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  • Articles  (129)
  • Mice, Inbred C57BL  (129)
  • Nature Publishing Group (NPG)  (129)
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  • 2010-2014  (129)
  • 1985-1989
  • 1955-1959
  • 1935-1939
  • 2012  (73)
  • 2010  (56)
  • 1956
  • 1937
  • Chemistry and Pharmacology  (129)
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  • Articles  (129)
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  • 2010-2014  (129)
  • 1985-1989
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  • 1935-1939
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  • 1
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    Myocardial infarction accelerates atherosclerosis (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-06
    Description: During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401326/" 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/PMC3401326/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dutta, Partha -- Courties, Gabriel -- Wei, Ying -- Leuschner, Florian -- Gorbatov, Rostic -- Robbins, Clinton S -- Iwamoto, Yoshiko -- Thompson, Brian -- Carlson, Alicia L -- Heidt, Timo -- Majmudar, Maulik D -- Lasitschka, Felix -- Etzrodt, Martin -- Waterman, Peter -- Waring, Michael T -- Chicoine, Adam T -- van der Laan, Anja M -- Niessen, Hans W M -- Piek, Jan J -- Rubin, Barry B -- Butany, Jagdish -- Stone, James R -- Katus, Hugo A -- Murphy, Sabina A -- Morrow, David A -- Sabatine, Marc S -- Vinegoni, Claudio -- Moskowitz, Michael A -- Pittet, Mikael J -- Libby, Peter -- Lin, Charles P -- Swirski, Filip K -- Weissleder, Ralph -- Nahrendorf, Matthias -- P50-CA086355/CA/NCI NIH HHS/ -- R01 AI084880/AI/NIAID NIH HHS/ -- R01 EB006432/EB/NIBIB NIH HHS/ -- R01 HL095612/HL/NHLBI NIH HHS/ -- R01 HL095629/HL/NHLBI NIH HHS/ -- R01 HL096576/HL/NHLBI NIH HHS/ -- R01-EB006432/EB/NIBIB NIH HHS/ -- R01-HL095629/HL/NHLBI NIH HHS/ -- R01-HL096576/HL/NHLBI NIH HHS/ -- T32 CA079443/CA/NCI NIH HHS/ -- T32-CA79443/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 19;487(7407):325-9. doi: 10.1038/nature11260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apolipoproteins E/genetics ; Atherosclerosis/*etiology/*pathology ; Hematopoietic Stem Cells/cytology ; Inflammation/complications ; Mice ; Mice, Inbred C57BL ; Monocytes/cytology ; Myocardial Infarction/*complications/*pathology ; Spleen/cytology ; Stem Cells/cytology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
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    IFITM3 restricts the morbidity and mortality associated with influenza (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-27
    Description: The 2009 H1N1 influenza pandemic showed the speed with which a novel respiratory virus can spread and the ability of a generally mild infection to induce severe morbidity and mortality in a subset of the population. Recent in vitro studies show that the interferon-inducible transmembrane (IFITM) protein family members potently restrict the replication of multiple pathogenic viruses. Both the magnitude and breadth of the IFITM proteins' in vitro effects suggest that they are critical for intrinsic resistance to such viruses, including influenza viruses. Using a knockout mouse model, we now test this hypothesis directly and find that IFITM3 is essential for defending the host against influenza A virus in vivo. Mice lacking Ifitm3 display fulminant viral pneumonia when challenged with a normally low-pathogenicity influenza virus, mirroring the destruction inflicted by the highly pathogenic 1918 'Spanish' influenza. Similar increased viral replication is seen in vitro, with protection rescued by the re-introduction of Ifitm3. To test the role of IFITM3 in human influenza virus infection, we assessed the IFITM3 alleles of individuals hospitalized with seasonal or pandemic influenza H1N1/09 viruses. We find that a statistically significant number of hospitalized subjects show enrichment for a minor IFITM3 allele (SNP rs12252-C) that alters a splice acceptor site, and functional assays show the minor CC genotype IFITM3 has reduced influenza virus restriction in vitro. Together these data reveal that the action of a single intrinsic immune effector, IFITM3, profoundly alters the course of influenza virus infection in mouse and humans.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648786/" 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/PMC3648786/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Everitt, Aaron R -- Clare, Simon -- Pertel, Thomas -- John, Sinu P -- Wash, Rachael S -- Smith, Sarah E -- Chin, Christopher R -- Feeley, Eric M -- Sims, Jennifer S -- Adams, David J -- Wise, Helen M -- Kane, Leanne -- Goulding, David -- Digard, Paul -- Anttila, Verneri -- Baillie, J Kenneth -- Walsh, Tim S -- Hume, David A -- Palotie, Aarno -- Xue, Yali -- Colonna, Vincenza -- Tyler-Smith, Chris -- Dunning, Jake -- Gordon, Stephen B -- GenISIS Investigators -- MOSAIC Investigators -- Smyth, Rosalind L -- Openshaw, Peter J -- Dougan, Gordon -- Brass, Abraham L -- Kellam, Paul -- 090382/Wellcome Trust/United Kingdom -- 090382/Z/09/Z/Wellcome Trust/United Kingdom -- 090385/Z/09/Z/Wellcome Trust/United Kingdom -- 098051/Wellcome Trust/United Kingdom -- 13031/Cancer Research UK/United Kingdom -- DHCS/04/G121/68/Department of Health/United Kingdom -- G0600371/Medical Research Council/United Kingdom -- G0600511/Medical Research Council/United Kingdom -- G0800767/Medical Research Council/United Kingdom -- G0800777/Medical Research Council/United Kingdom -- G0802752/Medical Research Council/United Kingdom -- G0901697/Medical Research Council/United Kingdom -- G1000758/Medical Research Council/United Kingdom -- MC_G1001212/Medical Research Council/United Kingdom -- MC_U122785833/Medical Research Council/United Kingdom -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI091786/AI/NIAID NIH HHS/ -- R01AI091786/AI/NIAID NIH HHS/ -- Chief Scientist Office/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2012 Mar 25;484(7395):519-23. doi: 10.1038/nature10921.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22446628" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Amino Acid Sequence ; Animals ; Cytokines/immunology ; England/epidemiology ; Gene Deletion ; Humans ; Influenza A Virus, H1N1 Subtype/classification/growth & development/pathogenicity ; Influenza A Virus, H3N2 Subtype/classification/growth & development/pathogenicity ; Influenza A virus/classification/growth & development/*pathogenicity ; Influenza B virus/classification/growth & development/pathogenicity ; Influenza, Human/complications/epidemiology/mortality/virology ; Leukocytes/immunology ; Lung/pathology/virology ; Membrane Proteins/chemistry/deficiency/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Orthomyxoviridae Infections/complications/*mortality/pathology ; Pneumonia, Viral/etiology/pathology/prevention & control ; Polymorphism, Single Nucleotide/genetics ; RNA-Binding Proteins/chemistry/genetics/*metabolism ; Scotland/epidemiology ; Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Sustained translational repression by eIF2alpha-P mediates prion neurodegeneration (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-05-25
    Description: The mechanisms leading to neuronal death in neurodegenerative disease are poorly understood. Many of these disorders, including Alzheimer's, Parkinson's and prion diseases, are associated with the accumulation of misfolded disease-specific proteins. The unfolded protein response is a protective cellular mechanism triggered by rising levels of misfolded proteins. One arm of this pathway results in the transient shutdown of protein translation, through phosphorylation of the alpha-subunit of eukaryotic translation initiation factor, eIF2. Activation of the unfolded protein response and/or increased eIF2alpha-P levels are seen in patients with Alzheimer's, Parkinson's and prion diseases, but how this links to neurodegeneration is unknown. Here we show that accumulation of prion protein during prion replication causes persistent translational repression of global protein synthesis by eIF2alpha-P, associated with synaptic failure and neuronal loss in prion-diseased mice. Further, we show that promoting translational recovery in hippocampi of prion-infected mice is neuroprotective. Overexpression of GADD34, a specific eIF2alpha-P phosphatase, as well as reduction of levels of prion protein by lentivirally mediated RNA interference, reduced eIF2alpha-P levels. As a result, both approaches restored vital translation rates during prion disease, rescuing synaptic deficits and neuronal loss, thereby significantly increasing survival. In contrast, salubrinal, an inhibitor of eIF2alpha-P dephosphorylation, increased eIF2alpha-P levels, exacerbating neurotoxicity and significantly reducing survival in prion-diseased mice. Given the prevalence of protein misfolding and activation of the unfolded protein response in several neurodegenerative diseases, our results suggest that manipulation of common pathways such as translational control, rather than disease-specific approaches, may lead to new therapies preventing synaptic failure and neuronal loss across the spectrum of these disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378208/" 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/PMC3378208/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moreno, Julie A -- Radford, Helois -- Peretti, Diego -- Steinert, Joern R -- Verity, Nicholas -- Martin, Maria Guerra -- Halliday, Mark -- Morgan, Jason -- Dinsdale, David -- Ortori, Catherine A -- Barrett, David A -- Tsaytler, Pavel -- Bertolotti, Anne -- Willis, Anne E -- Bushell, Martin -- Mallucci, Giovanna R -- MC_U105185860/Medical Research Council/United Kingdom -- MC_U123160654/Medical Research Council/United Kingdom -- MC_U132692719/Medical Research Council/United Kingdom -- MC_UP_A600_1023/Medical Research Council/United Kingdom -- MC_UP_A600_1024/Medical Research Council/United Kingdom -- U.1051.02.011.00001.01 (85860)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2012 May 6;485(7399):507-11. doi: 10.1038/nature11058.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Toxicology Unit, Hodgkin Building, University of Leicester, Lancaster Road, Leicester LE1 9HN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22622579" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Death/drug effects ; Cinnamates/pharmacology ; Eukaryotic Initiation Factor-2/analysis/*chemistry/*metabolism ; Hippocampus/cytology/metabolism/pathology ; Kaplan-Meier Estimate ; Mice ; Mice, Inbred C57BL ; Neurodegenerative Diseases/etiology/*metabolism/pathology ; Neurons/drug effects/pathology ; Neuroprotective Agents ; Phosphoproteins/analysis/*metabolism ; Phosphorylation ; PrPSc Proteins/analysis/metabolism/toxicity ; Prion Diseases/pathology ; Prions/biosynthesis/genetics/*metabolism ; *Protein Biosynthesis/drug effects ; Protein Folding/drug effects ; Protein Phosphatase 1/genetics/metabolism ; Repressor Proteins/analysis/chemistry/*metabolism ; Synapses/drug effects/metabolism/pathology ; Synaptic Transmission/drug effects ; Thiourea/analogs & derivatives/pharmacology ; Unfolded Protein Response/physiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Autistic-like social behaviour in Shank2-mutant mice improved by restoring NMDA receptor function (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-16
    Description: Autism spectrum disorder (ASD) is a group of conditions characterized by impaired social interaction and communication, and restricted and repetitive behaviours. ASD is a highly heritable disorder involving various genetic determinants. Shank2 (also known as ProSAP1) is a multi-domain scaffolding protein and signalling adaptor enriched at excitatory neuronal synapses, and mutations in the human SHANK2 gene have recently been associated with ASD and intellectual disability. Although ASD-associated genes are being increasingly identified and studied using various approaches, including mouse genetics, further efforts are required to delineate important causal mechanisms with the potential for therapeutic application. Here we show that Shank2-mutant (Shank2(-/-)) mice carrying a mutation identical to the ASD-associated microdeletion in the human SHANK2 gene exhibit ASD-like behaviours including reduced social interaction, reduced social communication by ultrasonic vocalizations, and repetitive jumping. These mice show a marked decrease in NMDA (N-methyl-D-aspartate) glutamate receptor (NMDAR) function. Direct stimulation of NMDARs with D-cycloserine, a partial agonist of NMDARs, normalizes NMDAR function and improves social interaction in Shank2(-/-) mice. Furthermore, treatment of Shank2(-/-) mice with a positive allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), which enhances NMDAR function via mGluR5 activation, also normalizes NMDAR function and markedly enhances social interaction. These results suggest that reduced NMDAR function may contribute to the development of ASD-like phenotypes in Shank2(-/-) mice, and mGluR modulation of NMDARs offers a potential strategy to treat ASD.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Won, Hyejung -- Lee, Hye-Ryeon -- Gee, Heon Yung -- Mah, Won -- Kim, Jae-Ick -- Lee, Jiseok -- Ha, Seungmin -- Chung, Changuk -- Jung, Eun Suk -- Cho, Yi Sul -- Park, Sae-Geun -- Lee, Jung-Soo -- Lee, Kyungmin -- Kim, Daesoo -- Bae, Yong Chul -- Kaang, Bong-Kiun -- Lee, Min Goo -- Kim, Eunjoon -- England -- Nature. 2012 Jun 13;486(7402):261-5. doi: 10.1038/nature11208.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biological Sciences, KAIST, Daejeon 305-701, Korea.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699620" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*genetics ; Animals ; Antimetabolites/pharmacology ; *Autistic Disorder/genetics/metabolism ; Behavior, Animal/*drug effects/physiology ; Benzamides/*pharmacology ; Cycloserine/*pharmacology ; Disease Models, Animal ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/*genetics ; Pyrazoles/*pharmacology ; Receptors, N-Methyl-D-Aspartate/*agonists/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    The aged niche disrupts muscle stem cell quiescence (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-02
    Description: The niche is a conserved regulator of stem cell quiescence and function. During ageing, stem cell function declines. To what extent and by what means age-related changes within the niche contribute to this phenomenon are unknown. Here we demonstrate that the aged muscle stem cell niche, the muscle fibre, expresses Fgf2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose their self-renewing capacity. We show in mice that relatively dormant aged satellite cells robustly express sprouty 1 (Spry1), an inhibitor of fibroblast growth factor (FGF) signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing Spry1 results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of Fgfr1 signalling or overexpression of Spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3605795/" 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/PMC3605795/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chakkalakal, Joe V -- Jones, Kieran M -- Basson, M Albert -- Brack, Andrew S -- 091475/Wellcome Trust/United Kingdom -- BB/F017626/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- R01 AR060868/AR/NIAMS NIH HHS/ -- R01 AR061002/AR/NIAMS NIH HHS/ -- WT091475/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Oct 18;490(7420):355-60. doi: 10.1038/nature11438. Epub 2012 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center of Regenerative Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023126" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Aging/*physiology ; Animals ; Cell Aging ; Cell Count ; *Cell Cycle ; Cell Differentiation ; Cyclin-Dependent Kinase Inhibitor p27/metabolism ; Fibroblast Growth Factor 2/genetics/metabolism ; Flow Cytometry ; Homeostasis ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Muscle Cells/*cytology ; Muscle, Skeletal/cytology ; PAX7 Transcription Factor/metabolism ; Phosphoproteins/metabolism ; Satellite Cells, Skeletal Muscle/*cytology/metabolism/transplantation ; Signal Transduction ; Stem Cell Niche/*physiology ; Time Factors
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Melanomas resist T-cell therapy through inflammation-induced reversible dedifferentiation (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-12
    Description: Adoptive cell transfer therapies (ACTs) with cytotoxic T cells that target melanocytic antigens can achieve remissions in patients with metastatic melanomas, but tumours frequently relapse. Hypotheses explaining the acquired resistance to ACTs include the selection of antigen-deficient tumour cell variants and the induction of T-cell tolerance. However, the lack of appropriate experimental melanoma models has so far impeded clear insights into the underlying mechanisms. Here we establish an effective ACT protocol in a genetically engineered mouse melanoma model that recapitulates tumour regression, remission and relapse as seen in patients. We report the unexpected observation that melanomas acquire ACT resistance through an inflammation-induced reversible loss of melanocytic antigens. In serial transplantation experiments, melanoma cells switch between a differentiated and a dedifferentiated phenotype in response to T-cell-driven inflammatory stimuli. We identified the proinflammatory cytokine tumour necrosis factor (TNF)-alpha as a crucial factor that directly caused reversible dedifferentiation of mouse and human melanoma cells. Tumour cells exposed to TNF-alpha were poorly recognized by T cells specific for melanocytic antigens, whereas recognition by T cells specific for non-melanocytic antigens was unaffected or even increased. Our results demonstrate that the phenotypic plasticity of melanoma cells in an inflammatory microenvironment contributes to tumour relapse after initially successful T-cell immunotherapy. On the basis of our work, we propose that future ACT protocols should simultaneously target melanocytic and non-melanocytic antigens to ensure broad recognition of both differentiated and dedifferentiated melanoma cells, and include strategies to sustain T-cell effector functions by blocking immune-inhibitory mechanisms in the tumour microenvironment.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Landsberg, Jennifer -- Kohlmeyer, Judith -- Renn, Marcel -- Bald, Tobias -- Rogava, Meri -- Cron, Mira -- Fatho, Martina -- Lennerz, Volker -- Wolfel, Thomas -- Holzel, Michael -- Tuting, Thomas -- England -- Nature. 2012 Oct 18;490(7420):412-6. doi: 10.1038/nature11538. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, D-53105 Bonn, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051752" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; *Cell Dedifferentiation ; Cell Differentiation ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Disease Models, Animal ; Humans ; *Immunotherapy ; Inflammation/immunology/*pathology ; Melanoma/immunology/metabolism/*pathology/*therapy ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; T-Lymphocytes, Cytotoxic/*immunology/*transplantation ; Tumor Microenvironment/immunology ; Tumor Necrosis Factor-alpha/immunology/pharmacology ; gp100 Melanoma Antigen/metabolism
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  • 7
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    Nonlinear dendritic integration of sensory and motor input during an active sensing task (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-11-13
    Description: Active dendrites provide neurons with powerful processing capabilities. However, little is known about the role of neuronal dendrites in behaviourally related circuit computations. Here we report that a novel global dendritic nonlinearity is involved in the integration of sensory and motor information within layer 5 pyramidal neurons during an active sensing behaviour. Layer 5 pyramidal neurons possess elaborate dendritic arborizations that receive functionally distinct inputs, each targeted to spatially separate regions. At the cellular level, coincident input from these segregated pathways initiates regenerative dendritic electrical events that produce bursts of action potential output and circuits featuring this powerful dendritic nonlinearity can implement computations based on input correlation. To examine this in vivo we recorded dendritic activity in layer 5 pyramidal neurons in the barrel cortex using two-photon calcium imaging in mice performing an object-localization task. Large-amplitude, global calcium signals were observed throughout the apical tuft dendrites when active touch occurred at particular object locations or whisker angles. Such global calcium signals are produced by dendritic plateau potentials that require both vibrissal sensory input and primary motor cortex activity. These data provide direct evidence of nonlinear dendritic processing of correlated sensory and motor information in the mammalian neocortex during active sensation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Ning-long -- Harnett, Mark T -- Williams, Stephen R -- Huber, Daniel -- O'Connor, Daniel H -- Svoboda, Karel -- Magee, Jeffrey C -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Dec 13;492(7428):247-51. doi: 10.1038/nature11601. Epub 2012 Nov 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23143335" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/*physiology ; Calcium/metabolism ; Dendrites/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Motor Activity/*physiology ; Patch-Clamp Techniques ; Pyramidal Cells/physiology ; Sensation/*physiology ; Signal Transduction
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Resurrection of endogenous retroviruses in antibody-deficient mice (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-30
    Description: The mammalian host has developed a long-standing symbiotic relationship with a considerable number of microbial species. These include the microbiota on environmental surfaces, such as the respiratory and gastrointestinal tracts, and also endogenous retroviruses (ERVs), comprising a substantial fraction of the mammalian genome. The long-term consequences for the host of interactions with these microbial species can range from mutualism to parasitism and are not always completely understood. The potential effect of one microbial symbiont on another is even less clear. Here we study the control of ERVs in the commonly used C57BL/6 (B6) mouse strain, which lacks endogenous murine leukaemia viruses (MLVs) able to replicate in murine cells. We demonstrate the spontaneous emergence of fully infectious ecotropic MLV in B6 mice with a range of distinct immune deficiencies affecting antibody production. These recombinant retroviruses establish infection of immunodeficient mouse colonies, and ultimately result in retrovirus-induced lymphomas. Notably, ERV activation in immunodeficient mice is prevented in husbandry conditions associated with reduced or absent intestinal microbiota. Our results shed light onto a previously unappreciated role for immunity in the control of ERVs and provide a potential mechanistic link between immune activation by microbial triggers and a range of pathologies associated with ERVs, including cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511586/" 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/PMC3511586/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Young, George R -- Eksmond, Urszula -- Salcedo, Rosalba -- Alexopoulou, Lena -- Stoye, Jonathan P -- Kassiotis, George -- MC_U117512710/Medical Research Council/United Kingdom -- MC_U117581330/Medical Research Council/United Kingdom -- U.1175.02.005.00005(60891)/Medical Research Council/United Kingdom -- U.1175.02.006.00007(81330)/Medical Research Council/United Kingdom -- U117512710/Medical Research Council/United Kingdom -- U117581330/Medical Research Council/United Kingdom -- England -- Nature. 2012 Nov 29;491(7426):774-8. doi: 10.1038/nature11599. Epub 2012 Oct 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunoregulation, MRC National Institute for Medical Research, The Ridgeway, London NW7 1AA, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23103862" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Husbandry ; Animals ; Antibodies, Viral/*biosynthesis/immunology ; Cell Transformation, Viral ; Endogenous Retroviruses/genetics/growth & development/immunology/*physiology ; Female ; Immunocompromised Host/*immunology ; Leukemia/virology ; Leukemia Virus, Murine/genetics/growth & development/immunology/physiology ; Lymphoma/virology ; Male ; Mice ; Mice, Inbred C57BL ; Receptors, Antigen, T-Cell/deficiency/genetics ; Recombination, Genetic ; Viremia/immunology/virology ; *Virus Activation
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: Obesity and type-2 diabetes have increased markedly over the past few decades, in parallel. One of the major links between these two disorders is chronic, low-grade inflammation. Prolonged nutrient excess promotes the accumulation and activation of leukocytes in visceral adipose tissue (VAT) and ultimately other tissues, leading to metabolic abnormalities such as insulin resistance, type-2 diabetes and fatty-liver disease. Although invasion of VAT by pro-inflammatory macrophages is considered to be a key event driving adipose-tissue inflammation and insulin resistance, little is known about the roles of other immune system cell types in these processes. A unique population of VAT-resident regulatory T (Treg) cells was recently implicated in control of the inflammatory state of adipose tissue and, thereby, insulin sensitivity. Here we identify peroxisome proliferator-activated receptor (PPAR)-gamma, the 'master regulator' of adipocyte differentiation, as a crucial molecular orchestrator of VAT Treg cell accumulation, phenotype and function. Unexpectedly, PPAR-gamma expression by VAT Treg cells was necessary for complete restoration of insulin sensitivity in obese mice by the thiazolidinedione drug pioglitazone. These findings suggest a previously unknown cellular mechanism for this important class of thiazolidinedione drugs, and provide proof-of-principle that discrete populations of Treg cells with unique functions can be precisely targeted to therapeutic ends.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387339/" 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/PMC3387339/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cipolletta, Daniela -- Feuerer, Markus -- Li, Amy -- Kamei, Nozomu -- Lee, Jongsoon -- Shoelson, Steven E -- Benoist, Christophe -- Mathis, Diane -- DK092541/DK/NIDDK NIH HHS/ -- DK51729/DK/NIDDK NIH HHS/ -- P30DK36836/DK/NIDDK NIH HHS/ -- R01 DK051729/DK/NIDDK NIH HHS/ -- R01 DK092541/DK/NIDDK NIH HHS/ -- R01 DK092541-02/DK/NIDDK NIH HHS/ -- R37 DK051729/DK/NIDDK NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Jun 28;486(7404):549-53. doi: 10.1038/nature11132.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722857" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/*cytology/immunology/pathology ; Animals ; Cell Differentiation ; Diabetes Mellitus, Type 2/drug therapy/metabolism/pathology ; Epididymis/cytology/immunology ; Forkhead Transcription Factors/metabolism ; Gene Expression ; Hypoglycemic Agents/pharmacology ; Inflammation/immunology/metabolism/pathology ; Insulin Resistance/physiology ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Obese ; Obesity/metabolism/pathology ; PPAR gamma/*metabolism ; Phenotype ; RNA, Messenger/genetics/metabolism ; T-Lymphocytes, Regulatory/*cytology/drug effects/*metabolism ; Thiazolidinediones/pharmacology ; Transcription, Genetic
    Print ISSN: 0028-0836
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  • 10
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    Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-06
    Description: Autism spectrum disorders (ASDs) are highly prevalent neurodevelopmental disorders, but the underlying pathogenesis remains poorly understood. Recent studies have implicated the cerebellum in these disorders, with post-mortem studies in ASD patients showing cerebellar Purkinje cell (PC) loss, and isolated cerebellar injury has been associated with a higher incidence of ASDs. However, the extent of cerebellar contribution to the pathogenesis of ASDs remains unclear. Tuberous sclerosis complex (TSC) is a genetic disorder with high rates of comorbid ASDs that result from mutation of either TSC1 or TSC2, whose protein products dimerize and negatively regulate mammalian target of rapamycin (mTOR) signalling. TSC is an intriguing model to investigate the cerebellar contribution to the underlying pathogenesis of ASDs, as recent studies in TSC patients demonstrate cerebellar pathology and correlate cerebellar pathology with increased ASD symptomatology. Functional imaging also shows that TSC patients with ASDs display hypermetabolism in deep cerebellar structures, compared to TSC patients without ASDs. However, the roles of Tsc1 and the sequelae of Tsc1 dysfunction in the cerebellum have not been investigated so far. Here we show that both heterozygous and homozygous loss of Tsc1 in mouse cerebellar PCs results in autistic-like behaviours, including abnormal social interaction, repetitive behaviour and vocalizations, in addition to decreased PC excitability. Treatment of mutant mice with the mTOR inhibitor, rapamycin, prevented the pathological and behavioural deficits. These findings demonstrate new roles for Tsc1 in PC function and define a molecular basis for a cerebellar contribution to cognitive disorders such as autism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3615424/" 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/PMC3615424/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tsai, Peter T -- Hull, Court -- Chu, YunXiang -- Greene-Colozzi, Emily -- Sadowski, Abbey R -- Leech, Jarrett M -- Steinberg, Jason -- Crawley, Jacqueline N -- Regehr, Wade G -- Sahin, Mustafa -- K12 NS079414/NS/NINDS NIH HHS/ -- P30HD18655/HD/NICHD NIH HHS/ -- R01 NS032405/NS/NINDS NIH HHS/ -- R01NS032405/NS/NINDS NIH HHS/ -- R01NS58956/NS/NINDS NIH HHS/ -- T32 MH020017/MH/NIMH NIH HHS/ -- T32 NS007473/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):647-51. doi: 10.1038/nature11310.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The F.M. Kirby Neurobiology Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. peter.tsai@childrens.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763451" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autistic Disorder/complications/genetics/pathology/*physiopathology ; Behavior, Animal/drug effects ; Cell Count ; Cell Shape/drug effects ; Cerebellum/drug effects/pathology/*physiopathology ; Grooming/drug effects/physiology ; Heterozygote ; Maze Learning/drug effects/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mutation/genetics ; Purkinje Cells/drug effects/*metabolism ; Rotarod Performance Test ; Sirolimus/pharmacology ; Synapses/metabolism ; TOR Serine-Threonine Kinases/antagonists & inhibitors/metabolism ; Tuberous Sclerosis/complications/genetics ; Tumor Suppressor Proteins/deficiency/*genetics/*metabolism ; Vocalization, Animal/drug effects/physiology
    Print ISSN: 0028-0836
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    A FOXO3-IRF7 gene regulatory circuit limits inflammatory sequelae of antiviral responses (2012)
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    Publication Date: 2012-09-18
    Description: Antiviral responses must be tightly regulated to defend rapidly against infection while minimizing inflammatory damage. Type 1 interferons (IFN-I) are crucial mediators of antiviral responses and their transcription is regulated by a variety of transcription factors; principal among these is the family of interferon regulatory factors (IRFs). The IRF gene regulatory networks are complex and contain multiple feedback loops. The tools of systems biology are well suited to elucidate the complex interactions that give rise to precise coordination of the interferon response. Here we have used an unbiased systems approach to predict that a member of the forkhead family of transcription factors, FOXO3, is a negative regulator of a subset of antiviral genes. This prediction was validated using macrophages isolated from Foxo3-null mice. Genome-wide location analysis combined with gene deletion studies identified the Irf7 gene as a critical target of FOXO3. FOXO3 was identified as a negative regulator of Irf7 transcription and we have further demonstrated that FOXO3, IRF7 and IFN-I form a coherent feed-forward regulatory circuit. Our data suggest that the FOXO3-IRF7 regulatory circuit represents a novel mechanism for establishing the requisite set points in the interferon pathway that balances the beneficial effects and deleterious sequelae of the antiviral response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3556990/" 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/PMC3556990/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Litvak, Vladimir -- Ratushny, Alexander V -- Lampano, Aaron E -- Schmitz, Frank -- Huang, Albert C -- Raman, Ayush -- Rust, Alistair G -- Bergthaler, Andreas -- Aitchison, John D -- Aderem, Alan -- HHSN272200700038C/AI/NIAID NIH HHS/ -- HHSN272200700038C/PHS HHS/ -- HHSN272200800058C/AI/NIAID NIH HHS/ -- HSN272200800058C/PHS HHS/ -- R01 AI025032/AI/NIAID NIH HHS/ -- R01 AI032972/AI/NIAID NIH HHS/ -- R01AI025032/AI/NIAID NIH HHS/ -- R01AI032972/AI/NIAID NIH HHS/ -- U19 AI100627/AI/NIAID NIH HHS/ -- U54 GM103511/GM/NIGMS NIH HHS/ -- U54 RR022220/RR/NCRR NIH HHS/ -- U54GM103511/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Oct 18;490(7420):421-5. doi: 10.1038/nature11428. Epub 2012 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Seattle Biomedical Research Institute, Seattle, Washington 98109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22982991" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Forkhead Transcription Factors/deficiency/genetics/*metabolism ; Gene Deletion ; Gene Expression Regulation/*immunology ; Inflammation/genetics/*immunology/*pathology ; Interferon Regulatory Factor-7/deficiency/genetics/*metabolism ; Interferon Type I/immunology ; Lung/immunology/pathology/virology ; Macrophages/immunology ; Mice ; Mice, Inbred C57BL ; Reproducibility of Results ; Vesiculovirus/*immunology
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    Novel Foxo1-dependent transcriptional programs control T(reg) cell function (2012)
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    Publication Date: 2012-11-09
    Description: Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3771531/" 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/PMC3771531/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ouyang, Weiming -- Liao, Will -- Luo, Chong T -- Yin, Na -- Huse, Morgan -- Kim, Myoungjoo V -- Peng, Min -- Chan, Pamela -- Ma, Qian -- Mo, Yifan -- Meijer, Dies -- Zhao, Keji -- Rudensky, Alexander Y -- Atwal, Gurinder -- Zhang, Michael Q -- Li, Ming O -- HG001696/HG/NHGRI NIH HHS/ -- R01 HG001696/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Nov 22;491(7425):554-9. doi: 10.1038/nature11581. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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/23135404" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Nucleus/metabolism/pathology ; Female ; Forkhead Transcription Factors/*metabolism ; Gene Expression Regulation/genetics ; Genome/genetics ; Immune Tolerance/genetics/immunology ; Interferon-gamma/deficiency/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-akt/metabolism ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction ; T-Lymphocytes, Regulatory/*immunology/*metabolism/pathology ; *Transcription, Genetic
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    Multi-isotope imaging mass spectrometry reveals slow protein turnover in hair-cell stereocilia (2012)
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    Publication Date: 2012-01-17
    Description: Hair cells of the inner ear are not normally replaced during an animal's life, and must continually renew components of their various organelles. Among these are the stereocilia, each with a core of several hundred actin filaments that arise from their apical surfaces and that bear the mechanotransduction apparatus at their tips. Actin turnover in stereocilia has previously been studied by transfecting neonatal rat hair cells in culture with a beta-actin-GFP fusion, and evidence was found that actin is replaced, from the top down, in 2-3 days. Overexpression of the actin-binding protein espin causes elongation of stereocilia within 12-24 hours, also suggesting rapid regulation of stereocilia lengths. Similarly, the mechanosensory 'tip links' are replaced in 5-10 hours after cleavage in chicken and mammalian hair cells. In contrast, turnover in chick stereocilia in vivo is much slower. It might be that only certain components of stereocilia turn over quickly, that rapid turnover occurs only in neonatal animals, only in culture, or only in response to a challenge like breakage or actin overexpression. Here we quantify protein turnover by feeding animals with a (15)N-labelled precursor amino acid and using multi-isotope imaging mass spectrometry to measure appearance of new protein. Surprisingly, in adult frogs and mice and in neonatal mice, in vivo and in vitro, the stereocilia were remarkably stable, incorporating newly synthesized protein at 〈10% per day. Only stereocilia tips had rapid turnover and no treadmilling was observed. Other methods confirmed this: in hair cells expressing beta-actin-GFP we bleached fiducial lines across hair bundles, but they did not move in 6 days. When we stopped expression of beta- or gamma-actin with tamoxifen-inducible recombination, neither actin isoform left the stereocilia, except at the tips. Thus, rapid turnover in stereocilia occurs only at the tips and not by a treadmilling process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267870/" 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/PMC3267870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Duan-Sun -- Piazza, Valeria -- Perrin, Benjamin J -- Rzadzinska, Agnieszka K -- Poczatek, J Collin -- Wang, Mei -- Prosser, Haydn M -- Ervasti, James M -- Corey, David P -- Lechene, Claude P -- 2P41RR0112553-12/RR/NCRR NIH HHS/ -- F32DC009539/DC/NIDCD NIH HHS/ -- P41EB001974/EB/NIBIB NIH HHS/ -- P41RR14579/RR/NCRR NIH HHS/ -- R01 AR042423/AR/NIAMS NIH HHS/ -- R01 AR042423-08/AR/NIAMS NIH HHS/ -- R01 AR049899/AR/NIAMS NIH HHS/ -- R01 DC000033/DC/NIDCD NIH HHS/ -- R01 DC002281/DC/NIDCD NIH HHS/ -- R01AR049899/AR/NIAMS NIH HHS/ -- R01D K58762/PHS HHS/ -- R01DC00033/DC/NIDCD NIH HHS/ -- R01DC02281/DC/NIDCD NIH HHS/ -- R01DC03463/DC/NIDCD NIH HHS/ -- R01DC04179/DC/NIDCD NIH HHS/ -- R01EY12963/EY/NEI NIH HHS/ -- R01GM47214/GM/NIGMS NIH HHS/ -- R37DK39773/DK/NIDDK NIH HHS/ -- WT079643/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 15;481(7382):520-4. doi: 10.1038/nature10745.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246323" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/metabolism ; Animals ; Animals, Newborn ; Bleaching Agents ; Chickens ; Epithelium/drug effects/metabolism ; Fiducial Markers ; Hair Cells, Auditory, Inner/*cytology ; Homologous Recombination/drug effects ; Mass Spectrometry/*methods ; Mice ; Mice, Inbred C57BL ; Proteins/*metabolism ; Rana catesbeiana ; Stereocilia/*metabolism ; Tamoxifen/pharmacology
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    The translational landscape of mTOR signalling steers cancer initiation and metastasis (2012)
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    Publication Date: 2012-03-01
    Description: The mammalian target of rapamycin (mTOR) kinase is a master regulator of protein synthesis that couples nutrient sensing to cell growth and cancer. However, the downstream translationally regulated nodes of gene expression that may direct cancer development are poorly characterized. Using ribosome profiling, we uncover specialized translation of the prostate cancer genome by oncogenic mTOR signalling, revealing a remarkably specific repertoire of genes involved in cell proliferation, metabolism and invasion. We extend these findings by functionally characterizing a class of translationally controlled pro-invasion messenger RNAs that we show direct prostate cancer invasion and metastasis downstream of oncogenic mTOR signalling. Furthermore, we develop a clinically relevant ATP site inhibitor of mTOR, INK128, which reprograms this gene expression signature with therapeutic benefit for prostate cancer metastasis, for which there is presently no cure. Together, these findings extend our understanding of how the 'cancerous' translation machinery steers specific cancer cell behaviours, including metastasis, and may be therapeutically targeted.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663483/" 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/PMC3663483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hsieh, Andrew C -- Liu, Yi -- Edlind, Merritt P -- Ingolia, Nicholas T -- Janes, Matthew R -- Sher, Annie -- Shi, Evan Y -- Stumpf, Craig R -- Christensen, Carly -- Bonham, Michael J -- Wang, Shunyou -- Ren, Pingda -- Martin, Michael -- Jessen, Katti -- Feldman, Morris E -- Weissman, Jonathan S -- Shokat, Kevan M -- Rommel, Christian -- Ruggero, Davide -- R01 CA140456/CA/NCI NIH HHS/ -- R01 CA154916/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 22;485(7396):55-61. doi: 10.1038/nature10912.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Medicine and Department of Urology, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367541" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Animals ; Benzoxazoles/pharmacology ; Cell Line, Tumor ; Cell Movement/drug effects/genetics ; Eukaryotic Initiation Factor-4E/metabolism ; Eukaryotic Initiation Factors/metabolism ; Gene Expression Regulation, Neoplastic/drug effects/genetics ; Genome/genetics ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Invasiveness/genetics ; *Neoplasm Metastasis/drug therapy/genetics ; Phosphoproteins/metabolism ; Prostatic Neoplasms/drug therapy/genetics/*pathology ; *Protein Biosynthesis ; Pyrimidines/pharmacology ; RNA, Messenger/genetics/metabolism ; Repressor Proteins/metabolism ; *Signal Transduction ; TOR Serine-Threonine Kinases/antagonists & inhibitors/*metabolism
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    Automated design of ligands to polypharmacological profiles (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-12-14
    Description: The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3653568/" 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/PMC3653568/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Besnard, Jeremy -- Ruda, Gian Filippo -- Setola, Vincent -- Abecassis, Keren -- Rodriguiz, Ramona M -- Huang, Xi-Ping -- Norval, Suzanne -- Sassano, Maria F -- Shin, Antony I -- Webster, Lauren A -- Simeons, Frederick R C -- Stojanovski, Laste -- Prat, Annik -- Seidah, Nabil G -- Constam, Daniel B -- Bickerton, G Richard -- Read, Kevin D -- Wetsel, William C -- Gilbert, Ian H -- Roth, Bryan L -- Hopkins, Andrew L -- 083481/Wellcome Trust/United Kingdom -- BB/FOF/PF/15/09/Biotechnology and Biological Sciences Research Council/United Kingdom -- BB/J010510/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- MH082441/MH/NIMH NIH HHS/ -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- WT 083481/Wellcome Trust/United Kingdom -- England -- Nature. 2012 Dec 13;492(7428):215-20. doi: 10.1038/nature11691.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23235874" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Automation ; Drug Delivery Systems ; *Drug Design ; Female ; *Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Theoretical ; Pharmacological Phenomena ; Reproducibility of Results
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  • 16
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    Novel role of PKR in inflammasome activation and HMGB1 release (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-07-18
    Description: The inflammasome regulates the release of caspase activation-dependent cytokines, including interleukin (IL)-1beta, IL-18 and high-mobility group box 1 (HMGB1). By studying HMGB1 release mechanisms, here we identify a role for double-stranded RNA-dependent protein kinase (PKR, also known as EIF2AK2) in inflammasome activation. Exposure of macrophages to inflammasome agonists induced PKR autophosphorylation. PKR inactivation by genetic deletion or pharmacological inhibition severely impaired inflammasome activation in response to double-stranded RNA, ATP, monosodium urate, adjuvant aluminium, rotenone, live Escherichia coli, anthrax lethal toxin, DNA transfection and Salmonella typhimurium infection. PKR deficiency significantly inhibited the secretion of IL-1beta, IL-18 and HMGB1 in E. coli-induced peritonitis. PKR physically interacts with several inflammasome components, including NOD-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), NLRP1, NLR family CARD domain-containing protein 4 (NLRC4), absent in melanoma 2 (AIM2), and broadly regulates inflammasome activation. PKR autophosphorylation in a cell-free system with recombinant NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC, also known as PYCARD) and pro-caspase-1 reconstitutes inflammasome activity. These results show a crucial role for PKR in inflammasome activation, and indicate that it should be possible to pharmacologically target this molecule to treat inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163918/" 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/PMC4163918/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lu, Ben -- Nakamura, Takahisa -- Inouye, Karen -- Li, Jianhua -- Tang, Yiting -- Lundback, Peter -- Valdes-Ferrer, Sergio I -- Olofsson, Peder S -- Kalb, Thomas -- Roth, Jesse -- Zou, Yongrui -- Erlandsson-Harris, Helena -- Yang, Huan -- Ting, Jenny P-Y -- Wang, Haichao -- Andersson, Ulf -- Antoine, Daniel J -- Chavan, Sangeeta S -- Hotamisligil, Gokhan S -- Tracey, Kevin J -- DK052539/DK/NIDDK NIH HHS/ -- G0700654/Medical Research Council/United Kingdom -- R01 DK052539/DK/NIDDK NIH HHS/ -- R01 GM057226/GM/NIGMS NIH HHS/ -- R01 GM062508/GM/NIGMS NIH HHS/ -- R01 GM62508/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):670-4. doi: 10.1038/nature11290.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, New York 11030, USA. blu@nshs.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801494" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/metabolism ; Adenosine Triphosphate/pharmacology ; Animals ; Antigens, Bacterial/pharmacology ; Apoptosis Regulatory Proteins/metabolism ; Bacterial Toxins/pharmacology ; CARD Signaling Adaptor Proteins/metabolism ; Calcium-Binding Proteins/metabolism ; Carrier Proteins/metabolism ; Cell Line ; Cells, Cultured ; Crystallins/metabolism ; Escherichia coli/immunology/physiology ; Escherichia coli Infections/immunology/metabolism ; Female ; HMGB1 Protein/blood/*secretion ; Humans ; Inflammasomes/agonists/*metabolism ; Interleukin-18/blood ; Interleukin-1beta/blood ; Interleukin-6/analysis/blood ; Macrophages, Peritoneal/drug effects/metabolism ; Male ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Peritonitis/metabolism ; Phosphorylation ; RNA, Double-Stranded/immunology/pharmacology ; Rotenone/pharmacology ; Salmonella Infections/immunology/metabolism ; Salmonella typhimurium/immunology/physiology ; Transfection ; Uric Acid/pharmacology ; eIF-2 Kinase/antagonists & inhibitors/deficiency/genetics/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 17
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    APJ acts as a dual receptor in cardiac hypertrophy (2012)
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    Publication Date: 2012-07-20
    Description: Cardiac hypertrophy is initiated as an adaptive response to sustained overload but progresses pathologically as heart failure ensues. Here we report that genetic loss of APJ, a G-protein-coupled receptor, confers resistance to chronic pressure overload by markedly reducing myocardial hypertrophy and heart failure. In contrast, mice lacking apelin (the endogenous APJ ligand) remain sensitive, suggesting an apelin-independent function of APJ. Freshly isolated APJ-null cardiomyocytes exhibit an attenuated response to stretch, indicating that APJ is a mechanosensor. Activation of APJ by stretch increases cardiomyocyte cell size and induces molecular markers of hypertrophy. Whereas apelin stimulates APJ to activate Galphai and elicits a protective response, stretch signals in an APJ-dependent, G-protein-independent fashion to induce hypertrophy. Stretch-mediated hypertrophy is prevented by knockdown of beta-arrestins or by pharmacological doses of apelin acting through Galphai. Taken together, our data indicate that APJ is a bifunctional receptor for both mechanical stretch and the endogenous peptide apelin. By sensing the balance between these stimuli, APJ occupies a pivotal point linking sustained overload to cardiomyocyte hypertrophy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3422434/" 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/PMC3422434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scimia, Maria Cecilia -- Hurtado, Cecilia -- Ray, Saugata -- Metzler, Scott -- Wei, Ke -- Wang, Jianming -- Woods, Chris E -- Purcell, Nicole H -- Catalucci, Daniele -- Akasaka, Takeshi -- Bueno, Orlando F -- Vlasuk, George P -- Kaliman, Perla -- Bodmer, Rolf -- Smith, Layton H -- Ashley, Euan -- Mercola, Mark -- Brown, Joan Heller -- Ruiz-Lozano, Pilar -- NS05422/NS/NINDS NIH HHS/ -- P01 HL085577/HL/NHLBI NIH HHS/ -- R01 HL054732/HL/NHLBI NIH HHS/ -- R01 HL086879/HL/NHLBI NIH HHS/ -- R01HL054732/HL/NHLBI NIH HHS/ -- R01HL083463/HL/NHLBI NIH HHS/ -- R01HL086879/HL/NHLBI NIH HHS/ -- R01HL28143/HL/NHLBI NIH HHS/ -- R37 HL028143/HL/NHLBI NIH HHS/ -- R37HL059502/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Aug 16;488(7411):394-8. doi: 10.1038/nature11263.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22810587" target="_blank"〉PubMed〈/a〉
    Keywords: Adipokines ; Animals ; Aorta/pathology ; Arrestins/deficiency/genetics/metabolism ; Blood Pressure ; Cardiomegaly/*metabolism/pathology/physiopathology/prevention & control ; Female ; GTP-Binding Protein alpha Subunits, Gi-Go/metabolism ; Intercellular Signaling Peptides and ; Proteins/deficiency/genetics/metabolism/pharmacology ; Male ; Mechanoreceptors/metabolism ; Mechanotransduction, Cellular/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac/drug effects/pathology ; Receptors, G-Protein-Coupled/agonists/deficiency/genetics/*metabolism ; Signal Transduction/drug effects
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    HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria (2012)
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    Publication Date: 2012-07-18
    Description: The herpes virus entry mediator (HVEM), a member of the tumour-necrosis factor receptor family, has diverse functions, augmenting or inhibiting the immune response. HVEM was recently reported as a colitis risk locus in patients, and in a mouse model of colitis we demonstrated an anti-inflammatory role for HVEM, but its mechanism of action in the mucosal immune system was unknown. Here we report an important role for epithelial HVEM in innate mucosal defence against pathogenic bacteria. HVEM enhances immune responses by NF-kappaB-inducing kinase-dependent Stat3 activation, which promotes the epithelial expression of genes important for immunity. During intestinal Citrobacter rodentium infection, a mouse model for enteropathogenic Escherichia coli infection, Hvem-/- mice showed decreased Stat3 activation, impaired responses in the colon, higher bacterial burdens and increased mortality. We identified the immunoglobulin superfamily molecule CD160 (refs 7 and 8), expressed predominantly by innate-like intraepithelial lymphocytes, as the ligand engaging epithelial HVEM for host protection. Likewise, in pulmonary Streptococcus pneumoniae infection, HVEM is also required for host defence. Our results pinpoint HVEM as an important orchestrator of mucosal immunity, integrating signals from innate lymphocytes to induce optimal epithelial Stat3 activation, which indicates that targeting HVEM with agonists could improve host defence.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477500/" 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/PMC3477500/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shui, Jr-Wen -- Larange, Alexandre -- Kim, Gisen -- Vela, Jose Luis -- Zahner, Sonja -- Cheroutre, Hilde -- Kronenberg, Mitchell -- F32 AI083029/AI/NIAID NIH HHS/ -- F32 DK082249/DK/NIDDK NIH HHS/ -- F32-AI083029/AI/NIAID NIH HHS/ -- F32-DK082249/DK/NIDDK NIH HHS/ -- P01 DK046763/DK/NIDDK NIH HHS/ -- P01 DK46763/DK/NIDDK NIH HHS/ -- R01 AI050265/AI/NIAID NIH HHS/ -- R01 AI061516/AI/NIAID NIH HHS/ -- R01 AI064584/AI/NIAID NIH HHS/ -- R01-AI061516/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Aug 9;488(7410):222-5. doi: 10.1038/nature11242.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Developmental Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22801499" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/immunology/metabolism ; Bacterial Load ; Cell Line ; Citrobacter rodentium/*immunology/*pathogenicity ; Disease Models, Animal ; Enterobacteriaceae Infections/immunology/microbiology ; Enteropathogenic Escherichia coli ; Epithelial Cells/immunology/metabolism ; Escherichia coli Infections ; GPI-Linked Proteins/immunology/metabolism ; Immunity, Mucosal/*immunology ; Intestines/immunology/microbiology ; Ligands ; Lung/immunology/microbiology ; Lymphocytes/immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Mucous Membrane/*immunology/metabolism/*microbiology ; Pneumococcal Infections/immunology/microbiology ; Protein-Serine-Threonine Kinases/metabolism ; Receptors, Immunologic/immunology/metabolism ; Receptors, Tumor Necrosis Factor, Member ; 14/deficiency/genetics/immunology/*metabolism ; STAT3 Transcription Factor/metabolism ; *Signal Transduction ; Streptococcus pneumoniae/immunology ; Survival Rate
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  • 19
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    Retinal waves coordinate patterned activity throughout the developing visual system (2012)
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    Publication Date: 2012-10-13
    Description: The morphological and functional development of the vertebrate nervous system is initially governed by genetic factors and subsequently refined by neuronal activity. However, fundamental features of the nervous system emerge before sensory experience is possible. Thus, activity-dependent development occurring before the onset of experience must be driven by spontaneous activity, but the origin and nature of activity in vivo remains largely untested. Here we use optical methods to show in live neonatal mice that waves of spontaneous retinal activity are present and propagate throughout the entire visual system before eye opening. This patterned activity encompassed the visual field, relied on cholinergic neurotransmission, preferentially initiated in the binocular retina and exhibited spatiotemporal correlations between the two hemispheres. Retinal waves were the primary source of activity in the midbrain and primary visual cortex, but only modulated ongoing activity in secondary visual areas. Thus, spontaneous retinal activity is transmitted through the entire visual system and carries patterned information capable of guiding the activity-dependent development of complex intra- and inter-hemispheric circuits before the onset of vision.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962269/" 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/PMC3962269/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ackman, James B -- Burbridge, Timothy J -- Crair, Michael C -- P30 EY000785/EY/NEI NIH HHS/ -- R01 EY015788/EY/NEI NIH HHS/ -- R01 EY023105/EY/NEI NIH HHS/ -- T15LM070506/LM/NLM NIH HHS/ -- T32 EY017353/EY/NEI NIH HHS/ -- T32 EY022312/EY/NEI NIH HHS/ -- T32 NS007224/NS/NINDS NIH HHS/ -- T32NS007224/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Oct 11;490(7419):219-25. doi: 10.1038/nature11529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23060192" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Bicyclo Compounds, Heterocyclic/pharmacology ; Calcium/metabolism ; Gene Expression Regulation, Developmental/drug effects ; Mice ; Mice, Inbred C57BL ; Nicotinic Agonists/pharmacology ; Pyridines/pharmacology ; Retina/drug effects/growth & development ; Retinal Neurons/cytology/drug effects ; Visual Cortex/cytology/drug effects/*growth & development
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  • 20
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    Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth (2012)
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    Publication Date: 2012-10-05
    Description: Approximately 2% of colorectal cancer is linked to pre-existing inflammation known as colitis-associated cancer, but most develops in patients without underlying inflammatory bowel disease. Colorectal cancer often follows a genetic pathway whereby loss of the adenomatous polyposis coli (APC) tumour suppressor and activation of beta-catenin are followed by mutations in K-Ras, PIK3CA and TP53, as the tumour emerges and progresses. Curiously, however, 'inflammatory signature' genes characteristic of colitis-associated cancer are also upregulated in colorectal cancer. Further, like most solid tumours, colorectal cancer exhibits immune/inflammatory infiltrates, referred to as 'tumour-elicited inflammation'. Although infiltrating CD4(+) T(H)1 cells and CD8(+) cytotoxic T cells constitute a positive prognostic sign in colorectal cancer, myeloid cells and T-helper interleukin (IL)-17-producing (T(H)17) cells promote tumorigenesis, and a 'T(H)17 expression signature' in stage I/II colorectal cancer is associated with a drastic decrease in disease-free survival. Despite its pathogenic importance, the mechanisms responsible for the appearance of tumour-elicited inflammation are poorly understood. Many epithelial cancers develop proximally to microbial communities, which are physically separated from immune cells by an epithelial barrier. We investigated mechanisms responsible for tumour-elicited inflammation in a mouse model of colorectal tumorigenesis, which, like human colorectal cancer, exhibits upregulation of IL-23 and IL-17. Here we show that IL-23 signalling promotes tumour growth and progression, and development of a tumoural IL-17 response. IL-23 is mainly produced by tumour-associated myeloid cells that are likely to be activated by microbial products, which penetrate the tumours but not adjacent tissue. Both early and late colorectal neoplasms exhibit defective expression of several barrier proteins. We propose that barrier deterioration induced by colorectal-cancer-initiating genetic lesions results in adenoma invasion by microbial products that trigger tumour-elicited inflammation, which in turn drives tumour growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3601659/" 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/PMC3601659/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grivennikov, Sergei I -- Wang, Kepeng -- Mucida, Daniel -- Stewart, C Andrew -- Schnabl, Bernd -- Jauch, Dominik -- Taniguchi, Koji -- Yu, Guann-Yi -- Osterreicher, Christoph H -- Hung, Kenneth E -- Datz, Christian -- Feng, Ying -- Fearon, Eric R -- Oukka, Mohamed -- Tessarollo, Lino -- Coppola, Vincenzo -- Yarovinsky, Felix -- Cheroutre, Hilde -- Eckmann, Lars -- Trinchieri, Giorgio -- Karin, Michael -- AI043477/AI/NIAID NIH HHS/ -- DK035108/DK/NIDDK NIH HHS/ -- DK080506/DK/NIDDK NIH HHS/ -- K08 DK081830/DK/NIDDK NIH HHS/ -- K99 DK088589/DK/NIDDK NIH HHS/ -- K99-DK088589/DK/NIDDK NIH HHS/ -- R01 AA020703/AA/NIAAA NIH HHS/ -- R01 AI043477/AI/NIAID NIH HHS/ -- R01 AI050265/AI/NIAID NIH HHS/ -- R01 CA082223/CA/NCI NIH HHS/ -- R01CA082223/CA/NCI NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):254-8. doi: 10.1038/nature11465.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23034650" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoma/genetics/immunology/*microbiology/*pathology ; Animals ; Bacteria/metabolism/pathogenicity ; Cell Division ; Cell Transformation, Neoplastic/*pathology ; Colitis/complications ; Colorectal Neoplasms/genetics/immunology/*microbiology/*pathology ; Disease Models, Animal ; Disease-Free Survival ; Genes, APC ; Humans ; Inflammation/genetics/immunology/microbiology/pathology ; Interleukin-17/genetics/*immunology ; Interleukin-23/deficiency/genetics/*immunology ; Mice ; Mice, Inbred C57BL ; Myeloid Cells/immunology/metabolism ; Myeloid Differentiation Factor 88/immunology/metabolism ; Signal Transduction ; Toll-Like Receptors/immunology/metabolism ; Tumor Microenvironment ; beta Catenin/metabolism
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    MEGF10 and MEGF11 mediate homotypic interactions required for mosaic spacing of retinal neurons (2012)
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    Publication Date: 2012-03-13
    Description: In many parts of the nervous system, neuronal somata display orderly spatial arrangements. In the retina, neurons of numerous individual subtypes form regular arrays called mosaics: they are less likely to be near neighbours of the same subtype than would occur by chance, resulting in 'exclusion zones' that separate them. Mosaic arrangements provide a mechanism to distribute each cell type evenly across the retina, ensuring that all parts of the visual field have access to a full set of processing elements. Remarkably, mosaics are independent of each other: although a neuron of one subtype is unlikely to be adjacent to another of the same subtype, there is no restriction on its spatial relationship to neighbouring neurons of other subtypes. This independence has led to the hypothesis that molecular cues expressed by specific subtypes pattern mosaics by mediating homotypic (within-subtype) short-range repulsive interactions. So far, however, no molecules have been identified that show such activity, so this hypothesis remains untested. Here we demonstrate in mouse that two related transmembrane proteins, MEGF10 and MEGF11, have critical roles in the formation of mosaics by two retinal interneuron subtypes, starburst amacrine cells and horizontal cells. MEGF10 and 11 and their invertebrate relatives Caenorhabditis elegans CED-1 and Drosophila Draper have hitherto been studied primarily as receptors necessary for engulfment of debris following apoptosis or axonal injury. Our results demonstrate that members of this gene family can also serve as subtype-specific ligands that pattern neuronal arrays.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3310952/" 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/PMC3310952/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kay, Jeremy N -- Chu, Monica W -- Sanes, Joshua R -- EY022073/EY/NEI NIH HHS/ -- NS029169/NS/NINDS NIH HHS/ -- R01 EY022073/EY/NEI NIH HHS/ -- R01 NS029169/NS/NINDS NIH HHS/ -- R01 NS029169-20/NS/NINDS NIH HHS/ -- R01 NS029169-21/NS/NINDS NIH HHS/ -- R01 NS029169-22/NS/NINDS NIH HHS/ -- R37 NS029169/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Mar 11;483(7390):465-9. doi: 10.1038/nature10877.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, 52 Oxford Street, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22407321" target="_blank"〉PubMed〈/a〉
    Keywords: Amacrine Cells/*cytology/metabolism ; Animals ; Cell Adhesion ; Gene Expression Regulation ; HEK293 Cells ; Humans ; Ligands ; Membrane Proteins/deficiency/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Photoreceptor Cells, Vertebrate/metabolism ; Retinal Horizontal Cells/*cytology/metabolism
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    An epigenetic silencing pathway controlling T helper 2 cell lineage commitment (2012)
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    Publication Date: 2012-07-06
    Description: During immune responses, naive CD4+ T cells differentiate into several T helper (TH) cell subsets under the control of lineage-specifying genes. These subsets (TH1, TH2 and TH17 cells and regulatory T cells) secrete distinct cytokines and are involved in protection against different types of infection. Epigenetic mechanisms are involved in the regulation of these developmental programs, and correlations have been drawn between the levels of particular epigenetic marks and the activity or silencing of specifying genes during differentiation. Nevertheless, the functional relevance of the epigenetic pathways involved in TH cell subset differentiation and commitment is still unclear. Here we explore the role of the SUV39H1-H3K9me3-HP1alpha silencing pathway in the control of TH2 lineage stability. This pathway involves the histone methylase SUV39H1, which participates in the trimethylation of histone H3 on lysine 9 (H3K9me3), a modification that provides binding sites for heterochromatin protein 1alpha (HP1alpha) and promotes transcriptional silencing. This pathway was initially associated with heterochromatin formation and maintenance but can also contribute to the regulation of euchromatic genes. We now propose that the SUV39H1-H3K9me3-HP1alpha pathway participates in maintaining the silencing of TH1 loci, ensuring TH2 lineage stability. In TH2 cells that are deficient in SUV39H1, the ratio between trimethylated and acetylated H3K9 is impaired, and the binding of HP1alpha at the promoters of silenced TH1 genes is reduced. Despite showing normal differentiation, both SUV39H1-deficient TH2 cells and HP1alpha-deficient TH2 cells, in contrast to wild-type cells, expressed TH1 genes when recultured under conditions that drive differentiation into TH1 cells. In a mouse model of TH2-driven allergic asthma, the chemical inhibition or loss of SUV39H1 skewed T-cell responses towards TH1 responses and decreased the lung pathology. These results establish a link between the SUV39H1-H3K9me3-HP1alpha pathway and the stability of TH2 cells, and they identify potential targets for therapeutic intervention in TH2-cell-mediated inflammatory diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Allan, Rhys S -- Zueva, Elina -- Cammas, Florence -- Schreiber, Heidi A -- Masson, Vanessa -- Belz, Gabrielle T -- Roche, Daniele -- Maison, Christele -- Quivy, Jean-Pierre -- Almouzni, Genevieve -- Amigorena, Sebastian -- England -- Nature. 2012 Jul 12;487(7406):249-53. doi: 10.1038/nature11173.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Curie Research Center, 26 rue d'Ulm, 75248 Paris Cedex 05, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763435" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Asthma/enzymology/immunology/pathology ; Cell Differentiation/genetics/immunology ; Cell Lineage/genetics/immunology ; Chromosomal Proteins, Non-Histone/metabolism ; Disease Models, Animal ; *Epigenesis, Genetic ; Female ; Gene Expression Regulation ; Gene Silencing ; Histones/metabolism ; Male ; Methyltransferases/deficiency/metabolism ; Mice ; Mice, Inbred C57BL ; Promoter Regions, Genetic ; Repressor Proteins/deficiency/metabolism ; Th1 Cells/metabolism ; Th2 Cells/*cytology/enzymology/*immunology
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    Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-12-25
    Description: The splenic marginal zone is a unique microenvironment where resident immune cells are exposed to the open blood circulation. Even though it has an important role in responses against blood-borne antigens, lymphocyte migration in the marginal zone has not been intravitally visualized due to challenges associated with achieving adequate imaging depth in this abdominal organ. Here we develop a two-photon microscopy procedure to study marginal zone and follicular B-cell movement in the live mouse spleen. We show that marginal zone B cells are highly motile and exhibit long membrane extensions. Marginal zone B cells shuttle between the marginal zone and follicles with at least one-fifth of the cells exchanging between compartments per hour, a behaviour that explains their ability to deliver antigens rapidly from the open blood circulation to the secluded follicles. Follicular B cells also transit from follicles to the marginal zone, but unlike marginal zone B cells, they fail to undergo integrin-mediated adhesion, become caught in fluid flow and are carried into the red pulp. Follicular B-cell egress via the marginal zone is sphingosine-1-phosphate receptor-1 (S1PR1)-dependent. This study shows that marginal zone B cells migrate continually between marginal zone and follicles and establishes the marginal zone as a site of S1PR1-dependent B-cell exit from follicles. The results also show how adhesive differences of similar cells critically influence their behaviour in the same microenvironment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3561487/" 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/PMC3561487/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arnon, Tal I -- Horton, Robert M -- Grigorova, Irina L -- Cyster, Jason G -- AI74847/AI/NIAID NIH HHS/ -- P30 DK063720/DK/NIDDK NIH HHS/ -- R01 AI074847/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Jan 31;493(7434):684-8. doi: 10.1038/nature11738. Epub 2012 Dec 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23263181" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/drug effects/immunology ; Cell Adhesion/immunology ; Cell Movement/drug effects/immunology ; Dendritic Cells, Follicular/cytology/immunology ; Fingolimod Hydrochloride ; Immunosuppressive Agents/pharmacology ; Mice ; Mice, Inbred C57BL ; Microscopy, Confocal ; Propylene Glycols/pharmacology ; Sphingosine/analogs & derivatives/pharmacology ; Spleen/*cytology/immunology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Suppression of neuroinflammation by astrocytic dopamine D2 receptors via alphaB-crystallin (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-12-18
    Description: Chronic neuroinflammation is a common feature of the ageing brain and some neurodegenerative disorders. However, the molecular and cellular mechanisms underlying the regulation of innate immunity in the central nervous system remain elusive. Here we show that the astrocytic dopamine D2 receptor (DRD2) modulates innate immunity through alphaB-crystallin (CRYAB), which is known to suppress neuroinflammation. We demonstrate that knockout mice lacking Drd2 showed remarkable inflammatory response in multiple central nervous system regions and increased the vulnerability of nigral dopaminergic neurons to neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Astrocytes null for Drd2 became hyper-responsive to immune stimuli with a marked reduction in the level of CRYAB. Preferential ablation of Drd2 in astrocytes robustly activated astrocytes in the substantia nigra. Gain- or loss-of-function studies showed that CRYAB is critical for DRD2-mediated modulation of innate immune response in astrocytes. Furthermore, treatment of wild-type mice with the selective DRD2 agonist quinpirole increased resistance of the nigral dopaminergic neurons to MPTP through partial suppression of inflammation. Our study indicates that astrocytic DRD2 activation normally suppresses neuroinflammation in the central nervous system through a CRYAB-dependent mechanism, and provides a new strategy for targeting the astrocyte-mediated innate immune response in the central nervous system during ageing and disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shao, Wei -- Zhang, Shu-zhen -- Tang, Mi -- Zhang, Xin-hua -- Zhou, Zheng -- Yin, Yan-qing -- Zhou, Qin-bo -- Huang, Yuan-yuan -- Liu, Ying-jun -- Wawrousek, Eric -- Chen, Teng -- Li, Sheng-bin -- Xu, Ming -- Zhou, Jiang-ning -- Hu, Gang -- Zhou, Jia-wei -- England -- Nature. 2013 Feb 7;494(7435):90-4. doi: 10.1038/nature11748. Epub 2012 Dec 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23242137" target="_blank"〉PubMed〈/a〉
    Keywords: 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine/pharmacology ; Animals ; Astrocytes/drug effects/*immunology/*metabolism ; Dopaminergic Neurons/drug effects ; Immunity, Innate/drug effects ; Inflammation/chemically induced/genetics/*immunology/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Microglia/cytology/immunology ; Neuroprotective Agents/metabolism ; Quinpirole/pharmacology ; Receptors, Dopamine D2/agonists/deficiency/genetics/*metabolism ; Substantia Nigra/cytology/drug effects ; alpha-Crystallin B Chain/genetics/*metabolism
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    Inhibition dominates sensory responses in the awake cortex (2012)
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    Publication Date: 2012-11-23
    Description: The activity of the cerebral cortex is thought to depend on the precise relationship between synaptic excitation and inhibition. In the visual cortex, in particular, intracellular measurements have related response selectivity to coordinated increases in excitation and inhibition. These measurements, however, have all been made during anaesthesia, which strongly influences cortical state and therefore sensory processing. The synaptic activity that is evoked by visual stimulation during wakefulness is unknown. Here we measured visually evoked responses--and the underlying synaptic conductances--in the visual cortex of anaesthetized and awake mice. Under anaesthesia, responses could be elicited from a large region of visual space and were prolonged. During wakefulness, responses were more spatially selective and much briefer. Whole-cell patch-clamp recordings of synaptic conductances showed a difference in synaptic inhibition between the two conditions. Under anaesthesia, inhibition tracked excitation in amplitude and spatial selectivity. By contrast, during wakefulness, inhibition was much stronger than excitation and had extremely broad spatial selectivity. We conclude that during wakefulness, cortical responses to visual stimulation are dominated by synaptic inhibition, restricting the spatial spread and temporal persistence of neural activity. These results provide a direct glimpse of synaptic mechanisms that control sensory responses in the awake cortex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537822/" 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/PMC3537822/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Haider, Bilal -- Hausser, Michael -- Carandini, Matteo -- 094077/Wellcome Trust/United Kingdom -- 095669/Wellcome Trust/United Kingdom -- G0800791/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Jan 3;493(7430):97-100. doi: 10.1038/nature11665. Epub 2012 Nov 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK. b.haider@ucl.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23172139" target="_blank"〉PubMed〈/a〉
    Keywords: Anesthesia ; Animals ; Female ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neural Inhibition/*physiology ; Patch-Clamp Techniques ; Photic Stimulation ; Synapses/metabolism ; Synaptic Transmission ; Time Factors ; Visual Cortex/*physiology ; Wakefulness/*physiology
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    Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists (2012)
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    Publication Date: 2012-03-31
    Description: Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-alpha and REV-ERB-beta have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" 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/PMC3343186/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Wang, Yongjun -- Banerjee, Subhashis -- Hughes, Travis -- Kojetin, Douglas J -- Lundasen, Thomas -- Shin, Youseung -- Liu, Jin -- Cameron, Michael D -- Noel, Romain -- Yoo, Seung-Hee -- Takahashi, Joseph S -- Butler, Andrew A -- Kamenecka, Theodore M -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- MH092769/MH/NIMH NIH HHS/ -- R01 DK073189/DK/NIDDK NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-05/DK/NIDDK NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- R01 MH092769-02/MH/NIMH NIH HHS/ -- R01 MH093429/MH/NIMH NIH HHS/ -- R01 MH093429-01A1/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 29;485(7396):62-8. doi: 10.1038/nature11030.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460951" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/drug effects/metabolism ; Animals ; Biological Clocks/drug effects/genetics/physiology ; Circadian Rhythm/*drug effects/genetics/*physiology ; Disease Models, Animal ; Energy Metabolism/*drug effects ; HEK293 Cells ; Humans ; Hypothalamus/drug effects/metabolism ; Liver/drug effects/metabolism ; Metabolome/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Muscle, Skeletal/drug effects/metabolism ; Nuclear Receptor Subfamily 1, Group D, Member 1/*antagonists & ; inhibitors/metabolism ; Obesity/chemically induced/drug therapy/metabolism ; Pyrrolidines/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors/metabolism ; Repressor Proteins/*antagonists & inhibitors/metabolism ; Thiophenes/*pharmacology
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    A biophysical signature of network affiliation and sensory processing in mitral cells (2012)
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    Publication Date: 2012-07-24
    Description: One defining characteristic of the mammalian brain is its neuronal diversity. For a given region, substructure, layer or even cell type, variability in neuronal morphology and connectivity persists. Although it is well known that such cellular properties vary considerably according to neuronal type, the substantial biophysical diversity of neurons of the same morphological class is typically averaged out and ignored. Here we show that the amplitude of hyperpolarization-evoked sag of membrane potential recorded in olfactory bulb mitral cells is an emergent, homotypic property of local networks and sensory information processing. Simultaneous whole-cell recordings from pairs of cells show that the amount of hyperpolarization-evoked sag potential and current (Ih) is stereotypic for mitral cells belonging to the same glomerular circuit. This is corroborated by a mosaic, glomerulus-based pattern of expression of the HCN2 (hyperpolarization-activated cyclic nucleotide-gated channel 2) subunit of the Ih channel. Furthermore, inter-glomerular differences in both membrane potential sag and HCN2 protein are diminished when sensory input to glomeruli is genetically and globally altered so that only one type of odorant receptor is universally expressed. Population diversity in this intrinsic property therefore reflects differential expression between local mitral cell networks processing distinct odour-related information.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3442227/" 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/PMC3442227/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Angelo, Kamilla -- Rancz, Ede A -- Pimentel, Diogo -- Hundahl, Christian -- Hannibal, Jens -- Fleischmann, Alexander -- Pichler, Bruno -- Margrie, Troy W -- 085509/Wellcome Trust/United Kingdom -- MC_U117597156/Medical Research Council/United Kingdom -- MC_U1175975156/Medical Research Council/United Kingdom -- U.9500(97156)/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Aug 16;488(7411):375-8. doi: 10.1038/nature11291.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22820253" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Gene Expression Profiling ; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels ; Ion Channels/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Neurological ; Nerve Net/*physiology ; Olfactory Bulb/*cytology/*physiology ; Potassium Channels ; Receptors, Odorant/metabolism ; Smell/*physiology
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    Targeting nuclear RNA for in vivo correction of myotonic dystrophy (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-08-04
    Description: Antisense oligonucleotides (ASOs) hold promise for gene-specific knockdown in diseases that involve RNA or protein gain-of-function effects. In the hereditary degenerative disease myotonic dystrophy type 1 (DM1), transcripts from the mutant allele contain an expanded CUG repeat and are retained in the nucleus. The mutant RNA exerts a toxic gain-of-function effect, making it an appropriate target for therapeutic ASOs. However, despite improvements in ASO chemistry and design, systemic use of ASOs is limited because uptake in many tissues, including skeletal and cardiac muscle, is not sufficient to silence target messenger RNAs. Here we show that nuclear-retained transcripts containing expanded CUG (CUG(exp)) repeats are unusually sensitive to antisense silencing. In a transgenic mouse model of DM1, systemic administration of ASOs caused a rapid knockdown of CUG(exp) RNA in skeletal muscle, correcting the physiological, histopathologic and transcriptomic features of the disease. The effect was sustained for up to 1 year after treatment was discontinued. Systemically administered ASOs were also effective for muscle knockdown of Malat1, a long non-coding RNA (lncRNA) that is retained in the nucleus. These results provide a general strategy to correct RNA gain-of-function effects and to modulate the expression of expanded repeats, lncRNAs and other transcripts with prolonged nuclear residence.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221572/" 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/PMC4221572/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wheeler, Thurman M -- Leger, Andrew J -- Pandey, Sanjay K -- MacLeod, A Robert -- Nakamori, Masayuki -- Cheng, Seng H -- Wentworth, Bruce M -- Bennett, C Frank -- Thornton, Charles A -- AR/NS48143/AR/NIAMS NIH HHS/ -- AR049077/AR/NIAMS NIH HHS/ -- K08 NS064293/NS/NINDS NIH HHS/ -- K08NS064293/NS/NINDS NIH HHS/ -- U01NS072323/NS/NINDS NIH HHS/ -- U54 NS048843/NS/NINDS NIH HHS/ -- U54NS48843/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):111-5. doi: 10.1038/nature11362.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, University of Rochester, 601 Elmwood Avenue, Rochester, New York 14642, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22859208" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Base Sequence ; Cell Nucleus/drug effects/*genetics ; Disease Models, Animal ; Gene Knockdown Techniques ; *Gene Silencing ; Humans ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Inbred mdx ; Mice, Transgenic ; Muscle, Skeletal/drug effects/metabolism ; Myotonic Dystrophy/*genetics/pathology/physiopathology/*therapy ; Myotonin-Protein Kinase ; Oligonucleotides, Antisense/genetics/pharmacology/therapeutic use ; Protein-Serine-Threonine Kinases/genetics ; RNA/*antagonists & inhibitors/*genetics/metabolism ; RNA, Long Noncoding ; RNA, Messenger/antagonists & inhibitors/genetics/metabolism ; RNA, Untranslated/genetics ; Ribonuclease H/metabolism ; Transcriptome/drug effects/genetics ; Trinucleotide Repeat Expansion/genetics
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    An ultraviolet-radiation-independent pathway to melanoma carcinogenesis in the red hair/fair skin background (2012)
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    Publication Date: 2012-11-06
    Description: People with pale skin, red hair, freckles and an inability to tan--the 'red hair/fair skin' phenotype--are at highest risk of developing melanoma, compared to all other pigmentation types. Genetically, this phenotype is frequently the product of inactivating polymorphisms in the melanocortin 1 receptor (MC1R) gene. MC1R encodes a cyclic AMP-stimulating G-protein-coupled receptor that controls pigment production. Minimal receptor activity, as in red hair/fair skin polymorphisms, produces the red/yellow pheomelanin pigment, whereas increasing MC1R activity stimulates the production of black/brown eumelanin. Pheomelanin has weak shielding capacity against ultraviolet radiation relative to eumelanin, and has been shown to amplify ultraviolet-A-induced reactive oxygen species. Several observations, however, complicate the assumption that melanoma risk is completely ultraviolet-radiation-dependent. For example, unlike non-melanoma skin cancers, melanoma is not restricted to sun-exposed skin and ultraviolet radiation signature mutations are infrequently oncogenic drivers. Although linkage of melanoma risk to ultraviolet radiation exposure is beyond doubt, ultraviolet-radiation-independent events are likely to have a significant role. Here we introduce a conditional, melanocyte-targeted allele of the most common melanoma oncoprotein, BRAF(V600E), into mice carrying an inactivating mutation in the Mc1r gene (these mice have a phenotype analogous to red hair/fair skin humans). We observed a high incidence of invasive melanomas without providing additional gene aberrations or ultraviolet radiation exposure. To investigate the mechanism of ultraviolet-radiation-independent carcinogenesis, we introduced an albino allele, which ablates all pigment production on the Mc1r(e/e) background. Selective absence of pheomelanin synthesis was protective against melanoma development. In addition, normal Mc1r(e/e) mouse skin was found to have significantly greater oxidative DNA and lipid damage than albino-Mc1r(e/e) mouse skin. These data suggest that the pheomelanin pigment pathway produces ultraviolet-radiation-independent carcinogenic contributions to melanomagenesis by a mechanism of oxidative damage. Although protection from ultraviolet radiation remains important, additional strategies may be required for optimal melanoma prevention.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3521494/" 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/PMC3521494/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitra, Devarati -- Luo, Xi -- Morgan, Ann -- Wang, Jin -- Hoang, Mai P -- Lo, Jennifer -- Guerrero, Candace R -- Lennerz, Jochen K -- Mihm, Martin C -- Wargo, Jennifer A -- Robinson, Kathleen C -- Devi, Suprabha P -- Vanover, Jillian C -- D'Orazio, John A -- McMahon, Martin -- Bosenberg, Marcus W -- Haigis, Kevin M -- Haber, Daniel A -- Wang, Yinsheng -- Fisher, David E -- 5R01 AR043369-16/AR/NIAMS NIH HHS/ -- F30 ES020663-01/ES/NIEHS NIH HHS/ -- R01 AR043369/AR/NIAMS NIH HHS/ -- R01 CA101864/CA/NCI NIH HHS/ -- R01 CA129933/CA/NCI NIH HHS/ -- R01 CA131075/CA/NCI NIH HHS/ -- R01 CA176839/CA/NCI NIH HHS/ -- R01-CA101864/CA/NCI NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):449-53. doi: 10.1038/nature11624. Epub 2012 Oct 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cutaneous Biology Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23123854" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Gene Expression Regulation/drug effects ; Hair Color/*genetics ; Indoles/pharmacology ; Melanins/metabolism ; Melanoma/*genetics ; Mice ; Mice, Inbred C57BL ; Monophenol Monooxygenase/genetics ; Peroxidases/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins B-raf/genetics ; Receptor, Melanocortin, Type 1/genetics ; Skin Pigmentation/*genetics ; Sulfonamides/pharmacology ; Survival Analysis ; Tumor Cells, Cultured ; *Ultraviolet Rays
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    Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells (2012)
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    Publication Date: 2012-06-23
    Description: Chemokines have a central role in regulating processes essential to the immune function of T cells, such as their migration within lymphoid tissues and targeting of pathogens in sites of inflammation. Here we track T cells using multi-photon microscopy to demonstrate that the chemokine CXCL10 enhances the ability of CD8+ T cells to control the pathogen Toxoplasma gondii in the brains of chronically infected mice. This chemokine boosts T-cell function in two different ways: it maintains the effector T-cell population in the brain and speeds up the average migration speed without changing the nature of the walk statistics. Notably, these statistics are not Brownian; rather, CD8+ T-cell motility in the brain is well described by a generalized Levy walk. According to our model, this unexpected feature enables T cells to find rare targets with more than an order of magnitude more efficiency than Brownian random walkers. Thus, CD8+ T-cell behaviour is similar to Levy strategies reported in organisms ranging from mussels to marine predators and monkeys, and CXCL10 aids T cells in shortening the average time taken to find rare targets.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3387349/" 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/PMC3387349/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harris, Tajie H -- Banigan, Edward J -- Christian, David A -- Konradt, Christoph -- Tait Wojno, Elia D -- Norose, Kazumi -- Wilson, Emma H -- John, Beena -- Weninger, Wolfgang -- Luster, Andrew D -- Liu, Andrea J -- Hunter, Christopher A -- AI-081478/AI/NIAID NIH HHS/ -- AI-090234/AI/NIAID NIH HHS/ -- AI-41158/AI/NIAID NIH HHS/ -- AI-42334/AI/NIAID NIH HHS/ -- CA-069212/CA/NCI NIH HHS/ -- EY-021314/EY/NEI NIH HHS/ -- F32 AI098374/AI/NIAID NIH HHS/ -- F32 AI098374-01/AI/NIAID NIH HHS/ -- R01 AI041158/AI/NIAID NIH HHS/ -- R01 AI041158-14/AI/NIAID NIH HHS/ -- R01 CA069212/CA/NCI NIH HHS/ -- R01 NS072298/NS/NINDS NIH HHS/ -- R21 EY021314/EY/NEI NIH HHS/ -- R21 EY021314-02/EY/NEI NIH HHS/ -- T32 AI007532/AI/NIAID NIH HHS/ -- T32 AI007532-15/AI/NIAID NIH HHS/ -- T32 AR007442/AR/NIAMS NIH HHS/ -- T32 AR007442-25/AR/NIAMS NIH HHS/ -- T32-AI-055400/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Jun 28;486(7404):545-8. doi: 10.1038/nature11098.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722867" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/immunology/microbiology ; CD8-Positive T-Lymphocytes/*cytology/*immunology ; *Cell Movement ; Chemokine CXCL10/antagonists & inhibitors/genetics/*immunology ; Female ; Ligands ; Male ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; Receptors, CXCR3/genetics/metabolism ; Time Factors ; Toxoplasma/growth & development/immunology
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    Input-specific control of reward and aversion in the ventral tegmental area (2012)
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    Publication Date: 2012-10-16
    Description: Ventral tegmental area (VTA) dopamine neurons have important roles in adaptive and pathological brain functions related to reward and motivation. However, it is unknown whether subpopulations of VTA dopamine neurons participate in distinct circuits that encode different motivational signatures, and whether inputs to the VTA differentially modulate such circuits. Here we show that, because of differences in synaptic connectivity, activation of inputs to the VTA from the laterodorsal tegmentum and the lateral habenula elicit reward and aversion in mice, respectively. Laterodorsal tegmentum neurons preferentially synapse on dopamine neurons projecting to the nucleus accumbens lateral shell, whereas lateral habenula neurons synapse primarily on dopamine neurons projecting to the medial prefrontal cortex as well as on GABAergic (gamma-aminobutyric-acid-containing) neurons in the rostromedial tegmental nucleus. These results establish that distinct VTA circuits generate reward and aversion, and thereby provide a new framework for understanding the circuit basis of adaptive and pathological motivated behaviours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493743/" 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/PMC3493743/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lammel, Stephan -- Lim, Byung Kook -- Ran, Chen -- Huang, Kee Wui -- Betley, Michael J -- Tye, Kay M -- Deisseroth, Karl -- Malenka, Robert C -- NS069375/NS/NINDS NIH HHS/ -- P50 MH086403/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):212-7. doi: 10.1038/nature11527. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, 265 Campus Drive, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23064228" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avoidance Learning/drug effects/*physiology ; Axons/metabolism ; Dopamine/metabolism ; Dopamine Antagonists/pharmacology ; Dopaminergic Neurons/metabolism ; GABAergic Neurons/metabolism ; Habenula/cytology/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neural Pathways/*physiology ; Receptors, Dopamine/metabolism ; *Reward ; Synapses/metabolism ; Ventral Tegmental Area/cytology/*physiology
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    Deciphering a neuronal circuit that mediates appetite (2012)
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    Publication Date: 2012-03-16
    Description: Hypothalamic neurons that co-express agouti-related protein (AgRP), neuropeptide Y and gamma-aminobutyric acid (GABA) are known to promote feeding and weight gain by integration of various nutritional, hormonal, and neuronal signals. Ablation of these neurons in mice leads to cessation of feeding that is accompanied by activation of Fos in most regions where they project. Previous experiments have indicated that the ensuing starvation is due to aberrant activation of the parabrachial nucleus (PBN) and it could be prevented by facilitating GABA(A) receptor signalling in the PBN within a critical adaptation period. We speculated that loss of GABA signalling from AgRP-expressing neurons (AgRP neurons) within the PBN results in unopposed excitation of the PBN, which in turn inhibits feeding. However, the source of the excitatory inputs to the PBN was unknown. Here we show that glutamatergic neurons in the nucleus tractus solitarius (NTS) and caudal serotonergic neurons control the excitability of PBN neurons and inhibit feeding. Blockade of serotonin (5-HT(3)) receptor signalling in the NTS by either the chronic administration of ondansetron or the genetic inactivation of Tph2 in caudal serotonergic neurons that project to the NTS protects against starvation when AgRP neurons are ablated. Likewise, genetic inactivation of glutamatergic signalling by the NTS onto N-methyl D-aspartate-type glutamate receptors in the PBN prevents starvation. We also show that suppressing glutamatergic output of the PBN reinstates normal appetite after AgRP neuron ablation, whereas it promotes weight gain without AgRP neuron ablation. Thus we identify the PBN as a hub that integrates signals from several brain regions to bidirectionally modulate feeding and body weight.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000532/" 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/PMC4000532/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Qi -- Clark, Michael S -- Palmiter, Richard D -- DA024908/DA/NIDA NIH HHS/ -- R01 DA024908/DA/NIDA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 14;483(7391):594-7. doi: 10.1038/nature10899.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Biochemistry, University of Washington School of Medicine, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22419158" target="_blank"〉PubMed〈/a〉
    Keywords: Agouti-Related Protein/metabolism ; Animals ; Appetite/drug effects/*physiology ; Body Weight/drug effects ; Feeding Behavior/drug effects/physiology ; Female ; Glutamic Acid/metabolism ; Hypothalamus/*cytology/drug effects/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Neurons/drug effects/*physiology ; Ondansetron/pharmacology ; Receptors, GABA-A/metabolism ; Receptors, N-Methyl-D-Aspartate/metabolism ; Serotonergic Neurons/drug effects/metabolism ; Solitary Nucleus/cytology ; Starvation/drug therapy/physiopathology/prevention & control ; Weight Gain/drug effects/physiology ; gamma-Aminobutyric Acid/metabolism
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    'Slings' enable neutrophil rolling at high shear (2012)
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    Publication Date: 2012-07-06
    Description: Most leukocytes can roll along the walls of venules at low shear stress (1 dyn cm-2), but neutrophils have the ability to roll at tenfold higher shear stress in microvessels in vivo. The mechanisms involved in this shear-resistant rolling are known to involve cell flattening and pulling of long membrane tethers at the rear. Here we show that these long tethers do not retract as postulated, but instead persist and appear as 'slings' at the front of rolling cells. We demonstrate slings in a model of acute inflammation in vivo and on P-selectin in vitro, where P-selectin-glycoprotein-ligand-1 (PSGL-1) is found in discrete sticky patches whereas LFA-1 is expressed over the entire length on slings. As neutrophils roll forward, slings wrap around the rolling cells and undergo a step-wise peeling from the P-selectin substrate enabled by the failure of PSGL-1 patches under hydrodynamic forces. The 'step-wise peeling of slings' is distinct from the 'pulling of tethers' reported previously. Each sling effectively lays out a cell-autonomous adhesive substrate in front of neutrophils rolling at high shear stress during inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433404/" 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/PMC3433404/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sundd, Prithu -- Gutierrez, Edgar -- Koltsova, Ekaterina K -- Kuwano, Yoshihiro -- Fukuda, Satoru -- Pospieszalska, Maria K -- Groisman, Alex -- Ley, Klaus -- EB02185/EB/NIBIB NIH HHS/ -- R01 EB002185/EB/NIBIB NIH HHS/ -- England -- Nature. 2012 Aug 16;488(7411):399-403. doi: 10.1038/nature11248.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763437" target="_blank"〉PubMed〈/a〉
    Keywords: Adhesiveness ; Animals ; Antigens, CD/metabolism ; Cell Adhesion ; Cell Adhesion Molecules/metabolism ; E-Selectin/metabolism ; Inflammation/immunology/metabolism/pathology ; Intercellular Adhesion Molecule-1/metabolism ; *Leukocyte Rolling ; Lymphocyte Function-Associated Antigen-1/metabolism ; Membrane Glycoproteins/metabolism ; Mice ; Mice, Inbred C57BL ; Microvessels/metabolism ; Neutrophils/*cytology/immunology/*metabolism ; P-Selectin/metabolism ; *Shear Strength ; Th1 Cells/cytology/immunology ; Venules/metabolism
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    Infection regulates pro-resolving mediators that lower antibiotic requirements (2012)
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    Publication Date: 2012-04-28
    Description: Underlying mechanisms for how bacterial infections contribute to active resolution of acute inflammation are unknown. Here, we performed exudate leukocyte trafficking and mediator-metabololipidomics of murine peritoneal Escherichia coli infections with temporal identification of pro-inflammatory (prostaglandins and leukotrienes) and specialized pro-resolving mediators (SPMs). In self-resolving E. coli exudates (10(5) colony forming units, c.f.u.), the dominant SPMs identified were resolvin (Rv) D5 and protectin D1 (PD1), which at 12 h were at significantly greater levels than in exudates from higher titre E. coli (10(7) c.f.u.)-challenged mice. Germ-free mice had endogenous RvD1 and PD1 levels higher than in conventional mice. RvD1 and RvD5 (nanograms per mouse) each reduced bacterial titres in blood and exudates, E. coli-induced hypothermia and increased survival, demonstrating the first actions of RvD5. With human polymorphonuclear neutrophils and macrophages, RvD1, RvD5 and PD1 each directly enhanced phagocytosis of E. coli, and RvD5 counter-regulated a panel of pro-inflammatory genes, including NF-kappaB and TNF-alpha. RvD5 activated the RvD1 receptor, GPR32, to enhance phagocytosis. With self-limited E. coli infections, RvD1 and the antibiotic ciprofloxacin accelerated resolution, each shortening resolution intervals (R(i)). Host-directed RvD1 actions enhanced ciprofloxacin's therapeutic actions. In 10(7) c.f.u. E. coli infections, SPMs (RvD1, RvD5, PD1) together with ciprofloxacin also heightened host antimicrobial responses. In skin infections, SPMs enhanced vancomycin clearance of Staphylococcus aureus. These results demonstrate that specific SPMs are temporally and differentially regulated during infections and that they are anti-phlogistic, enhance containment and lower antibiotic requirements for bacterial clearance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3340015/" 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/PMC3340015/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chiang, Nan -- Fredman, Gabrielle -- Backhed, Fredrik -- Oh, Sungwhan F -- Vickery, Thad -- Schmidt, Birgitta A -- Serhan, Charles N -- P01 GM095467/GM/NIGMS NIH HHS/ -- P01 GM095467-01/GM/NIGMS NIH HHS/ -- P01 GM095467-02/GM/NIGMS NIH HHS/ -- P01GM095467/GM/NIGMS NIH HHS/ -- R01 GM038765/GM/NIGMS NIH HHS/ -- R01 GM038765-24/GM/NIGMS NIH HHS/ -- R01 GM038765-25/GM/NIGMS NIH HHS/ -- R01 GM038765-26/GM/NIGMS NIH HHS/ -- R01GM38765/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Apr 25;484(7395):524-8. doi: 10.1038/nature11042.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22538616" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/*pharmacology/therapeutic use ; Docosahexaenoic Acids/*metabolism ; Escherichia coli/*drug effects/immunology ; Escherichia coli Infections/drug therapy/*metabolism/microbiology ; Humans ; Hypothermia/prevention & control ; Macrophages/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Microbial Viability/drug effects ; Neutrophils/immunology ; Peritonitis/drug therapy/metabolism/microbiology ; Phagocytosis ; Skin Diseases/drug therapy/metabolism/microbiology ; Staphylococcal Infections/drug therapy/*metabolism/microbiology ; Staphylococcus aureus/drug effects/immunology ; Vancomycin/pharmacology/therapeutic use
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    Pregnancy imprints regulatory memory that sustains anergy to fetal antigen (2012)
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    Publication Date: 2012-10-02
    Description: Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3(+) regulatory T cells (T(reg) cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal T(reg) expansion. Importantly, however, the antigen specificity and cellular origin of maternal T(reg) cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3(+) CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific T(reg) cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of T(reg) cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3(+) cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3(+) cells each contribute to T(reg) expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3(+) cell ablation. Thus, pregnancy imprints FOXP3(+) CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting T(reg) cell memory.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465465/" 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/PMC3465465/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rowe, Jared H -- Ertelt, James M -- Xin, Lijun -- Way, Sing Sing -- F30 DK084674/DK/NIDDK NIH HHS/ -- F30DK084674/DK/NIDDK NIH HHS/ -- R01 AI087830/AI/NIAID NIH HHS/ -- R01 AI100934/AI/NIAID NIH HHS/ -- R01AI087830/AI/NIAID NIH HHS/ -- R01AI100934/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Oct 4;490(7418):102-6. doi: 10.1038/nature11462. Epub 2012 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Minnesota School of Medicine, Department of Pediatrics, Minneapolis, Minnesota 55455, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023128" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Antigens/*immunology ; CD4-Positive T-Lymphocytes/cytology/immunology/metabolism/transplantation ; Clonal Anergy/*immunology ; Female ; Fetal Proteins/*immunology ; Fetus/immunology ; Forkhead Transcription Factors/metabolism ; Immunologic Memory/genetics/*immunology ; Interferon-gamma/immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Postpartum Period/immunology ; Pregnancy ; T-Lymphocytes, Regulatory/cytology/immunology/metabolism
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    Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions (2012)
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    Publication Date: 2012-10-16
    Description: B cells regulate immune responses by producing antigen-specific antibodies. However, specific B-cell subsets can also negatively regulate T-cell immune responses, and have been termed regulatory B cells. Human and mouse regulatory B cells (B10 cells) with the ability to express the inhibitory cytokine interleukin-10 (IL-10) have been identified. Although rare, B10 cells are potent negative regulators of antigen-specific inflammation and T-cell-dependent autoimmune diseases in mice. How B10-cell IL-10 production and regulation of antigen-specific immune responses are controlled in vivo without inducing systemic immunosuppression is unknown. Using a mouse model for multiple sclerosis, here we show that B10-cell maturation into functional IL-10-secreting effector cells that inhibit in vivo autoimmune disease requires IL-21 and CD40-dependent cognate interactions with T cells. Moreover, the ex vivo provision of CD40 and IL-21 receptor signals can drive B10-cell development and expansion by four-million-fold, and generate B10 effector cells producing IL-10 that markedly inhibit disease symptoms when transferred into mice with established autoimmune disease. The ex vivo expansion and reinfusion of autologous B10 cells may provide a novel and effective in vivo treatment for severe autoimmune diseases that are resistant to current therapies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3493692/" 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/PMC3493692/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshizaki, Ayumi -- Miyagaki, Tomomitsu -- DiLillo, David J -- Matsushita, Takashi -- Horikawa, Mayuka -- Kountikov, Evgueni I -- Spolski, Rosanne -- Poe, Jonathan C -- Leonard, Warren J -- Tedder, Thomas F -- AI057157/AI/NIAID NIH HHS/ -- AI56363/AI/NIAID NIH HHS/ -- U19 AI056363/AI/NIAID NIH HHS/ -- U54 AI057157/AI/NIAID NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):264-8. doi: 10.1038/nature11501. Epub 2012 Oct 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, 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/23064231" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD19/genetics/metabolism ; Antigens, CD40/immunology/metabolism ; Antigens, CD5/metabolism ; Autoimmunity/*immunology ; B-Lymphocytes, Regulatory/cytology/*immunology/metabolism/secretion ; Cell Division ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology/pathology ; Female ; Histocompatibility Antigens Class II/immunology ; Humans ; Interleukin-10/biosynthesis/immunology/secretion ; Interleukins/*immunology ; Mice ; Mice, Inbred C57BL ; Multiple Sclerosis/immunology/pathology ; Receptors, Interleukin-21/immunology/metabolism ; T-Lymphocytes/*immunology
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    Antibiotics in early life alter the murine colonic microbiome and adiposity (2012)
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    Publication Date: 2012-08-24
    Description: Antibiotics administered in low doses have been widely used as growth promoters in the agricultural industry since the 1950s, yet the mechanisms for this effect are unclear. Because antimicrobial agents of different classes and varying activity are effective across several vertebrate species, we proposed that such subtherapeutic administration alters the population structure of the gut microbiome as well as its metabolic capabilities. We generated a model of adiposity by giving subtherapeutic antibiotic therapy to young mice and evaluated changes in the composition and capabilities of the gut microbiome. Administration of subtherapeutic antibiotic therapy increased adiposity in young mice and increased hormone levels related to metabolism. We observed substantial taxonomic changes in the microbiome, changes in copies of key genes involved in the metabolism of carbohydrates to short-chain fatty acids, increases in colonic short-chain fatty acid levels, and alterations in the regulation of hepatic metabolism of lipids and cholesterol. In this model, we demonstrate the alteration of early-life murine metabolic homeostasis through antibiotic manipulation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3553221/" 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/PMC3553221/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Ilseung -- Yamanishi, Shingo -- Cox, Laura -- Methe, Barbara A -- Zavadil, Jiri -- Li, Kelvin -- Gao, Zhan -- Mahana, Douglas -- Raju, Kartik -- Teitler, Isabel -- Li, Huilin -- Alekseyenko, Alexander V -- Blaser, Martin J -- 1UL1-RR029893/RR/NCRR NIH HHS/ -- R01 DK090989/DK/NIDDK NIH HHS/ -- T-R01-DK090989/DK/NIDDK NIH HHS/ -- UL1 RR029893/RR/NCRR NIH HHS/ -- UL1 TR000038/TR/NCATS NIH HHS/ -- UL1-TR000038/TR/NCATS NIH HHS/ -- England -- Nature. 2012 Aug 30;488(7413):621-6. doi: 10.1038/nature11400.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, 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/22914093" target="_blank"〉PubMed〈/a〉
    Keywords: Adiposity/*drug effects/physiology ; Age Factors ; Animals ; Anti-Bacterial Agents/*administration & dosage/*pharmacology ; Body Composition/drug effects ; Body Weight/drug effects ; Bone Density/drug effects ; Bone Development/drug effects ; Cecum/drug effects/metabolism ; Cholesterol/metabolism ; Colon/*drug effects/*microbiology ; Fatty Acids, Volatile/metabolism ; Feces/microbiology ; Female ; Gastric Inhibitory Polypeptide/blood/metabolism ; Lipid Metabolism/drug effects ; Liver/drug effects/metabolism ; Male ; Metagenome/*drug effects ; Mice ; Mice, Inbred C57BL ; Polymerase Chain Reaction ; Weaning
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    Neuron-type-specific signals for reward and punishment in the ventral tegmental area (2012)
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    Publication Date: 2012-01-20
    Description: Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3271183/" 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/PMC3271183/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cohen, Jeremiah Y -- Haesler, Sebastian -- Vong, Linh -- Lowell, Bradford B -- Uchida, Naoshige -- F32 DK078478/DK/NIDDK NIH HHS/ -- F32 DK078478-01/DK/NIDDK NIH HHS/ -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30 DK046200-08/DK/NIDDK NIH HHS/ -- P30 DK057521/DK/NIDDK NIH HHS/ -- P30 DK057521-01/DK/NIDDK NIH HHS/ -- R01 DK075632/DK/NIDDK NIH HHS/ -- R01 DK075632-01/DK/NIDDK NIH HHS/ -- R01 DK075632-02/DK/NIDDK NIH HHS/ -- R01 DK075632-03/DK/NIDDK NIH HHS/ -- R01 DK075632-04/DK/NIDDK NIH HHS/ -- R01 DK075632-05/DK/NIDDK NIH HHS/ -- R01 DK075632-06/DK/NIDDK NIH HHS/ -- R01 DK075632-07/DK/NIDDK NIH HHS/ -- R01 DK089044/DK/NIDDK NIH HHS/ -- R01 DK089044-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 18;482(7383):85-8. doi: 10.1038/nature10754.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22258508" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cues ; Dopamine/metabolism ; Dopaminergic Neurons/*metabolism ; GABAergic Neurons/*metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Odors/analysis ; Principal Component Analysis ; *Punishment ; *Reward ; Rhodopsin/metabolism ; Ventral Tegmental Area/*cytology/*physiology ; gamma-Aminobutyric Acid/metabolism
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    A tumour suppressor network relying on the polyamine-hypusine axis (2012)
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    Publication Date: 2012-06-23
    Description: Tumour suppressor genes encode a broad class of molecules whose mutational attenuation contributes to malignant progression. In the canonical situation, the tumour suppressor is completely inactivated through a two-hit process involving a point mutation in one allele and chromosomal deletion of the other. Here, to identify tumour suppressor genes in lymphoma, we screen a short hairpin RNA library targeting genes deleted in human lymphomas. We functionally identify those genes whose suppression promotes tumorigenesis in a mouse lymphoma model. Of the nine tumour suppressors we identified, eight correspond to genes occurring in three physically linked 'clusters', suggesting that the common occurrence of large chromosomal deletions in human tumours reflects selective pressure to attenuate multiple genes. Among the new tumour suppressors are adenosylmethionine decarboxylase 1 (AMD1) and eukaryotic translation initiation factor 5A (eIF5A), two genes associated with hypusine, a unique amino acid produced as a product of polyamine metabolism through a highly conserved pathway. Through a secondary screen surveying the impact of all polyamine enzymes on tumorigenesis, we establish the polyamine-hypusine axis as a new tumour suppressor network regulating apoptosis. Unexpectedly, heterozygous deletions encompassing AMD1 and eIF5A often occur together in human lymphomas and co-suppression of both genes promotes lymphomagenesis in mice. Thus, some tumour suppressor functions can be disabled through a two-step process targeting different genes acting in the same pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530829/" 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/PMC3530829/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Scuoppo, Claudio -- Miething, Cornelius -- Lindqvist, Lisa -- Reyes, Jose -- Ruse, Cristian -- Appelmann, Iris -- Yoon, Seungtai -- Krasnitz, Alexander -- Teruya-Feldstein, Julie -- Pappin, Darryl -- Pelletier, Jerry -- Lowe, Scott W -- CA087497/CA/NCI NIH HHS/ -- CA148532/CA/NCI NIH HHS/ -- MOP-106530/Canadian Institutes of Health Research/Canada -- P01 CA013106/CA/NCI NIH HHS/ -- P01 CA087497/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jul 12;487(7406):244-8. doi: 10.1038/nature11126.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Watson School of Biological Sciences, Cold Spring Harbor Laboratory, New York 11724, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722845" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line, Tumor ; Disease Models, Animal ; Female ; Gene Deletion ; Gene Regulatory Networks ; Genetic Testing ; Humans ; Lymphoma, B-Cell/*genetics/physiopathology ; Lysine/*analogs & derivatives/chemistry ; Mice ; Mice, Inbred C57BL ; Polyamines/*chemistry ; RNA, Small Interfering/genetics/metabolism ; Reproducibility of Results ; Tumor Suppressor Proteins/*genetics
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    Rapid induction of inflammatory lipid mediators by the inflammasome in vivo (2012)
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    Publication Date: 2012-08-21
    Description: Detection of microbial products by host inflammasomes is an important mechanism of innate immune surveillance. Inflammasomes activate the caspase-1 (CASP1) protease, which processes the cytokines interleukin (IL)-1beta and IL-18, and initiates a lytic host cell death called pyroptosis. To identify novel CASP1 functions in vivo, we devised a strategy for cytosolic delivery of bacterial flagellin, a specific ligand for the NAIP5 (NLR family, apoptosis inhibitory protein 5)/NLRC4 (NLR family, CARD-domain-containing 4) inflammasome. Here we show that systemic inflammasome activation by flagellin leads to a loss of vascular fluid into the intestine and peritoneal cavity, resulting in rapid (less than 30 min) death in mice. This unexpected response depends on the inflammasome components NAIP5, NLRC4 and CASP1, but is independent of the production of IL-1beta or IL-18. Instead, inflammasome activation results, within minutes, in an 'eicosanoid storm'--a pathological release of signalling lipids, including prostaglandins and leukotrienes, that rapidly initiate inflammation and vascular fluid loss. Mice deficient in cyclooxygenase-1, a critical enzyme in prostaglandin biosynthesis, are resistant to these rapid pathological effects of systemic inflammasome activation by either flagellin or anthrax lethal toxin. Inflammasome-dependent biosynthesis of eicosanoids is mediated by the activation of cytosolic phospholipase A(2) in resident peritoneal macrophages, which are specifically primed for the production of eicosanoids by high expression of eicosanoid biosynthetic enzymes. Our results therefore identify eicosanoids as a previously unrecognized cell-type-specific signalling output of the inflammasome with marked physiological consequences in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3465483/" 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/PMC3465483/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉von Moltke, Jakob -- Trinidad, Norver J -- Moayeri, Mahtab -- Kintzer, Alexander F -- Wang, Samantha B -- van Rooijen, Nico -- Brown, Charles R -- Krantz, Bryan A -- Leppla, Stephen H -- Gronert, Karsten -- Vance, Russell E -- AI063302/AI/NIAID NIH HHS/ -- AI075039/AI/NIAID NIH HHS/ -- AI080749/AI/NIAID NIH HHS/ -- EY016136/EY/NEI NIH HHS/ -- EY022208/EY/NEI NIH HHS/ -- R01 EY016136/EY/NEI NIH HHS/ -- R01 EY022208/EY/NEI NIH HHS/ -- England -- Nature. 2012 Oct 4;490(7418):107-11. doi: 10.1038/nature11351. Epub 2012 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cell Biology, Division of Immunology and Pathogenesis, University of California at Berkeley, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22902502" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Bacterial/chemistry/genetics/metabolism ; Apoptosis Regulatory Proteins/deficiency/metabolism ; Bacterial Toxins/chemistry/genetics/metabolism ; Body Fluids/metabolism ; Body Temperature ; Calcium Signaling ; Calcium-Binding Proteins/deficiency/metabolism ; Capillary Permeability ; Caspase 1/deficiency/metabolism ; Cyclooxygenase 1/deficiency ; Cytosol/metabolism ; Death ; Eicosanoids/*biosynthesis/metabolism ; Female ; Flagellin/genetics/immunology/metabolism ; Fluid Shifts ; Hematocrit ; Immunity, Innate/immunology ; Inflammasomes/*metabolism ; Inflammation/immunology/metabolism/pathology ; Interleukin-18 ; Interleukin-1beta ; Intestines/metabolism ; Legionella pneumophila ; Macrophages, Peritoneal/immunology ; Male ; Mice ; Mice, Inbred C57BL ; Neuronal Apoptosis-Inhibitory Protein/deficiency/metabolism ; Peritoneal Cavity ; Peritoneal Lavage ; Recombinant Fusion Proteins/genetics/metabolism ; Salmonella Infections/immunology ; Salmonella typhimurium/immunology ; Time Factors
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    Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes (2012)
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    Publication Date: 2012-10-02
    Description: The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved beta-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hagberg, Carolina E -- Mehlem, Annika -- Falkevall, Annelie -- Muhl, Lars -- Fam, Barbara C -- Ortsater, Henrik -- Scotney, Pierre -- Nyqvist, Daniel -- Samen, Erik -- Lu, Li -- Stone-Elander, Sharon -- Proietto, Joseph -- Andrikopoulos, Sofianos -- Sjoholm, Ake -- Nash, Andrew -- Eriksson, Ulf -- England -- Nature. 2012 Oct 18;490(7420):426-30. doi: 10.1038/nature11464. Epub 2012 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tissue Biology Group, Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE-171 77 Stockholm, Sweden.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23023133" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Diabetes Mellitus, Type 2/*drug therapy/*metabolism ; Diet, High-Fat ; Disease Models, Animal ; Dyslipidemias/drug therapy/metabolism ; Endothelium, Vascular/metabolism ; Female ; Glucose/metabolism ; Glucose Tolerance Test ; *Insulin Resistance ; Islets of Langerhans/anatomy & histology/cytology/pathology ; Lipid Metabolism ; Male ; Metabolic Syndrome X/drug therapy/metabolism ; Mice ; Mice, Inbred C57BL ; *Molecular Targeted Therapy ; Muscles/metabolism ; Obesity/metabolism/pathology ; Rats ; Rats, Wistar ; Signal Transduction/drug effects/immunology ; Vascular Endothelial Growth Factor B/*antagonists & ; inhibitors/deficiency/genetics/*metabolism
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    Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors (2012)
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    Publication Date: 2012-06-23
    Description: In the developing central nervous system (CNS), the control of synapse number and function is critical to the formation of neural circuits. We previously demonstrated that astrocyte-secreted factors powerfully induce the formation of functional excitatory synapses between CNS neurons. Astrocyte-secreted thrombospondins induce the formation of structural synapses, but these synapses are postsynaptically silent. Here we use biochemical fractionation of astrocyte-conditioned medium to identify glypican 4 (Gpc4) and glypican 6 (Gpc6) as astrocyte-secreted signals sufficient to induce functional synapses between purified retinal ganglion cell neurons, and show that depletion of these molecules from astrocyte-conditioned medium significantly reduces its ability to induce postsynaptic activity. Application of Gpc4 to purified neurons is sufficient to increase the frequency and amplitude of glutamatergic synaptic events. This is achieved by increasing the surface level and clustering, but not overall cellular protein level, of the GluA1 subunit of the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) glutamate receptor (AMPAR). Gpc4 and Gpc6 are expressed by astrocytes in vivo in the developing CNS, with Gpc4 expression enriched in the hippocampus and Gpc6 enriched in the cerebellum. Finally, we demonstrate that Gpc4-deficient mice have defective synapse formation, with decreased amplitude of excitatory synaptic currents in the developing hippocampus and reduced recruitment of AMPARs to synapses. These data identify glypicans as a family of novel astrocyte-derived molecules that are necessary and sufficient to promote glutamate receptor clustering and receptivity and to induce the formation of postsynaptically functioning CNS synapses.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383085/" 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/PMC3383085/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Allen, Nicola J -- Bennett, Mariko L -- Foo, Lynette C -- Wang, Gordon X -- Chakraborty, Chandrani -- Smith, Stephen J -- Barres, Ben A -- R01 DA015043/DA/NIDA NIH HHS/ -- R01 DA015043-09/DA/NIDA NIH HHS/ -- R01 NS075252/NS/NINDS NIH HHS/ -- R01 NS075252-01/NS/NINDS NIH HHS/ -- R01 NS077601/NS/NINDS NIH HHS/ -- R01 NS077601-01/NS/NINDS NIH HHS/ -- R01DA015043/DA/NIDA NIH HHS/ -- R01NS0725252/NS/NINDS NIH HHS/ -- R01NS077601/NS/NINDS NIH HHS/ -- England -- Nature. 2012 May 27;486(7403):410-4. doi: 10.1038/nature11059.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stanford University School of Medicine, Department of Neurobiology, 299 Campus Drive, Fairchild Science Building D231, Stanford, California 94305-5125, USA. nallen@salk.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722203" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/cytology/*metabolism/secretion ; Cerebellum/cytology/metabolism ; Culture Media, Conditioned/metabolism/pharmacology ; Excitatory Postsynaptic Potentials/*physiology ; Female ; Glypicans/deficiency/*metabolism/pharmacology ; Hippocampus/cytology/metabolism ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Rats ; Rats, Sprague-Dawley ; Receptors, AMPA/*metabolism ; Retinal Ganglion Cells/cytology/drug effects/metabolism ; Synapses/drug effects/*metabolism/pathology
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    NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice (2012)
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    Publication Date: 2012-12-21
    Description: Alzheimer's disease is the world's most common dementing illness. Deposition of amyloid-beta peptide drives cerebral neuroinflammation by activating microglia. Indeed, amyloid-beta activation of the NLRP3 inflammasome in microglia is fundamental for interleukin-1beta maturation and subsequent inflammatory events. However, it remains unknown whether NLRP3 activation contributes to Alzheimer's disease in vivo. Here we demonstrate strongly enhanced active caspase-1 expression in human mild cognitive impairment and brains with Alzheimer's disease, suggesting a role for the inflammasome in this neurodegenerative disease. Nlrp3(-/-) or Casp1(-/-) mice carrying mutations associated with familial Alzheimer's disease were largely protected from loss of spatial memory and other sequelae associated with Alzheimer's disease, and demonstrated reduced brain caspase-1 and interleukin-1beta activation as well as enhanced amyloid-beta clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP/PS1 model of Alzheimer's disease. These results show an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer's disease, and suggest that NLRP3 inflammasome inhibition represents a new therapeutic intervention for the disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3812809/" 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/PMC3812809/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Heneka, Michael T -- Kummer, Markus P -- Stutz, Andrea -- Delekate, Andrea -- Schwartz, Stephanie -- Vieira-Saecker, Ana -- Griep, Angelika -- Axt, Daisy -- Remus, Anita -- Tzeng, Te-Chen -- Gelpi, Ellen -- Halle, Annett -- Korte, Martin -- Latz, Eicke -- Golenbock, Douglas T -- R01 AI083713/AI/NIAID NIH HHS/ -- R01 GM054060/GM/NIGMS NIH HHS/ -- R01 HL093262/HL/NHLBI NIH HHS/ -- U19 AI084048/AI/NIAID NIH HHS/ -- England -- Nature. 2013 Jan 31;493(7434):674-8. doi: 10.1038/nature11729. Epub 2012 Dec 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Clinical Neuroscience Unit, Department of Neurology, University of Bonn, Sigmund-Freud-Strasse 25, 53127 Bonn, Germany. michael.Heneka@ukb.uni-bonn.de〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23254930" target="_blank"〉PubMed〈/a〉
    Keywords: Aged ; Aged, 80 and over ; Alzheimer Disease/enzymology/genetics/*pathology ; Amyloid beta-Peptides/metabolism ; Animals ; Behavior, Animal ; Brain/enzymology/*pathology ; Carrier Proteins/genetics/*metabolism ; Caspase 1/genetics/metabolism ; Gene Expression Regulation, Enzymologic ; Humans ; Inflammasomes/metabolism ; Interleukin-1beta/metabolism ; Memory ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mild Cognitive Impairment/enzymology/physiopathology ; Nitric Oxide Synthase Type II/metabolism ; Phagocytosis/genetics
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    Neuronal circuitry mechanism regulating adult quiescent neural stem-cell fate decision (2012)
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    Publication Date: 2012-07-31
    Description: Adult neurogenesis arises from neural stem cells within specialized niches. Neuronal activity and experience, presumably acting on this local niche, regulate multiple stages of adult neurogenesis, from neural progenitor proliferation to new neuron maturation, synaptic integration and survival. It is unknown whether local neuronal circuitry has a direct impact on adult neural stem cells. Here we show that, in the adult mouse hippocampus, nestin-expressing radial glia-like quiescent neural stem cells (RGLs) respond tonically to the neurotransmitter gamma-aminobutyric acid (GABA) by means of gamma2-subunit-containing GABAA receptors. Clonal analysis of individual RGLs revealed a rapid exit from quiescence and enhanced symmetrical self-renewal after conditional deletion of gamma2. RGLs are in close proximity to terminals expressing 67-kDa glutamic acid decarboxylase (GAD67) of parvalbumin-expressing (PV+) interneurons and respond tonically to GABA released from these neurons. Functionally, optogenetic control of the activity of dentate PV+ interneurons, but not that of somatostatin-expressing or vasoactive intestinal polypeptide (VIP)-expressing interneurons, can dictate the RGL choice between quiescence and activation. Furthermore, PV+ interneuron activation restores RGL quiescence after social isolation, an experience that induces RGL activation and symmetrical division. Our study identifies a niche cell-signal-receptor trio and a local circuitry mechanism that control the activation and self-renewal mode of quiescent adult neural stem cells in response to neuronal activity and experience.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438284/" 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/PMC3438284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Song, Juan -- Zhong, Chun -- Bonaguidi, Michael A -- Sun, Gerald J -- Hsu, Derek -- Gu, Yan -- Meletis, Konstantinos -- Huang, Z Josh -- Ge, Shaoyu -- Enikolopov, Grigori -- Deisseroth, Karl -- Luscher, Bernhard -- Christian, Kimberly M -- Ming, Guo-li -- Song, Hongjun -- AG040209/AG/NIA NIH HHS/ -- HD069184/HD/NICHD NIH HHS/ -- MH089111/MH/NIMH NIH HHS/ -- NS048271/NS/NINDS NIH HHS/ -- R01 AG040209/AG/NIA NIH HHS/ -- R01 HD069184/HD/NICHD NIH HHS/ -- R01 NS047344/NS/NINDS NIH HHS/ -- R01 NS048271/NS/NINDS NIH HHS/ -- R01 NS065915/NS/NINDS NIH HHS/ -- R21 ES021957/ES/NIEHS NIH HHS/ -- R56 NS047344/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Sep 6;489(7414):150-4. doi: 10.1038/nature11306.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22842902" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Lineage/drug effects ; Cell Proliferation/drug effects ; Dentate Gyrus/cytology/drug effects/metabolism ; Female ; GABA Modulators/pharmacology ; GABA-A Receptor Agonists/pharmacology ; GABA-A Receptor Antagonists/pharmacology ; Interneurons/cytology/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Neural Pathways/drug effects/*physiology ; Neural Stem Cells/*cytology/drug effects/metabolism ; *Neurogenesis/drug effects ; Neuroglia/cytology/drug effects/metabolism ; Parvalbumins/metabolism ; Receptors, GABA-A/metabolism ; Signal Transduction/drug effects ; Somatostatin/metabolism ; Stem Cell Niche/drug effects/physiology ; Vasoactive Intestinal Peptide/metabolism ; gamma-Aminobutyric Acid/metabolism
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    Intrinsically determined cell death of developing cortical interneurons (2012)
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    Publication Date: 2012-10-09
    Description: Cortical inhibitory circuits are formed by gamma-aminobutyric acid (GABA)-secreting interneurons, a cell population that originates far from the cerebral cortex in the embryonic ventral forebrain. Given their distant developmental origins, it is intriguing how the number of cortical interneurons is ultimately determined. One possibility, suggested by the neurotrophic hypothesis, is that cortical interneurons are overproduced, and then after their migration into cortex the excess interneurons are eliminated through a competition for extrinsically derived trophic signals. Here we characterize the developmental cell death of mouse cortical interneurons in vivo, in vitro and after transplantation. We found that 40% of developing cortical interneurons were eliminated through Bax (Bcl-2-associated X)-dependent apoptosis during postnatal life. When cultured in vitro or transplanted into the cortex, interneuron precursors died at a cellular age similar to that at which endogenous interneurons died during normal development. Over transplant sizes that varied 200-fold, a constant fraction of the transplanted population underwent cell death. The death of transplanted neurons was not affected by the cell-autonomous disruption of TrkB (tropomyosin kinase receptor B), the main neurotrophin receptor expressed by neurons of the central nervous system. Transplantation expanded the cortical interneuron population by up to 35%, but the frequency of inhibitory synaptic events did not scale with the number of transplanted interneurons. Taken together, our findings indicate that interneuron cell death is determined intrinsically, either cell-autonomously or through a population-autonomous competition for survival signals derived from other interneurons.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3726009/" 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/PMC3726009/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Southwell, Derek G -- Paredes, Mercedes F -- Galvao, Rui P -- Jones, Daniel L -- Froemke, Robert C -- Sebe, Joy Y -- Alfaro-Cervello, Clara -- Tang, Yunshuo -- Garcia-Verdugo, Jose M -- Rubenstein, John L -- Baraban, Scott C -- Alvarez-Buylla, Arturo -- F32NS061497/NS/NINDS NIH HHS/ -- R01 NS048528/NS/NINDS NIH HHS/ -- R01 NS071785/NS/NINDS NIH HHS/ -- T32 GM007618/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 1;491(7422):109-13. doi: 10.1038/nature11523. Epub 2012 Oct 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Neuroscience Graduate Program, University of California, San Francisco, California 94143, USA. dereksouthwell@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23041929" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; *Apoptosis ; Caspase 3/metabolism ; Cell Aging/physiology ; Cell Count ; Cell Survival ; Female ; Inhibitory Postsynaptic Potentials ; Interneurons/*cytology/metabolism/transplantation ; Male ; Membrane Glycoproteins/deficiency/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Neocortex/*cytology/growth & development ; Neural Stem Cells/cytology/metabolism/transplantation ; Protein-Tyrosine Kinases/deficiency/genetics/metabolism ; Pyramidal Cells/cytology/metabolism ; bcl-2-Associated X Protein/deficiency/genetics/metabolism
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    Control of ground-state pluripotency by allelic regulation of Nanog (2012)
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    Publication Date: 2012-02-14
    Description: Pluripotency is established through genome-wide reprogramming during mammalian pre-implantation development, resulting in the formation of the naive epiblast. Reprogramming involves both the resetting of epigenetic marks and the activation of pluripotent-cell-specific genes such as Nanog and Oct4 (also known as Pou5f1). The tight regulation of these genes is crucial for reprogramming, but the mechanisms that regulate their expression in vivo have not been uncovered. Here we show that Nanog--but not Oct4--is monoallelically expressed in early pre-implantation embryos. Nanog then undergoes a progressive switch to biallelic expression during the transition towards ground-state pluripotency in the naive epiblast of the late blastocyst. Embryonic stem (ES) cells grown in leukaemia inhibitory factor (LIF) and serum express Nanog mainly monoallelically and show asynchronous replication of the Nanog locus, a feature of monoallelically expressed genes, but ES cells activate both alleles when cultured under 2i conditions, which mimic the pluripotent ground state in vitro. Live-cell imaging with reporter ES cells confirmed the allelic expression of Nanog and revealed allelic switching. The allelic expression of Nanog is regulated through the fibroblast growth factor-extracellular signal-regulated kinase signalling pathway, and it is accompanied by chromatin changes at the proximal promoter but occurs independently of DNA methylation. Nanog-heterozygous blastocysts have fewer inner-cell-mass derivatives and delayed primitive endoderm formation, indicating a role for the biallelic expression of Nanog in the timely maturation of the inner cell mass into a fully reprogrammed pluripotent epiblast. We suggest that the tight regulation of Nanog dose at the chromosome level is necessary for the acquisition of ground-state pluripotency during development. Our data highlight an unexpected role for allelic expression in controlling the dose of pluripotency factors in vivo, adding an extra level to the regulation of reprogramming.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Miyanari, Yusuke -- Torres-Padilla, Maria-Elena -- England -- Nature. 2012 Feb 12;483(7390):470-3. doi: 10.1038/nature10807.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM U964, Universite de Strasbourg, F-67404 Illkirch, Cite Universitaire de Strasbourg, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22327294" target="_blank"〉PubMed〈/a〉
    Keywords: *Alleles ; Animals ; Blastocyst/cytology/*metabolism ; Blastocyst Inner Cell Mass/cytology/metabolism ; Cell Cycle Proteins/metabolism ; Cellular Reprogramming/*genetics ; Chromosomal Proteins, Non-Histone/metabolism ; DNA Replication ; Embryonic Stem Cells/drug effects/metabolism ; Female ; *Gene Expression Regulation, Developmental ; Genomic Imprinting ; Germ Layers/cytology/metabolism ; Homeodomain Proteins/*genetics/*metabolism ; In Situ Hybridization, Fluorescence ; Leukemia Inhibitory Factor/pharmacology ; Male ; Mediator Complex/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Inbred CBA ; Octamer Transcription Factor-3 ; Pluripotent Stem Cells/cytology/*metabolism ; Time Factors
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    Deleted in colorectal carcinoma suppresses metastasis in p53-deficient mammary tumours (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-24
    Description: Since its discovery in the early 1990s the deleted in colorectal cancer (DCC) gene, located on chromosome 18q21, has been proposed as a tumour suppressor gene as its loss is implicated in the majority of advanced colorectal and many other cancers. DCC belongs to the family of netrin 1 receptors, which function as dependence receptors as they control survival or apoptosis depending on ligand binding. However, the role of DCC as a tumour suppressor remains controversial because of the rarity of DCC-specific mutations and the presence of other tumour suppressor genes in the same chromosomal region. Here we show that in a mouse model of mammary carcinoma based on somatic inactivation of p53, additional loss of DCC promotes metastasis formation without affecting the primary tumour phenotype. Furthermore, we demonstrate that in cell cultures derived from p53-deficient mouse mammary tumours DCC expression controls netrin-1-dependent cell survival, providing a mechanistic basis for the enhanced metastatic capacity of tumour cells lacking DCC. Consistent with this idea, in vivo tumour-cell survival is enhanced by DCC loss. Together, our data support the function of DCC as a context-dependent tumour suppressor that limits survival of disseminated tumour cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krimpenfort, Paul -- Song, Ji-Ying -- Proost, Natalie -- Zevenhoven, John -- Jonkers, Jos -- Berns, Anton -- England -- Nature. 2012 Feb 22;482(7386):538-41. doi: 10.1038/nature10790.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22358843" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/genetics ; Cell Line, Tumor ; Cell Survival/genetics ; Disease Models, Animal ; Female ; Genes, p53/*genetics ; Mammary Neoplasms, Experimental/*genetics/metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/*genetics/*pathology ; Nerve Growth Factors/deficiency/genetics/metabolism ; Receptors, Cell Surface/deficiency/genetics/*metabolism ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
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    Choice-specific sequences in parietal cortex during a virtual-navigation decision task (2012)
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    Publication Date: 2012-03-16
    Description: The posterior parietal cortex (PPC) has an important role in many cognitive behaviours; however, the neural circuit dynamics underlying PPC function are not well understood. Here we optically imaged the spatial and temporal activity patterns of neuronal populations in mice performing a PPC-dependent task that combined a perceptual decision and memory-guided navigation in a virtual environment. Individual neurons had transient activation staggered relative to one another in time, forming a sequence of neuronal activation spanning the entire length of a task trial. Distinct sequences of neurons were triggered on trials with opposite behavioural choices and defined divergent, choice-specific trajectories through a state space of neuronal population activity. Cells participating in the different sequences and at distinct time points in the task were anatomically intermixed over microcircuit length scales (〈100 micrometres). During working memory decision tasks, the PPC may therefore perform computations through sequence-based circuit dynamics, rather than long-lived stable states, implemented using anatomically intermingled microcircuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321074/" 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/PMC3321074/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Harvey, Christopher D -- Coen, Philip -- Tank, David W -- R01 MH083686/MH/NIMH NIH HHS/ -- R01 MH083686-05/MH/NIMH NIH HHS/ -- R01-MH083686/MH/NIMH NIH HHS/ -- RC1 NS068148/NS/NINDS NIH HHS/ -- RC1 NS068148-02/NS/NINDS NIH HHS/ -- RC1-NS068148/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Mar 14;484(7392):62-8. doi: 10.1038/nature10918.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Princeton Neuroscience Institute, Princeton University, Princeton, New Jersey 08544, USA. christopher_harvey@hms.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22419153" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/physiology ; Animals ; Decision Making/*physiology ; Male ; Maze Learning/*physiology ; Memory/*physiology ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Parietal Lobe/cytology/*physiology ; Photic Stimulation ; *User-Computer Interface
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    Multi-isotope imaging mass spectrometry quantifies stem cell division and metabolism (2012)
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    Publication Date: 2012-01-17
    Description: Mass spectrometry with stable isotope labels has been seminal in discovering the dynamic state of living matter, but is limited to bulk tissues or cells. We developed multi-isotope imaging mass spectrometry (MIMS) that allowed us to view and measure stable isotope incorporation with submicrometre resolution. Here we apply MIMS to diverse organisms, including Drosophila, mice and humans. We test the 'immortal strand hypothesis', which predicts that during asymmetric stem cell division chromosomes containing older template DNA are segregated to the daughter destined to remain a stem cell, thus insuring lifetime genetic stability. After labelling mice with (15)N-thymidine from gestation until post-natal week 8, we find no (15)N label retention by dividing small intestinal crypt cells after a four-week chase. In adult mice administered (15)N-thymidine pulse-chase, we find that proliferating crypt cells dilute the (15)N label, consistent with random strand segregation. We demonstrate the broad utility of MIMS with proof-of-principle studies of lipid turnover in Drosophila and translation to the human haematopoietic system. These studies show that MIMS provides high-resolution quantification of stable isotope labels that cannot be obtained using other techniques and that is broadly applicable to biological and medical research.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3267887/" 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/PMC3267887/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Steinhauser, Matthew L -- Bailey, Andrew P -- Senyo, Samuel E -- Guillermier, Christelle -- Perlstein, Todd S -- Gould, Alex P -- Lee, Richard T -- Lechene, Claude P -- AG032977/AG/NIA NIH HHS/ -- AG034641/AG/NIA NIH HHS/ -- EB001974/EB/NIBIB NIH HHS/ -- K08 DK090147/DK/NIDDK NIH HHS/ -- MC_U117584237/Medical Research Council/United Kingdom -- R01 AG032977/AG/NIA NIH HHS/ -- R01 AG032977-04/AG/NIA NIH HHS/ -- R01 AG040019/AG/NIA NIH HHS/ -- R01 AG040019-02/AG/NIA NIH HHS/ -- U117584237/Medical Research Council/United Kingdom -- England -- Nature. 2012 Jan 15;481(7382):516-9. doi: 10.1038/nature10734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22246326" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; *Cell Division ; DNA/biosynthesis/genetics/metabolism ; Drosophila melanogaster/cytology ; Enterocytes/cytology ; Fibroblasts/cytology ; Humans ; Intestine, Small/cytology ; Isotope Labeling ; Isotopes ; Leukocytes/cytology ; Lipid Metabolism ; Lymphopoiesis ; Mass Spectrometry/*methods ; Mice ; Mice, Inbred C57BL ; Models, Biological ; Stem Cells/*cytology/*metabolism/pathology ; Templates, Genetic ; Thymidine/metabolism
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    Opposite effects of fear conditioning and extinction on dendritic spine remodelling (2012)
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    Publication Date: 2012-02-22
    Description: It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lai, Cora Sau Wan -- Franke, Thomas F -- Gan, Wen-Biao -- NS047325/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Feb 19;483(7387):87-91. doi: 10.1038/nature10792.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Program, Skirball Institute, Department of Physiology and Neuroscience, New York University School of Medicine, 540 First Avenue, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22343895" target="_blank"〉PubMed〈/a〉
    Keywords: Acoustic Stimulation ; Animals ; Conditioning, Classical/*physiology ; Cues ; Dendritic Spines/*physiology ; Electric Stimulation ; Extinction, Psychological/*physiology ; Extremities ; Fear/*physiology ; Frontal Lobe/cytology/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Models, Neurological ; Neuronal Plasticity/*physiology ; Pyramidal Cells/cytology/physiology
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    Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity (2012)
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    Publication Date: 2012-02-03
    Description: Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-alpha expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3276682/" 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/PMC3276682/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Henao-Mejia, Jorge -- Elinav, Eran -- Jin, Chengcheng -- Hao, Liming -- Mehal, Wajahat Z -- Strowig, Till -- Thaiss, Christoph A -- Kau, Andrew L -- Eisenbarth, Stephanie C -- Jurczak, Michael J -- Camporez, Joao-Paulo -- Shulman, Gerald I -- Gordon, Jeffrey I -- Hoffman, Hal M -- Flavell, Richard A -- K08A1085038/PHS HHS/ -- P30 DK-45735/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-14/DK/NIDDK NIH HHS/ -- R01 DK-40936/DK/NIDDK NIH HHS/ -- R01 DK040936/DK/NIDDK NIH HHS/ -- R01DK076674-01/DK/NIDDK NIH HHS/ -- R24 DK-085638/DK/NIDDK NIH HHS/ -- T32HL007974/HL/NHLBI NIH HHS/ -- U24 DK-059635/DK/NIDDK NIH HHS/ -- U24 DK059635/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 1;482(7384):179-85. doi: 10.1038/nature10809.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, 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/22297845" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins ; Carrier Proteins/metabolism ; Choline ; Colon/microbiology ; Cytoskeletal Proteins/deficiency ; Disease Models, Animal ; *Disease Progression ; Fatty Liver/genetics/*metabolism/*pathology ; Inflammasomes/*metabolism ; Inflammation/metabolism/pathology ; Interleukin-18/deficiency ; Male ; Metagenome ; Methionine/deficiency ; Mice ; Mice, Inbred C57BL ; Non-alcoholic Fatty Liver Disease ; Obesity/*metabolism/*pathology ; RNA, Ribosomal, 16S/genetics ; Receptors, Cell Surface/metabolism ; Toll-Like Receptor 4/deficiency/metabolism ; Toll-Like Receptor 9/deficiency/metabolism ; Tumor Necrosis Factor-alpha/deficiency/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Maintenance of muscle stem-cell quiescence by microRNA-489 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-02-24
    Description: Among the key properties that distinguish adult mammalian stem cells from their more differentiated progeny is the ability of stem cells to remain in a quiescent state for prolonged periods of time. However, the molecular pathways for the maintenance of stem-cell quiescence remain elusive. Here we use adult mouse muscle stem cells (satellite cells) as a model system and show that the microRNA (miRNA) pathway is essential for the maintenance of the quiescent state. Satellite cells that lack a functional miRNA pathway spontaneously exit quiescence and enter the cell cycle. We identified quiescence-specific miRNAs in the satellite-cell lineage by microarray analysis. Among these, miRNA-489 (miR-489) is highly expressed in quiescent satellite cells and is quickly downregulated during satellite-cell activation. Further analysis revealed that miR-489 functions as a regulator of satellite-cell quiescence, as it post-transcriptionally suppresses the oncogene Dek, the protein product of which localizes to the more differentiated daughter cell during asymmetric division of satellite cells and promotes the transient proliferative expansion of myogenic progenitors. Our results provide evidence of the miRNA pathway in general, and of a specific miRNA, miR-489, in actively maintaining the quiescent state of an adult stem-cell population.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3292200/" 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/PMC3292200/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cheung, Tom H -- Quach, Navaline L -- Charville, Gregory W -- Liu, Ling -- Park, Lidia -- Edalati, Abdolhossein -- Yoo, Bryan -- Hoang, Phuong -- Rando, Thomas A -- DP1 OD000392/OD/NIH HHS/ -- DP1 OD000392-05/OD/NIH HHS/ -- F30 AG035521/AG/NIA NIH HHS/ -- P01 AG036695/AG/NIA NIH HHS/ -- P01 AG036695-01A1/AG/NIA NIH HHS/ -- P01AG036695/AG/NIA NIH HHS/ -- R01 AG023806/AG/NIA NIH HHS/ -- R01 AG023806-05/AG/NIA NIH HHS/ -- R01 AR056849/AR/NIAMS NIH HHS/ -- R01 AR056849-03/AR/NIAMS NIH HHS/ -- R01 AR062185/AR/NIAMS NIH HHS/ -- R01 AR062185-01/AR/NIAMS NIH HHS/ -- R01AG23806/AG/NIA NIH HHS/ -- R37 AG023806/AG/NIA NIH HHS/ -- England -- Nature. 2012 Feb 23;482(7386):524-8. doi: 10.1038/nature10834.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Paul F. Glenn Laboratories for the Biology of Aging, 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/22358842" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Cycle/drug effects/*genetics ; Cell Differentiation/drug effects ; Cell Lineage/drug effects ; Cell Survival/drug effects/genetics ; DEAD-box RNA Helicases/genetics/metabolism ; DNA-Binding Proteins/genetics ; *Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*genetics ; Myoblasts/*cytology/drug effects/*metabolism ; Oligonucleotide Array Sequence Analysis ; Oncogene Proteins/genetics ; Ribonuclease III/genetics/metabolism ; Satellite Cells, Skeletal Muscle/cytology/drug effects/metabolism ; Tamoxifen/pharmacology ; Transcription, Genetic/drug effects
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Regulation of circadian behaviour and metabolism by REV-ERB-alpha and REV-ERB-beta (2012)
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    Publication Date: 2012-03-31
    Description: The circadian clock acts at the genomic level to coordinate internal behavioural and physiological rhythms via the CLOCK-BMAL1 transcriptional heterodimer. Although the nuclear receptors REV-ERB-alpha and REV-ERB-beta have been proposed to form an accessory feedback loop that contributes to clock function, their precise roles and importance remain unresolved. To establish their regulatory potential, we determined the genome-wide cis-acting targets (cistromes) of both REV-ERB isoforms in murine liver, which revealed shared recognition at over 50% of their total DNA binding sites and extensive overlap with the master circadian regulator BMAL1. Although REV-ERB-alpha has been shown to regulate Bmal1 expression directly, our cistromic analysis reveals a more profound connection between BMAL1 and the REV-ERB-alpha and REV-ERB-beta genomic regulatory circuits than was previously suspected. Genes within the intersection of the BMAL1, REV-ERB-alpha and REV-ERB-beta cistromes are highly enriched for both clock and metabolic functions. As predicted by the cistromic analysis, dual depletion of Rev-erb-alpha and Rev-erb-beta function by creating double-knockout mice profoundly disrupted circadian expression of core circadian clock and lipid homeostatic gene networks. As a result, double-knockout mice show markedly altered circadian wheel-running behaviour and deregulated lipid metabolism. These data now unite REV-ERB-alpha and REV-ERB-beta with PER, CRY and other components of the principal feedback loop that drives circadian expression and indicate a more integral mechanism for the coordination of circadian rhythm and metabolism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3367514/" 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/PMC3367514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cho, Han -- Zhao, Xuan -- Hatori, Megumi -- Yu, Ruth T -- Barish, Grant D -- Lam, Michael T -- Chong, Ling-Wa -- DiTacchio, Luciano -- Atkins, Annette R -- Glass, Christopher K -- Liddle, Christopher -- Auwerx, Johan -- Downes, Michael -- Panda, Satchidananda -- Evans, Ronald M -- DK057978/DK/NIDDK NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- DK091618/DK/NIDDK NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R01 DK091618/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R01 HL105278-21/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R24 DK090962-02/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- R37 DK057978-34/DK/NIDDK NIH HHS/ -- T32 HL007770/HL/NHLBI NIH HHS/ -- T32 HL007770-15/HL/NHLBI NIH HHS/ -- T32-HL007770/HL/NHLBI NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19 DK062434-10/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 29;485(7396):123-7. doi: 10.1038/nature11048.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, 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/22460952" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Clocks/drug effects/genetics ; Circadian Rhythm/genetics/*physiology ; Cryptochromes/deficiency/genetics/metabolism ; *Energy Metabolism/genetics ; Feedback, Physiological ; Gene Expression Regulation ; Gene Regulatory Networks/genetics ; Homeostasis/genetics ; *Lipid Metabolism/genetics ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Molecular Sequence Data ; Motor Activity/genetics/physiology ; Nuclear Receptor Subfamily 1, Group D, Member 1/deficiency/genetics/*metabolism ; Period Circadian Proteins/deficiency/genetics/metabolism ; Receptors, Cytoplasmic and Nuclear/deficiency/genetics/*metabolism ; Repressor Proteins/deficiency/genetics/*metabolism ; Transcriptome/genetics
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    BATF-JUN is critical for IRF4-mediated transcription in T cells (2012)
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    Publication Date: 2012-09-21
    Description: Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS-IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4(+) T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1-IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1-IRF composite elements (AICEs). Moreover, BATF-JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4(+) T cells stimulated with IL-21 and in T(H)17 differentiated cells. Importantly, BATF binding was diminished in Irf4(-/-) T cells and IRF4 binding was diminished in Batf(-/-) T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in T(H)17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3537508/" 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/PMC3537508/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Peng -- Spolski, Rosanne -- Liao, Wei -- Wang, Lu -- Murphy, Theresa L -- Murphy, Kenneth M -- Leonard, Warren J -- ZIA HL005402-20/Intramural NIH HHS/ -- ZIA HL005402-21/Intramural NIH HHS/ -- ZIA HL005408-05/Intramural NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):543-6. doi: 10.1038/nature11530. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Immunology and Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-1674, USA. lip3@nhlbi.nih.gov〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992523" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Motifs ; Animals ; B-Lymphocytes/metabolism ; Base Sequence ; Basic-Leucine Zipper Transcription Factors/deficiency/genetics/*metabolism ; Binding Sites ; CD4-Positive T-Lymphocytes/cytology/*metabolism ; Cell Differentiation ; Female ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/genetics ; Interleukins/immunology ; Lymphocyte Activation ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Nucleotide Motifs ; Proto-Oncogene Proteins/metabolism ; Proto-Oncogene Proteins c-jun/*metabolism ; Signal Transduction ; Th17 Cells/cytology/immunology ; Trans-Activators/metabolism ; Transcription Factor AP-1/metabolism ; *Transcription, Genetic ; Up-Regulation
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    Clonally related visual cortical neurons show similar stimulus feature selectivity (2012)
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    Publication Date: 2012-06-09
    Description: A fundamental feature of the mammalian neocortex is its columnar organization. In the visual cortex, functional columns consisting of neurons with similar orientation preferences have been characterized extensively, but how these columns are constructed during development remains unclear. The radial unit hypothesis posits that the ontogenetic columns formed by clonally related neurons migrating along the same radial glial fibre during corticogenesis provide the basis for functional columns in adult neocortex. However, a direct correspondence between the ontogenetic and functional columns has not been demonstrated. Here we show that, despite the lack of a discernible orientation map in mouse visual cortex, sister neurons in the same radial clone exhibit similar orientation preferences. Using a retroviral vector encoding green fluorescent protein to label radial clones of excitatory neurons, and in vivo two-photon calcium imaging to measure neuronal response properties, we found that sister neurons preferred similar orientations whereas nearby non-sister neurons showed no such relationship. Interestingly, disruption of gap junction coupling by viral expression of a dominant-negative mutant of Cx26 (also known as Gjb2) or by daily administration of a gap junction blocker, carbenoxolone, during the first postnatal week greatly diminished the functional similarity between sister neurons, suggesting that the maturation of ontogenetic into functional columns requires intercellular communication through gap junctions. Together with the recent finding of preferential excitatory connections among sister neurons, our results support the radial unit hypothesis and unify the ontogenetic and functional columns in the visual cortex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3375857/" 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/PMC3375857/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Ye -- Lu, Hui -- Cheng, Pei-lin -- Ge, Shaoyu -- Xu, Huatai -- Shi, Song-Hai -- Dan, Yang -- R01 DA024681/DA/NIDA NIH HHS/ -- R01 EY018861/EY/NEI NIH HHS/ -- R01 NS065915/NS/NINDS NIH HHS/ -- R21NS072483/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 2;486(7401):118-21. doi: 10.1038/nature11110.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22678292" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Carbenoxolone/pharmacology ; *Cell Communication ; Clone Cells/cytology ; Connexins/genetics/metabolism ; Female ; Gap Junctions/drug effects/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neurons/*physiology ; Visual Cortex/*cytology
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    Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive (2012)
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    Publication Date: 2012-09-21
    Description: Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3475726/" 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/PMC3475726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lemos, Julia C -- Wanat, Matthew J -- Smith, Jeffrey S -- Reyes, Beverly A S -- Hollon, Nick G -- Van Bockstaele, Elisabeth J -- Chavkin, Charles -- Phillips, Paul E M -- F31 MH086269/MH/NIMH NIH HHS/ -- F31-MH086269/MH/NIMH NIH HHS/ -- F32-DA026273/DA/NIDA NIH HHS/ -- K05 DA020570/DA/NIDA NIH HHS/ -- R01 DA009082/DA/NIDA NIH HHS/ -- R01 DA016782/DA/NIDA NIH HHS/ -- R01 DA030074/DA/NIDA NIH HHS/ -- R01 MH079292/MH/NIMH NIH HHS/ -- R01-DA009082/DA/NIDA NIH HHS/ -- R01-DA016782/DA/NIDA NIH HHS/ -- R01-DA030074/DA/NIDA NIH HHS/ -- R01-MH079292/MH/NIMH NIH HHS/ -- England -- Nature. 2012 Oct 18;490(7420):402-6. doi: 10.1038/nature11436. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992525" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Appetitive Behavior/drug effects/*physiology ; Avoidance Learning/drug effects/*physiology ; Corticotropin-Releasing Hormone/*metabolism/pharmacology ; Dopamine/metabolism/secretion ; Male ; Mice ; Mice, Inbred C57BL ; Nucleus Accumbens/*metabolism/physiopathology ; Receptors, Corticotropin-Releasing Hormone/agonists/antagonists & ; inhibitors/deficiency/metabolism ; Signal Transduction/drug effects ; Stress, Psychological/*metabolism/physiopathology
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    Compensatory dendritic cell development mediated by BATF-IRF interactions (2012)
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    Publication Date: 2012-09-21
    Description: The AP1 transcription factor Batf3 is required for homeostatic development of CD8alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" 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/PMC3482832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tussiwand, Roxane -- Lee, Wan-Ling -- Murphy, Theresa L -- Mashayekhi, Mona -- KC, Wumesh -- Albring, Jorn C -- Satpathy, Ansuman T -- Rotondo, Jeffrey A -- Edelson, Brian T -- Kretzer, Nicole M -- Wu, Xiaodi -- Weiss, Leslie A -- Glasmacher, Elke -- Li, Peng -- Liao, Wei -- Behnke, Michael -- Lam, Samuel S K -- Aurthur, Cora T -- Leonard, Warren J -- Singh, Harinder -- Stallings, Christina L -- Sibley, L David -- Schreiber, Robert D -- Murphy, Kenneth M -- AI076427-02/AI/NIAID NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R01 AI036629/AI/NIAID NIH HHS/ -- R01 AI076427/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigen Presentation ; Antigens, CD/metabolism ; Antigens, CD8/immunology/metabolism ; Basic-Leucine Zipper Transcription ; Factors/chemistry/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology ; CTLA-4 Antigen/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Dendritic Cells/*cytology/immunology/*metabolism ; Female ; Fibrosarcoma/immunology/metabolism/pathology ; Gene Expression Regulation ; Integrin alpha Chains/metabolism ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/metabolism ; Interleukin-12/immunology/metabolism ; Leucine Zippers ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Oncogene Protein p65(gag-jun)/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/deficiency/genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism ; Toxoplasma/immunology
    Print ISSN: 0028-0836
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    Autistic-like behaviours and hyperactivity in mice lacking ProSAP1/Shank2 (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-16
    Description: Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3alphabeta(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schmeisser, Michael J -- Ey, Elodie -- Wegener, Stephanie -- Bockmann, Juergen -- Stempel, A Vanessa -- Kuebler, Angelika -- Janssen, Anna-Lena -- Udvardi, Patrick T -- Shiban, Ehab -- Spilker, Christina -- Balschun, Detlef -- Skryabin, Boris V -- Dieck, Susanne tom -- Smalla, Karl-Heinz -- Montag, Dirk -- Leblond, Claire S -- Faure, Philippe -- Torquet, Nicolas -- Le Sourd, Anne-Marie -- Toro, Roberto -- Grabrucker, Andreas M -- Shoichet, Sarah A -- Schmitz, Dietmar -- Kreutz, Michael R -- Bourgeron, Thomas -- Gundelfinger, Eckart D -- Boeckers, Tobias M -- England -- Nature. 2012 Apr 29;486(7402):256-60. doi: 10.1038/nature11015.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Anatomy and Cell Biology, Ulm University, 89081 Ulm, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699619" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*genetics ; Animals ; Autistic Disorder/*genetics/pathology ; Behavior, Animal/*physiology ; Dendritic Spines/genetics ; Female ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/*genetics ; Psychomotor Agitation/*genetics/pathology ; Receptors, Ionotropic Glutamate/metabolism ; Synapses/metabolism ; Up-Regulation ; Vocalization, Animal/physiology
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    Genotoxic consequences of endogenous aldehydes on mouse haematopoietic stem cell function (2012)
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    Publication Date: 2012-08-28
    Description: Haematopoietic stem cells (HSCs) regenerate blood cells throughout the lifespan of an organism. With age, the functional quality of HSCs declines, partly owing to the accumulation of damaged DNA. However, the factors that damage DNA and the protective mechanisms that operate in these cells are poorly understood. We have recently shown that the Fanconi anaemia DNA-repair pathway counteracts the genotoxic effects of reactive aldehydes. Mice with combined inactivation of aldehyde catabolism (through Aldh2 knockout) and the Fanconi anaemia DNA-repair pathway (Fancd2 knockout) display developmental defects, a predisposition to leukaemia, and are susceptible to the toxic effects of ethanol-an exogenous source of acetaldehyde. Here we report that aged Aldh2(-/-) Fancd2(-/-) mutant mice that do not develop leukaemia spontaneously develop aplastic anaemia, with the concomitant accumulation of damaged DNA within the haematopoietic stem and progenitor cell (HSPC) pool. Unexpectedly, we find that only HSPCs, and not more mature blood precursors, require Aldh2 for protection against acetaldehyde toxicity. Additionally, the aldehyde-oxidizing activity of HSPCs, as measured by Aldefluor stain, is due to Aldh2 and correlates with this protection. Finally, there is more than a 600-fold reduction in the HSC pool of mice deficient in both Fanconi anaemia pathway-mediated DNA repair and acetaldehyde detoxification. Therefore, the emergence of bone marrow failure in Fanconi anaemia is probably due to aldehyde-mediated genotoxicity restricted to the HSPC pool. These findings identify a new link between endogenous reactive metabolites and DNA damage in HSCs, and define the protective mechanisms that counteract this threat.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Garaycoechea, Juan I -- Crossan, Gerry P -- Langevin, Frederic -- Daly, Maria -- Arends, Mark J -- Patel, Ketan J -- MC_U105178811/Medical Research Council/United Kingdom -- England -- Nature. 2012 Sep 27;489(7417):571-5. doi: 10.1038/nature11368. Epub 2012 Aug 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22922648" target="_blank"〉PubMed〈/a〉
    Keywords: Acetaldehyde/metabolism/toxicity ; Aging ; Aldehyde Dehydrogenase/deficiency/genetics/metabolism ; Aldehydes/metabolism/*toxicity ; Animals ; Bone Marrow/pathology ; DNA Damage/drug effects/genetics ; DNA Repair ; Ethanol/toxicity ; Fanconi Anemia/pathology ; Fanconi Anemia Complementation Group D2 Protein/deficiency/genetics ; Female ; Hematopoietic Stem Cells/*cytology/*drug effects/enzymology/metabolism ; Kaplan-Meier Estimate ; Leukemia/metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mutagens/*toxicity
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Circadian rhythms govern cardiac repolarization and arrhythmogenesis (2012)
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    Publication Date: 2012-03-01
    Description: Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada's syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, kruppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3297978/" 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/PMC3297978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jeyaraj, Darwin -- Haldar, Saptarsi M -- Wan, Xiaoping -- McCauley, Mark D -- Ripperger, Jurgen A -- Hu, Kun -- Lu, Yuan -- Eapen, Betty L -- Sharma, Nikunj -- Ficker, Eckhard -- Cutler, Michael J -- Gulick, James -- Sanbe, Atsushi -- Robbins, Jeffrey -- Demolombe, Sophie -- Kondratov, Roman V -- Shea, Steven A -- Albrecht, Urs -- Wehrens, Xander H T -- Rosenbaum, David S -- Jain, Mukesh K -- HL054807/HL/NHLBI NIH HHS/ -- HL066991/HL/NHLBI NIH HHS/ -- HL075427/HL/NHLBI NIH HHS/ -- HL076754/HL/NHLBI NIH HHS/ -- HL084154/HL/NHLBI NIH HHS/ -- HL086548/HL/NHLBI NIH HHS/ -- HL086614/HL/NHLBI NIH HHS/ -- HL089598/HL/NHLBI NIH HHS/ -- HL091947/HL/NHLBI NIH HHS/ -- HL094660/HL/NHLBI NIH HHS/ -- HL097595/HL/NHLBI NIH HHS/ -- HL102241/HL/NHLBI NIH HHS/ -- HL76446/HL/NHLBI NIH HHS/ -- K24 HL076446/HL/NHLBI NIH HHS/ -- K99 HL102241/HL/NHLBI NIH HHS/ -- M01-RR02635/RR/NCRR NIH HHS/ -- R00 HL102241/HL/NHLBI NIH HHS/ -- R01 HL084154/HL/NHLBI NIH HHS/ -- R01 HL084154-04/HL/NHLBI NIH HHS/ -- R01 HL086548/HL/NHLBI NIH HHS/ -- R01 HL086548-05/HL/NHLBI NIH HHS/ -- R01 HL097593/HL/NHLBI NIH HHS/ -- R01 HL097593-03/HL/NHLBI NIH HHS/ -- R01 HL110630/HL/NHLBI NIH HHS/ -- R01 HL110630-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2012 Feb 22;483(7387):96-9. doi: 10.1038/nature10852.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Case Cardiovascular Research Institute, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA. darwinjeyaraj@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22367544" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrhythmias, Cardiac/complications/genetics/*physiopathology ; Cells, Cultured ; Circadian Rhythm/genetics/*physiology ; DNA-Binding Proteins/deficiency/genetics/metabolism ; Death, Sudden, Cardiac/etiology ; Electrocardiography ; Gene Expression Regulation ; Heart Conduction System/*physiology ; Heart Rate/physiology ; Heart Ventricles/cytology ; Kv Channel-Interacting Proteins/biosynthesis/genetics ; Male ; Mice ; Mice, Inbred C57BL ; Muscle Cells/cytology ; Promoter Regions, Genetic/genetics ; Rats ; Time Factors ; Transcription Factors/deficiency/genetics/metabolism
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    Skin infection generates non-migratory memory CD8+ T(RM) cells providing global skin immunity (2012)
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    Publication Date: 2012-03-06
    Description: Protective T-cell memory has long been thought to reside in blood and lymph nodes, but recently the concept of immune memory in peripheral tissues mediated by resident memory T (T(RM)) cells has been proposed. Here we show in mice that localized vaccinia virus (VACV) skin infection generates long-lived non-recirculating CD8(+) skin T(RM) cells that reside within the entire skin. These skin T(RM) cells are potent effector cells, and are superior to circulating central memory T (T(CM)) cells at providing rapid long-term protection against cutaneous re-infection. We find that CD8(+) T cells are rapidly recruited to skin after acute VACV infection. CD8(+) T-cell recruitment to skin is independent of CD4(+) T cells and interferon-gamma, but requires the expression of E- and P-selectin ligands by CD8(+) T cells. Using parabiotic mice, we further show that circulating CD8(+) T(CM) and CD8(+) skin T(RM) cells are both generated after skin infection; however, CD8(+) T(CM) cells recirculate between blood and lymph nodes whereas T(RM) cells remain in the skin. Cutaneous CD8(+) T(RM) cells produce effector cytokines and persist for at least 6 months after infection. Mice with CD8(+) skin T(RM) cells rapidly cleared a subsequent re-infection with VACV whereas mice with circulating T(CM) but no skin T(RM) cells showed greatly impaired viral clearance, indicating that T(RM) cells provide superior protection. Finally, we show that T(RM) cells generated as a result of localized VACV skin infection reside not only in the site of infection, but also populate the entire skin surface and remain present for many months. Repeated re-infections lead to progressive accumulation of highly protective T(RM) cells in non-involved skin. These findings have important implications for our understanding of protective immune memory at epithelial interfaces with the environment, and suggest novel strategies for vaccines that protect against tissue tropic organisms.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437663/" 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/PMC3437663/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Xiaodong -- Clark, Rachael A -- Liu, Luzheng -- Wagers, Amy J -- Fuhlbrigge, Robert C -- Kupper, Thomas S -- R01 AI025082/AI/NIAID NIH HHS/ -- R01 AI041707/AI/NIAID NIH HHS/ -- R01 AI097128/AI/NIAID NIH HHS/ -- R01 AR056720/AR/NIAMS NIH HHS/ -- R01 AR065807/AR/NIAMS NIH HHS/ -- R01AI041707/AI/NIAID NIH HHS/ -- R37AI025082/AI/NIAID NIH HHS/ -- TR01AI097128/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Feb 29;483(7388):227-31. doi: 10.1038/nature10851.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Dermatology and Harvard Skin Disease Research Center, 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/22388819" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes/*cytology/*immunology ; Cell Movement ; E-Selectin/metabolism ; Female ; Immunologic Memory/*immunology ; Interferon-gamma ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; P-Selectin/metabolism ; Skin/*immunology/metabolism/*virology ; Vaccinia/immunology/virology ; Vaccinia virus/immunology/physiology
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    Exploiting a natural conformational switch to engineer an interleukin-2 'superkine' (2012)
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    Publication Date: 2012-03-27
    Description: The immunostimulatory cytokine interleukin-2 (IL-2) is a growth factor for a wide range of leukocytes, including T cells and natural killer (NK) cells. Considerable effort has been invested in using IL-2 as a therapeutic agent for a variety of immune disorders ranging from AIDS to cancer. However, adverse effects have limited its use in the clinic. On activated T cells, IL-2 signals through a quaternary 'high affinity' receptor complex consisting of IL-2, IL-2Ralpha (termed CD25), IL-2Rbeta and IL-2Rgamma. Naive T cells express only a low density of IL-2Rbeta and IL-2Rgamma, and are therefore relatively insensitive to IL-2, but acquire sensitivity after CD25 expression, which captures the cytokine and presents it to IL-2Rbeta and IL-2Rgamma. Here, using in vitro evolution, we eliminated the functional requirement of IL-2 for CD25 expression by engineering an IL-2 'superkine' (also called super-2) with increased binding affinity for IL-2Rbeta. Crystal structures of the IL-2 superkine in free and receptor-bound forms showed that the evolved mutations are principally in the core of the cytokine, and molecular dynamics simulations indicated that the evolved mutations stabilized IL-2, reducing the flexibility of a helix in the IL-2Rbeta binding site, into an optimized receptor-binding conformation resembling that when bound to CD25. The evolved mutations in the IL-2 superkine recapitulated the functional role of CD25 by eliciting potent phosphorylation of STAT5 and vigorous proliferation of T cells irrespective of CD25 expression. Compared to IL-2, the IL-2 superkine induced superior expansion of cytotoxic T cells, leading to improved antitumour responses in vivo, and elicited proportionally less expansion of T regulatory cells and reduced pulmonary oedema. Collectively, we show that in vitro evolution has mimicked the functional role of CD25 in enhancing IL-2 potency and regulating target cell specificity, which has implications for immunotherapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3338870/" 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/PMC3338870/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Levin, Aron M -- Bates, Darren L -- Ring, Aaron M -- Krieg, Carsten -- Lin, Jack T -- Su, Leon -- Moraga, Ignacio -- Raeber, Miro E -- Bowman, Gregory R -- Novick, Paul -- Pande, Vijay S -- Fathman, C Garrison -- Boyman, Onur -- Garcia, K Christopher -- AR050942/AR/NIAMS NIH HHS/ -- GM07365/GM/NIGMS NIH HHS/ -- R01 AI051321/AI/NIAID NIH HHS/ -- R01 AI051321-05/AI/NIAID NIH HHS/ -- R01 CA065237/CA/NCI NIH HHS/ -- R01-GM062868/GM/NIGMS NIH HHS/ -- R01AI51321/AI/NIAID NIH HHS/ -- R37 AI051321/AI/NIAID NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- U01 DK078123/DK/NIDDK NIH HHS/ -- U19 AI 082719/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 25;484(7395):529-33. doi: 10.1038/nature10975.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, 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/22446627" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Cell Line ; Cell Proliferation ; Crystallography, X-Ray ; *Directed Molecular Evolution ; Humans ; Immunotherapy ; Interleukin-2/*chemistry/genetics/*immunology/pharmacology ; Interleukin-2 Receptor alpha Subunit/chemistry/deficiency/immunology/metabolism ; Interleukin-2 Receptor beta Subunit/chemistry/metabolism ; Killer Cells, Natural/immunology ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Molecular Dynamics Simulation ; Mutant Proteins/*chemistry/genetics/*immunology/pharmacology ; Mutation ; Neoplasm Transplantation ; Neoplasms/drug therapy/immunology ; Phosphorylation ; Protein Conformation ; *Protein Engineering ; STAT5 Transcription Factor/metabolism ; Surface Plasmon Resonance ; T-Lymphocytes/cytology/immunology
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    The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma (2012)
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    Publication Date: 2012-06-16
    Description: Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3376394/" 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/PMC3376394/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perez-Mancera, Pedro A -- Rust, Alistair G -- van der Weyden, Louise -- Kristiansen, Glen -- Li, Allen -- Sarver, Aaron L -- Silverstein, Kevin A T -- Grutzmann, Robert -- Aust, Daniela -- Rummele, Petra -- Knosel, Thomas -- Herd, Colin -- Stemple, Derek L -- Kettleborough, Ross -- Brosnan, Jacqueline A -- Li, Ang -- Morgan, Richard -- Knight, Spencer -- Yu, Jun -- Stegeman, Shane -- Collier, Lara S -- ten Hoeve, Jelle J -- de Ridder, Jeroen -- Klein, Alison P -- Goggins, Michael -- Hruban, Ralph H -- Chang, David K -- Biankin, Andrew V -- Grimmond, Sean M -- Australian Pancreatic Cancer Genome Initiative -- Wessels, Lodewyk F A -- Wood, Stephen A -- Iacobuzio-Donahue, Christine A -- Pilarsky, Christian -- Largaespada, David A -- Adams, David J -- Tuveson, David A -- 13031/Cancer Research UK/United Kingdom -- 2P50CA101955/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA122183/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- K01 CA122183/CA/NCI NIH HHS/ -- K01 CA122183-05/CA/NCI NIH HHS/ -- P50 CA101955/CA/NCI NIH HHS/ -- P50CA62924/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2012 Apr 29;486(7402):266-70. doi: 10.1038/nature11114.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22699621" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anoikis/genetics ; Carcinoma, Pancreatic Ductal/*enzymology/genetics/pathology ; Cell Line, Tumor ; Disease Models, Animal ; Endopeptidases ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Mice ; Mice, Inbred C57BL ; Pancreatic Neoplasms/*enzymology/genetics/pathology ; U937 Cells ; Ubiquitin Thiolesterase/*genetics/*metabolism
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    CaMKII determines mitochondrial stress responses in heart (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-12
    Description: Myocardial cell death is initiated by excessive mitochondrial Ca(2+) entry causing Ca(2+) overload, mitochondrial permeability transition pore (mPTP) opening and dissipation of the mitochondrial inner membrane potential (DeltaPsim). However, the signalling pathways that control mitochondrial Ca(2+) entry through the inner membrane mitochondrial Ca(2+) uniporter (MCU) are not known. The multifunctional Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is activated in ischaemia reperfusion, myocardial infarction and neurohumoral injury, common causes of myocardial death and heart failure; these findings suggest that CaMKII could couple disease stress to mitochondrial injury. Here we show that CaMKII promotes mPTP opening and myocardial death by increasing MCU current (I(MCU)). Mitochondrial-targeted CaMKII inhibitory protein or cyclosporin A, an mPTP antagonist with clinical efficacy in ischaemia reperfusion injury, equivalently prevent mPTP opening, DeltaPsim deterioration and diminish mitochondrial disruption and programmed cell death in response to ischaemia reperfusion injury. Mice with myocardial and mitochondrial-targeted CaMKII inhibition have reduced I(MCU) and are resistant to ischaemia reperfusion injury, myocardial infarction and neurohumoral injury, suggesting that pathological actions of CaMKII are substantially mediated by increasing I(MCU). Our findings identify CaMKII activity as a central mechanism for mitochondrial Ca(2+) entry in myocardial cell death, and indicate that mitochondrial-targeted CaMKII inhibition could prevent or reduce myocardial death and heart failure in response to common experimental forms of pathophysiological stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471377/" 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/PMC3471377/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Joiner, Mei-Ling A -- Koval, Olha M -- Li, Jingdong -- He, B Julie -- Allamargot, Chantal -- Gao, Zhan -- Luczak, Elizabeth D -- Hall, Duane D -- Fink, Brian D -- Chen, Biyi -- Yang, Jinying -- Moore, Steven A -- Scholz, Thomas D -- Strack, Stefan -- Mohler, Peter J -- Sivitz, William I -- Song, Long-Sheng -- Anderson, Mark E -- R01 HL062494/HL/NHLBI NIH HHS/ -- R01 HL070250/HL/NHLBI NIH HHS/ -- R01 HL079031/HL/NHLBI NIH HHS/ -- R01 HL083422/HL/NHLBI NIH HHS/ -- R01 HL084583/HL/NHLBI NIH HHS/ -- R01 HL090905/HL/NHLBI NIH HHS/ -- R01 HL113001/HL/NHLBI NIH HHS/ -- R01 HL62494/HL/NHLBI NIH HHS/ -- R01 HL70250/HL/NHLBI NIH HHS/ -- R56 NS056244/NS/NINDS NIH HHS/ -- England -- Nature. 2012 Nov 8;491(7423):269-73. doi: 10.1038/nature11444. Epub 2012 Oct 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Internal Medicine and Cardiovascular Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA. mei-ling-joiner@uiowa.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23051746" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/drug effects ; Calcium/*metabolism/pharmacology ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & ; inhibitors/chemistry/*metabolism ; Cyclosporine/pharmacology ; Female ; Heart/drug effects/physiopathology ; Heart Failure/drug therapy/prevention & control ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Mitochondria, Heart/enzymology/*metabolism/*pathology ; Mitochondrial Membrane Transport Proteins/metabolism ; Myocardial Infarction/drug therapy/prevention & control ; Myocardium/*enzymology/metabolism/*pathology ; Reperfusion Injury/enzymology/metabolism/pathology/prevention & control ; Serine/metabolism ; *Stress, Physiological/drug effects
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A vaccine strategy that protects against genital herpes by establishing local memory T cells (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-10-19
    Description: Most successful existing vaccines rely on neutralizing antibodies, which may not require specific anatomical localization of B cells. However, efficacious vaccines that rely on T cells for protection have been difficult to develop, as robust systemic memory T-cell responses do not necessarily correlate with host protection. In peripheral sites, tissue-resident memory T cells provide superior protection compared to circulating memory T cells. Here we describe a simple and non-inflammatory vaccine strategy that enables the establishment of a protective memory T-cell pool within peripheral tissue. The female genital tract, which is a portal of entry for sexually transmitted infections, is an immunologically restrictive tissue that prevents entry of activated T cells in the absence of inflammation or infection. To overcome this obstacle, we developed a vaccine strategy that we term 'prime and pull' to establish local tissue-resident memory T cells at a site of potential viral exposure. This approach relies on two steps: conventional parenteral vaccination to elicit systemic T-cell responses (prime), followed by recruitment of activated T cells by means of topical chemokine application to the restrictive genital tract (pull), where such T cells establish a long-term niche and mediate protective immunity. In mice, prime and pull protocol reduces the spread of infectious herpes simplex virus 2 into the sensory neurons and prevents development of clinical disease. These results reveal a promising vaccination strategy against herpes simplex virus 2, and potentially against other sexually transmitted infections such as human immunodeficiency virus.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499630/" 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/PMC3499630/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shin, Haina -- Iwasaki, Akiko -- AI054359/AI/NIAID NIH HHS/ -- AI062428/AI/NIAID NIH HHS/ -- F32 AI091024/AI/NIAID NIH HHS/ -- F32AI091024/AI/NIAID NIH HHS/ -- R01 AI054359/AI/NIAID NIH HHS/ -- R01 AI062428/AI/NIAID NIH HHS/ -- R56 AI062428/AI/NIAID NIH HHS/ -- England -- Nature. 2012 Nov 15;491(7424):463-7. doi: 10.1038/nature11522. Epub 2012 Oct 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23075848" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Topical ; Animals ; Antibodies, Viral/analysis ; Cell Count ; Chemokine CXCL10/administration & dosage ; Chemokine CXCL9/administration & dosage ; Female ; Herpes Genitalis/*immunology/*prevention & control ; Immunologic Memory/*immunology ; Mice ; Mice, Inbred C57BL ; Survival Analysis ; T-Lymphocytes/cytology/immunology ; *Vaccination ; Vagina/immunology ; Viral Load ; Viral Vaccines/*immunology
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    Activity in motor-sensory projections reveals distributed coding in somatosensation (2012)
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    Publication Date: 2012-08-28
    Description: Cortical-feedback projections to primary sensory areas terminate most heavily in layer 1 (L1) of the neocortex, where they make synapses with tuft dendrites of pyramidal neurons. L1 input is thought to provide 'contextual' information, but the signals transmitted by L1 feedback remain uncharacterized. In the rodent somatosensory system, the spatially diffuse feedback projection from vibrissal motor cortex (vM1) to vibrissal somatosensory cortex (vS1, also known as the barrel cortex) may allow whisker touch to be interpreted in the context of whisker position to compute object location. When mice palpate objects with their whiskers to localize object features, whisker touch excites vS1 and later vM1 in a somatotopic manner. Here we use axonal calcium imaging to track activity in vM1--〉vS1 afferents in L1 of the barrel cortex while mice performed whisker-dependent object localization. Spatially intermingled individual axons represent whisker movements, touch and other behavioural features. In a subpopulation of axons, activity depends on object location and persists for seconds after touch. Neurons in the barrel cortex thus have information to integrate movements and touches of multiple whiskers over time, key components of object identification and navigation by active touch.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443316/" 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/PMC3443316/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Petreanu, Leopoldo -- Gutnisky, Diego A -- Huber, Daniel -- Xu, Ning-long -- O'Connor, Dan H -- Tian, Lin -- Looger, Loren -- Svoboda, Karel -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Sep 13;489(7415):299-303. doi: 10.1038/nature11321.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Janelia Farm Research Campus, Howard Hughes Medical Institute, Ashburn, Virginia 20147, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22922646" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/metabolism ; Calcium Signaling ; Feedback, Physiological ; Male ; Mice ; Mice, Inbred C57BL ; Motor Cortex/cytology/*physiology ; Motor Neurons/metabolism ; Movement/physiology ; *Neural Pathways ; Physical Stimulation ; Somatosensory Cortex/cytology/*physiology ; Touch/*physiology ; Vibrissae/*physiology
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    A PPARgamma-FGF1 axis is required for adaptive adipose remodelling and metabolic homeostasis (2012)
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    Publication Date: 2012-04-24
    Description: Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood. Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPARgamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs. FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes. Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions. We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPARgamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPARgamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358516/" 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/PMC3358516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jonker, Johan W -- Suh, Jae Myoung -- Atkins, Annette R -- Ahmadian, Maryam -- Li, Pingping -- Whyte, Jamie -- He, Mingxiao -- Juguilon, Henry -- Yin, Yun-Qiang -- Phillips, Colin T -- Yu, Ruth T -- Olefsky, Jerrold M -- Henry, Robert R -- Downes, Michael -- Evans, Ronald M -- DK057978/DK/NIDDK NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- DK063491/DK/NIDDK NIH HHS/ -- DK090962/DK/NIDDK NIH HHS/ -- HL105278/HL/NHLBI NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- P30 DK063491/DK/NIDDK NIH HHS/ -- R01 DK033651/DK/NIDDK NIH HHS/ -- R01 HL105278/HL/NHLBI NIH HHS/ -- R01 HL105278-21/HL/NHLBI NIH HHS/ -- R24 DK090962/DK/NIDDK NIH HHS/ -- R24 DK090962-02/DK/NIDDK NIH HHS/ -- R37 DK033651/DK/NIDDK NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- R37 DK057978-34/DK/NIDDK NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19 DK062434-10/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 May 17;485(7398):391-4. doi: 10.1038/nature10998.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22522926" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/drug effects/metabolism/pathology ; Animals ; Base Sequence ; Cell Size/drug effects ; Diabetes Mellitus, Experimental/chemically induced/genetics/pathology ; Diet, High-Fat/adverse effects ; Fibroblast Growth Factor 1/deficiency/*genetics/*metabolism ; *Homeostasis/drug effects ; Humans ; Inflammation/genetics ; Insulin/metabolism ; Insulin Resistance ; Intra-Abdominal Fat/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Necrosis/enzymology ; PPAR gamma/*metabolism ; Promoter Regions, Genetic/genetics ; Response Elements/genetics
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    Endothelial and perivascular cells maintain haematopoietic stem cells (2012)
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    Publication Date: 2012-01-28
    Description: Several cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem cell factor (SCF; also known as KITL) is a key niche component that maintains HSCs. Here, using Scf(gfp) knock-in mice, we found that Scf was primarily expressed by perivascular cells throughout the bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, nestin-cre- or nestin-creER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. Thus, HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270376/" 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/PMC3270376/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ding, Lei -- Saunders, Thomas L -- Enikolopov, Grigori -- Morrison, Sean J -- 5R01HL097760/HL/NHLBI NIH HHS/ -- R01 AG040209/AG/NIA NIH HHS/ -- R01 HL097760/HL/NHLBI NIH HHS/ -- R01 HL097760-04/HL/NHLBI NIH HHS/ -- R01AG040209/AG/NIA NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Jan 25;481(7382):457-62. doi: 10.1038/nature10783.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Pediatrics, 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/22281595" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Endothelium/*cytology/*metabolism ; Gene Knock-In Techniques ; Hematopoietic Stem Cells/*cytology/*metabolism ; Intermediate Filament Proteins/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/metabolism ; Nestin ; Osteoblasts/cytology/metabolism ; Pericytes/cytology/metabolism ; Receptors, Leptin/metabolism ; Stem Cell Factor/deficiency/genetics/metabolism ; Stem Cell Niche/*physiology ; Stromal Cells/*cytology/*metabolism
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    Black mamba venom peptides target acid-sensing ion channels to abolish pain (2012)
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    Publication Date: 2012-10-05
    Description: Polypeptide toxins have played a central part in understanding physiological and physiopathological functions of ion channels. In the field of pain, they led to important advances in basic research and even to clinical applications. Acid-sensing ion channels (ASICs) are generally considered principal players in the pain pathway, including in humans. A snake toxin activating peripheral ASICs in nociceptive neurons has been recently shown to evoke pain. Here we show that a new class of three-finger peptides from another snake, the black mamba, is able to abolish pain through inhibition of ASICs expressed either in central or peripheral neurons. These peptides, which we call mambalgins, are not toxic in mice but show a potent analgesic effect upon central and peripheral injection that can be as strong as morphine. This effect is, however, resistant to naloxone, and mambalgins cause much less tolerance than morphine and no respiratory distress. Pharmacological inhibition by mambalgins combined with the use of knockdown and knockout animals indicates that blockade of heteromeric channels made of ASIC1a and ASIC2a subunits in central neurons and of ASIC1b-containing channels in nociceptors is involved in the analgesic effect of mambalgins. These findings identify new potential therapeutic targets for pain and introduce natural peptides that block them to produce a potent analgesia.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diochot, Sylvie -- Baron, Anne -- Salinas, Miguel -- Douguet, Dominique -- Scarzello, Sabine -- Dabert-Gay, Anne-Sophie -- Debayle, Delphine -- Friend, Valerie -- Alloui, Abdelkrim -- Lazdunski, Michel -- Lingueglia, Eric -- England -- Nature. 2012 Oct 25;490(7421):552-5. doi: 10.1038/nature11494. Epub 2012 Oct 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275, 06560 Valbonne, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23034652" target="_blank"〉PubMed〈/a〉
    Keywords: Acid Sensing Ion Channel Blockers/chemistry/*pharmacology/therapeutic use ; Acid Sensing Ion Channels/classification/genetics/*metabolism ; Analgesics/adverse effects/chemistry/*pharmacology/therapeutic use ; Animals ; Drug Tolerance ; Elapid Venoms/administration & dosage/chemistry/*pharmacology/therapeutic use ; Injections, Spinal ; Male ; Mice ; Mice, Inbred C57BL ; Molecular Sequence Data ; Morphine/adverse effects/pharmacology ; Naloxone/pharmacology ; Nociceptors/chemistry/metabolism ; Oocytes/drug effects/metabolism ; Pain/*drug therapy/metabolism ; Peptides/administration & dosage/chemistry/*pharmacology/*therapeutic use ; Protein Subunits/antagonists & inhibitors/metabolism ; Rats ; Respiratory Insufficiency/chemically induced ; Xenopus laevis
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    A map of the cis-regulatory sequences in the mouse genome (2012)
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    Publication Date: 2012-07-06
    Description: The laboratory mouse is the most widely used mammalian model organism in biomedical research. The 2.6 x 10(9) bases of the mouse genome possess a high degree of conservation with the human genome, so a thorough annotation of the mouse genome will be of significant value to understanding the function of the human genome. So far, most of the functional sequences in the mouse genome have yet to be found, and the cis-regulatory sequences in particular are still poorly annotated. Comparative genomics has been a powerful tool for the discovery of these sequences, but on its own it cannot resolve their temporal and spatial functions. Recently, ChIP-Seq has been developed to identify cis-regulatory elements in the genomes of several organisms including humans, Drosophila melanogaster and Caenorhabditis elegans. Here we apply the same experimental approach to a diverse set of 19 tissues and cell types in the mouse to produce a map of nearly 300,000 murine cis-regulatory sequences. The annotated sequences add up to 11% of the mouse genome, and include more than 70% of conserved non-coding sequences. We define tissue-specific enhancers and identify potential transcription factors regulating gene expression in each tissue or cell type. Finally, we show that much of the mouse genome is organized into domains of coordinately regulated enhancers and promoters. Our results provide a resource for the annotation of functional elements in the mammalian genome and for the study of mechanisms regulating tissue-specific gene expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4041622/" 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/PMC4041622/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shen, Yin -- Yue, Feng -- McCleary, David F -- Ye, Zhen -- Edsall, Lee -- Kuan, Samantha -- Wagner, Ulrich -- Dixon, Jesse -- Lee, Leonard -- Lobanenkov, Victor V -- Ren, Bing -- R01HG003991/HG/NHGRI NIH HHS/ -- T32 GM007198/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Aug 2;488(7409):116-20. doi: 10.1038/nature11243.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ludwig Institute for Cancer Research, 9500 Gilman Drive, La Jolla, California 92093-0653, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22763441" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Animals ; Chromatin/metabolism ; Chromatin Immunoprecipitation ; Conserved Sequence ; Enhancer Elements, Genetic/genetics ; Evolution, Molecular ; Gene Expression Regulation/*genetics ; Genome/*genetics ; Male ; Methylation ; Mice/*genetics ; Mice, Inbred C57BL ; Molecular Sequence Annotation ; Nucleotide Motifs ; Organ Specificity ; *Physical Chromosome Mapping ; Promoter Regions, Genetic/genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Sequence Analysis, DNA ; Transcription Factors/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Wild-type microglia arrest pathology in a mouse model of Rett syndrome (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-20
    Description: Rett syndrome is an X-linked autism spectrum disorder. The disease is characterized in most cases by mutation of the MECP2 gene, which encodes a methyl-CpG-binding protein. Although MECP2 is expressed in many tissues, the disease is generally attributed to a primary neuronal dysfunction. However, as shown recently, glia, specifically astrocytes, also contribute to Rett pathophysiology. Here we examine the role of another form of glia, microglia, in a murine model of Rett syndrome. Transplantation of wild-type bone marrow into irradiation-conditioned Mecp2-null hosts resulted in engraftment of brain parenchyma by bone-marrow-derived myeloid cells of microglial phenotype, and arrest of disease development. However, when cranial irradiation was blocked by lead shield, and microglial engraftment was prevented, disease was not arrested. Similarly, targeted expression of MECP2 in myeloid cells, driven by Lysm(cre) on an Mecp2-null background, markedly attenuated disease symptoms. Thus, through multiple approaches, wild-type Mecp2-expressing microglia within the context of an Mecp2-null male mouse arrested numerous facets of disease pathology: lifespan was increased, breathing patterns were normalized, apnoeas were reduced, body weight was increased to near that of wild type, and locomotor activity was improved. Mecp2(+/-) females also showed significant improvements as a result of wild-type microglial engraftment. These benefits mediated by wild-type microglia, however, were diminished when phagocytic activity was inhibited pharmacologically by using annexin V to block phosphatydilserine residues on apoptotic targets, thus preventing recognition and engulfment by tissue-resident phagocytes. These results suggest the importance of microglial phagocytic activity in Rett syndrome. Our data implicate microglia as major players in the pathophysiology of this devastating disorder, and suggest that bone marrow transplantation might offer a feasible therapeutic approach for it.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321067/" 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/PMC3321067/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Derecki, Noel C -- Cronk, James C -- Lu, Zhenjie -- Xu, Eric -- Abbott, Stephen B G -- Guyenet, Patrice G -- Kipnis, Jonathan -- AG034113/AG/NIA NIH HHS/ -- HD056293/HD/NICHD NIH HHS/ -- R01 AG034113/AG/NIA NIH HHS/ -- R01 AG034113-01A2/AG/NIA NIH HHS/ -- R21 HD056293/HD/NICHD NIH HHS/ -- R21 HD056293-01A2/HD/NICHD NIH HHS/ -- England -- Nature. 2012 Mar 18;484(7392):105-9. doi: 10.1038/nature10907.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, 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/22425995" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Annexin A5/administration & dosage/metabolism/pharmacology ; Apoptosis/drug effects ; Body Weight/physiology ; Bone Marrow Transplantation ; Brain/cytology ; Disease Models, Animal ; *Disease Progression ; Female ; Insulin-Like Growth Factor I/metabolism ; Locomotion ; Male ; Methyl-CpG-Binding Protein 2/deficiency/genetics/*metabolism ; Mice ; Mice, Inbred C57BL ; Microglia/*cytology/pathology/*physiology/transplantation ; Phagocytosis/drug effects ; Phosphatidylserines/metabolism ; Respiration/drug effects ; Rett Syndrome/genetics/*pathology/physiopathology/therapy ; Rotarod Performance Test
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    The sirtuin SIRT6 regulates lifespan in male mice (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-01
    Description: The significant increase in human lifespan during the past century confronts us with great medical challenges. To meet these challenges, the mechanisms that determine healthy ageing must be understood and controlled. Sirtuins are highly conserved deacetylases that have been shown to regulate lifespan in yeast, nematodes and fruitflies. However, the role of sirtuins in regulating worm and fly lifespan has recently become controversial. Moreover, the role of the seven mammalian sirtuins, SIRT1 to SIRT7 (homologues of the yeast sirtuin Sir2), in regulating lifespan is unclear. Here we show that male, but not female, transgenic mice overexpressing Sirt6 (ref. 4) have a significantly longer lifespan than wild-type mice. Gene expression analysis revealed significant differences between male Sirt6-transgenic mice and male wild-type mice: transgenic males displayed lower serum levels of insulin-like growth factor 1 (IGF1), higher levels of IGF-binding protein 1 and altered phosphorylation levels of major components of IGF1 signalling, a key pathway in the regulation of lifespan. This study shows the regulation of mammalian lifespan by a sirtuin family member and has important therapeutic implications for age-related diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kanfi, Yariv -- Naiman, Shoshana -- Amir, Gail -- Peshti, Victoria -- Zinman, Guy -- Nahum, Liat -- Bar-Joseph, Ziv -- Cohen, Haim Y -- 1R01GM085022/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 22;483(7388):218-21. doi: 10.1038/nature10815.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Mina & 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/22367546" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Female ; Gene Expression ; Gene Expression Profiling ; Insulin-Like Growth Factor I/analysis ; Kaplan-Meier Estimate ; Longevity/genetics/*physiology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Oligonucleotide Array Sequence Analysis ; *Sex Characteristics ; Sirtuins/genetics/*metabolism
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    Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-06-23
    Description: The composite human microbiome of Western populations has probably changed over the past century, brought on by new environmental triggers that often have a negative impact on human health. Here we show that consumption of a diet high in saturated (milk-derived) fat, but not polyunsaturated (safflower oil) fat, changes the conditions for microbial assemblage and promotes the expansion of a low-abundance, sulphite-reducing pathobiont, Bilophila wadsworthia. This was associated with a pro-inflammatory T helper type 1 (T(H)1) immune response and increased incidence of colitis in genetically susceptible Il10(-/-), but not wild-type mice. These effects are mediated by milk-derived-fat-promoted taurine conjugation of hepatic bile acids, which increases the availability of organic sulphur used by sulphite-reducing microorganisms like B. wadsworthia. When mice were fed a low-fat diet supplemented with taurocholic acid, but not with glycocholic acid, for example, a bloom of B. wadsworthia and development of colitis were observed in Il10(-/-) mice. Together these data show that dietary fats, by promoting changes in host bile acid composition, can markedly alter conditions for gut microbial assemblage, resulting in dysbiosis that can perturb immune homeostasis. The data provide a plausible mechanistic basis by which Western-type diets high in certain saturated fats might increase the prevalence of complex immune-mediated diseases like inflammatory bowel disease in genetically susceptible hosts.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3393783/" 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/PMC3393783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Devkota, Suzanne -- Wang, Yunwei -- Musch, Mark W -- Leone, Vanessa -- Fehlner-Peach, Hannah -- Nadimpalli, Anuradha -- Antonopoulos, Dionysios A -- Jabri, Bana -- Chang, Eugene B -- DK-42086/DK/NIDDK NIH HHS/ -- DK47722/DK/NIDDK NIH HHS/ -- F31AT006073/AT/NCCIH NIH HHS/ -- P30 DK042086/DK/NIDDK NIH HHS/ -- R01 DK047722/DK/NIDDK NIH HHS/ -- R01 DK097268/DK/NIDDK NIH HHS/ -- R37 DK047722/DK/NIDDK NIH HHS/ -- T32 DK007074/DK/NIDDK NIH HHS/ -- UH3DK083993/DK/NIDDK NIH HHS/ -- England -- Nature. 2012 Jul 5;487(7405):104-8. doi: 10.1038/nature11225.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Section of Gastroenterology, The University of Chicago, Knapp Center for Biomedical Discovery, 900 East 57th Street, Chicago, Illinois 60637, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22722865" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Acids and Salts/metabolism ; Bilophila/*drug effects/growth & development ; Colitis/*chemically induced/immunology/*microbiology/pathology ; Diet, Fat-Restricted ; Dietary Fats/*pharmacology ; Inflammation/chemically induced/immunology/microbiology ; Inflammatory Bowel Diseases/chemically induced/microbiology/pathology ; Interleukin-10/*deficiency/genetics ; Metagenome/*drug effects ; Mice ; Mice, Inbred C57BL ; Milk/chemistry ; Molecular Sequence Data ; Safflower Oil/pharmacology ; Sulfites/metabolism ; Taurine/metabolism ; Taurocholic Acid/*metabolism/pharmacology ; Th1 Cells/drug effects/immunology
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    Regulation of myeloid leukaemia by the cell-fate determinant Musashi (2010)
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    Publication Date: 2010-07-20
    Description: Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/" 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/PMC2918284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takahiro -- Kwon, Hyog Young -- Zimdahl, Bryan -- Congdon, Kendra L -- Blum, Jordan -- Lento, William E -- Zhao, Chen -- Lagoo, Anand -- Gerrard, Gareth -- Foroni, Letizia -- Goldman, John -- Goh, Harriet -- Kim, Soo-Hyun -- Kim, Dong-Wook -- Chuah, Charles -- Oehler, Vivian G -- Radich, Jerald P -- Jordan, Craig T -- Reya, Tannishtha -- AI067798/AI/NIAID NIH HHS/ -- CA122206/CA/NCI NIH HHS/ -- CA140371/CA/NCI NIH HHS/ -- CA18029/CA/NCI NIH HHS/ -- DK072234/DK/NIDDK NIH HHS/ -- DK63031/DK/NIDDK NIH HHS/ -- DP1 CA174422/CA/NCI NIH HHS/ -- DP1 OD006430/OD/NIH HHS/ -- DP1 OD006430-01/OD/NIH HHS/ -- DP1 OD006430-02/OD/NIH HHS/ -- DP1OD006430/OD/NIH HHS/ -- HL097767/HL/NHLBI NIH HHS/ -- P01 CA018029/CA/NCI NIH HHS/ -- R01 CA140371/CA/NCI NIH HHS/ -- R01 DK063031/DK/NIDDK NIH HHS/ -- R01 DK063031-01/DK/NIDDK NIH HHS/ -- R01 DK063031-01S1/DK/NIDDK NIH HHS/ -- R01 DK063031-02/DK/NIDDK NIH HHS/ -- R01 DK063031-03/DK/NIDDK NIH HHS/ -- R01 DK063031-04/DK/NIDDK NIH HHS/ -- R01 DK063031-05/DK/NIDDK NIH HHS/ -- R01 DK063031-06/DK/NIDDK NIH HHS/ -- R01 DK063031-07/DK/NIDDK NIH HHS/ -- R01 DK063031-07S1/DK/NIDDK NIH HHS/ -- R01 DK063031-08/DK/NIDDK NIH HHS/ -- R01 DK072234/DK/NIDDK NIH HHS/ -- R01 DK072234-01A1/DK/NIDDK NIH HHS/ -- R01 DK072234-02/DK/NIDDK NIH HHS/ -- R01 DK072234-03/DK/NIDDK NIH HHS/ -- R01 DK072234-04/DK/NIDDK NIH HHS/ -- R01 HL097767/HL/NHLBI NIH HHS/ -- R01 HL097767-01/HL/NHLBI NIH HHS/ -- R01 HL097767-02/HL/NHLBI NIH HHS/ -- T32 GM007184-33/GM/NIGMS NIH HHS/ -- U19 AI067798/AI/NIAID NIH HHS/ -- U19 AI067798-010006/AI/NIAID NIH HHS/ -- U19 AI067798-020006/AI/NIAID NIH HHS/ -- U19 AI067798-030006/AI/NIAID NIH HHS/ -- U19 AI067798-040006/AI/NIAID NIH HHS/ -- U19 AI067798-050006/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):765-8. doi: 10.1038/nature09171. Epub 2010 Jul 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, 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/20639863" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blast Crisis/genetics/metabolism/pathology ; *Cell Differentiation/genetics ; Disease Progression ; Fusion Proteins, bcr-abl/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Homeodomain Proteins/genetics/metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/*metabolism/*pathology ; Membrane Proteins/biosynthesis/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; Oncogene Proteins, Fusion/genetics/metabolism ; Prognosis ; RNA-Binding Proteins/biosynthesis/genetics/*metabolism ; Receptor, Notch1/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
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    Induction of tumour immunity by targeted inhibition of nonsense-mediated mRNA decay (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-05-14
    Description: The main reason why tumours are not controlled by the immune system is that, unlike pathogens, they do not express potent tumour rejection antigens (TRAs). Tumour vaccination aims at stimulating a systemic immune response targeted to, mostly weak, antigens expressed in the disseminated tumour lesions. Main challenges in developing effective vaccination protocols are the identification of potent and broadly expressed TRAs and effective adjuvants to stimulate a robust and durable immune response. Here we describe an alternative approach in which the expression of new, and thereby potent, antigens are induced in tumour cells by inhibiting nonsense-mediated messenger RNA decay (NMD). Small interfering RNA (siRNA)-mediated inhibition of NMD in tumour cells led to the expression of new antigenic determinants and their immune-mediated rejection. In subcutaneous and metastatic tumour models, tumour-targeted delivery of NMD factor-specific siRNAs conjugated to oligonucleotide aptamer ligands led to significant inhibition of tumour growth that was superior to that of vaccination with granulocyte-macrophage colony-stimulating factor (GM-CSF)-expressing irradiated tumour cells, and could be further enhanced by co-stimulation. Tumour-targeted NMD inhibition forms the basis of a simple, broadly useful, and clinically feasible approach to enhance the antigenicity of disseminated tumours leading to their immune recognition and rejection. The cell-free chemically synthesized oligonucleotide backbone of aptamer-siRNAs reduces the risk of immunogenicity and enhances the feasibility of generating reagents suitable for clinical use.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107067/" 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/PMC3107067/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pastor, Fernando -- Kolonias, Despina -- Giangrande, Paloma H -- Gilboa, Eli -- R01 CA138503/CA/NCI NIH HHS/ -- R01 CA151857-02/CA/NCI NIH HHS/ -- England -- Nature. 2010 May 13;465(7295):227-30. doi: 10.1038/nature08999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology & Immunology, Dodson Interdisciplinary Immunotherapy Institute, University of Miami Miller School of Medicine Miami, Florida 33134, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20463739" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, Neoplasm/*genetics/*immunology ; Aptamers, Nucleotide/genetics ; Cancer Vaccines/genetics/immunology/metabolism ; Carrier Proteins/genetics ; Cell Line, Tumor ; Chickens/genetics ; Colonic Neoplasms/*genetics/*immunology/pathology ; Gene Expression Regulation, Neoplastic ; Granulocyte-Macrophage Colony-Stimulating Factor/genetics/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Nude ; Neoplasm Transplantation ; RNA Interference ; RNA Stability/*genetics ; RNA, Small Interfering/*genetics/therapeutic use ; Xenograft Model Antitumor Assays
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    Lkb1 regulates quiescence and metabolic homeostasis of haematopoietic stem cells (2010)
    Nature Publishing Group (NPG)
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    Publication Date: 2010-12-03
    Description: The capacity to fine-tune cellular bioenergetics with the demands of stem-cell maintenance and regeneration is central to normal development and ageing, and to organismal survival during periods of acute stress. How energy metabolism and stem-cell homeostatic processes are coordinated is not well understood. Lkb1 acts as an evolutionarily conserved regulator of cellular energy metabolism in eukaryotic cells and functions as the major upstream kinase to phosphorylate AMP-activated protein kinase (AMPK) and 12 other AMPK-related kinases. Whether Lkb1 regulates stem-cell maintenance remains unknown. Here we show that Lkb1 has an essential role in haematopoietic stem cell (HSC) homeostasis. We demonstrate that ablation of Lkb1 in adult mice results in severe pancytopenia and subsequent lethality. Loss of Lkb1 leads to impaired survival and escape from quiescence of HSCs, resulting in exhaustion of the HSC pool and a marked reduction of HSC repopulating potential in vivo. Lkb1 deletion has an impact on cell proliferation in HSCs, but not on more committed compartments, pointing to context-specific functions for Lkb1 in haematopoiesis. The adverse impact of Lkb1 deletion on haematopoiesis was predominantly cell-autonomous and mTOR complex 1 (mTORC1)-independent, and involves multiple mechanisms converging on mitochondrial apoptosis and possibly downregulation of PGC-1 coactivators and their transcriptional network, which have critical roles in mitochondrial biogenesis and function. Thus, Lkb1 serves as an essential regulator of HSCs and haematopoiesis, and more generally, points to the critical importance of coupling energy metabolism and stem-cell homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058342/" 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/PMC3058342/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gan, Boyi -- Hu, Jian -- Jiang, Shan -- Liu, Yingchun -- Sahin, Ergun -- Zhuang, Li -- Fletcher-Sananikone, Eliot -- Colla, Simona -- Wang, Y Alan -- Chin, Lynda -- Depinho, Ronald A -- 01CA141508/CA/NCI NIH HHS/ -- R21 CA135057/CA/NCI NIH HHS/ -- R21 CA135057-01/CA/NCI NIH HHS/ -- R21CA135057/CA/NCI NIH HHS/ -- U01 CA141508/CA/NCI NIH HHS/ -- U01 CA141508-01/CA/NCI NIH HHS/ -- England -- Nature. 2010 Dec 2;468(7324):701-4. doi: 10.1038/nature09595.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Belfer Institute for Applied Cancer Science, 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/21124456" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Cell Cycle/*physiology ; Cell Proliferation ; Cell Survival ; *Energy Metabolism ; Female ; Gene Deletion ; Hematopoiesis ; Hematopoietic Stem Cells/*cytology/*metabolism/pathology ; *Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondria/metabolism/pathology ; Multiprotein Complexes ; Pancytopenia/genetics ; Phenotype ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Proteins/metabolism ; Survival Analysis ; TOR Serine-Threonine Kinases ; Transcription Factors/metabolism
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    Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication (2010)
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    Publication Date: 2010-01-19
    Description: Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karlas, Alexander -- Machuy, Nikolaus -- Shin, Yujin -- Pleissner, Klaus-Peter -- Artarini, Anita -- Heuer, Dagmar -- Becker, Daniel -- Khalil, Hany -- Ogilvie, Lesley A -- Hess, Simone -- Maurer, Andre P -- Muller, Elke -- Wolff, Thorsten -- Rudel, Thomas -- Meyer, Thomas F -- England -- Nature. 2010 Feb 11;463(7282):818-22. doi: 10.1038/nature08760. Epub 2010 Jan 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Max Planck Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20081832" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Factors/genetics/metabolism ; Cell Line ; Cells, Cultured ; Chick Embryo ; Cyclin-Dependent Kinase Inhibitor p27/deficiency/genetics/metabolism ; Epithelial Cells/virology ; Genome, Human/genetics ; *Host-Pathogen Interactions/genetics/physiology ; Humans ; Influenza A Virus, H1N1 Subtype/classification/*growth & development ; Influenza, Human/*genetics/*virology ; Lung/cytology ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/genetics ; Protein-Tyrosine Kinases/genetics ; *RNA Interference ; Virus Replication/*physiology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis (2010)
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    Publication Date: 2010-10-01
    Description: RANK ligand (RANKL), a TNF-related molecule, is essential for osteoclast formation, function and survival through interaction with its receptor RANK. Mammary glands of RANK- and RANKL-deficient mice develop normally during sexual maturation, but fail to form lobuloalveolar structures during pregnancy because of defective proliferation and increased apoptosis of mammary epithelium. It has been shown that RANKL is responsible for the major proliferative response of mouse mammary epithelium to progesterone during mammary lactational morphogenesis, and in mouse models, manipulated to induce activation of the RANK/RANKL pathway in the absence of strict hormonal control, inappropriate mammary proliferation is observed. However, there is no evidence so far of a functional contribution of RANKL to tumorigenesis. Here we show that RANK and RANKL are expressed within normal, pre-malignant and neoplastic mammary epithelium, and using complementary gain-of-function (mouse mammary tumour virus (MMTV)-RANK transgenic mice) and loss-of function (pharmacological inhibition of RANKL) approaches, define a direct contribution of this pathway in mammary tumorigenesis. Accelerated pre-neoplasias and increased mammary tumour formation were observed in MMTV-RANK transgenic mice after multiparity or treatment with carcinogen and hormone (progesterone). Reciprocally, selective pharmacological inhibition of RANKL attenuated mammary tumour development not only in hormone- and carcinogen-treated MMTV-RANK and wild-type mice, but also in the MMTV-neu transgenic spontaneous tumour model. The reduction in tumorigenesis upon RANKL inhibition was preceded by a reduction in pre-neoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation and cyclin D1 levels. Collectively, our results indicate that RANKL inhibition is acting directly on hormone-induced mammary epithelium at early stages in tumorigenesis, and the permissive contribution of progesterone to increased mammary cancer incidence is due to RANKL-dependent proliferative changes in the mammary epithelium. The current study highlights a potential role for RANKL inhibition in the management of proliferative breast disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gonzalez-Suarez, Eva -- Jacob, Allison P -- Jones, Jon -- Miller, Robert -- Roudier-Meyer, Martine P -- Erwert, Ryan -- Pinkas, Jan -- Branstetter, Dan -- Dougall, William C -- England -- Nature. 2010 Nov 4;468(7320):103-7. doi: 10.1038/nature09495. Epub 2010 Sep 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Hematology/Oncology Research, Amgen Inc, Seattle, Washington 98119, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20881963" target="_blank"〉PubMed〈/a〉
    Keywords: 9,10-Dimethyl-1,2-benzanthracene/administration & dosage/adverse effects ; Animals ; Breast Neoplasms/metabolism/pathology ; Cell Proliferation/drug effects ; Cell Transformation, Neoplastic/*chemically induced/*drug effects/pathology ; Disease Models, Animal ; Epithelial Cells/drug effects/metabolism/pathology ; Female ; Humans ; Lung Neoplasms/secondary ; Mammary Neoplasms, Experimental/*chemically ; induced/genetics/metabolism/*pathology ; Mammary Tumor Virus, Mouse/genetics/physiology ; Medroxyprogesterone Acetate/administration & dosage/adverse effects ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neoplasm Invasiveness ; Precancerous Conditions/pathology/prevention & control ; Progesterone/administration & dosage/adverse effects ; Progestins/administration & dosage/*adverse effects ; RANK Ligand/antagonists & inhibitors/genetics/*metabolism ; Receptor Activator of Nuclear Factor-kappa B/genetics/metabolism
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    Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands (2010)
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    Publication Date: 2010-10-12
    Description: Reciprocity of inflammation, oxidative stress and neovascularization is emerging as an important mechanism underlying numerous processes from tissue healing and remodelling to cancer progression. Whereas the mechanism of hypoxia-driven angiogenesis is well understood, the link between inflammation-induced oxidation and de novo blood vessel growth remains obscure. Here we show that the end products of lipid oxidation, omega-(2-carboxyethyl)pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in ageing tissues in mice and in highly vascularized tumours in both murine and human melanoma. The molecular patterns of carboxyalkylpyrroles are recognized by Toll-like receptor 2 (TLR2), but not TLR4 or scavenger receptors on endothelial cells, leading to an angiogenic response that is independent of vascular endothelial growth factor. CEP promoted angiogenesis in hindlimb ischaemia and wound healing models through MyD88-dependent TLR2 signalling. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumour angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of Rac1 and endothelial migration. Taken together, these findings establish a new function of TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity and angiogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2990914/" 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/PMC2990914/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉West, Xiaoxia Z -- Malinin, Nikolay L -- Merkulova, Alona A -- Tischenko, Mira -- Kerr, Bethany A -- Borden, Ernest C -- Podrez, Eugene A -- Salomon, Robert G -- Byzova, Tatiana V -- CA126847/CA/NCI NIH HHS/ -- GM021249/GM/NIGMS NIH HHS/ -- HL071625/HL/NHLBI NIH HHS/ -- HL073311/HL/NHLBI NIH HHS/ -- HL077213/HL/NHLBI NIH HHS/ -- R01 HL071625/HL/NHLBI NIH HHS/ -- R01 HL071625-07/HL/NHLBI NIH HHS/ -- R01 HL071625-08/HL/NHLBI NIH HHS/ -- R01 HL077213/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):972-6. doi: 10.1038/nature09421. Epub 2010 Oct 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Cardiology, J. J. Jacobs Center for Thrombosis and Vascular Biology, NB50, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20927103" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/metabolism ; Animals ; Antigens, CD31/metabolism ; Aorta/cytology/drug effects ; Cell Line ; Cell Movement ; Endothelial Cells/metabolism ; Hindlimb/metabolism ; Humans ; Immunity, Innate/immunology ; Inflammation/metabolism ; Ischemia/metabolism ; Ligands ; Melanoma/blood supply/metabolism ; Mice ; Mice, Inbred C57BL ; Myeloid Differentiation Factor 88/metabolism ; Neovascularization, Pathologic/*metabolism ; *Neovascularization, Physiologic/drug effects ; Oxidation-Reduction ; Oxidative Stress/*physiology ; Propionates ; Pyrroles/chemistry/*metabolism/pharmacology ; Receptors, Scavenger/metabolism ; Signal Transduction/drug effects ; Toll-Like Receptor 2/agonists/*metabolism ; Toll-Like Receptor 4/metabolism ; Vascular Endothelial Growth Factor A/metabolism ; Wound Healing/drug effects/physiology ; rac1 GTP-Binding Protein/metabolism
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    Structural basis of semaphorin-plexin signalling (2010)
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    Publication Date: 2010-09-30
    Description: Cell-cell signalling of semaphorin ligands through interaction with plexin receptors is important for the homeostasis and morphogenesis of many tissues and is widely studied for its role in neural connectivity, cancer, cell migration and immune responses. SEMA4D and Sema6A exemplify two diverse vertebrate, membrane-spanning semaphorin classes (4 and 6) that are capable of direct signalling through members of the two largest plexin classes, B and A, respectively. In the absence of any structural information on the plexin ectodomain or its interaction with semaphorins the extracellular specificity and mechanism controlling plexin signalling has remained unresolved. Here we present crystal structures of cognate complexes of the semaphorin-binding regions of plexins B1 and A2 with semaphorin ectodomains (human PLXNB1(1-2)-SEMA4D(ecto) and murine PlxnA2(1-4)-Sema6A(ecto)), plus unliganded structures of PlxnA2(1-4) and Sema6A(ecto). These structures, together with biophysical and cellular assays of wild-type and mutant proteins, reveal that semaphorin dimers independently bind two plexin molecules and that signalling is critically dependent on the avidity of the resulting bivalent 2:2 complex (monomeric semaphorin binds plexin but fails to trigger signalling). In combination, our data favour a cell-cell signalling mechanism involving semaphorin-stabilized plexin dimerization, possibly followed by clustering, which is consistent with previous functional data. Furthermore, the shared generic architecture of the complexes, formed through conserved contacts of the amino-terminal seven-bladed beta-propeller (sema) domains of both semaphorin and plexin, suggests that a common mode of interaction triggers all semaphorin-plexin based signalling, while distinct insertions within or between blades of the sema domains determine binding specificity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587840/" 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/PMC3587840/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janssen, Bert J C -- Robinson, Ross A -- Perez-Branguli, Francesc -- Bell, Christian H -- Mitchell, Kevin J -- Siebold, Christian -- Jones, E Yvonne -- 082301/Wellcome Trust/United Kingdom -- 083111/Wellcome Trust/United Kingdom -- 10976/Cancer Research UK/United Kingdom -- A10976/Cancer Research UK/United Kingdom -- A3964/Cancer Research UK/United Kingdom -- A5261/Cancer Research UK/United Kingdom -- G0700232/Medical Research Council/United Kingdom -- G0700232(82098)/Medical Research Council/United Kingdom -- G0900084/Medical Research Council/United Kingdom -- G9900061/Medical Research Council/United Kingdom -- G9900061(69203)/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2010 Oct 28;467(7319):1118-22. doi: 10.1038/nature09468. Epub 2010 Sep 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20877282" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/chemistry/genetics/metabolism ; Binding Sites ; Cell Adhesion Molecules/*chemistry/genetics/*metabolism ; Cell Communication ; Crystallography, X-Ray ; Humans ; Ligands ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; NIH 3T3 Cells ; Nerve Tissue Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Receptors, Cell Surface/chemistry/genetics/metabolism ; Semaphorins/*chemistry/genetics/*metabolism ; *Signal Transduction ; Structure-Activity Relationship
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    Subcapsular sinus macrophages prevent CNS invasion on peripheral infection with a neurotropic virus (2010)
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    Publication Date: 2010-06-26
    Description: Lymph nodes (LNs) capture microorganisms that breach the body's external barriers and enter draining lymphatics, limiting the systemic spread of pathogens. Recent work has shown that CD11b(+)CD169(+) macrophages, which populate the subcapsular sinus (SCS) of LNs, are critical for the clearance of viruses from the lymph and for initiating antiviral humoral immune responses. Here we show, using vesicular stomatitis virus (VSV), a relative of rabies virus transmitted by insect bites, that SCS macrophages perform a third vital function: they prevent lymph-borne neurotropic viruses from infecting the central nervous system (CNS). On local depletion of LN macrophages, about 60% of mice developed ascending paralysis and died 7-10 days after subcutaneous infection with a small dose of VSV, whereas macrophage-sufficient animals remained asymptomatic and cleared the virus. VSV gained access to the nervous system through peripheral nerves in macrophage-depleted LNs. In contrast, within macrophage-sufficient LNs VSV replicated preferentially in SCS macrophages but not in adjacent nerves. Removal of SCS macrophages did not compromise adaptive immune responses against VSV, but decreased type I interferon (IFN-I) production within infected LNs. VSV-infected macrophages recruited IFN-I-producing plasmacytoid dendritic cells to the SCS and in addition were a major source of IFN-I themselves. Experiments in bone marrow chimaeric mice revealed that IFN-I must act on both haematopoietic and stromal compartments, including the intranodal nerves, to prevent lethal infection with VSV. These results identify SCS macrophages as crucial gatekeepers to the CNS that prevent fatal viral invasion of the nervous system on peripheral infection.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892812/" 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/PMC2892812/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Iannacone, Matteo -- Moseman, E Ashley -- Tonti, Elena -- Bosurgi, Lidia -- Junt, Tobias -- Henrickson, Sarah E -- Whelan, Sean P -- Guidotti, Luca G -- von Andrian, Ulrich H -- AI069259/AI/NIAID NIH HHS/ -- AI072252/AI/NIAID NIH HHS/ -- AI078897/AI/NIAID NIH HHS/ -- AR42689/AR/NIAMS NIH HHS/ -- P01 AI078897/AI/NIAID NIH HHS/ -- P01 AI078897-01/AI/NIAID NIH HHS/ -- P01 CA071932/CA/NCI NIH HHS/ -- P01 CA071932-12S29003/CA/NCI NIH HHS/ -- R01 AI069259/AI/NIAID NIH HHS/ -- R01 AI069259-06/AI/NIAID NIH HHS/ -- R01 AI072252/AI/NIAID NIH HHS/ -- R01 AI072252-04/AI/NIAID NIH HHS/ -- T32 GM007753/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 24;465(7301):1079-83. doi: 10.1038/nature09118.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immune Disease Institute and Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA. Matteo_Iannacone@hms.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20577213" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Central Nervous System/cytology/*immunology/*virology ; Dendritic Cells/immunology ; Injections ; Interferon Type I/immunology ; Lymph Nodes/cytology/*immunology/innervation/*virology ; Macrophages/*immunology/virology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Paralysis/complications/virology ; Peripheral Nerves/virology ; Receptor, Interferon alpha-beta/deficiency ; Rhabdoviridae Infections/complications/*immunology/virology ; Survival Rate ; Vesicular stomatitis Indiana virus/immunology/pathogenicity/physiology ; Vesicular stomatitis New Jersey virus/immunology/pathogenicity/physiology ; Vesiculovirus/*immunology/pathogenicity/physiology
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    Dendritic organization of sensory input to cortical neurons in vivo (2010)
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    Publication Date: 2010-04-30
    Description: In sensory cortex regions, neurons are tuned to specific stimulus features. For example, in the visual cortex, many neurons fire predominantly in response to moving objects of a preferred orientation. However, the characteristics of the synaptic input that cortical neurons receive to generate their output firing pattern remain unclear. Here we report a novel approach for the visualization and functional mapping of sensory inputs to the dendrites of cortical neurons in vivo. By combining high-speed two-photon imaging with electrophysiological recordings, we identify local subthreshold calcium signals that correspond to orientation-specific synaptic inputs. We find that even inputs that share the same orientation preference are widely distributed throughout the dendritic tree. At the same time, inputs of different orientation preference are interspersed, so that adjacent dendritic segments are tuned to distinct orientations. Thus, orientation-tuned neurons can compute their characteristic firing pattern by integrating spatially distributed synaptic inputs coding for multiple stimulus orientations.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jia, Hongbo -- Rochefort, Nathalie L -- Chen, Xiaowei -- Konnerth, Arthur -- England -- Nature. 2010 Apr 29;464(7293):1307-12. doi: 10.1038/nature08947.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Neuroscience and Center for Integrated Protein Science, Technical University Munich, Biedersteinerstrasse 29, 80802 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428163" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Calcium Signaling ; Dendrites/*physiology ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Sensory Receptor Cells/cytology/*physiology ; Synapses/metabolism ; Visual Cortex/*cytology
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    Start/stop signals emerge in nigrostriatal circuits during sequence learning (2010)
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    Publication Date: 2010-07-24
    Description: Learning new action sequences subserves a plethora of different abilities such as escaping a predator, playing the piano, or producing fluent speech. Proper initiation and termination of each action sequence is critical for the organization of behaviour, and is compromised in nigrostriatal disorders like Parkinson's and Huntington's diseases. Using a self-paced operant task in which mice learn to perform a particular sequence of actions to obtain an outcome, we found neural activity in nigrostriatal circuits specifically signalling the initiation or the termination of each action sequence. This start/stop activity emerged during sequence learning, was specific for particular actions, and did not reflect interval timing, movement speed or action value. Furthermore, genetically altering the function of striatal circuits disrupted the development of start/stop activity and selectively impaired sequence learning. These results have important implications for understanding the functional organization of actions and the sequence initiation and termination impairments observed in basal ganglia disorders.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3477867/" 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/PMC3477867/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jin, Xin -- Costa, Rui M -- 243393/European Research Council/International -- Z01 AA000416-02/Intramural NIH HHS/ -- England -- Nature. 2010 Jul 22;466(7305):457-62. doi: 10.1038/nature09263.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, Maryland 20892-9412, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20651684" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Animals ; Behavior, Animal/physiology ; Dopamine/metabolism ; Glutamic Acid/metabolism ; Learning/*physiology ; Male ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neostriatum/*physiology ; Neural Pathways/*physiology ; Receptors, N-Methyl-D-Aspartate/deficiency/genetics/metabolism ; Substantia Nigra/*physiology
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    Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate (2010)
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    Publication Date: 2010-01-15
    Description: Immune homeostasis is dependent on tight control over the size of a population of regulatory T (T(reg)) cells capable of suppressing over-exuberant immune responses. The T(reg) cell subset is comprised of cells that commit to the T(reg) lineage by upregulating the transcription factor Foxp3 either in the thymus (tT(reg)) or in the periphery (iT(reg)). Considering a central role for Foxp3 in T(reg) cell differentiation and function, we proposed that conserved non-coding DNA sequence (CNS) elements at the Foxp3 locus encode information defining the size, composition and stability of the T(reg) cell population. Here we describe the function of three Foxp3 CNS elements (CNS1-3) in T(reg) cell fate determination in mice. The pioneer element CNS3, which acts to potently increase the frequency of T(reg) cells generated in the thymus and the periphery, binds c-Rel in in vitro assays. In contrast, CNS1, which contains a TGF-beta-NFAT response element, is superfluous for tT(reg) cell differentiation, but has a prominent role in iT(reg) cell generation in gut-associated lymphoid tissues. CNS2, although dispensable for Foxp3 induction, is required for Foxp3 expression in the progeny of dividing T(reg) cells. Foxp3 binds to CNS2 in a Cbf-beta-Runx1 and CpG DNA demethylation-dependent manner, suggesting that Foxp3 recruitment to this 'cellular memory module' facilitates the heritable maintenance of the active state of the Foxp3 locus and, therefore, T(reg) lineage stability. Together, our studies demonstrate that the composition, size and maintenance of the T(reg) cell population are controlled by Foxp3 CNS elements engaged in response to distinct cell-extrinsic or -intrinsic cues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2884187/" 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/PMC2884187/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Ye -- Josefowicz, Steven -- Chaudhry, Ashutosh -- Peng, Xiao P -- Forbush, Katherine -- Rudensky, Alexander Y -- R37 AI034206/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Feb 11;463(7282):808-12. doi: 10.1038/nature08750. Epub 2010 Jan 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute and Department of Immunology, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20072126" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Lineage/*genetics ; Chromatin Assembly and Disassembly ; Conserved Sequence/*genetics ; CpG Islands/genetics ; DNA Methylation ; Female ; Forkhead Transcription Factors/*genetics/metabolism ; Gene Expression Regulation ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Proto-Oncogene Proteins c-rel/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Response Elements/genetics ; T-Lymphocytes, Regulatory/*cytology/immunology/*metabolism ; Thymus Gland/cytology/immunology/metabolism
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    Encoding of conditioned fear in central amygdala inhibitory circuits (2010)
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    Publication Date: 2010-11-12
    Description: The central amygdala (CEA), a nucleus predominantly composed of GABAergic inhibitory neurons, is essential for fear conditioning. How the acquisition and expression of conditioned fear are encoded within CEA inhibitory circuits is not understood. Using in vivo electrophysiological, optogenetic and pharmacological approaches in mice, we show that neuronal activity in the lateral subdivision of the central amygdala (CEl) is required for fear acquisition, whereas conditioned fear responses are driven by output neurons in the medial subdivision (CEm). Functional circuit analysis revealed that inhibitory CEA microcircuits are highly organized and that cell-type-specific plasticity of phasic and tonic activity in the CEl to CEm pathway may gate fear expression and regulate fear generalization. Our results define the functional architecture of CEA microcircuits and their role in the acquisition and regulation of conditioned fear behaviour.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ciocchi, Stephane -- Herry, Cyril -- Grenier, Francois -- Wolff, Steffen B E -- Letzkus, Johannes J -- Vlachos, Ioannis -- Ehrlich, Ingrid -- Sprengel, Rolf -- Deisseroth, Karl -- Stadler, Michael B -- Muller, Christian -- Luthi, Andreas -- England -- Nature. 2010 Nov 11;468(7321):277-82. doi: 10.1038/nature09559.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068837" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials ; Amygdala/anatomy & histology/cytology/*physiology ; Animals ; Conditioning, Classical/*physiology ; Fear/*physiology ; Freezing Reaction, Cataleptic ; Male ; Mice ; Mice, Inbred C57BL ; Neural Inhibition/*physiology ; Neural Pathways/cytology/*physiology ; Neuronal Plasticity/physiology ; Neurons/physiology ; gamma-Aminobutyric Acid/metabolism
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    mTORC1 controls fasting-induced ketogenesis and its modulation by ageing (2010)
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    Publication Date: 2010-12-24
    Description: The multi-component mechanistic target of rapamycin complex 1 (mTORC1) kinase is the central node of a mammalian pathway that coordinates cell growth with the availability of nutrients, energy and growth factors. Progress has been made in the identification of mTORC1 pathway components and in understanding their functions in cells, but there is relatively little known about the role of the pathway in vivo. Specifically, we have little knowledge regarding the role mTOCR1 has in liver physiology. In fasted animals, the liver performs numerous functions that maintain whole-body homeostasis, including the production of ketone bodies for peripheral tissues to use as energy sources. Here we show that mTORC1 controls ketogenesis in mice in response to fasting. We find that liver-specific loss of TSC1 (tuberous sclerosis 1), an mTORC1 inhibitor, leads to a fasting-resistant increase in liver size, and to a pronounced defect in ketone body production and ketogenic gene expression on fasting. The loss of raptor (regulatory associated protein of mTOR, complex 1) an essential mTORC1 component, has the opposite effects. In addition, we find that the inhibition of mTORC1 is required for the fasting-induced activation of PPARalpha (peroxisome proliferator activated receptor alpha), the master transcriptional activator of ketogenic genes, and that suppression of NCoR1 (nuclear receptor co-repressor 1), a co-repressor of PPARalpha, reactivates ketogenesis in cells and livers with hyperactive mTORC1 signalling. Like livers with activated mTORC1, livers from aged mice have a defect in ketogenesis, which correlates with an increase in mTORC1 signalling. Moreover, we show that the suppressive effects of mTORC1 activation and ageing on PPARalpha activity and ketone production are not additive, and that mTORC1 inhibition is sufficient to prevent the ageing-induced defect in ketogenesis. Thus, our findings reveal that mTORC1 is a key regulator of PPARalpha function and hepatic ketogenesis and suggest a role for mTORC1 activity in promoting the ageing of the liver.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sengupta, Shomit -- Peterson, Timothy R -- Laplante, Mathieu -- Oh, Stephanie -- Sabatini, David M -- CA103866/CA/NCI NIH HHS/ -- CA129105/CA/NCI NIH HHS/ -- R01 CA129105/CA/NCI NIH HHS/ -- R01 CA129105-04/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 23;468(7327):1100-4. doi: 10.1038/nature09584.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21179166" target="_blank"〉PubMed〈/a〉
    Keywords: *Aging ; Animals ; Cell Line ; Fasting/*metabolism ; *Gene Expression Regulation ; Humans ; Ketone Bodies/*biosynthesis/metabolism ; Liver/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Multiprotein Complexes ; Nuclear Receptor Co-Repressor 1/metabolism ; PPAR alpha/antagonists & inhibitors/metabolism ; Proteins/genetics/*metabolism ; TOR Serine-Threonine Kinases
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    Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke (2010)
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    Publication Date: 2010-11-05
    Description: Stroke is a leading cause of disability, but no pharmacological therapy is currently available for promoting recovery. The brain region adjacent to stroke damage-the peri-infarct zone-is critical for rehabilitation, as it shows heightened neuroplasticity, allowing sensorimotor functions to re-map from damaged areas. Thus, understanding the neuronal properties constraining this plasticity is important for the development of new treatments. Here we show that after a stroke in mice, tonic neuronal inhibition is increased in the peri-infarct zone. This increased tonic inhibition is mediated by extrasynaptic GABA(A) receptors and is caused by an impairment in GABA (gamma-aminobutyric acid) transporter (GAT-3/GAT-4) function. To counteract the heightened inhibition, we administered in vivo a benzodiazepine inverse agonist specific for alpha5-subunit-containing extrasynaptic GABA(A) receptors at a delay after stroke. This treatment produced an early and sustained recovery of motor function. Genetically lowering the number of alpha5- or delta-subunit-containing GABA(A) receptors responsible for tonic inhibition also proved beneficial for recovery after stroke, consistent with the therapeutic potential of diminishing extrasynaptic GABA(A) receptor function. Together, our results identify new pharmacological targets and provide the rationale for a novel strategy to promote recovery after stroke and possibly other brain injuries.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058798/" 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/PMC3058798/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clarkson, Andrew N -- Huang, Ben S -- Macisaac, Sarah E -- Mody, Istvan -- Carmichael, S Thomas -- NS30549/NS/NINDS NIH HHS/ -- R01 NS030549/NS/NINDS NIH HHS/ -- R01 NS030549-18/NS/NINDS NIH HHS/ -- England -- Nature. 2010 Nov 11;468(7321):305-9. doi: 10.1038/nature09511. Epub 2010 Nov 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology, The David Geffen School of Medicine at UCLA, 635 Charles Young Drive South, Los Angeles, California 90095, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21048709" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzodiazepines/pharmacology ; Cerebral Infarction/metabolism/pathology/physiopathology ; Disease Models, Animal ; Drug Inverse Agonism ; GABA Antagonists/pharmacology ; GABA Plasma Membrane Transport Proteins/metabolism ; Imidazoles/pharmacology ; Male ; Membrane Potentials/drug effects ; Mice ; Mice, Inbred C57BL ; Motor Cortex/metabolism/pathology/*physiology/*physiopathology ; Neuronal Plasticity/physiology ; Receptors, GABA/deficiency/genetics/metabolism ; Recovery of Function/*physiology ; Stroke/drug therapy/*metabolism/pathology ; Synapses/metabolism ; Time Factors ; gamma-Aminobutyric Acid/*metabolism
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    The prion protein as a receptor for amyloid-beta (2010)
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    Publication Date: 2010-08-13
    Description: Increased levels of brain amyloid-beta, a secreted peptide cleavage product of amyloid precursor protein (APP), is believed to be critical in the aetiology of Alzheimer's disease. Increased amyloid-beta can cause synaptic depression, reduce the number of spine protrusions (that is, sites of synaptic contacts) and block long-term synaptic potentiation (LTP), a form of synaptic plasticity; however, the receptor through which amyloid-beta produces these synaptic perturbations has remained elusive. Lauren et al. suggested that binding between oligomeric amyloid-beta (a form of amyloid-beta thought to be most active) and the cellular prion protein (PrP(C)) is necessary for synaptic perturbations. Here we show that PrP(C) is not required for amyloid-beta-induced synaptic depression, reduction in spine density, or blockade of LTP; our results indicate that amyloid-beta-mediated synaptic defects do not require PrP(c).〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057871/" 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/PMC3057871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kessels, Helmut W -- Nguyen, Louis N -- Nabavi, Sadegh -- Malinow, Roberto -- R01 AG032132/AG/NIA NIH HHS/ -- R01 AG032132-14/AG/NIA NIH HHS/ -- R01 AG032132-15/AG/NIA NIH HHS/ -- R01 AG032132-17/AG/NIA NIH HHS/ -- R01 AG032132-18/AG/NIA NIH HHS/ -- R01 MH049159/MH/NIMH NIH HHS/ -- R01 MH049159-09/MH/NIMH NIH HHS/ -- R01 MH049159-21/MH/NIMH NIH HHS/ -- R01 MH049159-22/MH/NIMH NIH HHS/ -- England -- Nature. 2010 Aug 12;466(7308):E3-4; discussion E4-5. doi: 10.1038/nature09217.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neural Circuits and Behavior, 9500 Gilman Drive 0634, University of California at San Diego, La Jolla, California 92093, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20703260" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/chemistry/genetics/*metabolism ; Animals ; Learning/physiology ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; PrPC Proteins/deficiency/genetics/*metabolism ; Reproducibility of Results ; Serotonin/metabolism ; Synapses/*metabolism/*pathology ; Synaptic Transmission
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    Notch and EGFR pathway interaction regulates neural stem cell number and self-renewal (2010)
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    Publication Date: 2010-09-17
    Description: Specialized cellular microenvironments, or 'niches', modulate stem cell properties, including cell number, self-renewal and fate decisions. In the adult brain, niches that maintain a source of neural stem cells (NSCs) and neural progenitor cells (NPCs) are the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus. The size of the NSC population of the SVZ at any time is the result of several ongoing processes, including self-renewal, cell differentiation, and cell death. Maintaining the balance between NSCs and NPCs in the SVZ niche is critical to supply the brain with specific neural populations, both under normal conditions or after injury. A fundamental question relevant to both normal development and to cell-based repair strategies in the central nervous system is how the balance of different NSC and NPC populations is maintained in the niche. EGFR (epidermal growth factor receptor) and Notch signalling pathways have fundamental roles during development of multicellular organisms. In Drosophila and in Caenorhabditis elegans these pathways may have either cooperative or antagonistic functions. In the SVZ, Notch regulates NSC identity and self-renewal, whereas EGFR specifically affects NPC proliferation and migration. This suggests that interplay of these two pathways may maintain the balance between NSC and NPC numbers. Here we show that functional cell-cell interaction between NPCs and NSCs through EGFR and Notch signalling has a crucial role in maintaining the balance between these cell populations in the SVZ. Enhanced EGFR signalling in vivo results in the expansion of the NPC pool, and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signalling. Our findings define a novel interaction between EGFR and Notch pathways in the adult SVZ, and thus provide a mechanism for NSC and NPC pool maintenance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2941915/" 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/PMC2941915/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Aguirre, Adan -- Rubio, Maria E -- Gallo, Vittorio -- K99NS057944/NS/NINDS NIH HHS/ -- P30HD40677/HD/NICHD NIH HHS/ -- R00 NS057944/NS/NINDS NIH HHS/ -- R01 DC006881/DC/NIDCD NIH HHS/ -- R01 DC006881-03/DC/NIDCD NIH HHS/ -- R01 DC006881-04/DC/NIDCD NIH HHS/ -- R01DC006881/DC/NIDCD NIH HHS/ -- R01NS045702/NS/NINDS NIH HHS/ -- R01NS056427/NS/NINDS NIH HHS/ -- R0O NS057944-03/NS/NINDS NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):323-7. doi: 10.1038/nature09347.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neuroscience Research, Children's National Medical Center, Washington, District of Columbia 20010, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20844536" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Count ; Cell Division ; Humans ; Membrane Proteins/deficiency/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/deficiency/genetics/metabolism ; Neurons/*cytology ; Protein Binding ; Receptor, Epidermal Growth Factor/genetics/*metabolism ; Receptor, Notch1/metabolism ; Receptors, Notch/*metabolism ; *Signal Transduction ; Stem Cell Niche/cytology ; Stem Cells/*cytology ; Ubiquitination
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    NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals (2010)
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    Publication Date: 2010-04-30
    Description: The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946640/" 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/PMC2946640/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duewell, Peter -- Kono, Hajime -- Rayner, Katey J -- Sirois, Cherilyn M -- Vladimer, Gregory -- Bauernfeind, Franz G -- Abela, George S -- Franchi, Luigi -- Nunez, Gabriel -- Schnurr, Max -- Espevik, Terje -- Lien, Egil -- Fitzgerald, Katherine A -- Rock, Kenneth L -- Moore, Kathryn J -- Wright, Samuel D -- Hornung, Veit -- Latz, Eicke -- R01 AI075318/AI/NIAID NIH HHS/ -- R01 AI083713/AI/NIAID NIH HHS/ -- R01 AI083713-01/AI/NIAID NIH HHS/ -- R01 HL093262/HL/NHLBI NIH HHS/ -- R01 HL093262-01A1/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Apr 29;464(7293):1357-61. doi: 10.1038/nature08938.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20428172" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins ; Atherosclerosis/chemically induced/*metabolism/*pathology ; Bone Marrow Transplantation ; Carrier Proteins/genetics/*metabolism ; Cathepsin B/metabolism ; Cathepsin L/metabolism ; Cholesterol/*chemistry/*metabolism/pharmacology ; Crystallization ; Cytoskeletal Proteins/deficiency ; Diet, Atherogenic ; Female ; Humans ; Inflammation/chemically induced/metabolism/pathology ; Interleukin-1/deficiency ; Interleukin-18/metabolism ; Lysosomes/drug effects/pathology ; Mice ; Mice, Inbred C57BL ; Peritoneal Cavity/pathology ; Phagocytes/drug effects/pathology/physiology ; Receptors, LDL/deficiency ; Time Factors
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    TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs (2010)
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    Publication Date: 2010-10-22
    Description: Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055799/" 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/PMC3055799/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Su, Xiaohua -- Chakravarti, Deepavali -- Cho, Min Soon -- Liu, Lingzhi -- Gi, Young Jin -- Lin, Yu-Li -- Leung, Marco L -- El-Naggar, Adel -- Creighton, Chad J -- Suraokar, Milind B -- Wistuba, Ignacio -- Flores, Elsa R -- 01DE019765/DE/NIDCR NIH HHS/ -- CA16672/CA/NCI NIH HHS/ -- P30 CA016672-27/CA/NCI NIH HHS/ -- P50 CA070907/CA/NCI NIH HHS/ -- P50 CA070907-10/CA/NCI NIH HHS/ -- P50 CA091846/CA/NCI NIH HHS/ -- P50 CA091846-10/CA/NCI NIH HHS/ -- P50CA070907/CA/NCI NIH HHS/ -- P50CA091846/CA/NCI NIH HHS/ -- U01 DE019765/DE/NIDCR NIH HHS/ -- U01 DE019765-03/DE/NIDCR NIH HHS/ -- England -- Nature. 2010 Oct 21;467(7318):986-90. doi: 10.1038/nature09459.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20962848" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging ; Cell Line ; Cell Line, Tumor ; DEAD-box RNA Helicases/biosynthesis/deficiency/genetics/*metabolism ; Endoribonucleases/genetics/*metabolism ; Female ; *Gene Expression Regulation, Neoplastic ; Genes, Tumor Suppressor/physiology ; Genomic Instability ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/*biosynthesis/genetics/metabolism ; Neoplasm Metastasis/*genetics ; Neoplasms/genetics/pathology/secretion ; Phosphoproteins/deficiency/genetics/*metabolism ; Promoter Regions, Genetic/genetics ; Ribonuclease III/biosynthesis/deficiency/genetics/*metabolism ; Trans-Activators/deficiency/genetics/*metabolism ; Transcription Factors ; Transcriptional Activation ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
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    TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia (2010)
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    Publication Date: 2010-02-05
    Description: Chronic myeloid leukaemia (CML) is caused by a defined genetic abnormality that generates BCR-ABL, a constitutively active tyrosine kinase. It is widely believed that BCR-ABL activates Akt signalling that suppresses the forkhead O transcription factors (FOXO), supporting the proliferation or inhibiting the apoptosis of CML cells. Although the use of the tyrosine kinase inhibitor imatinib is a breakthrough for CML therapy, imatinib does not deplete the leukaemia-initiating cells (LICs) that drive the recurrence of CML. Here, using a syngeneic transplantation system and a CML-like myeloproliferative disease mouse model, we show that Foxo3a has an essential role in the maintenance of CML LICs. We find that cells with nuclear localization of Foxo3a and decreased Akt phosphorylation are enriched in the LIC population. Serial transplantation of LICs generated from Foxo3a(+/+) and Foxo3a(-/-) mice shows that the ability of LICs to cause disease is significantly decreased by Foxo3a deficiency. Furthermore, we find that TGF-beta is a critical regulator of Akt activation in LICs and controls Foxo3a localization. A combination of TGF-beta inhibition, Foxo3a deficiency and imatinib treatment led to efficient depletion of CML in vivo. Furthermore, the treatment of human CML LICs with a TGF-beta inhibitor impaired their colony-forming ability in vitro. Our results demonstrate a critical role for the TGF-beta-FOXO pathway in the maintenance of LICs, and strengthen our understanding of the mechanisms that specifically maintain CML LICs in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naka, Kazuhito -- Hoshii, Takayuki -- Muraguchi, Teruyuki -- Tadokoro, Yuko -- Ooshio, Takako -- Kondo, Yukio -- Nakao, Shinji -- Motoyama, Noboru -- Hirao, Atsushi -- England -- Nature. 2010 Feb 4;463(7281):676-80. doi: 10.1038/nature08734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan. kazunaka@kenroku.kanazawa-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20130650" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/therapeutic use ; Apoptosis ; Benzamides ; Cell Differentiation ; Cell Line, Tumor ; Cell Nucleus/metabolism ; Disease Models, Animal ; Enzyme Activation ; Forkhead Transcription Factors/deficiency/genetics/*metabolism ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug ; therapy/*metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/drug effects/*metabolism/*pathology ; Phosphorylation ; Piperazines/therapeutic use ; Protein Kinase Inhibitors/therapeutic use ; Protein Transport ; Protein-Tyrosine Kinases/antagonists & inhibitors ; Proto-Oncogene Proteins c-akt/metabolism ; Pyrimidines/therapeutic use ; *Signal Transduction/drug effects ; Transforming Growth Factor beta/antagonists & inhibitors/*metabolism ; Tumor Stem Cell Assay
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    Lkb1 regulates cell cycle and energy metabolism in haematopoietic stem cells (2010)
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    Publication Date: 2010-12-03
    Description: Little is known about metabolic regulation in stem cells and how this modulates tissue regeneration or tumour suppression. We studied the Lkb1 tumour suppressor and its substrate AMP-activated protein kinase (AMPK), kinases that coordinate metabolism with cell growth. Deletion of the Lkb1 (also called Stk11) gene in mice caused increased haematopoietic stem cell (HSC) division, rapid HSC depletion and pancytopenia. HSCs depended more acutely on Lkb1 for cell-cycle regulation and survival than many other haematopoietic cells. HSC depletion did not depend on mTOR activation or oxidative stress. Lkb1-deficient HSCs, but not myeloid progenitors, had reduced mitochondrial membrane potential and ATP levels. HSCs deficient for two catalytic alpha-subunits of AMPK (AMPK-deficient HSCs) showed similar changes in mitochondrial function but remained able to reconstitute irradiated mice. Lkb1-deficient HSCs, but not AMPK-deficient HSCs, exhibited defects in centrosomes and mitotic spindles in culture, and became aneuploid. Lkb1 is therefore required for HSC maintenance through AMPK-dependent and AMPK-independent mechanisms, revealing differences in metabolic and cell-cycle regulation between HSCs and some other haematopoietic progenitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3059717/" 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/PMC3059717/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakada, Daisuke -- Saunders, Thomas L -- Morrison, Sean J -- CA46592/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2010 Dec 2;468(7324):653-8. doi: 10.1038/nature09571.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Life Sciences Institute, Center for Stem Cell Biology, University of Michigan, Ann Arbor, Michigan 48109-2216, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21124450" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/chemistry/deficiency/genetics/metabolism ; Aneuploidy ; Animals ; Catalytic Domain/genetics ; Cell Cycle/*physiology ; Cell Death ; Cell Division ; Cell Survival ; Centrosome/pathology ; Energy Metabolism/*physiology ; Enzyme Activation ; Female ; Gene Deletion ; Hematopoietic Stem Cells/*cytology/drug effects/*metabolism/pathology ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria/metabolism/pathology ; Multiprotein Complexes ; Pancytopenia/genetics ; Protein-Serine-Threonine Kinases/deficiency/genetics/*metabolism ; Proteins/metabolism ; Regeneration ; Signal Transduction ; Sirolimus/pharmacology ; Spindle Apparatus/pathology ; TOR Serine-Threonine Kinases/metabolism
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    Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity (2010)
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    Publication Date: 2010-03-05
    Description: Innate immunity provides the first line of defence against invading pathogens and provides important cues for the development of adaptive immunity. Type-2 immunity-responsible for protective immune responses to helminth parasites and the underlying cause of the pathogenesis of allergic asthma-consists of responses dominated by the cardinal type-2 cytokines interleukin (IL)4, IL5 and IL13 (ref. 5). T cells are an important source of these cytokines in adaptive immune responses, but the innate cell sources remain to be comprehensively determined. Here, through the use of novel Il13-eGFP reporter mice, we present the identification and functional characterization of a new innate type-2 immune effector leukocyte that we have named the nuocyte. Nuocytes expand in vivo in response to the type-2-inducing cytokines IL25 and IL33, and represent the predominant early source of IL13 during helminth infection with Nippostrongylus brasiliensis. In the combined absence of IL25 and IL33 signalling, nuocytes fail to expand, resulting in a severe defect in worm expulsion that is rescued by the adoptive transfer of in vitro cultured wild-type, but not IL13-deficient, nuocytes. Thus, nuocytes represent a critically important innate effector cell in type-2 immunity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862165/" 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/PMC2862165/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Neill, Daniel R -- Wong, See Heng -- Bellosi, Agustin -- Flynn, Robin J -- Daly, Maria -- Langford, Theresa K A -- Bucks, Christine -- Kane, Colleen M -- Fallon, Padraic G -- Pannell, Richard -- Jolin, Helen E -- McKenzie, Andrew N J -- MC_U105178805/Medical Research Council/United Kingdom -- U.1051.03.007(78805)/Medical Research Council/United Kingdom -- England -- Nature. 2010 Apr 29;464(7293):1367-70. doi: 10.1038/nature08900. Epub 2010 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20200518" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Cells, Cultured ; Immunity, Innate/*immunology ; Interleukin-13/biosynthesis/deficiency/genetics ; Interleukin-17/deficiency/genetics ; Interleukins/biosynthesis/deficiency/genetics/*immunology ; Leukocytes/cytology/*immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Nippostrongylus/immunology ; Strongylida Infections/immunology ; Th2 Cells/*immunology
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    Neural bases for addictive properties of benzodiazepines (2010)
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    Publication Date: 2010-02-12
    Description: Benzodiazepines are widely used in clinics and for recreational purposes, but will lead to addiction in vulnerable individuals. Addictive drugs increase the levels of dopamine and also trigger long-lasting synaptic adaptations in the mesolimbic reward system that ultimately may induce the pathological behaviour. The neural basis for the addictive nature of benzodiazepines, however, remains elusive. Here we show that benzodiazepines increase firing of dopamine neurons of the ventral tegmental area through the positive modulation of GABA(A) (gamma-aminobutyric acid type A) receptors in nearby interneurons. Such disinhibition, which relies on alpha1-containing GABA(A) receptors expressed in these cells, triggers drug-evoked synaptic plasticity in excitatory afferents onto dopamine neurons and underlies drug reinforcement. Taken together, our data provide evidence that benzodiazepines share defining pharmacological features of addictive drugs through cell-type-specific expression of alpha1-containing GABA(A) receptors in the ventral tegmental area. The data also indicate that subunit-selective benzodiazepines sparing alpha1 may be devoid of addiction liability.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2871668/" 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/PMC2871668/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tan, Kelly R -- Brown, Matthew -- Labouebe, Gwenael -- Yvon, Cedric -- Creton, Cyril -- Fritschy, Jean-Marc -- Rudolph, Uwe -- Luscher, Christian -- DA019022/DA/NIDA NIH HHS/ -- R01 DA019022/DA/NIDA NIH HHS/ -- R01 DA019022-04/DA/NIDA NIH HHS/ -- England -- Nature. 2010 Feb 11;463(7282):769-74. doi: 10.1038/nature08758.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Basic Neurosciences, Medical Faculty, University of Geneva, CH-1211 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20148031" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/drug effects ; Administration, Oral ; Animals ; Behavior, Addictive/*chemically induced/pathology/*physiopathology ; Benzodiazepines/administration & dosage/*adverse effects/*pharmacology ; Dopamine/metabolism ; Electric Conductivity ; Glutamic Acid/metabolism ; In Vitro Techniques ; Inhibitory Postsynaptic Potentials/drug effects/physiology ; Interneurons/drug effects/metabolism ; Mice ; Mice, Inbred C57BL ; Midazolam/administration & dosage/adverse effects/pharmacology ; Models, Biological ; Morphine/pharmacology ; Neuronal Plasticity/drug effects ; Neurons/*drug effects/metabolism ; Organ Specificity ; Receptors, AMPA/metabolism ; Receptors, GABA-A/deficiency/genetics/metabolism ; Substrate Specificity ; Ventral Tegmental Area/cytology/drug effects/metabolism ; gamma-Aminobutyric Acid/metabolism
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    Unexpected requirement for ELMO1 in clearance of apoptotic germ cells in vivo (2010)
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    Publication Date: 2010-09-17
    Description: Apoptosis and the subsequent clearance of dying cells occurs throughout development and adult life in many tissues. Failure to promptly clear apoptotic cells has been linked to many diseases. ELMO1 is an evolutionarily conserved cytoplasmic engulfment protein that functions downstream of the phosphatidylserine receptor BAI1, and, along with DOCK1 and the GTPase RAC1, promotes internalization of the dying cells. Here we report the generation of ELMO1-deficient mice, which we found to be unexpectedly viable and grossly normal. However, they had a striking testicular pathology, with disrupted seminiferous epithelium, multinucleated giant cells, uncleared apoptotic germ cells and decreased sperm output. Subsequent in vitro and in vivo analyses revealed a crucial role for ELMO1 in the phagocytic clearance of apoptotic germ cells by Sertoli cells lining the seminiferous epithelium. The engulfment receptor BAI1 and RAC1 (upstream and downstream of ELMO1, respectively) were also important for Sertoli-cell-mediated engulfment. Collectively, these findings uncover a selective requirement for ELMO1 in Sertoli-cell-mediated removal of apoptotic germ cells and make a compelling case for a relationship between engulfment and tissue homeostasis in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773546/" 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/PMC3773546/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Elliott, Michael R -- Zheng, Shuqiu -- Park, Daeho -- Woodson, Robin I -- Reardon, Michael A -- Juncadella, Ignacio J -- Kinchen, Jason M -- Zhang, Jun -- Lysiak, Jeffrey J -- Ravichandran, Kodi S -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 HD057242/HD/NICHD NIH HHS/ -- England -- Nature. 2010 Sep 16;467(7313):333-7. doi: 10.1038/nature09356.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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/20844538" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics/*metabolism ; Angiogenic Proteins/metabolism ; Animals ; *Apoptosis ; Cell Line ; Homeostasis ; Male ; Mice ; Mice, Inbred C57BL ; Neuropeptides/metabolism ; Phagocytosis/*physiology ; Phosphatidylserines/metabolism ; Seminiferous Epithelium/cytology/pathology ; Sertoli Cells/*cytology/*metabolism/pathology ; Signal Transduction ; Spermatozoa/*cytology/pathology ; rac GTP-Binding Proteins/metabolism ; rac1 GTP-Binding Protein
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    Pericytes regulate the blood-brain barrier (2010)
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    Publication Date: 2010-10-15
    Description: The blood-brain barrier (BBB) consists of specific physical barriers, enzymes and transporters, which together maintain the necessary extracellular environment of the central nervous system (CNS). The main physical barrier is found in the CNS endothelial cell, and depends on continuous complexes of tight junctions combined with reduced vesicular transport. Other possible constituents of the BBB include extracellular matrix, astrocytes and pericytes, but the relative contribution of these different components to the BBB remains largely unknown. Here we demonstrate a direct role of pericytes at the BBB in vivo. Using a set of adult viable pericyte-deficient mouse mutants we show that pericyte deficiency increases the permeability of the BBB to water and a range of low-molecular-mass and high-molecular-mass tracers. The increased permeability occurs by endothelial transcytosis, a process that is rapidly arrested by the drug imatinib. Furthermore, we show that pericytes function at the BBB in at least two ways: by regulating BBB-specific gene expression patterns in endothelial cells, and by inducing polarization of astrocyte end-feet surrounding CNS blood vessels. Our results indicate a novel and critical role for pericytes in the integration of endothelial and astrocyte functions at the neurovascular unit, and in the regulation of the BBB.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Armulik, Annika -- Genove, Guillem -- Mae, Maarja -- Nisancioglu, Maya H -- Wallgard, Elisabet -- Niaudet, Colin -- He, Liqun -- Norlin, Jenny -- Lindblom, Per -- Strittmatter, Karin -- Johansson, Bengt R -- Betsholtz, Christer -- England -- Nature. 2010 Nov 25;468(7323):557-61. doi: 10.1038/nature09522. Epub 2010 Oct 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Biochemistry and Biophysics, Division of Vascular Biology, Karolinska Institute, Scheeles vag 2, SE-171 77 Stockholm, Sweden. annika.armulik@ki.se〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20944627" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/metabolism ; Benzamides ; Blood-Brain Barrier/*cytology/*metabolism ; Central Nervous System/blood supply ; Endothelial Cells/metabolism ; Gene Expression Regulation ; Imatinib Mesylate ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Pericytes/*metabolism ; Piperazines/pharmacology ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/pharmacology ; Transcytosis/drug effects
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    Suppression of inflammation by a synthetic histone mimic (2010)
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    Publication Date: 2010-11-12
    Description: Interaction of pathogens with cells of the immune system results in activation of inflammatory gene expression. This response, although vital for immune defence, is frequently deleterious to the host due to the exaggerated production of inflammatory proteins. The scope of inflammatory responses reflects the activation state of signalling proteins upstream of inflammatory genes as well as signal-induced assembly of nuclear chromatin complexes that support mRNA expression. Recognition of post-translationally modified histones by nuclear proteins that initiate mRNA transcription and support mRNA elongation is a critical step in the regulation of gene expression. Here we present a novel pharmacological approach that targets inflammatory gene expression by interfering with the recognition of acetylated histones by the bromodomain and extra terminal domain (BET) family of proteins. We describe a synthetic compound (I-BET) that by 'mimicking' acetylated histones disrupts chromatin complexes responsible for the expression of key inflammatory genes in activated macrophages, and confers protection against lipopolysaccharide-induced endotoxic shock and bacteria-induced sepsis. Our findings suggest that synthetic compounds specifically targeting proteins that recognize post-translationally modified histones can serve as a new generation of immunomodulatory drugs.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nicodeme, Edwige -- Jeffrey, Kate L -- Schaefer, Uwe -- Beinke, Soren -- Dewell, Scott -- Chung, Chun-Wa -- Chandwani, Rohit -- Marazzi, Ivan -- Wilson, Paul -- Coste, Herve -- White, Julia -- Kirilovsky, Jorge -- Rice, Charles M -- Lora, Jose M -- Prinjha, Rab K -- Lee, Kevin -- Tarakhovsky, Alexander -- England -- Nature. 2010 Dec 23;468(7327):1119-23. doi: 10.1038/nature09589. Epub 2010 Nov 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre de Recherche GSK, 27 Avenue du Quebec, 91140 Villebon Sur Yvette, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21068722" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation/drug effects ; Animals ; Anti-Inflammatory Agents/chemistry/*pharmacology/therapeutic use ; Benzodiazepines ; Cells, Cultured ; Epigenomics ; Gene Expression Regulation/*drug effects ; Genome-Wide Association Study ; Heterocyclic Compounds with 4 or More Rings/chemistry/*pharmacology/therapeutic ; use ; Histone Deacetylase Inhibitors/pharmacology ; Hydroxamic Acids/pharmacology ; *Inflammation/drug therapy/prevention & control ; Kaplan-Meier Estimate ; Lipopolysaccharides/pharmacology ; Macrophages/*drug effects ; Mice ; Mice, Inbred C57BL ; Models, Molecular ; Protein Structure, Tertiary ; Protein-Serine-Threonine Kinases/metabolism ; Salmonella Infections/drug therapy/immunology/physiopathology/prevention & ; control ; Salmonella typhimurium ; Sepsis/drug therapy/prevention & control ; Shock, Septic/drug therapy/prevention & control
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    Chemoprevention of colorectal cancer by targeting APC-deficient cells for apoptosis (2010)
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    Publication Date: 2010-03-30
    Description: Cancer chemoprevention uses natural, synthetic, or biological substances to reverse, suppress, or prevent either the initial phase of carcinogenesis or the progression of neoplastic cells to cancer. It holds promise for overcoming problems associated with the treatment of late-stage cancers. However, the broad application of chemoprevention is compromised at present by limited effectiveness and potential toxicity. To overcome these challenges, here we developed a new chemoprevention approach that specifically targets premalignant tumour cells for apoptosis. We show that a deficiency in the adenomatous polyposis coli (APC) gene and subsequent activation of beta-catenin lead to the repression of cellular caspase-8 inhibitor c-FLIP (also known as CFLAR) expression through activation of c-Myc, and that all-trans-retinyl acetate (RAc) independently upregulates tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptors and suppresses decoy receptors. Thus, the combination of TRAIL and RAc induces apoptosis in APC-deficient premalignant cells without affecting normal cells in vitro. In addition, we show that short-term and non-continuous TRAIL and RAc treatment induce apoptosis specifically in intestinal polyps, strongly inhibit tumour growth, and prolong survival in multiple intestinal neoplasms C57BL/6J-Apc(Min)/J (Apc(Min)) mice. With our approach, we further demonstrate that TRAIL and RAc induce significant cell death in human colon polyps, providing a potentially selective approach for colorectal cancer chemoprevention by targeting APC-deficient cells for apoptosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425353/" 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/PMC3425353/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Ling -- Ren, Xiaoyang -- Alt, Eckhard -- Bai, Xiaowen -- Huang, Shaoyi -- Xu, Zhengming -- Lynch, Patrick M -- Moyer, Mary P -- Wen, Xian-Feng -- Wu, Xiangwei -- AI063063/AI/NIAID NIH HHS/ -- R01 AI063063/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Apr 15;464(7291):1058-61. doi: 10.1038/nature08871. Epub 2010 Mar 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20348907" target="_blank"〉PubMed〈/a〉
    Keywords: Adenomatous Polyposis Coli Protein/*deficiency/genetics ; Animals ; Apoptosis/*drug effects ; CASP8 and FADD-Like Apoptosis Regulating Protein/metabolism ; Cell Proliferation/drug effects ; Colorectal Neoplasms/genetics/metabolism/*pathology/*prevention & control ; Gene Expression Regulation/drug effects ; Genes, APC ; Humans ; Intestinal Polyps/drug therapy/pathology ; Mice ; Mice, Inbred C57BL ; Precancerous Conditions/drug therapy/genetics/metabolism/pathology ; Proto-Oncogene Proteins c-myc/metabolism ; Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism ; Signal Transduction/drug effects ; Survival Rate ; TNF-Related Apoptosis-Inducing Ligand/administration & ; dosage/pharmacology/therapeutic use ; Time Factors ; Vitamin A/administration & dosage/*analogs & derivatives/pharmacology/therapeutic ; use ; beta Catenin/metabolism
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    Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection (2010)
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    Publication Date: 2010-06-11
    Description: Lymphocytes and neutrophils are rapidly depleted by systemic infection. Progenitor cells of the haematopoietic system, such as common myeloid progenitors and common lymphoid progenitors, increase the production of immune cells to restore and maintain homeostasis during chronic infection, but the contribution of haematopoietic stem cells (HSCs) to this process is largely unknown. Here we show, using an in vivo mouse model of Mycobacterium avium infection, that an increased proportion of long-term repopulating HSCs proliferate during M. avium infection, and that this response requires interferon-gamma (IFN-gamma) but not interferon-alpha (IFN-alpha) signalling. Thus, the haematopoietic response to chronic bacterial infection involves the activation not only of intermediate blood progenitors but of long-term repopulating HSCs as well. IFN-gamma is sufficient to promote long-term repopulating HSC proliferation in vivo; furthermore, HSCs from IFN-gamma-deficient mice have a lower proliferative rate, indicating that baseline IFN-gamma tone regulates HSC activity. These findings implicate IFN-gamma both as a regulator of HSCs during homeostasis and under conditions of infectious stress. Our studies contribute to a deeper understanding of haematological responses in patients with chronic infections such as HIV/AIDS or tuberculosis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935898/" 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/PMC2935898/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baldridge, Megan T -- King, Katherine Y -- Boles, Nathan C -- Weksberg, David C -- Goodell, Margaret A -- K08 HL098898/HL/NHLBI NIH HHS/ -- P50 CA126752/CA/NCI NIH HHS/ -- P50 CA126752-030005/CA/NCI NIH HHS/ -- R01 DK058192/DK/NIDDK NIH HHS/ -- R01 DK058192-10/DK/NIDDK NIH HHS/ -- R01 EB005173/EB/NIBIB NIH HHS/ -- R01 EB005173-05/EB/NIBIB NIH HHS/ -- R01 HL096360/HL/NHLBI NIH HHS/ -- T32 HL092332/HL/NHLBI NIH HHS/ -- T32 HL092332-07/HL/NHLBI NIH HHS/ -- U54 HL081007-05/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Jun 10;465(7299):793-7. doi: 10.1038/nature09135.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535209" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Transplantation ; Cell Count ; Cell Proliferation ; Chronic Disease ; Hematopoietic Stem Cells/*cytology/*immunology ; Homeostasis/*immunology/physiology ; Interferon-alpha ; Interferon-gamma/deficiency/*immunology/*metabolism ; Mice ; Mice, Inbred C57BL ; Multipotent Stem Cells/cytology/immunology ; Mycobacterium avium/immunology ; Signal Transduction ; Tuberculosis/blood/*immunology/microbiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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