*immunology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/immunology ; Vaccines, Subunit/genetics/*immunology ; Vaccines, Synthetic/genetics/*immunology
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  • 92
    Publication Date: 2014-03-05
    Description: Characterization of how the microenvironment, or niche, regulates stem cell activity is central to understanding stem cell biology and to developing strategies for the therapeutic manipulation of stem cells. Low oxygen tension (hypoxia) is commonly thought to be a shared niche characteristic in maintaining quiescence in multiple stem cell types. However, support for the existence of a hypoxic niche has largely come from indirect evidence such as proteomic analysis, expression of hypoxia inducible factor-1alpha (Hif-1alpha) and related genes, and staining with surrogate hypoxic markers (for example, pimonidazole). Here we perform direct in vivo measurements of local oxygen tension (pO2) in the bone marrow of live mice. Using two-photon phosphorescence lifetime microscopy, we determined the absolute pO2 of the bone marrow to be quite low (〈32 mm Hg) despite very high vascular density. We further uncovered heterogeneities in local pO2, with the lowest pO2 ( approximately 9.9 mm Hg, or 1.3%) found in deeper peri-sinusoidal regions. The endosteal region, by contrast, is less hypoxic as it is perfused with small arteries that are often positive for the marker nestin. These pO2 values change markedly after radiation and chemotherapy, pointing to the role of stress in altering the stem cell metabolic microenvironment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984353/" 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/PMC3984353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Spencer, Joel A -- Ferraro, Francesca -- Roussakis, Emmanuel -- Klein, Alyssa -- Wu, Juwell -- Runnels, Judith M -- Zaher, Walid -- Mortensen, Luke J -- Alt, Clemens -- Turcotte, Raphael -- Yusuf, Rushdia -- Cote, Daniel -- Vinogradov, Sergei A -- Scadden, David T -- Lin, Charles P -- EB017274/EB/NIBIB NIH HHS/ -- HL096372/HL/NHLBI NIH HHS/ -- HL097748/HL/NHLBI NIH HHS/ -- HL097794/HL/NHLBI NIH HHS/ -- R01 EB014703/EB/NIBIB NIH HHS/ -- R01 EB017274/EB/NIBIB NIH HHS/ -- R01 HL097748/HL/NHLBI NIH HHS/ -- R01 HL097794/HL/NHLBI NIH HHS/ -- R03 HL096372/HL/NHLBI NIH HHS/ -- U01 HL100402/HL/NHLBI NIH HHS/ -- England -- Nature. 2014 Apr 10;508(7495):269-73. doi: 10.1038/nature13034. Epub 2014 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Department of Biomedical Engineering, Tufts University, Medford, Massachusetts 02155, USA. ; 1] Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA [3] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA. ; 1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ; 1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Stem Cell Unit, Department of Anatomy, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia. ; 1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Department of Biomedical Engineering, Boston University, Boston, Massachusetts 02215, USA. ; Departement de Physique, Genie Physique et Optique and Centre de Recherche de l'Institut Universitaire en Sante Mentale de Quebec, Universite Laval, Quebec City, Quebec G1J 2G3, Canada. ; Department of Biochemistry and Biophysics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA. ; 1] Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24590072" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoxia/diagnosis/metabolism ; Arteries/metabolism ; Bone Marrow/blood supply/drug effects/*metabolism/radiation effects ; Busulfan/pharmacology ; Cell Hypoxia ; Hematopoietic Stem Cells/cytology/metabolism ; Luminescent Measurements ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy ; Nestin/metabolism ; Oxygen/*analysis/metabolism ; Photons ; Stem Cell Niche/drug effects/radiation effects
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  • 93
    Publication Date: 2014-11-28
    Description: Human tumours typically harbour a remarkable number of somatic mutations. If presented on major histocompatibility complex class I molecules (MHCI), peptides containing these mutations could potentially be immunogenic as they should be recognized as 'non-self' neo-antigens by the adaptive immune system. Recent work has confirmed that mutant peptides can serve as T-cell epitopes. However, few mutant epitopes have been described because their discovery required the laborious screening of patient tumour-infiltrating lymphocytes for their ability to recognize antigen libraries constructed following tumour exome sequencing. We sought to simplify the discovery of immunogenic mutant peptides by characterizing their general properties. We developed an approach that combines whole-exome and transcriptome sequencing analysis with mass spectrometry to identify neo-epitopes in two widely used murine tumour models. Of the 〉1,300 amino acid changes identified, approximately 13% were predicted to bind MHCI, a small fraction of which were confirmed by mass spectrometry. The peptides were then structurally modelled bound to MHCI. Mutations that were solvent-exposed and therefore accessible to T-cell antigen receptors were predicted to be immunogenic. Vaccination of mice confirmed the approach, with each predicted immunogenic peptide yielding therapeutically active T-cell responses. The predictions also enabled the generation of peptide-MHCI dextramers that could be used to monitor the kinetics and distribution of the anti-tumour T-cell response before and after vaccination. These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yadav, Mahesh -- Jhunjhunwala, Suchit -- Phung, Qui T -- Lupardus, Patrick -- Tanguay, Joshua -- Bumbaca, Stephanie -- Franci, Christian -- Cheung, Tommy K -- Fritsche, Jens -- Weinschenk, Toni -- Modrusan, Zora -- Mellman, Ira -- Lill, Jennie R -- Delamarre, Lelia -- England -- Nature. 2014 Nov 27;515(7528):572-6. doi: 10.1038/nature14001.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genentech, South San Francisco, California 94080, USA. ; Immatics Biotechnologies GmbH, 72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25428506" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD8-Positive T-Lymphocytes/immunology ; Cancer Vaccines/immunology ; Cell Line, Tumor ; Exome/*genetics ; Female ; Gene Expression Profiling ; Immunity, Cellular/immunology ; Immunogenetic Phenomena/*genetics ; Immunoprecipitation ; *Mass Spectrometry ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; *Mutation ; Neoplasms/*genetics/immunology ; Peptides/genetics ; Protein Structure, Tertiary
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  • 94
    Publication Date: 2014-05-30
    Description: A unique property of many adult stem cells is their ability to exist in a non-cycling, quiescent state. Although quiescence serves an essential role in preserving stem cell function until the stem cell is needed in tissue homeostasis or repair, defects in quiescence can lead to an impairment in tissue function. The extent to which stem cells can regulate quiescence is unknown. Here we show that the stem cell quiescent state is composed of two distinct functional phases, G0 and an 'alert' phase we term G(Alert). Stem cells actively and reversibly transition between these phases in response to injury-induced systemic signals. Using genetic mouse models specific to muscle stem cells (or satellite cells), we show that mTORC1 activity is necessary and sufficient for the transition of satellite cells from G0 into G(Alert) and that signalling through the HGF receptor cMet is also necessary. We also identify G0-to-G(Alert) transitions in several populations of quiescent stem cells. Quiescent stem cells that transition into G(Alert) possess enhanced tissue regenerative function. We propose that the transition of quiescent stem cells into G(Alert) functions as an 'alerting' mechanism, an adaptive response that positions stem cells to respond rapidly under conditions of injury and stress, priming them for cell cycle entry.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065227/" 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/PMC4065227/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rodgers, Joseph T -- King, Katherine Y -- Brett, Jamie O -- Cromie, Melinda J -- Charville, Gregory W -- Maguire, Katie K -- Brunson, Christopher -- Mastey, Namrata -- Liu, Ling -- Tsai, Chang-Ru -- Goodell, Margaret A -- Rando, Thomas A -- F30 AG035521/AG/NIA NIH HHS/ -- I01 BX002324/BX/BLRD VA/ -- K08 HL098898/HL/NHLBI NIH HHS/ -- P01 AG036695/AG/NIA NIH HHS/ -- R01 AG023806/AG/NIA NIH HHS/ -- R01 AG047820/AG/NIA NIH HHS/ -- R01 AG23806/AG/NIA NIH HHS/ -- R01 AR062185/AR/NIAMS NIH HHS/ -- R01 DK092883/DK/NIDDK NIH HHS/ -- R37 AG023806/AG/NIA NIH HHS/ -- England -- Nature. 2014 Jun 19;510(7505):393-6. doi: 10.1038/nature13255. Epub 2014 May 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA. ; Department of Pediatrics and Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA. ; 1] Paul F. Glenn Laboratories for the Biology of Aging, Stanford University School of Medicine, Stanford, California 94305, USA [2] Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA [3] Neurology Service and Rehabilitation Research and Development Center of Excellence, Veterans Affairs Palo Alto Health Care System, Palo Alto, California 94304, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24870234" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle/genetics/*physiology ; Cells, Cultured ; G0 Phase/genetics/*physiology ; Gene Expression Profiling ; Gene Expression Regulation ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/genetics/*metabolism ; Muscle, Skeletal/*cytology/injuries/metabolism ; Regeneration/physiology ; Satellite Cells, Skeletal Muscle/*cytology/metabolism ; TOR Serine-Threonine Kinases/genetics/*metabolism
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  • 95
    Publication Date: 2014-04-04
    Description: Comprehensive knowledge of the brain's wiring diagram is fundamental for understanding how the nervous system processes information at both local and global scales. However, with the singular exception of the C. elegans microscale connectome, there are no complete connectivity data sets in other species. Here we report a brain-wide, cellular-level, mesoscale connectome for the mouse. The Allen Mouse Brain Connectivity Atlas uses enhanced green fluorescent protein (EGFP)-expressing adeno-associated viral vectors to trace axonal projections from defined regions and cell types, and high-throughput serial two-photon tomography to image the EGFP-labelled axons throughout the brain. This systematic and standardized approach allows spatial registration of individual experiments into a common three dimensional (3D) reference space, resulting in a whole-brain connectivity matrix. A computational model yields insights into connectional strength distribution, symmetry and other network properties. Virtual tractography illustrates 3D topography among interconnected regions. Cortico-thalamic pathway analysis demonstrates segregation and integration of parallel pathways. The Allen Mouse Brain Connectivity Atlas is a freely available, foundational resource for structural and functional investigations into the neural circuits that support behavioural and cognitive processes in health and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Oh, Seung Wook -- Harris, Julie A -- Ng, Lydia -- Winslow, Brent -- Cain, Nicholas -- Mihalas, Stefan -- Wang, Quanxin -- Lau, Chris -- Kuan, Leonard -- Henry, Alex M -- Mortrud, Marty T -- Ouellette, Benjamin -- Nguyen, Thuc Nghi -- Sorensen, Staci A -- Slaughterbeck, Clifford R -- Wakeman, Wayne -- Li, Yang -- Feng, David -- Ho, Anh -- Nicholas, Eric -- Hirokawa, Karla E -- Bohn, Phillip -- Joines, Kevin M -- Peng, Hanchuan -- Hawrylycz, Michael J -- Phillips, John W -- Hohmann, John G -- Wohnoutka, Paul -- Gerfen, Charles R -- Koch, Christof -- Bernard, Amy -- Dang, Chinh -- Jones, Allan R -- Zeng, Hongkui -- England -- Nature. 2014 Apr 10;508(7495):207-14. doi: 10.1038/nature13186. Epub 2014 Apr 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Allen Institute for Brain Science, Seattle, Washington 98103, USA [2]. ; Allen Institute for Brain Science, Seattle, Washington 98103, USA. ; Laboratory of Systems Neuroscience, National Institute of Mental Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24695228" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Atlases as Topic ; Axons/physiology ; Brain/*anatomy & histology/*cytology ; Cerebral Cortex/cytology ; *Connectome ; Corpus Striatum/cytology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neuroanatomical Tract-Tracing Techniques ; Thalamus/cytology
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  • 96
    Publication Date: 2014-07-22
    Description: FOXP3(+) regulatory T cells (Treg cells) are abundant in the intestine, where they prevent dysregulated inflammatory responses to self and environmental stimuli. It is now appreciated that Treg cells acquire tissue-specific adaptations that facilitate their survival and function; however, key host factors controlling the Treg response in the intestine are poorly understood. The interleukin (IL)-1 family member IL-33 is constitutively expressed in epithelial cells at barrier sites, where it functions as an endogenous danger signal, or alarmin, in response to tissue damage. Recent studies in humans have described high levels of IL-33 in inflamed lesions of inflammatory bowel disease patients, suggesting a role for this cytokine in disease pathogenesis. In the intestine, both protective and pathological roles for IL-33 have been described in murine models of acute colitis, but its contribution to chronic inflammation remains ill defined. Here we show in mice that the IL-33 receptor ST2 is preferentially expressed on colonic Treg cells, where it promotes Treg function and adaptation to the inflammatory environment. IL-33 signalling in T cells stimulates Treg responses in several ways. First, it enhances transforming growth factor (TGF)-beta1-mediated differentiation of Treg cells and, second, it provides a necessary signal for Treg-cell accumulation and maintenance in inflamed tissues. Strikingly, IL-23, a key pro-inflammatory cytokine in the pathogenesis of inflammatory bowel disease, restrained Treg responses through inhibition of IL-33 responsiveness. These results demonstrate a hitherto unrecognized link between an endogenous mediator of tissue damage and a major anti-inflammatory pathway, and suggest that the balance between IL-33 and IL-23 may be a key controller of intestinal immune responses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4339042/" 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/PMC4339042/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schiering, Chris -- Krausgruber, Thomas -- Chomka, Agnieszka -- Frohlich, Anja -- Adelmann, Krista -- Wohlfert, Elizabeth A -- Pott, Johanna -- Griseri, Thibault -- Bollrath, Julia -- Hegazy, Ahmed N -- Harrison, Oliver J -- Owens, Benjamin M J -- Lohning, Max -- Belkaid, Yasmine -- Fallon, Padraic G -- Powrie, Fiona -- 086335/Wellcome Trust/United Kingdom -- 095688/Wellcome Trust/United Kingdom -- 097109/Wellcome Trust/United Kingdom -- 099814/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2014 Sep 25;513(7519):564-8. doi: 10.1038/nature13577. Epub 2014 Jul 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK [2] Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK (C.S.); Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York 14214-3000, USA (E.A.W.). [3]. ; 1] Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK [2]. ; Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, Experimental Medicine Division, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK. ; Experimental Immunology, Department of Rheumatology and Clinical Immunology, Charite - University Medicine Berlin, and German Rheumatism Research Center (DRFZ), D-10117 Berlin, Germany. ; 1] Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA [2] Division of Molecular Immunology, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK (C.S.); Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo (SUNY), Buffalo, New York 14214-3000, USA (E.A.W.). ; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK. ; Program in Barrier Immunity and Repair, Mucosal Immunology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland 20892, USA. ; Trinity Biomedical Sciences Institute, Trinity College Dublin, Pearse Street, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043027" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Colitis/immunology/pathology ; Colon/cytology/immunology/pathology ; Disease Models, Animal ; Female ; Immunity, Mucosal ; Inflammation/immunology/metabolism/pathology ; Interleukin-23/immunology ; Interleukin-33 ; Interleukins/antagonists & inhibitors/*immunology/metabolism ; Intestines/*cytology/*immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Interleukin/metabolism ; Signal Transduction/immunology ; T-Lymphocytes, Regulatory/cytology/*immunology ; Thymus Gland/cytology ; Transforming Growth Factor beta/metabolism
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  • 97
    Publication Date: 2014-11-20
    Description: Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARgamma (peroxisome proliferator-activated receptor gamma) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARgamma, such as the thiazolidinediones and PPARgamma partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARgamma phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARgamma phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARgamma in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARgamma function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297557/" 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/PMC4297557/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Banks, Alexander S -- McAllister, Fiona E -- Camporez, Joao Paulo G -- Zushin, Peter-James H -- Jurczak, Michael J -- Laznik-Bogoslavski, Dina -- Shulman, Gerald I -- Gygi, Steven P -- Spiegelman, Bruce M -- DK31405/DK/NIDDK NIH HHS/ -- DK93638/DK/NIDDK NIH HHS/ -- K01 DK093638/DK/NIDDK NIH HHS/ -- R01 DK031405/DK/NIDDK NIH HHS/ -- England -- Nature. 2015 Jan 15;517(7534):391-5. doi: 10.1038/nature13887. Epub 2014 Nov 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA. ; Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA. ; Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA. ; 1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25409143" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/enzymology/metabolism ; Adipose Tissue/cytology/enzymology/metabolism ; Animals ; Cell Proliferation ; Cells, Cultured ; Cyclin-Dependent Kinase 5/deficiency/*metabolism ; Diabetes Mellitus/*metabolism ; Diet, High-Fat ; Extracellular Signal-Regulated MAP Kinases/*metabolism ; Humans ; Insulin Resistance ; MAP Kinase Kinase 2/antagonists & inhibitors/metabolism ; MAP Kinase Signaling System ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; PPAR gamma/chemistry/*metabolism ; Phosphorylation
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  • 98
    Publication Date: 2014-12-18
    Description: More than twenty types of retinal ganglion cells conduct visual information from the eye to the rest of the brain. Each retinal ganglion cell type tessellates the retina in a regular mosaic, so that every point in visual space is processed for visual primitives such as contrast and motion. This information flows to two principal brain centres: the visual cortex and the superior colliculus. The superior colliculus plays an evolutionarily conserved role in visual behaviours, but its functional architecture is poorly understood. Here we report on population recordings of visual responses from neurons in the mouse superior colliculus. Many neurons respond preferentially to lines of a certain orientation or movement axis. We show that cells with similar orientation preferences form large patches that span the vertical thickness of the retinorecipient layers. This organization is strikingly different from the randomly interspersed orientation preferences in the mouse's visual cortex; instead, it resembles the orientation columns observed in the visual cortices of large mammals. Notably, adjacent superior colliculus orientation columns have only limited receptive field overlap. This is in contrast to the organization of visual cortex, where each point in the visual field activates neurons with all preferred orientations. Instead, the superior colliculus favours specific contour orientations within approximately 30 degrees regions of the visual field, a finding with implications for behavioural responses mediated by this brain centre.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Feinberg, Evan H -- Meister, Markus -- T32 NS007484/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2015 Mar 12;519(7542):229-32. doi: 10.1038/nature14103. Epub 2014 Dec 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA. ; 1] Center for Brain Science, Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA [2] 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/25517100" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain Mapping ; Calcium/analysis/metabolism ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Motion ; Neurons/physiology ; Orientation/*physiology ; Photic Stimulation ; Superior Colliculi/anatomy & histology/*cytology/*physiology ; Visual Cortex/anatomy & histology/cytology/physiology ; Visual Fields/physiology ; Wakefulness
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  • 99
    Publication Date: 2014-09-16
    Description: Memory formation is a multi-stage process that initially requires cellular consolidation in the hippocampus, after which memories are downloaded to the cortex for maintenance, in a process termed systems consolidation. Epigenetic mechanisms regulate both types of consolidation, but histone variant exchange, in which canonical histones are replaced with their variant counterparts, is an entire branch of epigenetics that has received limited attention in the brain and has never, to our knowledge, been studied in relation to cognitive function. Here we show that histone H2A.Z, a variant of histone H2A, is actively exchanged in response to fear conditioning in the hippocampus and the cortex, where it mediates gene expression and restrains the formation of recent and remote memory. Our data provide evidence for H2A.Z involvement in cognitive function and specifically implicate H2A.Z as a negative regulator of hippocampal consolidation and systems consolidation, probably through downstream effects on gene expression. Moreover, alterations in H2A.Z binding at later stages of systems consolidation suggest that this histone has the capacity to mediate stable molecular modifications required for memory retention. Overall, our data introduce histone variant exchange as a novel mechanism contributing to the molecular basis of cognitive function and implicate H2A.Z as a potential therapeutic target for memory disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768489/" 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/PMC4768489/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zovkic, Iva B -- Paulukaitis, Brynna S -- Day, Jeremy J -- Etikala, Deepa M -- Sweatt, J David -- MH091122/MH/NIMH NIH HHS/ -- MH57014/MH/NIMH NIH HHS/ -- R01 MH057014/MH/NIMH NIH HHS/ -- England -- Nature. 2014 Nov 27;515(7528):582-6. doi: 10.1038/nature13707. Epub 2014 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology and Evelyn F. McKnight Brain Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25219850" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cognition/physiology ; Conditioning (Psychology)/physiology ; *Epigenesis, Genetic ; Fear/physiology ; Gene Expression Regulation ; Gene Knockdown Techniques ; Hippocampus/physiology ; Histones/*genetics/*metabolism ; Male ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Protein Binding
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 100
    Publication Date: 2014-07-22
    Description: The somatic mutations present in the genome of a cell accumulate over the lifetime of a multicellular organism. These mutations can provide insights into the developmental lineage tree, the number of divisions that each cell has undergone and the mutational processes that have been operative. Here we describe whole genomes of clonal lines derived from multiple tissues of healthy mice. Using somatic base substitutions, we reconstructed the early cell divisions of each animal, demonstrating the contributions of embryonic cells to adult tissues. Differences were observed between tissues in the numbers and types of mutations accumulated by each cell, which likely reflect differences in the number of cell divisions they have undergone and varying contributions of different mutational processes. If somatic mutation rates are similar to those in mice, the results indicate that precise insights into development and mutagenesis of normal human cells will be possible.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4227286/" 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/PMC4227286/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Behjati, Sam -- Huch, Meritxell -- van Boxtel, Ruben -- Karthaus, Wouter -- Wedge, David C -- Tamuri, Asif U -- Martincorena, Inigo -- Petljak, Mia -- Alexandrov, Ludmil B -- Gundem, Gunes -- Tarpey, Patrick S -- Roerink, Sophie -- Blokker, Joyce -- Maddison, Mark -- Mudie, Laura -- Robinson, Ben -- Nik-Zainal, Serena -- Campbell, Peter -- Goldman, Nick -- van de Wetering, Marc -- Cuppen, Edwin -- Clevers, Hans -- Stratton, Michael R -- 077012/Z/05/Z/Wellcome Trust/United Kingdom -- 088340/Wellcome Trust/United Kingdom -- 092096/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 104151/Wellcome Trust/United Kingdom -- WT100183MA/Wellcome Trust/United Kingdom -- England -- Nature. 2014 Sep 18;513(7518):422-5. doi: 10.1038/nature13448. Epub 2014 Jun 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] Department of Paediatrics, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK. ; 1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands [2] [3] Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK. ; 1] Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands [2]. ; Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. ; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. ; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences, CancerGenomiCs.nl &University Medical Center Utrecht, 3584 CT, Utrecht, The Netherlands. ; 1] Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK [2] East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043003" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Clocks/genetics ; Cell Division ; Cell Lineage/*genetics ; Cells, Cultured ; Clone Cells/*cytology/*metabolism ; Embryo, Mammalian/cytology ; Genome/*genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mutagenesis/*genetics ; Mutation/*genetics ; Mutation Rate ; Organoids/cytology/metabolism ; Phylogeny ; Sequence Analysis, DNA ; Tail/cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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