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  • 1
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    Telomere dysfunction induces metabolic and mitochondrial compromise (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-11
    Description: Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1alpha and PGC-1beta, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1alpha expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1alpha and PGC-1beta promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741661/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahin, Ergun -- Colla, Simona -- Liesa, Marc -- Moslehi, Javid -- Muller, Florian L -- Guo, Mira -- Cooper, Marcus -- Kotton, Darrell -- Fabian, Attila J -- Walkey, Carl -- Maser, Richard S -- Tonon, Giovanni -- Foerster, Friedrich -- Xiong, Robert -- Wang, Y Alan -- Shukla, Sachet A -- Jaskelioff, Mariela -- Martin, Eric S -- Heffernan, Timothy P -- Protopopov, Alexei -- Ivanova, Elena -- Mahoney, John E -- Kost-Alimova, Maria -- Perry, Samuel R -- Bronson, Roderick -- Liao, Ronglih -- Mulligan, Richard -- Shirihai, Orian S -- Chin, Lynda -- DePinho, Ronald A -- P30 DK046200/DK/NIDDK NIH HHS/ -- P30DK079638/DK/NIDDK NIH HHS/ -- R01 CA084628/CA/NCI NIH HHS/ -- R01 DK035914/DK/NIDDK NIH HHS/ -- R01 DK056690/DK/NIDDK NIH HHS/ -- R01 DK063356/DK/NIDDK NIH HHS/ -- R01 DK089185/DK/NIDDK NIH HHS/ -- U24 DK-59635/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Feb 17;470(7334):359-65. doi: 10.1038/nature09787. Epub 2011 Feb 9.〈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/21307849" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/biosynthesis ; Aging/metabolism/pathology ; Animals ; Cardiomyopathies/chemically induced/metabolism/pathology/physiopathology ; Cell Proliferation ; DNA, Mitochondrial/analysis ; Doxorubicin/toxicity ; Gluconeogenesis ; Hematopoietic Stem Cells/metabolism/pathology ; Liver/cytology/metabolism ; Mice ; Mitochondria/*metabolism/*pathology ; Myocardium/cytology/metabolism ; RNA/genetics ; Reactive Oxygen Species/metabolism ; Telomerase/deficiency/genetics ; Telomere/enzymology/genetics/*metabolism/*pathology ; Transcription Factors/antagonists & inhibitors/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
    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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    SHARPIN is a component of the NF-kappaB-activating linear ubiquitin chain assembly complex (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-04-02
    Description: Cpdm (chronic proliferative dermatitis) mice develop chronic dermatitis and an immunodeficiency with increased serum IgM, symptoms that resemble those of patients with X-linked hyper-IgM syndrome and hypohydrotic ectodermal dysplasia (XHM-ED), which is caused by mutations in NEMO (NF-kappaB essential modulator; also known as IKBKG). Spontaneous null mutations in the Sharpin (SHANK-associated RH domain interacting protein in postsynaptic density) gene are responsible for the cpdm phenotype in mice. SHARPIN shows significant similarity to HOIL-1L (also known as RBCK1), a component of linear ubiquitin chain assembly complex (LUBAC), which induces NF-kappaB activation through conjugation of linear polyubiquitin chains to NEMO. Here, we identify SHARPIN as an additional component of LUBAC. SHARPIN-containing complexes can linearly ubiquitinate NEMO and activated NF-kappaB. Thus, we re-define LUBAC as a complex containing SHARPIN, HOIL-1L, and HOIP (also known as RNF31). Deletion of SHARPIN drastically reduced the amount of LUBAC, which resulted in attenuated TNF-alpha- and CD40-mediated activation of NF-kappaB in mouse embryonic fibroblasts (MEFs) or B cells from cpdm mice. Considering the pleomorphic phenotype of cpdm mice, these results confirm the predicted role of LUBAC-mediated linear polyubiquitination in NF-kappaB activation induced by various stimuli, and strongly suggest the involvement of LUBAC-induced NF-kappaB activation in various disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tokunaga, Fuminori -- Nakagawa, Tomoko -- Nakahara, Masaki -- Saeki, Yasushi -- Taniguchi, Masami -- Sakata, Shin-ichi -- Tanaka, Keiji -- Nakano, Hiroyasu -- Iwai, Kazuhiro -- England -- Nature. 2011 Mar 31;471(7340):633-6. doi: 10.1038/nature09815.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysics and Biochemistry, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21455180" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD40 Ligand/metabolism ; Carrier Proteins/metabolism ; Cells, Cultured ; HEK293 Cells ; Humans ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Multiprotein Complexes/*chemistry/*metabolism ; NF-kappa B/*metabolism ; Nerve Tissue Proteins/deficiency/genetics/*metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Ubiquitin/*metabolism ; Ubiquitin-Protein Ligase Complexes/chemistry/metabolism ; Ubiquitin-Protein Ligases/metabolism
    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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    Induction of functional hepatocyte-like cells from mouse fibroblasts by defined factors (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-05-13
    Description: The generation of functional hepatocytes independent of donor liver organs is of great therapeutic interest with regard to regenerative medicine and possible cures for liver disease. Induced hepatic differentiation has been achieved previously using embryonic stem cells or induced pluripotent stem cells. Particularly, hepatocytes generated from a patient's own induced pluripotent stem cells could theoretically avoid immunological rejection. However, the induction of hepatocytes from induced pluripotent stem cells is a complicated process that would probably be replaced with the arrival of improved technology. Overexpression of lineage-specific transcription factors directly converts terminally differentiated cells into some other lineages, including neurons, cardiomyocytes and blood progenitors; however, it remains unclear whether these lineage-converted cells could repair damaged tissues in vivo. Here we demonstrate the direct induction of functional hepatocyte-like (iHep) cells from mouse tail-tip fibroblasts by transduction of Gata4, Hnf1alpha and Foxa3, and inactivation of p19(Arf). iHep cells show typical epithelial morphology, express hepatic genes and acquire hepatocyte functions. Notably, transplanted iHep cells repopulate the livers of fumarylacetoacetate-hydrolase-deficient (Fah(-/-)) mice and rescue almost half of recipients from death by restoring liver functions. Our study provides a novel strategy to generate functional hepatocyte-like cells for the purpose of liver engineering and regenerative medicine.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Pengyu -- He, Zhiying -- Ji, Shuyi -- Sun, Huawang -- Xiang, Dao -- Liu, Changcheng -- Hu, Yiping -- Wang, Xin -- Hui, Lijian -- England -- Nature. 2011 May 11;475(7356):386-9. doi: 10.1038/nature10116.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy for Sciences, Yueyang Road 320, 200031 Shanghai, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21562492" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation/genetics ; Cell Lineage ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics ; DNA-Binding Proteins/deficiency ; Fibroblasts/*cytology/*metabolism ; GATA4 Transcription Factor/genetics/metabolism ; Gene Expression Profiling ; Hepatocyte Nuclear Factor 1-alpha/genetics/metabolism ; Hepatocyte Nuclear Factor 3-gamma/genetics/metabolism ; Hepatocytes/*cytology/*metabolism/physiology/transplantation ; Hydrolases/deficiency/genetics ; Liver/cytology/enzymology/physiology/physiopathology ; Liver Diseases/enzymology/pathology/physiopathology/therapy ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Regenerative Medicine/methods ; Survival Rate ; Tail/cytology ; Tissue Engineering/methods ; Transduction, Genetic
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Prion propagation and toxicity in vivo occur in two distinct mechanistic phases (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-26
    Description: Mammalian prions cause fatal neurodegenerative conditions including Creutzfeldt-Jakob disease in humans and scrapie and bovine spongiform encephalopathy in animals. Prion infections are typically associated with remarkably prolonged but highly consistent incubation periods followed by a rapid clinical phase. The relationship between prion propagation, generation of neurotoxic species and clinical onset has remained obscure. Prion incubation periods in experimental animals are known to vary inversely with expression level of cellular prion protein. Here we demonstrate that prion propagation in brain proceeds via two distinct phases: a clinically silent exponential phase not rate-limited by prion protein concentration which rapidly reaches a maximal prion titre, followed by a distinct switch to a plateau phase. The latter determines time to clinical onset in a manner inversely proportional to prion protein concentration. These findings demonstrate an uncoupling of infectivity and toxicity. We suggest that prions themselves are not neurotoxic but catalyse the formation of such species from PrP(C). Production of neurotoxic species is triggered when prion propagation saturates, leading to a switch from autocatalytic production of infectivity (phase 1) to a toxic (phase 2) pathway.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sandberg, Malin K -- Al-Doujaily, Huda -- Sharps, Bernadette -- Clarke, Anthony R -- Collinge, John -- MC_U123160656/Medical Research Council/United Kingdom -- MC_U123192748/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2011 Feb 24;470(7335):540-2. doi: 10.1038/nature09768.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350487" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biocatalysis ; Biological Assay ; Disease Models, Animal ; Gene Expression ; Kinetics ; Mice ; Mice, Transgenic ; Models, Biological ; PrPC Proteins/analysis/biosynthesis/genetics/metabolism ; PrPSc Proteins/biosynthesis/*metabolism/*pathogenicity/toxicity ; Prion Diseases/*metabolism/*pathology/physiopathology/transmission ; Survival Rate ; Time Factors ; Toxicity Tests
    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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    Stem cells: iPS cells under attack (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-06-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Apostolou, Effie -- Hochedlinger, Konrad -- England -- Nature. 2011 Jun 8;474(7350):165-6. doi: 10.1038/474165a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654792" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cellular Reprogramming/genetics/immunology ; Graft Rejection/*genetics/*immunology ; Induced Pluripotent Stem Cells/cytology/*immunology/metabolism/*transplantation ; Mice ; Teratoma/genetics/immunology ; Transplantation, Homologous/immunology ; Transplantation, Isogeneic/immunology ; Up-Regulation/genetics/immunology
    Print ISSN: 0028-0836
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  • 6
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    Coronin 2A mediates actin-dependent de-repression of inflammatory response genes (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-19
    Description: Toll-like receptors (TLRs) function as initiators of inflammation through their ability to sense pathogen-associated molecular patterns and products of tissue damage. Transcriptional activation of many TLR-responsive genes requires an initial de-repression step in which nuclear receptor co-repressor (NCoR) complexes are actively removed from the promoters of target genes to relieve basal repression. Ligand-dependent SUMOylation of liver X receptors (LXRs) has been found to suppress TLR4-induced transcription potently by preventing the NCoR clearance step, but the underlying mechanisms remain enigmatic. Here we provide evidence that coronin 2A (CORO2A), a component of the NCoR complex of previously unknown function, mediates TLR-induced NCoR turnover by a mechanism involving interaction with oligomeric nuclear actin. SUMOylated LXRs block NCoR turnover by binding to a conserved SUMO2/SUMO3-interaction motif in CORO2A and preventing actin recruitment. Intriguingly, the LXR transrepression pathway can itself be inactivated by inflammatory signals that induce calcium/calmodulin-dependent protein kinase IIgamma (CaMKIIgamma)-dependent phosphorylation of LXRs, leading to their deSUMOylation by the SUMO protease SENP3 and release from CORO2A. These findings uncover a CORO2A-actin-dependent mechanism for the de-repression of inflammatory response genes that can be differentially regulated by phosphorylation and by nuclear receptor signalling pathways that control immunity and homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464905/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3464905/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Huang, Wendy -- Ghisletti, Serena -- Saijo, Kaoru -- Gandhi, Meghal -- Aouadi, Myriam -- Tesz, Greg J -- Zhang, Dawn X -- Yao, Joyee -- Czech, Michael P -- Goode, Bruce L -- Rosenfeld, Michael G -- Glass, Christopher K -- 1F31DK083913/DK/NIDDK NIH HHS/ -- CA52599/CA/NCI NIH HHS/ -- DK074868/DK/NIDDK NIH HHS/ -- DK085853/DK/NIDDK NIH HHS/ -- HC088093/HC/NHLBI NIH HHS/ -- P01 DK074868/DK/NIDDK NIH HHS/ -- P50 HL056989/HL/NHLBI NIH HHS/ -- R01 CA052599/CA/NCI NIH HHS/ -- R01 CA097134/CA/NCI NIH HHS/ -- R01 DK091183/DK/NIDDK NIH HHS/ -- R01 HL065445/HL/NHLBI NIH HHS/ -- R01 NS034934/NS/NINDS NIH HHS/ -- R37 DK039949/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 17;470(7334):414-8. doi: 10.1038/nature09703.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular and Molecular Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0651, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331046" target="_blank"〉PubMed〈/a〉
    Keywords: Actins/chemistry/*metabolism ; Animals ; Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism ; Cell Line ; *Gene Expression Regulation/drug effects ; Gene Knockdown Techniques ; HeLa Cells ; Homeostasis/genetics ; Humans ; Inflammation/*genetics ; Lipopolysaccharides/pharmacology ; Mice ; Microfilament Proteins/chemistry/deficiency/genetics/*metabolism ; Orphan Nuclear Receptors/metabolism ; Peptide Hydrolases/metabolism ; Peritonitis/chemically induced/metabolism ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Structure, Tertiary ; Signal Transduction ; Sumoylation ; Thioglycolates/pharmacology ; Toll-Like Receptors/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Translational medicine: Cancer lessons from mice to humans (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tuveson, David -- Hanahan, Douglas -- England -- Nature. 2011 Mar 17;471(7338):316-7. doi: 10.1038/471316a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21412332" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Clinical Trials, Phase III as Topic ; *Disease Models, Animal ; *Drug Evaluation, Preclinical ; Everolimus ; Humans ; Indoles/*pharmacology/therapeutic use ; Mice ; Neuroendocrine Tumors/*drug therapy/enzymology/metabolism/pathology ; Pancreatic Neoplasms/*drug therapy/enzymology/metabolism/pathology ; Pyrroles/*pharmacology/therapeutic use ; Signal Transduction/drug effects ; Sirolimus/*analogs & derivatives/pharmacology/therapeutic use ; Survival Rate ; *Translational Medical Research
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Detection of prokaryotic mRNA signifies microbial viability and promotes immunity (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-05-24
    Description: Live vaccines have long been known to trigger far more vigorous immune responses than their killed counterparts. This has been attributed to the ability of live microorganisms to replicate and express specialized virulence factors that facilitate invasion and infection of their hosts. However, protective immunization can often be achieved with a single injection of live, but not dead, attenuated microorganisms stripped of their virulence factors. Pathogen-associated molecular patterns (PAMPs), which are detected by the immune system, are present in both live and killed vaccines, indicating that certain poorly characterized aspects of live microorganisms, not incorporated in dead vaccines, are particularly effective at inducing protective immunity. Here we show that the mammalian innate immune system can directly sense microbial viability through detection of a special class of viability-associated PAMPs (vita-PAMPs). We identify prokaryotic messenger RNA as a vita-PAMP present only in viable bacteria, the recognition of which elicits a unique innate response and a robust adaptive antibody response. Notably, the innate response evoked by viability and prokaryotic mRNA was thus far considered to be reserved for pathogenic bacteria, but we show that even non-pathogenic bacteria in sterile tissues can trigger similar responses, provided that they are alive. Thus, the immune system actively gauges the infectious risk by searching PAMPs for signatures of microbial life and thus infectivity. Detection of vita-PAMPs triggers a state of alert not warranted for dead bacteria. Vaccine formulations that incorporate vita-PAMPs could thus combine the superior protection of live vaccines with the safety of dead vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289942/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3289942/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sander, Leif E -- Davis, Michael J -- Boekschoten, Mark V -- Amsen, Derk -- Dascher, Christopher C -- Ryffel, Bernard -- Swanson, Joel A -- Muller, Michael -- Blander, J Magarian -- AI080959A/AI/NIAID NIH HHS/ -- R01 AI064668/AI/NIAID NIH HHS/ -- R01 AI095245/AI/NIAID NIH HHS/ -- R21 AI080959/AI/NIAID NIH HHS/ -- R21 AI080959-01A1/AI/NIAID NIH HHS/ -- England -- Nature. 2011 May 22;474(7351):385-9. doi: 10.1038/nature10072.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunology Institute, Department of Medicine, Mount Sinai School of Medicine, 1425 Madison Avenue, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21602824" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Vesicular Transport/deficiency/immunology ; Animals ; Antibodies, Bacterial/immunology ; Bacteria/genetics/immunology/pathogenicity ; Bacterial Vaccines/genetics/immunology ; Carrier Proteins/metabolism ; Cells, Cultured ; Dendritic Cells/cytology/immunology/microbiology ; Immunity, Innate/*immunology ; Inflammasomes/immunology/metabolism ; Interferon-beta/genetics/immunology ; Macrophages/cytology/immunology/microbiology ; Mice ; Mice, Inbred C57BL ; Microbial Viability/*genetics/*immunology ; Phagocytosis ; Phagosomes/immunology/microbiology ; RNA, Bacterial/genetics/*immunology ; RNA, Messenger/genetics/*immunology ; Vaccines, Attenuated/genetics/immunology ; Vaccines, Inactivated/immunology ; Virulence Factors
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 9
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    In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-06-10
    Description: Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725645/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725645/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujisaki, Joji -- Wu, Juwell -- Carlson, Alicia L -- Silberstein, Lev -- Putheti, Prabhakar -- Larocca, Rafael -- Gao, Wenda -- Saito, Toshiki I -- Lo Celso, Cristina -- Tsuyuzaki, Hitoshi -- Sato, Tatsuyuki -- Cote, Daniel -- Sykes, Megan -- Strom, Terry B -- Scadden, David T -- Lin, Charles P -- AI041521/AI/NIAID NIH HHS/ -- CA111519/CA/NCI NIH HHS/ -- HL097748/HL/NHLBI NIH HHS/ -- HL97794/HL/NHLBI NIH HHS/ -- P01 AI041521/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P01 CA111519/CA/NCI NIH HHS/ -- P01 CA111519-05/CA/NCI NIH HHS/ -- R01 HL097748/HL/NHLBI NIH HHS/ -- R01 HL097748-02/HL/NHLBI NIH HHS/ -- R01 HL097794/HL/NHLBI NIH HHS/ -- R01 HL097794-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Jun 8;474(7350):216-9. doi: 10.1038/nature10160.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. jfujisaki@partners.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654805" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Survival/immunology ; Cells, Cultured ; Forkhead Transcription Factors/metabolism ; Graft Survival/*immunology ; Hematopoietic Stem Cells/cytology/*immunology ; Humans ; *Imaging, Three-Dimensional ; Interleukin-10/deficiency/genetics/immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Stem Cell Niche/cytology/*immunology ; T-Lymphocytes, Regulatory/*immunology/metabolism ; Time Factors ; Transplantation, Homologous/immunology
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    Microenvironment: Neighbourhood watch (2011)
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    Publication Date: 2011-12-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hughes, Virginia -- England -- Nature. 2011 Dec 14;480(7377):S48-9. doi: 10.1038/480S48a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22169803" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Transplantation ; Drug Resistance, Neoplasm/drug effects ; Humans ; Mice ; Mice, SCID ; Multiple Myeloma/*drug therapy/*pathology ; Neoplasm Transplantation ; Tumor Microenvironment/drug effects/*physiology ; Xenograft Model Antitumor Assays
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    Bioinformatics: Curation generation (2011)
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    Publication Date: 2011-02-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanderson, Katharine -- England -- Nature. 2011 Feb 10;470(7333):295-6.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21348148" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Computational Biology/education/*manpower ; *Databases, Factual/standards/trends/utilization ; *Documentation/trends ; Humans ; Job Satisfaction ; Mice ; Molecular Sequence Annotation/methods/trends ; Software
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    Evolution of human BCR-ABL1 lymphoblastic leukaemia-initiating cells (2011)
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    Publication Date: 2011-01-21
    Description: Many tumours are composed of genetically diverse cells; however, little is known about how diversity evolves or the impact that diversity has on functional properties. Here, using xenografting and DNA copy number alteration (CNA) profiling of human BCR-ABL1 lymphoblastic leukaemia, we demonstrate that genetic diversity occurs in functionally defined leukaemia-initiating cells and that many diagnostic patient samples contain multiple genetically distinct leukaemia-initiating cell subclones. Reconstructing the subclonal genetic ancestry of several samples by CNA profiling demonstrated a branching multi-clonal evolution model of leukaemogenesis, rather than linear succession. For some patient samples, the predominant diagnostic clone repopulated xenografts, whereas in others it was outcompeted by minor subclones. Reconstitution with the predominant diagnosis clone was associated with more aggressive growth properties in xenografts, deletion of CDKN2A and CDKN2B, and a trend towards poorer patient outcome. Our findings link clonal diversity with leukaemia-initiating-cell function and underscore the importance of developing therapies that eradicate all intratumoral subclones.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Notta, Faiyaz -- Mullighan, Charles G -- Wang, Jean C Y -- Poeppl, Armando -- Doulatov, Sergei -- Phillips, Letha A -- Ma, Jing -- Minden, Mark D -- Downing, James R -- Dick, John E -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2011 Jan 20;469(7330):362-7. doi: 10.1038/nature09733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Stem Cell and Developmental Biology, Campbell Family Institute for Cancer Research/Ontario Cancer Institute, Toronto, Ontario M5G 1L7, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248843" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Survival ; Clone Cells/*metabolism/*pathology ; Cyclin-Dependent Kinase Inhibitor p15/deficiency/genetics ; DNA Copy Number Variations/genetics ; Disease Progression ; *Evolution, Molecular ; Fusion Proteins, bcr-abl/*genetics ; Genes, p16 ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Models, Biological ; Neoplasm Transplantation ; Oligonucleotide Array Sequence Analysis ; Philadelphia Chromosome ; Polymorphism, Single Nucleotide/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics/*pathology ; Survival Rate ; Transplantation, Heterologous
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    MicroRNAs 103 and 107 regulate insulin sensitivity (2011)
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    Publication Date: 2011-06-10
    Description: Defects in insulin signalling are among the most common and earliest defects that predispose an individual to the development of type 2 diabetes. MicroRNAs have been identified as a new class of regulatory molecules that influence many biological functions, including metabolism. However, the direct regulation of insulin sensitivity by microRNAs in vivo has not been demonstrated. Here we show that the expression of microRNAs 103 and 107 (miR-103/107) is upregulated in obese mice. Silencing of miR-103/107 leads to improved glucose homeostasis and insulin sensitivity. In contrast, gain of miR-103/107 function in either liver or fat is sufficient to induce impaired glucose homeostasis. We identify caveolin-1, a critical regulator of the insulin receptor, as a direct target gene of miR-103/107. We demonstrate that caveolin-1 is upregulated upon miR-103/107 inactivation in adipocytes and that this is concomitant with stabilization of the insulin receptor, enhanced insulin signalling, decreased adipocyte size and enhanced insulin-stimulated glucose uptake. These findings demonstrate the central importance of miR-103/107 to insulin sensitivity and identify a new target for the treatment of type 2 diabetes and obesity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trajkovski, Mirko -- Hausser, Jean -- Soutschek, Jurgen -- Bhat, Bal -- Akin, Akinc -- Zavolan, Mihaela -- Heim, Markus H -- Stoffel, Markus -- England -- Nature. 2011 Jun 8;474(7353):649-53. doi: 10.1038/nature10112.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Molecular Systems Biology, ETH Zurich, Wolfgang-Pauli Strasse 16, CH-8093 Zurich, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654750" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/metabolism ; Animals ; Caveolin 1/metabolism ; Cell Size ; Diabetes Mellitus, Type 2/physiopathology ; Disease Models, Animal ; Gene Expression ; Gene Expression Regulation ; Gene Silencing ; Glucose/metabolism ; Homeostasis ; Hyperglycemia/physiopathology ; Insulin/*metabolism ; Liver/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; MicroRNAs/genetics/*metabolism ; Signal Transduction ; Up-Regulation
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    Different patterns of peripheral migration by memory CD4+ and CD8+ T cells (2011)
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    Publication Date: 2011-08-16
    Description: Infections localized to peripheral tissues such as the skin result in the priming of T-cell responses that act to control pathogens. Activated T cells undergo migrational imprinting within the draining lymph nodes, resulting in memory T cells that provide local and systemic protection. Combinations of migrating and resident memory T cells have been implicated in long-term peripheral immunity, especially at the surfaces that form pathogen entry points into the body. However, T-cell immunity consists of separate CD4(+) helper T cells and CD8(+) killer T cells, with distinct effector and memory programming requirements. Whether these subsets also differ in their ability to form a migrating pool involved in peripheral immunosurveillance or a separate resident population responsible for local infection control has not been explored. Here, using mice, we show key differences in the migration and tissue localization of memory CD4(+) and CD8(+) T cells following infection of the skin by herpes simplex virus. On resolution of infection, the skin contained two distinct virus-specific memory subsets; a slow-moving population of sequestered CD8(+) T cells that were resident in the epidermis and confined largely to the original site of infection, and a dynamic population of CD4(+) T cells that trafficked rapidly through the dermis as part of a wider recirculation pattern. Unique homing-molecule expression by recirculating CD4(+) T effector-memory cells mirrored their preferential skin-migratory capacity. Overall, these results identify a complexity in memory T-cell migration, illuminating previously unappreciated differences between the CD4(+) and CD8(+) subsets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gebhardt, Thomas -- Whitney, Paul G -- Zaid, Ali -- Mackay, Laura K -- Brooks, Andrew G -- Heath, William R -- Carbone, Francis R -- Mueller, Scott N -- England -- Nature. 2011 Aug 14;477(7363):216-9. doi: 10.1038/nature10339.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, The University of Melbourne, Melbourne, Victoria 3010, Australia. gebhardt@unimelb.edu.au〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21841802" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; CD4-Positive T-Lymphocytes/*cytology/immunology/metabolism ; CD8-Positive T-Lymphocytes/*cytology/immunology/metabolism ; *Cell Movement ; E-Selectin/metabolism ; Genomic Imprinting ; Herpes Simplex/immunology/virology ; *Immunologic Memory ; Immunologic Surveillance/immunology ; Ligands ; Mice ; P-Selectin/metabolism ; Simplexvirus/immunology ; Skin/cytology/immunology/virology ; T-Lymphocytes, Helper-Inducer/cytology/immunology
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    Animal behaviour: the nexus of sex and violence (2011)
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    Publication Date: 2011-02-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saper, Clifford B -- England -- Nature. 2011 Feb 10;470(7333):179-81. doi: 10.1038/470179a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307926" target="_blank"〉PubMed〈/a〉
    Keywords: Aggression/drug effects/*physiology ; Animals ; Cats ; Electric Stimulation ; Female ; Gene Expression Regulation/genetics ; Genes, fos/genetics ; Humans ; Male ; Mice ; Neural Inhibition/drug effects/genetics/physiology ; Neural Pathways/drug effects/physiology ; Neurons/drug effects/physiology ; Rats ; Sex Characteristics ; Sexual Behavior, Animal/drug effects/physiology ; Time Factors ; Ventromedial Hypothalamic Nucleus/anatomy & histology/*cytology/drug ; effects/*physiology ; Violence
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    The circadian molecular clock creates epidermal stem cell heterogeneity (2011)
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    Publication Date: 2011-11-15
    Description: Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Janich, Peggy -- Pascual, Gloria -- Merlos-Suarez, Anna -- Batlle, Eduard -- Ripperger, Jurgen -- Albrecht, Urs -- Cheng, Hai-Ying M -- Obrietan, Karl -- Di Croce, Luciano -- Benitah, Salvador Aznar -- England -- Nature. 2011 Nov 9;480(7376):209-14. doi: 10.1038/nature10649.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Genomic Regulation and UPF, 08003 Barcelona, Spain.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080954" target="_blank"〉PubMed〈/a〉
    Keywords: ARNTL Transcription Factors/deficiency/genetics/metabolism ; Animals ; Carcinoma, Squamous Cell/genetics/pathology ; Cell Adhesion/genetics ; Cell Aging ; Cell Cycle/genetics ; Cells, Cultured ; Circadian Clocks/genetics/*physiology ; Circadian Rhythm/genetics/*physiology ; Cues ; Female ; Gene Expression Regulation/genetics ; Hair Follicle/*cytology ; Homeostasis/genetics/physiology ; Male ; Mice ; Mice, Knockout ; Skin Neoplasms/genetics/pathology ; Stem Cell Niche ; Stem Cells/*cytology/metabolism ; Transforming Growth Factor beta/genetics ; Wnt Signaling Pathway/genetics
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    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses (2011)
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    Publication Date: 2011-06-17
    Description: Clinical studies consistently demonstrate that a single sub-psychomimetic dose of ketamine, an ionotropic glutamatergic NMDAR (N-methyl-D-aspartate receptor) antagonist, produces fast-acting antidepressant responses in patients suffering from major depressive disorder, although the underlying mechanism is unclear. Depressed patients report the alleviation of major depressive disorder symptoms within two hours of a single, low-dose intravenous infusion of ketamine, with effects lasting up to two weeks, unlike traditional antidepressants (serotonin re-uptake inhibitors), which take weeks to reach efficacy. This delay is a major drawback to current therapies for major depressive disorder and faster-acting antidepressants are needed, particularly for suicide-risk patients. The ability of ketamine to produce rapidly acting, long-lasting antidepressant responses in depressed patients provides a unique opportunity to investigate underlying cellular mechanisms. Here we show that ketamine and other NMDAR antagonists produce fast-acting behavioural antidepressant-like effects in mouse models, and that these effects depend on the rapid synthesis of brain-derived neurotrophic factor. We find that the ketamine-mediated blockade of NMDAR at rest deactivates eukaryotic elongation factor 2 (eEF2) kinase (also called CaMKIII), resulting in reduced eEF2 phosphorylation and de-suppression of translation of brain-derived neurotrophic factor. Furthermore, we find that inhibitors of eEF2 kinase induce fast-acting behavioural antidepressant-like effects. Our findings indicate that the regulation of protein synthesis by spontaneous neurotransmission may serve as a viable therapeutic target for the development of fast-acting antidepressants.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172695/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3172695/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Autry, Anita E -- Adachi, Megumi -- Nosyreva, Elena -- Na, Elisa S -- Los, Maarten F -- Cheng, Peng-fei -- Kavalali, Ege T -- Monteggia, Lisa M -- MH066198/MH/NIMH NIH HHS/ -- MH070727/MH/NIMH NIH HHS/ -- R01 MH066198/MH/NIMH NIH HHS/ -- R01 MH066198-07/MH/NIMH NIH HHS/ -- R01 MH066198-08/MH/NIMH NIH HHS/ -- T32 MH 76690-02/MH/NIMH NIH HHS/ -- England -- Nature. 2011 Jun 15;475(7354):91-5. doi: 10.1038/nature10130.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9111, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21677641" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antidepressive Agents/*pharmacology ; Behavior, Animal/drug effects/physiology ; Brain-Derived Neurotrophic Factor/biosynthesis/deficiency/genetics/pharmacology ; Depression/drug therapy ; Disease Models, Animal ; Dizocilpine Maleate/pharmacology ; Elongation Factor 2 Kinase/metabolism ; Gene Expression Regulation/drug effects ; Ketamine/*pharmacology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphorylation/drug effects ; Piperazines/pharmacology ; Protein Biosynthesis/drug effects ; Receptors, N-Methyl-D-Aspartate/*antagonists & inhibitors/metabolism ; Rest/*physiology ; Suicide/prevention & control ; Synapses/drug effects/metabolism ; Synaptic Transmission/drug effects ; Time Factors
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    JASON past, present, and future: the world's most independent defence science advisers (2011)
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    Publication Date: 2011-09-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Finkbeiner, Ann -- England -- Nature. 2011 Sep 21;477(7365):397-9. doi: 10.1038/477397a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉anniekf@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21938048" target="_blank"〉PubMed〈/a〉
    Keywords: Advisory Committees/economics/*history/*organization & administration/trends ; Biological Warfare/prevention & control ; Consultants ; *Federal Government ; History, 20th Century ; History, 21st Century ; Military Science/economics/*history/*manpower ; Security Measures ; United States ; United States Department of Defense/economics/organization & administration
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    BRCA1 tumour suppression occurs via heterochromatin-mediated silencing (2011)
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    Publication Date: 2011-09-09
    Description: Mutations in the tumour suppressor gene BRCA1 lead to breast and/or ovarian cancer. Here we show that loss of Brca1 in mice results in transcriptional de-repression of the tandemly repeated satellite DNA. Brca1 deficiency is accompanied by a reduction of condensed DNA regions in the genome and loss of ubiquitylation of histone H2A at satellite repeats. BRCA1 binds to satellite DNA regions and ubiquitylates H2A in vivo. Ectopic expression of H2A fused to ubiquitin reverses the effects of BRCA1 loss, indicating that BRCA1 maintains heterochromatin structure via ubiquitylation of histone H2A. Satellite DNA de-repression was also observed in mouse and human BRCA1-deficient breast cancers. Ectopic expression of satellite DNA can phenocopy BRCA1 loss in centrosome amplification, cell-cycle checkpoint defects, DNA damage and genomic instability. We propose that the role of BRCA1 in maintaining global heterochromatin integrity accounts for many of its tumour suppressor functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240576/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3240576/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhu, Quan -- Pao, Gerald M -- Huynh, Alexis M -- Suh, Hoonkyo -- Tonnu, Nina -- Nederlof, Petra M -- Gage, Fred H -- Verma, Inder M -- NS50217/NS/NINDS NIH HHS/ -- NS52842/NS/NINDS NIH HHS/ -- R01 NS050217/NS/NINDS NIH HHS/ -- R01 NS050217-05/NS/NINDS NIH HHS/ -- R01 NS052842/NS/NINDS NIH HHS/ -- R01 NS052842-04/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Sep 7;477(7363):179-84. doi: 10.1038/nature10371.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Genetics, The Salk Institute for Biological Studies, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21901007" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; BRCA1 Protein/deficiency/genetics/*metabolism ; Breast/cytology ; Breast Neoplasms/*genetics/pathology ; Cell Line, Tumor ; Cells, Cultured ; DNA, Satellite/genetics ; Epithelial Cells/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; *Gene Silencing ; Genes, BRCA1/*physiology ; Genomic Instability/genetics ; HeLa Cells ; Heterochromatin/*genetics/*metabolism ; Histones/metabolism ; Humans ; Mice ; Ovarian Neoplasms/genetics ; RNA, Messenger/genetics ; Transcription, Genetic/genetics ; Ubiquitin-Protein Ligases/metabolism ; Ubiquitinated Proteins/metabolism ; Ubiquitination
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    Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein (2011)
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    Publication Date: 2011-08-23
    Description: Rapid and efficient removal of apoptotic cells by phagocytes is important during development, tissue homeostasis and in immune responses. Efficient clearance depends on the capacity of a single phagocyte to ingest multiple apoptotic cells successively, and to process the corpse-derived cellular material. However, the factors that influence continued clearance by phagocytes are not known. Here we show that the mitochondrial membrane potential of the phagocyte critically controls engulfment capacity, with lower potential enhancing engulfment and vice versa. The mitochondrial membrane protein Ucp2, which acts to lower the mitochondrial membrane potential, was upregulated in phagocytes engulfing apoptotic cells. Loss of Ucp2 reduced phagocytic capacity, whereas Ucp2 overexpression enhanced engulfment. Mutational and pharmacological studies indicated a direct role for Ucp2-mediated mitochondrial function in phagocytosis. Macrophages from Ucp2-deficient mice were impaired in phagocytosis in vitro, and Ucp2-deficient mice showed profound in vivo defects in clearing dying cells in the thymus and testes. Collectively, these data indicate that mitochondrial membrane potential and Ucp2 are key molecular determinants of apoptotic cell clearance. As Ucp2 is linked to metabolic diseases and atherosclerosis, this newly discovered role for Ucp2 in apoptotic cell clearance has implications for the complex aetiology and pathogenesis of these diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513690/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3513690/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Park, Daeho -- Han, Claudia Z -- Elliott, Michael R -- Kinchen, Jason M -- Trampont, Paul C -- Das, Soumita -- Collins, Sheila -- Lysiak, Jeffrey J -- Hoehn, Kyle L -- Ravichandran, Kodi S -- R01 GM064709/GM/NIGMS NIH HHS/ -- R01 HD057242/HD/NICHD NIH HHS/ -- T32 GM008136/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Aug 21;477(7363):220-4. doi: 10.1038/nature10340.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Cell Clearance, University of Virginia, Charlottesville, Virginia 22908, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21857682" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; Cell Line ; Cell Size/drug effects ; Cells, Cultured ; Ion Channels/deficiency/genetics/*metabolism ; Membrane Potential, Mitochondrial/drug effects/physiology ; Mice ; Mitochondrial Proteins/deficiency/genetics/*metabolism ; Phagocytes/*cytology/drug effects/*metabolism ; Phagocytosis/drug effects/*physiology ; Thymus Gland/cytology
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    Photoentrainment and pupillary light reflex are mediated by distinct populations of ipRGCs (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-19
    Description: Intrinsically photosensitive retinal ganglion cells (ipRGCs) express the photopigment melanopsin and regulate a wide array of light-dependent physiological processes. Genetic ablation of ipRGCs eliminates circadian photoentrainment and severely disrupts the pupillary light reflex (PLR). Here we show that ipRGCs consist of distinct subpopulations that differentially express the Brn3b transcription factor, and can be functionally distinguished. Brn3b-negative M1 ipRGCs innervate the suprachiasmatic nucleus (SCN) of the hypothalamus, whereas Brn3b-positive ipRGCs innervate all other known brain targets, including the olivary pretectal nucleus. Consistent with these innervation patterns, selective ablation of Brn3b-positive ipRGCs severely disrupts the PLR, but does not impair circadian photoentrainment. Thus, we find that molecularly distinct subpopulations of M1 ipRGCs, which are morphologically and electrophysiologically similar, innervate different brain regions to execute specific light-induced functions.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150726/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150726/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, S-K -- Badea, T C -- Hattar, S -- GM076430/GM/NIGMS NIH HHS/ -- R01 GM076430/GM/NIGMS NIH HHS/ -- R01 GM076430-01/GM/NIGMS NIH HHS/ -- R01 GM076430-02/GM/NIGMS NIH HHS/ -- R01 GM076430-03/GM/NIGMS NIH HHS/ -- R01 GM076430-03S1/GM/NIGMS NIH HHS/ -- R01 GM076430-04/GM/NIGMS NIH HHS/ -- R01 GM076430-05/GM/NIGMS NIH HHS/ -- R01 GM076430-06/GM/NIGMS NIH HHS/ -- R01 GM076430-07/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jul 17;476(7358):92-5. doi: 10.1038/nature10206.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biology, Johns Hopkins University, Baltimore, Maryland 21218, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21765429" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Circadian Rhythm/genetics/*physiology/*radiation effects ; Homeodomain Proteins/metabolism ; Male ; Mice ; Models, Neurological ; Olivary Nucleus/metabolism ; Reflex, Pupillary/genetics/*physiology/*radiation effects ; Retinal Ganglion Cells/cytology/*physiology/*radiation effects ; Rod Opsins/genetics/metabolism ; Suprachiasmatic Nucleus/metabolism ; Transcription Factor Brn-3B/deficiency/metabolism
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    Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development (2011)
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    Publication Date: 2011-04-08
    Description: X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Okamoto, Ikuhiro -- Patrat, Catherine -- Thepot, Dominique -- Peynot, Nathalie -- Fauque, Patricia -- Daniel, Nathalie -- Diabangouaya, Patricia -- Wolf, Jean-Philippe -- Renard, Jean-Paul -- Duranthon, Veronique -- Heard, Edith -- England -- Nature. 2011 Apr 21;472(7343):370-4. doi: 10.1038/nature09872. Epub 2011 Apr 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Mammalian Developmental Epigenetics Group, Institut Curie, CNRS UMR 3215, INSERM U934, Paris 75248, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21471966" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Evolution ; Blastocyst/metabolism ; Chromosomes, Mammalian/*genetics ; Dosage Compensation, Genetic/genetics ; Embryo, Mammalian/embryology/metabolism ; Female ; Gene Expression Regulation, Developmental/*genetics ; Genes, X-Linked/genetics ; Genomic Imprinting/genetics ; Histones/metabolism ; Humans ; Hypoxanthine Phosphoribosyltransferase/genetics ; Male ; Mammals/embryology/*genetics ; Mice ; Parthenogenesis ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Rabbits ; Species Specificity ; Up-Regulation/genetics ; X Chromosome/*genetics ; X Chromosome Inactivation/*genetics
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    Vaccines: chasing the dream (2011)
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    Publication Date: 2011-07-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schnabel, Jim -- England -- Nature. 2011 Jul 13;475(7355):S18-9. doi: 10.1038/475S18a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21760578" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/immunology/metabolism/*prevention & control/*therapy ; Alzheimer Vaccines/adverse effects/*immunology/*therapeutic use ; Amyloid/antagonists & inhibitors/chemistry/immunology/metabolism ; Amyloid beta-Peptides/adverse effects/*antagonists & ; inhibitors/chemistry/immunology/metabolism/therapeutic use ; Animals ; Antibodies, Monoclonal/adverse effects/immunology/therapeutic use ; Antibodies, Monoclonal, Humanized ; Clinical Trials as Topic ; Humans ; Immunoglobulins, Intravenous/economics/*immunology/*therapeutic use ; Mice ; tau Proteins/antagonists & inhibitors/chemistry/metabolism
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    Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders (2011)
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    Publication Date: 2011-11-04
    Description: Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3468323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Baker, Darren J -- Wijshake, Tobias -- Tchkonia, Tamar -- LeBrasseur, Nathan K -- Childs, Bennett G -- van de Sluis, Bart -- Kirkland, James L -- van Deursen, Jan M -- AG13925/AG/NIA NIH HHS/ -- CA96985/CA/NCI NIH HHS/ -- P30 DK050456/DK/NIDDK NIH HHS/ -- R01 AG013925/AG/NIA NIH HHS/ -- R01 AG013925-14/AG/NIA NIH HHS/ -- R01 CA096985/CA/NCI NIH HHS/ -- R01 CA096985-10/CA/NCI NIH HHS/ -- England -- Nature. 2011 Nov 2;479(7372):232-6. doi: 10.1038/nature10600.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22048312" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/cytology/drug effects/pathology ; Aging/drug effects/*physiology ; Animals ; Bone Marrow Cells/cytology/drug effects ; Cell Aging/drug effects/*physiology ; Cell Count ; Cell Cycle Proteins ; Cells, Cultured ; Cyclin-Dependent Kinase Inhibitor p16/*metabolism ; Eye/cytology/drug effects/pathology ; Female ; Gene Expression ; Genotype ; Longevity/drug effects/physiology ; Male ; Mice ; Mice, Transgenic ; Muscle, Skeletal/cytology/drug effects/pathology ; Phenotype ; Progeria/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Tacrolimus/analogs & derivatives/pharmacology ; Time Factors ; Weaning
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    China's water crisis needs more than words (2011)
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    Publication Date: 2011-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Chaoqing -- England -- Nature. 2011 Feb 17;470(7334):307. doi: 10.1038/470307a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331001" target="_blank"〉PubMed〈/a〉
    Keywords: China ; Conservation of Natural Resources/*legislation & jurisprudence/trends ; Droughts ; Ecosystem ; *Federal Government ; Food Supply ; Fresh Water/analysis/chemistry ; Public Policy/*legislation & jurisprudence ; Water Pollution/prevention & control ; *Water Supply/analysis/economics/legislation & jurisprudence/standards
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    Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation (2011)
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    Publication Date: 2011-04-05
    Description: Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084370/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084370/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sahay, Amar -- Scobie, Kimberly N -- Hill, Alexis S -- O'Carroll, Colin M -- Kheirbek, Mazen A -- Burghardt, Nesha S -- Fenton, Andre A -- Dranovsky, Alex -- Hen, Rene -- 1K99MH86615-01/MH/NIMH NIH HHS/ -- K08 MH079088/MH/NIMH NIH HHS/ -- K08 MH079088-01/MH/NIMH NIH HHS/ -- K08 MH079088-02/MH/NIMH NIH HHS/ -- K08 MH079088-03/MH/NIMH NIH HHS/ -- K08 MH079088-03S1/MH/NIMH NIH HHS/ -- K08 MH079088-04/MH/NIMH NIH HHS/ -- K08 MH079088-05/MH/NIMH NIH HHS/ -- K99 MH086615/MH/NIMH NIH HHS/ -- K99 MH086615-02/MH/NIMH NIH HHS/ -- R01 MH068542/MH/NIMH NIH HHS/ -- R01 MH091844/MH/NIMH NIH HHS/ -- R01 MH091844-01/MH/NIMH NIH HHS/ -- R01 MH091844-02/MH/NIMH NIH HHS/ -- R01 MH091844-03/MH/NIMH NIH HHS/ -- T32 HD007430/HD/NICHD NIH HHS/ -- England -- Nature. 2011 Apr 28;472(7344):466-70. doi: 10.1038/nature09817. Epub 2011 Apr 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Columbia University, New York, New York 10032, USA. as2619@columbia.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21460835" target="_blank"〉PubMed〈/a〉
    Keywords: Affect/*physiology ; Aging/drug effects/pathology/*physiology ; Animals ; Antidepressive Agents/pharmacology ; Anxiety/physiopathology/therapy ; Apoptosis/drug effects ; Cell Survival/drug effects ; Cognition/drug effects/*physiology ; Conditioning, Classical/drug effects/physiology ; Dentate Gyrus/cytology/pathology/physiology/physiopathology ; Exploratory Behavior/drug effects/physiology ; Extinction, Psychological/drug effects/physiology ; Fear/physiology/psychology ; Female ; Hippocampus/*cytology/pathology/*physiology/physiopathology ; Learning/drug effects/physiology ; Long-Term Potentiation/drug effects/physiology ; Male ; Memory/drug effects/physiology ; Mice ; Mice, Knockout ; Mice, Transgenic ; *Models, Neurological ; Neural Stem Cells/cytology/drug effects/metabolism ; Neurogenesis/drug effects/*physiology ; Neuronal Plasticity/drug effects/physiology ; Physical Conditioning, Animal/physiology ; Synapses/drug effects/metabolism ; bcl-2-Associated X Protein/deficiency/genetics/metabolism
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    Military science: The JASONs bought into the Vietnam War (2011)
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    Publication Date: 2011-10-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schwartz, Joseph -- England -- Nature. 2011 Oct 12;478(7368):188. doi: 10.1038/478188c.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21993750" target="_blank"〉PubMed〈/a〉
    Keywords: Advisory Committees/*history/*organization & administration ; *Federal Government ; Military Science/*history/*manpower
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    Distinct stem cells contribute to mammary gland development and maintenance (2011)
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    Publication Date: 2011-10-11
    Description: The mammary epithelium is composed of several cell lineages including luminal, alveolar and myoepithelial cells. Transplantation studies have suggested that the mammary epithelium is maintained by the presence of multipotent mammary stem cells. To define the cellular hierarchy of the mammary gland during physiological conditions, we performed genetic lineage-tracing experiments and clonal analysis of the mouse mammary gland during development, adulthood and pregnancy. We found that in postnatal unperturbed mammary gland, both luminal and myoepithelial lineages contain long-lived unipotent stem cells that display extensive renewing capacities, as demonstrated by their ability to clonally expand during morphogenesis and adult life as well as undergo massive expansion during several cycles of pregnancy. The demonstration that the mammary gland contains different types of long-lived stem cells has profound implications for our understanding of mammary gland physiology and will be instrumental in unravelling the cells at the origin of breast cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Keymeulen, Alexandra -- Rocha, Ana Sofia -- Ousset, Marielle -- Beck, Benjamin -- Bouvencourt, Gaelle -- Rock, Jason -- Sharma, Neha -- Dekoninck, Sophie -- Blanpain, Cedric -- England -- Nature. 2011 Oct 9;479(7372):189-93. doi: 10.1038/nature10573.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Universite Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21983963" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Cell Differentiation ; *Cell Lineage ; Cell Transplantation ; Epithelium ; Female ; Homeostasis ; Lactation/physiology ; Mammary Glands, Animal/*cytology/*growth & development/physiology/transplantation ; Mice ; Multipotent Stem Cells/cytology ; Pregnancy ; Stem Cells/*cytology/metabolism
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    SCF(FBW7) regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction (2011)
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    Publication Date: 2011-03-04
    Description: The effective use of targeted therapy is highly dependent on the identification of responder patient populations. Loss of FBW7, which encodes a tumour-suppressor protein, is frequently found in various types of human cancer, including breast cancer, colon cancer and T-cell acute lymphoblastic leukaemia (T-ALL). In line with these genomic data, engineered deletion of Fbw7 in mouse T cells results in T-ALL, validating FBW7 as a T-ALL tumour suppressor. Determining the precise molecular mechanisms by which FBW7 exerts antitumour activity is an area of intensive investigation. These mechanisms are thought to relate in part to FBW7-mediated destruction of key proteins relevant to cancer, including Jun, Myc, cyclin E and notch 1 (ref. 9), all of which have oncoprotein activity and are overexpressed in various human cancers, including leukaemia. In addition to accelerating cell growth, overexpression of Jun, Myc or notch 1 can also induce programmed cell death. Thus, considerable uncertainty surrounds how FBW7-deficient cells evade cell death in the setting of upregulated Jun, Myc and/or notch 1. Here we show that the E3 ubiquitin ligase SCF(FBW7) (a SKP1-cullin-1-F-box complex that contains FBW7 as the F-box protein) governs cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitylation and destruction in a manner that depends on phosphorylation by glycogen synthase kinase 3. Human T-ALL cell lines showed a close relationship between FBW7 loss and MCL1 overexpression. Correspondingly, T-ALL cell lines with defective FBW7 are particularly sensitive to the multi-kinase inhibitor sorafenib but resistant to the BCL2 antagonist ABT-737. On the genetic level, FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737, establishing MCL1 as a therapeutically relevant bypass survival mechanism that enables FBW7-deficient cells to evade apoptosis. Therefore, our work provides insight into the molecular mechanism of direct tumour suppression by FBW7 and has implications for the targeted treatment of patients with FBW7-deficient T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076007/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3076007/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Inuzuka, Hiroyuki -- Shaik, Shavali -- Onoyama, Ichiro -- Gao, Daming -- Tseng, Alan -- Maser, Richard S -- Zhai, Bo -- Wan, Lixin -- Gutierrez, Alejandro -- Lau, Alan W -- Xiao, Yonghong -- Christie, Amanda L -- Aster, Jon -- Settleman, Jeffrey -- Gygi, Steven P -- Kung, Andrew L -- Look, Thomas -- Nakayama, Keiichi I -- DePinho, Ronald A -- Wei, Wenyi -- GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763/GM/NIGMS NIH HHS/ -- R01 GM089763-01/GM/NIGMS NIH HHS/ -- R01 GM089763-02/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Mar 3;471(7336):104-9. doi: 10.1038/nature09732.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21368833" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; *Apoptosis/drug effects ; Benzenesulfonates/pharmacology ; Biphenyl Compounds/pharmacology ; Cell Cycle Proteins/genetics/*metabolism ; Cell Line, Tumor ; F-Box Proteins/genetics/*metabolism ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Molecular Sequence Data ; Myeloid Cell Leukemia Sequence 1 Protein ; Niacinamide/analogs & derivatives ; Nitrophenols/pharmacology ; Phenylurea Compounds ; Phosphorylation ; Piperazines/pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Protein Binding/drug effects ; Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/*chemistry/*metabolism ; Pyridines/pharmacology ; SKP Cullin F-Box Protein Ligases/*chemistry/*metabolism ; Sulfonamides/pharmacology ; Tumor Suppressor Proteins/deficiency/genetics/metabolism ; Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism ; *Ubiquitination/drug effects
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Epigenetics: Tet proteins in the limelight (2011)
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    Publication Date: 2011-05-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Veron, Nathalie -- Peters, Antoine H F M -- England -- Nature. 2011 May 19;473(7347):293-4. doi: 10.1038/473293a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21593859" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chromatin/genetics/metabolism ; CpG Islands/genetics ; Cytosine/*analogs & derivatives/analysis/metabolism ; *DNA Methylation ; DNA-Binding Proteins/*metabolism ; Embryonic Stem Cells/*metabolism ; *Epigenesis, Genetic ; *Gene Expression Regulation, Developmental/genetics ; Genome/genetics ; Mice ; Polycomb-Group Proteins ; Promoter Regions, Genetic/genetics ; Proto-Oncogene Proteins/*metabolism ; Repressor Proteins/metabolism ; Transcription, Genetic/genetics
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Mitochondrial uncoupling protein 2 structure determined by NMR molecular fragment searching (2011)
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    Publication Date: 2011-07-26
    Description: Mitochondrial uncoupling protein 2 (UCP2) is an integral membrane protein in the mitochondrial anion carrier protein family, the members of which facilitate the transport of small molecules across the mitochondrial inner membrane. When the mitochondrial respiratory complex pumps protons from the mitochondrial matrix to the intermembrane space, it builds up an electrochemical potential. A fraction of this electrochemical potential is dissipated as heat, in a process involving leakage of protons back to the matrix. This leakage, or 'uncoupling' of the proton electrochemical potential, is mediated primarily by uncoupling proteins. However, the mechanism of UCP-mediated proton translocation across the lipid bilayer is unknown. Here we describe a solution-NMR method for structural characterization of UCP2. The method, which overcomes some of the challenges associated with membrane-protein structure determination, combines orientation restraints derived from NMR residual dipolar couplings (RDCs) and semiquantitative distance restraints from paramagnetic relaxation enhancement (PRE) measurements. The local and secondary structures of the protein were determined by piecing together molecular fragments from the Protein Data Bank that best fit experimental RDCs from samples weakly aligned in a DNA nanotube liquid crystal. The RDCs also determine the relative orientation of the secondary structural segments, and the PRE restraints provide their spatial arrangement in the tertiary fold. UCP2 closely resembles the bovine ADP/ATP carrier (the only carrier protein of known structure), but the relative orientations of the helical segments are different, resulting in a wider opening on the matrix side of the inner membrane. Moreover, the nitroxide-labelled GDP binds inside the channel and seems to be closer to transmembrane helices 1-4. We believe that this biophysical approach can be applied to other membrane proteins and, in particular, to other mitochondrial carriers, not only for structure determination but also to characterize various conformational states of these proteins linked to substrate transport.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150631/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3150631/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Berardi, Marcelo J -- Shih, William M -- Harrison, Stephen C -- Chou, James J -- 1DP2OD004641/OD/NIH HHS/ -- 1U54GM094608/GM/NIGMS NIH HHS/ -- R21 DK075963/DK/NIDDK NIH HHS/ -- R21 DK075963-01/DK/NIDDK NIH HHS/ -- R21 DK075963-02/DK/NIDDK NIH HHS/ -- U54 GM094608/GM/NIGMS NIH HHS/ -- U54 GM094608-01/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 24;476(7358):109-13. doi: 10.1038/nature10257.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jack and Eileen Connors Structural Biology Laboratory, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21785437" target="_blank"〉PubMed〈/a〉
    Keywords: Adenine Nucleotide Translocator 1/chemistry/metabolism ; Animals ; Binding Sites ; Cattle ; Databases, Protein ; Guanosine Diphosphate/chemistry/metabolism ; Ion Channels/*chemistry/metabolism ; Mice ; Mitochondrial ADP, ATP Translocases/chemistry ; Mitochondrial Proteins/*chemistry/metabolism ; Models, Molecular ; Nitrogen Oxides/chemistry/metabolism ; Nuclear Magnetic Resonance, Biomolecular/*methods ; Protein Conformation
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    Cancer: when antioxidants are bad (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Perera, Rushika M -- Bardeesy, Nabeel -- England -- Nature. 2011 Jul 6;475(7354):43-4. doi: 10.1038/475043a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Massachusetts General Hospital, Cancer Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02114, USA. rperera@partners.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734699" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Animals ; Antioxidants/metabolism ; Cell Transformation, Neoplastic/genetics/*metabolism/*pathology ; Cytoskeletal Proteins/genetics/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-E2-Related Factor 2/genetics/*metabolism ; Neoplasms/genetics/metabolism/pathology ; Oncogenes/*genetics ; Reactive Oxygen Species/*metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    The ageing systemic milieu negatively regulates neurogenesis and cognitive function (2011)
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    Publication Date: 2011-09-03
    Description: In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170097/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3170097/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Villeda, Saul A -- Luo, Jian -- Mosher, Kira I -- Zou, Bende -- Britschgi, Markus -- Bieri, Gregor -- Stan, Trisha M -- Fainberg, Nina -- Ding, Zhaoqing -- Eggel, Alexander -- Lucin, Kurt M -- Czirr, Eva -- Park, Jeong-Soo -- Couillard-Despres, Sebastien -- Aigner, Ludwig -- Li, Ge -- Peskind, Elaine R -- Kaye, Jeffrey A -- Quinn, Joseph F -- Galasko, Douglas R -- Xie, Xinmin S -- Rando, Thomas A -- Wyss-Coray, Tony -- 1 F31 AG034045-01/AG/NIA NIH HHS/ -- 1 F31 NS066676-01A1/NS/NINDS NIH HHS/ -- DP1 OD000392/OD/NIH HHS/ -- DP1 OD000392-01/OD/NIH HHS/ -- DP1 OD000392-02/OD/NIH HHS/ -- DP1 OD000392-03/OD/NIH HHS/ -- DP1 OD000392-04/OD/NIH HHS/ -- DP1 OD000392-05/OD/NIH HHS/ -- F31 AG034045/AG/NIA NIH HHS/ -- F31 AG034045-01/AG/NIA NIH HHS/ -- F31 AG034045-02/AG/NIA NIH HHS/ -- F31 AG034045-03/AG/NIA NIH HHS/ -- P30AG08017/AG/NIA NIH HHS/ -- P50 AG005136/AG/NIA NIH HHS/ -- R01 AG027505/AG/NIA NIH HHS/ -- R01 AG027505-01A1/AG/NIA NIH HHS/ -- R01 AG027505-02/AG/NIA NIH HHS/ -- R01 AG027505-03/AG/NIA NIH HHS/ -- R01 AG027505-04/AG/NIA NIH HHS/ -- R01 AG027505-05/AG/NIA NIH HHS/ -- R01 AR056849/AR/NIAMS NIH HHS/ -- R01 MH078194/MH/NIMH NIH HHS/ -- R01AG027505/AG/NIA NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 31;477(7362):90-4. doi: 10.1038/nature10357.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurology and Neurological Sciences, 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/21886162" target="_blank"〉PubMed〈/a〉
    Keywords: Aging ; Animals ; Chemokine CCL11/blood/cerebrospinal fluid/metabolism/pharmacology ; Chemokines/*blood/cerebrospinal fluid/*metabolism ; Female ; Learning/drug effects/*physiology ; Learning Disorders/blood/cerebrospinal fluid/physiopathology ; Male ; Memory Disorders/blood/cerebrospinal fluid/physiopathology ; Mice ; Mice, Inbred C57BL ; Neurogenesis/drug effects/*physiology ; Parabiosis ; Plasma/chemistry ; Time Factors
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    A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours (2011)
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    Publication Date: 2011-10-21
    Description: Angiogenesis is critical during tumour initiation and malignant progression. Different strategies aimed at blocking vascular endothelial growth factor (VEGF) and its receptors have been developed to inhibit angiogenesis in cancer patients. It has become increasingly clear that in addition to its effect on angiogenesis, other mechanisms including a direct effect of VEGF on tumour cells may account for the efficiency of VEGF-blockade therapies. Cancer stem cells (CSCs) have been described in various cancers including squamous tumours of the skin. Here we use a mouse model of skin tumours to investigate the impact of the vascular niche and VEGF signalling on controlling the stemness (the ability to self renew and differentiate) of squamous skin tumours during the early stages of tumour progression. We show that CSCs of skin papillomas are localized in a perivascular niche, in the immediate vicinity of endothelial cells. Furthermore, blocking VEGFR2 caused tumour regression not only by decreasing the microvascular density, but also by reducing CSC pool size and impairing CSC renewal properties. Conditional deletion of Vegfa in tumour epithelial cells caused tumours to regress, whereas VEGF overexpression by tumour epithelial cells accelerated tumour growth. In addition to its well-known effect on angiogenesis, VEGF affected skin tumour growth by promoting cancer stemness and symmetric CSC division, leading to CSC expansion. Moreover, deletion of neuropilin-1 (Nrp1), a VEGF co-receptor expressed in cutaneous CSCs, blocked VEGF's ability to promote cancer stemness and renewal. Our results identify a dual role for tumour-cell-derived VEGF in promoting cancer stemness: by stimulating angiogenesis in a paracrine manner, VEGF creates a perivascular niche for CSCs, and by directly affecting CSCs through Nrp1 in an autocrine loop, VEGF stimulates cancer stemness and renewal. Finally, deletion of Nrp1 in normal epidermis prevents skin tumour initiation. These results may have important implications for the prevention and treatment of skin cancers.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Beck, Benjamin -- Driessens, Gregory -- Goossens, Steven -- Youssef, Khalil Kass -- Kuchnio, Anna -- Caauwe, Amelie -- Sotiropoulou, Panagiota A -- Loges, Sonja -- Lapouge, Gaelle -- Candi, Aurelie -- Mascre, Guilhem -- Drogat, Benjamin -- Dekoninck, Sophie -- Haigh, Jody J -- Carmeliet, Peter -- Blanpain, Cedric -- England -- Nature. 2011 Oct 19;478(7369):399-403. doi: 10.1038/nature10525.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IRIBHM, Universite Libre de Bruxelles, 808 route de Lennik, 1070 Brussels, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22012397" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carcinoma, Squamous Cell/*blood supply/*pathology ; Cell Differentiation ; Cell Proliferation ; Cells, Cultured ; Disease Models, Animal ; Epithelial Cells/cytology ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Mice ; Neoplastic Stem Cells ; Neuropilin-1/genetics/*metabolism ; *Signal Transduction ; Skin Neoplasms/*blood supply/*pathology ; Vascular Endothelial Growth Factor A/genetics/*metabolism
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    Programmed cell death: Apoptosis meets necrosis (2011)
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    Publication Date: 2011-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Peter, Marcus E -- England -- Nature. 2011 Mar 17;471(7338):310-2. doi: 10.1038/471310a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21412328" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD95/metabolism ; *Apoptosis ; CASP8 and FADD-Like Apoptosis Regulating Protein/*metabolism ; Caspase 8/genetics/*metabolism ; Cell Proliferation ; Embryo Loss/enzymology/genetics/metabolism ; Embryo, Mammalian/cytology/embryology/enzymology/metabolism ; Fas-Associated Death Domain Protein/deficiency/genetics/*metabolism ; GTPase-Activating Proteins/deficiency/genetics/*metabolism ; Humans ; Lymphocytes/cytology/immunology ; Mice ; *Necrosis/genetics ; Receptor-Interacting Protein Serine-Threonine ; Kinases/deficiency/genetics/*metabolism
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    Direct conversion of mouse fibroblasts to hepatocyte-like cells by defined factors (2011)
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    Publication Date: 2011-07-01
    Description: The location and timing of cellular differentiation must be stringently controlled for proper organ formation. Normally, hepatocytes differentiate from hepatic progenitor cells to form the liver during development. However, previous studies have shown that the hepatic program can also be activated in non-hepatic lineage cells after exposure to particular stimuli or fusion with hepatocytes. These unexpected findings suggest that factors critical to hepatocyte differentiation exist and become activated to induce hepatocyte-specific properties in different cell types. Here, by screening the effects of twelve candidate factors, we identify three specific combinations of two transcription factors, comprising Hnf4alpha plus Foxa1, Foxa2 or Foxa3, that can convert mouse embryonic and adult fibroblasts into cells that closely resemble hepatocytes in vitro. The induced hepatocyte-like (iHep) cells have multiple hepatocyte-specific features and reconstitute damaged hepatic tissues after transplantation. The generation of iHep cells may provide insights into the molecular nature of hepatocyte differentiation and potential therapies for liver diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sekiya, Sayaka -- Suzuki, Atsushi -- England -- Nature. 2011 Jun 29;475(7356):390-3. doi: 10.1038/nature10263.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21716291" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation/genetics ; Cells, Cultured ; Embryo, Mammalian/cytology ; Fibroblasts/*cytology ; Hepatocyte Nuclear Factor 3-alpha/genetics/metabolism ; Hepatocyte Nuclear Factor 3-beta/genetics/metabolism ; Hepatocyte Nuclear Factor 3-gamma/genetics/metabolism ; Hepatocyte Nuclear Factor 4/genetics/metabolism ; Hepatocytes/*cytology/metabolism/transplantation ; Hydrolases/deficiency ; Liver/cytology/enzymology/physiology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL
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    Reproductive biology: bone returns the favour (2011)
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    Publication Date: 2011-04-09
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Schuh-Huerta, Sonya M -- Pera, Renee A Reijo -- England -- Nature. 2011 Apr 7;472(7341):46-7. doi: 10.1038/472046a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475191" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Bone and Bones/*metabolism ; Energy Metabolism ; Estrogens/physiology ; Female ; Fertility/genetics/*physiology ; Humans ; Male ; Mice ; Osteoblasts/secretion ; Osteocalcin/deficiency/genetics/*metabolism/secretion ; Osteogenesis/physiology ; Receptors, G-Protein-Coupled/metabolism ; Sex Characteristics ; Testis/physiology/secretion ; Testosterone/*biosynthesis/blood
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    DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration (2011)
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    Publication Date: 2011-02-08
    Description: Geographic atrophy (GA), an untreatable advanced form of age-related macular degeneration, results from retinal pigmented epithelium (RPE) cell degeneration. Here we show that the microRNA (miRNA)-processing enzyme DICER1 is reduced in the RPE of humans with GA, and that conditional ablation of Dicer1, but not seven other miRNA-processing enzymes, induces RPE degeneration in mice. DICER1 knockdown induces accumulation of Alu RNA in human RPE cells and Alu-like B1 and B2 RNAs in mouse RPE. Alu RNA is increased in the RPE of humans with GA, and this pathogenic RNA induces human RPE cytotoxicity and RPE degeneration in mice. Antisense oligonucleotides targeting Alu/B1/B2 RNAs prevent DICER1 depletion-induced RPE degeneration despite global miRNA downregulation. DICER1 degrades Alu RNA, and this digested Alu RNA cannot induce RPE degeneration in mice. These findings reveal a miRNA-independent cell survival function for DICER1 involving retrotransposon transcript degradation, show that Alu RNA can directly cause human pathology, and identify new targets for a major cause of blindness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077055/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077055/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaneko, Hiroki -- Dridi, Sami -- Tarallo, Valeria -- Gelfand, Bradley D -- Fowler, Benjamin J -- Cho, Won Gil -- Kleinman, Mark E -- Ponicsan, Steven L -- Hauswirth, William W -- Chiodo, Vince A -- Kariko, Katalin -- Yoo, Jae Wook -- Lee, Dong-ki -- Hadziahmetovic, Majda -- Song, Ying -- Misra, Smita -- Chaudhuri, Gautam -- Buaas, Frank W -- Braun, Robert E -- Hinton, David R -- Zhang, Qing -- Grossniklaus, Hans E -- Provis, Jan M -- Madigan, Michele C -- Milam, Ann H -- Justice, Nikki L -- Albuquerque, Romulo J C -- Blandford, Alexander D -- Bogdanovich, Sasha -- Hirano, Yoshio -- Witta, Jassir -- Fuchs, Elaine -- Littman, Dan R -- Ambati, Balamurali K -- Rudin, Charles M -- Chong, Mark M W -- Provost, Patrick -- Kugel, Jennifer F -- Goodrich, James A -- Dunaief, Joshua L -- Baffi, Judit Z -- Ambati, Jayakrishna -- NIHU10EY013729/EY/NEI NIH HHS/ -- P30 EY006360/EY/NEI NIH HHS/ -- P30 EY014800/EY/NEI NIH HHS/ -- P30 EY014800-07/EY/NEI NIH HHS/ -- P30 EY021721/EY/NEI NIH HHS/ -- P30EY003040/EY/NEI NIH HHS/ -- P30EY008571/EY/NEI NIH HHS/ -- P30EY06360/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-05/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-04/EY/NEI NIH HHS/ -- R01 EY020672/EY/NEI NIH HHS/ -- R01 EY020672-02/EY/NEI NIH HHS/ -- R01 GM068414/GM/NIGMS NIH HHS/ -- R01EY001545/EY/NEI NIH HHS/ -- R01EY011123/EY/NEI NIH HHS/ -- R01EY015240/EY/NEI NIH HHS/ -- R01EY015422/EY/NEI NIH HHS/ -- R01EY017182/EY/NEI NIH HHS/ -- R01EY017950/EY/NEI NIH HHS/ -- R01EY018350/EY/NEI NIH HHS/ -- R01EY018836/EY/NEI NIH HHS/ -- R01EY020672/EY/NEI NIH HHS/ -- R01GM068414/GM/NIGMS NIH HHS/ -- R01HD027215/HD/NICHD NIH HHS/ -- R21 EY019778/EY/NEI NIH HHS/ -- R21 EY019778-02/EY/NEI NIH HHS/ -- R21AI076757/AI/NIAID NIH HHS/ -- R21EY019778/EY/NEI NIH HHS/ -- RC1 EY020442/EY/NEI NIH HHS/ -- RC1 EY020442-02/EY/NEI NIH HHS/ -- RC1EY020442/EY/NEI NIH HHS/ -- T32HL091812/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 17;471(7338):325-30. doi: 10.1038/nature09830. Epub 2011 Feb 6.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Sciences, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21297615" target="_blank"〉PubMed〈/a〉
    Keywords: Alu Elements/*genetics ; Animals ; Cell Death ; Cell Survival ; Cells, Cultured ; DEAD-box RNA Helicases/*deficiency/genetics/metabolism ; Gene Knockdown Techniques ; Humans ; Macular Degeneration/*genetics/*pathology ; Mice ; MicroRNAs/metabolism ; Molecular Sequence Data ; Oligonucleotides, Antisense ; Phenotype ; RNA/*genetics/*metabolism ; Retinal Pigment Epithelium/enzymology/metabolism/pathology ; Ribonuclease III/*deficiency/genetics/metabolism
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    US science faces big chill (2011)
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    Publication Date: 2011-01-07
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Semeniuk, Ivan -- Wadman, Meredith -- Samuel Reich, Eugenie -- Tollefson, Jeff -- England -- Nature. 2011 Jan 6;469(7328):9-10. doi: 10.1038/469009a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21209632" target="_blank"〉PubMed〈/a〉
    Keywords: Climate Change ; Conservation of Energy Resources/legislation & jurisprudence ; *Federal Government ; Food Safety ; Nuclear Weapons/legislation & jurisprudence ; *Politics ; Public Policy/economics/legislation & jurisprudence ; Research Support as Topic/*legislation & jurisprudence ; Science/*economics/*legislation & jurisprudence ; Stem Cell Research/economics/legislation & jurisprudence ; United States ; United States Food and Drug Administration/legislation & jurisprudence
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-04-09
    Description: Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086762/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3086762/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wang, Zeneng -- Klipfell, Elizabeth -- Bennett, Brian J -- Koeth, Robert -- Levison, Bruce S -- Dugar, Brandon -- Feldstein, Ariel E -- Britt, Earl B -- Fu, Xiaoming -- Chung, Yoon-Mi -- Wu, Yuping -- Schauer, Phil -- Smith, Jonathan D -- Allayee, Hooman -- Tang, W H Wilson -- DiDonato, Joseph A -- Lusis, Aldons J -- Hazen, Stanley L -- K99 HL102223/HL/NHLBI NIH HHS/ -- K99 HL102223-01A1/HL/NHLBI NIH HHS/ -- P01 HL028481/HL/NHLBI NIH HHS/ -- P01 HL028481-26A1/HL/NHLBI NIH HHS/ -- P01 HL030568/HL/NHLBI NIH HHS/ -- P01 HL030568-27/HL/NHLBI NIH HHS/ -- P01 HL076491/HL/NHLBI NIH HHS/ -- P01 HL076491-05/HL/NHLBI NIH HHS/ -- P01 HL087018/HL/NHLBI NIH HHS/ -- P01 HL087018-02/HL/NHLBI NIH HHS/ -- P01 HL098055/HL/NHLBI NIH HHS/ -- P01 HL098055-02/HL/NHLBI NIH HHS/ -- P01 HL28481/HL/NHLBI NIH HHS/ -- P01 HL30568/HL/NHLBI NIH HHS/ -- P01HL087018-020001/HL/NHLBI NIH HHS/ -- P20 AA017837/AA/NIAAA NIH HHS/ -- R01 DK080732/DK/NIDDK NIH HHS/ -- R01 DK080732-02/DK/NIDDK NIH HHS/ -- R01 HL098193/HL/NHLBI NIH HHS/ -- R01 HL103866/HL/NHLBI NIH HHS/ -- R01 HL103866-02/HL/NHLBI NIH HHS/ -- R01 HL103931/HL/NHLBI NIH HHS/ -- R01 HL103931-02/HL/NHLBI NIH HHS/ -- T32 DK007789/DK/NIDDK NIH HHS/ -- T32 DK007789-10/DK/NIDDK NIH HHS/ -- T32-DK07789/DK/NIDDK NIH HHS/ -- UL1 RR024989/RR/NCRR NIH HHS/ -- UL1 RR024989-05/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):57-63. doi: 10.1038/nature09922.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475195" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Atherosclerosis/chemically induced/genetics/metabolism/microbiology ; Betaine/blood/metabolism ; Biomarkers/blood/metabolism ; Cardiovascular Diseases/blood/diagnosis/*metabolism/*microbiology ; Cholesterol, HDL/blood ; Choline/administration & dosage/blood/metabolism/pharmacology ; Diet/adverse effects ; Dietary Fats/blood/metabolism/pharmacology ; Female ; Gastrointestinal Tract/*metabolism/*microbiology ; Gene Expression Regulation ; Germ-Free Life ; Humans ; Liver/enzymology ; Macrophages/metabolism ; Metabolomics ; Methylamines/blood/metabolism/pharmacology ; Mice ; Mice, Inbred C57BL ; Oxygenases/genetics/metabolism ; Phenotype ; Phosphatidylcholines/administration & dosage/blood/*metabolism/pharmacology ; Receptors, Scavenger/metabolism ; Risk Assessment
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    A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-05-13
    Description: Notch signalling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit gamma-secretase (gammaSE) complex. Although Notch signalling can play both oncogenic and tumour-suppressor roles in solid tumours, in the haematopoietic system it is exclusively oncogenic, notably in T-cell acute lymphoblastic leukaemia, a disease characterized by Notch1-activating mutations. Here we identify novel somatic-inactivating Notch pathway mutations in a fraction of patients with chronic myelomonocytic leukaemia (CMML). Inactivation of Notch signalling in mouse haematopoietic stem cells (HSCs) results in an aberrant accumulation of granulocyte/monocyte progenitors (GMPs), extramedullary haematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signalling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signalling during early haematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumour-promoting and -suppressive roles within the same tissue.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093658/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3093658/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Klinakis, Apostolos -- Lobry, Camille -- Abdel-Wahab, Omar -- Oh, Philmo -- Haeno, Hiroshi -- Buonamici, Silvia -- van De Walle, Inge -- Cathelin, Severine -- Trimarchi, Thomas -- Araldi, Elisa -- Liu, Cynthia -- Ibrahim, Sherif -- Beran, Miroslav -- Zavadil, Jiri -- Efstratiadis, Argiris -- Taghon, Tom -- Michor, Franziska -- Levine, Ross L -- Aifantis, Iannis -- 1P01CA97403/CA/NCI NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA105129-07/CA/NCI NIH HHS/ -- R01 CA133379/CA/NCI NIH HHS/ -- R01 CA133379-04/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01 CA149655-03/CA/NCI NIH HHS/ -- R01CA105129/CA/NCI NIH HHS/ -- R01CA1328234/CA/NCI NIH HHS/ -- R01CA133379/CA/NCI NIH HHS/ -- R01CA149655/CA/NCI NIH HHS/ -- R21 CA141399/CA/NCI NIH HHS/ -- R21 CA141399-02/CA/NCI NIH HHS/ -- R21CA141399/CA/NCI NIH HHS/ -- U54CA143798/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 12;473(7346):230-3. doi: 10.1038/nature09999.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Biomedical Research Foundation, Academy of Athens, Athens, Greece.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21562564" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cell Differentiation ; Cells, Cultured ; Gene Expression Profiling ; *Gene Expression Regulation, Neoplastic ; Gene Silencing ; Genes, Tumor Suppressor/*physiology ; Granulocyte-Macrophage Progenitor Cells/cytology/metabolism ; Hematopoietic Stem Cells/cytology/metabolism ; Homeodomain Proteins/metabolism ; Humans ; Leukemia, Myelomonocytic, Chronic/*genetics/*pathology ; Mice ; Mice, Inbred C57BL ; Mutation ; Receptors, Notch/deficiency/*genetics/*metabolism ; *Signal Transduction ; Tumor Cells, Cultured
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    Functional specificity of local synaptic connections in neocortical networks (2011)
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    Publication Date: 2011-04-12
    Description: Neuronal connectivity is fundamental to information processing in the brain. Therefore, understanding the mechanisms of sensory processing requires uncovering how connection patterns between neurons relate to their function. On a coarse scale, long-range projections can preferentially link cortical regions with similar responses to sensory stimuli. But on the local scale, where dendrites and axons overlap substantially, the functional specificity of connections remains unknown. Here we determine synaptic connectivity between nearby layer 2/3 pyramidal neurons in vitro, the response properties of which were first characterized in mouse visual cortex in vivo. We found that connection probability was related to the similarity of visually driven neuronal activity. Neurons with the same preference for oriented stimuli connected at twice the rate of neurons with orthogonal orientation preferences. Neurons responding similarly to naturalistic stimuli formed connections at much higher rates than those with uncorrelated responses. Bidirectional synaptic connections were found more frequently between neuronal pairs with strongly correlated visual responses. Our results reveal the degree of functional specificity of local synaptic connections in the visual cortex, and point to the existence of fine-scale subnetworks dedicated to processing related sensory information.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089591/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089591/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ko, Ho -- Hofer, Sonja B -- Pichler, Bruno -- Buchanan, Katherine A -- Sjostrom, P Jesper -- Mrsic-Flogel, Thomas D -- FP7 243914/Medical Research Council/United Kingdom -- G0700188/Medical Research Council/United Kingdom -- G0700188(81448)/Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2011 May 5;473(7345):87-91. doi: 10.1038/nature09880. Epub 2011 Apr 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neuroscience, Physiology and Pharmacology, University College London, 21 University Street, London WC1E 6DE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21478872" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/chemistry ; Calcium Signaling/physiology ; Computer Simulation ; Electrical Synapses/*physiology ; Mice ; Mice, Inbred C57BL ; Nerve Net/*physiology ; Patch-Clamp Techniques ; Photic Stimulation ; Pyramidal Cells/physiology ; Visual Cortex/*physiology
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    A critical role for TCF-1 in T-lineage specification and differentiation (2011)
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    Publication Date: 2011-08-05
    Description: The vertebrate thymus provides an inductive environment for T-cell development. Within the mouse thymus, Notch signals are indispensable for imposing the T-cell fate on multipotential haematopoietic progenitors, but the downstream effectors that impart T-lineage specification and commitment are not well understood. Here we show that a transcription factor, T-cell factor 1 (TCF-1; also known as transcription factor 7, T-cell specific, TCF7), is a critical regulator in T-cell specification. TCF-1 is highly expressed in the earliest thymic progenitors, and its expression is upregulated by Notch signals. Most importantly, when TCF-1 is forcibly expressed in bone marrow (BM) progenitors, it drives the development of T-lineage cells in the absence of T-inductive Notch1 signals. Further characterization of these TCF-1-induced cells revealed expression of many T-lineage genes, including T-cell-specific transcription factors Gata3 and Bcl11b, and components of the T-cell receptor. Our data suggest a model where Notch signals induce TCF-1, and TCF-1 in turn imprints the T-cell fate by upregulating expression of T-cell essential genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156435/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3156435/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Weber, Brittany Nicole -- Chi, Anthony Wei-Shine -- Chavez, Alejandro -- Yashiro-Ohtani, Yumi -- Yang, Qi -- Shestova, Olga -- Bhandoola, Avinash -- AI059621/AI/NIAID NIH HHS/ -- R01 AI059621/AI/NIAID NIH HHS/ -- R01 AI059621-09/AI/NIAID NIH HHS/ -- RC1 HL099758/HL/NHLBI NIH HHS/ -- RC1 HL099758-01/HL/NHLBI NIH HHS/ -- T32 AI055428/AI/NIAID NIH HHS/ -- T32 CA009140/CA/NCI NIH HHS/ -- T32AI055428/AI/NIAID NIH HHS/ -- T32CA09140/CA/NCI NIH HHS/ -- England -- Nature. 2011 Aug 3;476(7358):63-8. doi: 10.1038/nature10279.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21814277" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; *Cell Lineage ; Female ; Genes, Essential ; HEK293 Cells ; Hepatocyte Nuclear Factor 1-alpha ; Humans ; Lymphoid Enhancer-Binding Factor 1/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Receptor, Notch1/metabolism ; Signal Transduction ; T Cell Transcription Factor 1/deficiency/genetics/*metabolism ; T-Lymphocytes/*cytology/*metabolism ; Up-Regulation
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    Network anatomy and in vivo physiology of visual cortical neurons (2011)
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    Publication Date: 2011-03-11
    Description: In the cerebral cortex, local circuits consist of tens of thousands of neurons, each of which makes thousands of synaptic connections. Perhaps the biggest impediment to understanding these networks is that we have no wiring diagrams of their interconnections. Even if we had a partial or complete wiring diagram, however, understanding the network would also require information about each neuron's function. Here we show that the relationship between structure and function can be studied in the cortex with a combination of in vivo physiology and network anatomy. We used two-photon calcium imaging to characterize a functional property--the preferred stimulus orientation--of a group of neurons in the mouse primary visual cortex. Large-scale electron microscopy of serial thin sections was then used to trace a portion of these neurons' local network. Consistent with a prediction from recent physiological experiments, inhibitory interneurons received convergent anatomical input from nearby excitatory neurons with a broad range of preferred orientations, although weak biases could not be rejected.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095821/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3095821/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bock, Davi D -- Lee, Wei-Chung Allen -- Kerlin, Aaron M -- Andermann, Mark L -- Hood, Greg -- Wetzel, Arthur W -- Yurgenson, Sergey -- Soucy, Edward R -- Kim, Hyon Suk -- Reid, R Clay -- EY10115/EY/NEI NIH HHS/ -- EY18532/EY/NEI NIH HHS/ -- EY18742/EY/NEI NIH HHS/ -- F32 EY018532/EY/NEI NIH HHS/ -- F32 EY018532-01A1/EY/NEI NIH HHS/ -- P41 RR06009/RR/NCRR NIH HHS/ -- England -- Nature. 2011 Mar 10;471(7337):177-82. doi: 10.1038/nature09802.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390124" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium Signaling ; Interneurons/physiology ; Male ; Mice ; Microscopy, Electron, Transmission ; Microscopy, Fluorescence ; Microtomy ; Nerve Net/*anatomy & histology/*cytology/physiology/ultrastructure ; Neural Inhibition/physiology ; Neurons/*physiology/ultrastructure ; Pyramidal Cells/physiology/ultrastructure ; Synapses/physiology ; Visual Cortex/*anatomy & histology/*cytology/physiology/ultrastructure
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    CTCF-binding elements mediate control of V(D)J recombination (2011)
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    Publication Date: 2011-09-13
    Description: Immunoglobulin heavy chain (IgH) variable region exons are assembled from V(H), D and J(H) gene segments in developing B lymphocytes. Within the 2.7-megabase mouse Igh locus, V(D)J recombination is regulated to ensure specific and diverse antibody repertoires. Here we report in mice a key Igh V(D)J recombination regulatory region, termed intergenic control region 1 (IGCR1), which lies between the V(H) and D clusters. Functionally, IGCR1 uses CTCF looping/insulator factor-binding elements and, correspondingly, mediates Igh loops containing distant enhancers. IGCR1 promotes normal B-cell development and balances antibody repertoires by inhibiting transcription and rearrangement of D(H)-proximal V(H) gene segments and promoting rearrangement of distal V(H) segments. IGCR1 maintains ordered and lineage-specific V(H)(D)J(H) recombination by suppressing V(H) joining to D segments not joined to J(H) segments, and V(H) to DJ(H) joins in thymocytes, respectively. IGCR1 is also required for feedback regulation and allelic exclusion of proximal V(H)-to-DJ(H) recombination. Our studies elucidate a long-sought Igh V(D)J recombination control region and indicate a new role for the generally expressed CTCF protein.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3342812/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guo, Chunguang -- Yoon, Hye Suk -- Franklin, Andrew -- Jain, Suvi -- Ebert, Anja -- Cheng, Hwei-Ling -- Hansen, Erica -- Despo, Orion -- Bossen, Claudia -- Vettermann, Christian -- Bates, Jamie G -- Richards, Nicholas -- Myers, Darienne -- Patel, Harin -- Gallagher, Michael -- Schlissel, Mark S -- Murre, Cornelis -- Busslinger, Meinrad -- Giallourakis, Cosmas C -- Alt, Frederick W -- AI40227/AI/NIAID NIH HHS/ -- CA054198-20/CA/NCI NIH HHS/ -- K08 AI070839/AI/NIAID NIH HHS/ -- P30 DK043351/DK/NIDDK NIH HHS/ -- R01 AI020047/AI/NIAID NIH HHS/ -- R01 AI020047-27/AI/NIAID NIH HHS/ -- R01 AI020047-28/AI/NIAID NIH HHS/ -- R01 AI020047-29/AI/NIAID NIH HHS/ -- R01 AI20047/AI/NIAID NIH HHS/ -- R01 HL48702/HL/NHLBI NIH HHS/ -- R37 AI040227/AI/NIAID NIH HHS/ -- T32 CA009151/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Sep 11;477(7365):424-30. doi: 10.1038/nature10495.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, The Children's Hospital, The Immune Disease Institute, Department of Genetics, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21909113" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/cytology/metabolism ; Cell Lineage/genetics ; Chromosomes, Mammalian/genetics/metabolism ; DNA, Intergenic/*genetics ; Enhancer Elements, Genetic/genetics ; Feedback, Physiological ; Gene Rearrangement, B-Lymphocyte, Heavy Chain/*genetics ; Germ Cells/metabolism ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin Variable Region/genetics ; Mice ; Mutation/genetics ; Recombination, Genetic/*genetics ; Regulatory Sequences, Nucleic Acid/*genetics ; Repressor Proteins/*metabolism ; Thymus Gland/cytology ; Transcription, Genetic/genetics ; VDJ Exons/*genetics
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    Perception of sniff phase in mouse olfaction (2011)
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    Publication Date: 2011-10-14
    Description: Olfactory systems encode odours by which neurons respond and by when they respond. In mammals, every sniff evokes a precise, odour-specific sequence of activity across olfactory neurons. Likewise, in a variety of neural systems, ranging from sensory periphery to cognitive centres, neuronal activity is timed relative to sampling behaviour and/or internally generated oscillations. As in these neural systems, relative timing of activity may represent information in the olfactory system. However, there is no evidence that mammalian olfactory systems read such cues. To test whether mice perceive the timing of olfactory activation relative to the sniff cycle ('sniff phase'), we used optogenetics in gene-targeted mice to generate spatially constant, temporally controllable olfactory input. Here we show that mice can behaviourally report the sniff phase of optogenetically driven activation of olfactory sensory neurons. Furthermore, mice can discriminate between light-evoked inputs that are shifted in the sniff cycle by as little as 10 milliseconds, which is similar to the temporal precision of olfactory bulb odour responses. Electrophysiological recordings in the olfactory bulb of awake mice show that individual cells encode the timing of photoactivation in relation to the sniff in both the timing and the amplitude of their responses. Our work provides evidence that the mammalian olfactory system can read temporal patterns, and suggests that timing of activity relative to sampling behaviour is a potent cue that may enable accurate olfactory percepts to form quickly.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Smear, Matthew -- Shusterman, Roman -- O'Connor, Rodney -- Bozza, Thomas -- Rinberg, Dmitry -- R01DC009640/DC/NIDCD NIH HHS/ -- R21DC010911/DC/NIDCD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Oct 12;479(7373):397-400. doi: 10.1038/nature10521.〈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/21993623" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cues ; Electrophysiology ; Male ; Mice ; Models, Neurological ; Odors/analysis ; Olfactory Bulb/physiology/radiation effects ; Olfactory Receptor Neurons/physiology/radiation effects ; Photic Stimulation ; Physical Stimulation ; Smell/*physiology/radiation effects ; Time Factors
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    Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-08
    Description: Reactive oxygen species (ROS) are mutagenic and may thereby promote cancer. Normally, ROS levels are tightly controlled by an inducible antioxidant program that responds to cellular stressors and is predominantly regulated by the transcription factor Nrf2 (also known as Nfe2l2) and its repressor protein Keap1 (refs 2-5). In contrast to the acute physiological regulation of Nrf2, in neoplasia there is evidence for increased basal activation of Nrf2. Indeed, somatic mutations that disrupt the Nrf2-Keap1 interaction to stabilize Nrf2 and increase the constitutive transcription of Nrf2 target genes were recently identified, indicating that enhanced ROS detoxification and additional Nrf2 functions may in fact be pro-tumorigenic. Here, we investigated ROS metabolism in primary murine cells following the expression of endogenous oncogenic alleles of Kras, Braf and Myc, and found that ROS are actively suppressed by these oncogenes. K-Ras(G12D), B-Raf(V619E) and Myc(ERT2) each increased the transcription of Nrf2 to stably elevate the basal Nrf2 antioxidant program and thereby lower intracellular ROS and confer a more reduced intracellular environment. Oncogene-directed increased expression of Nrf2 is a new mechanism for the activation of the Nrf2 antioxidant program, and is evident in primary cells and tissues of mice expressing K-Ras(G12D) and B-Raf(V619E), and in human pancreatic cancer. Furthermore, genetic targeting of the Nrf2 pathway impairs K-Ras(G12D)-induced proliferation and tumorigenesis in vivo. Thus, the Nrf2 antioxidant and cellular detoxification program represents a previously unappreciated mediator of oncogenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404470/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404470/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉DeNicola, Gina M -- Karreth, Florian A -- Humpton, Timothy J -- Gopinathan, Aarthi -- Wei, Cong -- Frese, Kristopher -- Mangal, Dipti -- Yu, Kenneth H -- Yeo, Charles J -- Calhoun, Eric S -- Scrimieri, Francesca -- Winter, Jordan M -- Hruban, Ralph H -- Iacobuzio-Donahue, Christine -- Kern, Scott E -- Blair, Ian A -- Tuveson, David A -- CA084291/CA/NCI NIH HHS/ -- CA101973/CA/NCI NIH HHS/ -- CA105490/CA/NCI NIH HHS/ -- CA106610/CA/NCI NIH HHS/ -- CA111294/CA/NCI NIH HHS/ -- CA128920/CA/NCI NIH HHS/ -- CA62924/CA/NCI NIH HHS/ -- R01 CA101973/CA/NCI NIH HHS/ -- R01 CA101973-05/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- England -- Nature. 2011 Jul 6;475(7354):106-9. doi: 10.1038/nature10189.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Li Ka Shing Centre, Cancer Research UK Cambridge Institute, Robinson Way, Cambridge CB2 0RE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734707" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/genetics/metabolism ; Alleles ; Animals ; Antioxidants/metabolism ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/genetics/*metabolism/*pathology ; Cells, Cultured ; Cytoskeletal Proteins/genetics/metabolism ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Fibroblasts/metabolism ; Genes, myc/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; JNK Mitogen-Activated Protein Kinases/metabolism ; MAP Kinase Signaling System ; Mice ; Mitogen-Activated Protein Kinase Kinases/metabolism ; NF-E2-Related Factor 2/deficiency/genetics/*metabolism ; NIH 3T3 Cells ; Oncogenes/*genetics ; Oxidation-Reduction ; Pancreatic Neoplasms/genetics/*metabolism/*pathology ; Proto-Oncogene Proteins B-raf/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Reactive Oxygen Species/*metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    The RAG2 C terminus suppresses genomic instability and lymphomagenesis (2011)
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    Publication Date: 2011-03-04
    Description: Misrepair of DNA double-strand breaks produced by the V(D)J recombinase (the RAG1/RAG2 proteins) at immunoglobulin (Ig) and T cell receptor (Tcr) loci has been implicated in pathogenesis of lymphoid malignancies in humans and in mice. Defects in DNA damage response factors such as ataxia telangiectasia mutated (ATM) protein and combined deficiencies in classical non-homologous end joining and p53 predispose to RAG-initiated genomic rearrangements and lymphomagenesis. Although we showed previously that RAG1/RAG2 shepherd the broken DNA ends to classical non-homologous end joining for proper repair, roles for the RAG proteins in preserving genomic stability remain poorly defined. Here we show that the RAG2 carboxy (C) terminus, although dispensable for recombination, is critical for maintaining genomic stability. Thymocytes from 'core' Rag2 homozygotes (Rag2(c/c) mice) show dramatic disruption of Tcralpha/delta locus integrity. Furthermore, all Rag2(c/c) p53(-/-) mice, unlike Rag1(c/c) p53(-/-) and p53(-/-) animals, rapidly develop thymic lymphomas bearing complex chromosomal translocations, amplifications and deletions involving the Tcralpha/delta and Igh loci. We also find these features in lymphomas from Atm(-/-) mice. We show that, like ATM-deficiency, core RAG2 severely destabilizes the RAG post-cleavage complex. These results reveal a novel genome guardian role for RAG2 and suggest that similar 'end release/end persistence' mechanisms underlie genomic instability and lymphomagenesis in Rag2(c/c) p53(-/-) and Atm(-/-) mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174233/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174233/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deriano, Ludovic -- Chaumeil, Julie -- Coussens, Marc -- Multani, Asha -- Chou, YiFan -- Alekseyenko, Alexander V -- Chang, Sandy -- Skok, Jane A -- Roth, David B -- 1PN2EY018244/EY/NEI NIH HHS/ -- 1UL1RR029893/RR/NCRR NIH HHS/ -- CA104588/CA/NCI NIH HHS/ -- R01 GM086852/GM/NIGMS NIH HHS/ -- R01 GM086852-01A2/GM/NIGMS NIH HHS/ -- R01CA145746-01/CA/NCI NIH HHS/ -- R01GM086852/GM/NIGMS NIH HHS/ -- RC1 CA145746/CA/NCI NIH HHS/ -- RC1 CA145746-02/CA/NCI NIH HHS/ -- England -- Nature. 2011 Mar 3;471(7336):119-23. doi: 10.1038/nature09755.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21368836" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics ; Chromosome Deletion ; Chromosomes, Mammalian/genetics ; DNA-Binding Proteins/*chemistry/deficiency/genetics/*metabolism ; *Disease Progression ; Gene Rearrangement, T-Lymphocyte/genetics ; Genes, Immunoglobulin Heavy Chain/genetics ; Genes, p53/genetics ; *Genomic Instability ; In Situ Hybridization, Fluorescence ; Kaplan-Meier Estimate ; Lymphoma/*genetics/*pathology ; Mice ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Receptors, Antigen, T-Cell/genetics ; Recombination, Genetic/genetics ; Thymus Gland/cytology ; Translocation, Genetic/genetics ; Tumor Suppressor Proteins/chemistry/deficiency/genetics/metabolism
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    Chemoprevention: First line of defence (2011)
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    Publication Date: 2011-03-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gravitz, Lauren -- England -- Nature. 2011 Mar 24;471(7339):S5-7. doi: 10.1038/471S5a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430719" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aspirin/adverse effects/pharmacology ; Celecoxib ; Clinical Trials, Phase II as Topic ; Colonic Neoplasms/drug therapy/genetics/pathology ; Cyclooxygenase Inhibitors/adverse effects/pharmacology ; Disease Models, Animal ; Disease Progression ; Female ; Focal Adhesion Protein-Tyrosine Kinases/antagonists & inhibitors/metabolism ; Genistein/pharmacology ; Humans ; Inflammation/drug therapy/prevention & control ; Male ; Matrix Metalloproteinase 2/biosynthesis/metabolism ; Mice ; Neoplasm Metastasis/drug therapy/prevention & control ; Neoplasms/blood supply/drug therapy/*pathology/*prevention & control ; Neovascularization, Pathologic/drug therapy/prevention & control ; Polyamines/metabolism ; Precancerous Conditions/drug therapy/metabolism/pathology/prevention & control ; Prostatic Neoplasms/drug therapy/pathology ; Pyrazoles/adverse effects/pharmacology ; Risk Assessment ; Sulfonamides/adverse effects/pharmacology
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    Ageing: Blood ties (2011)
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    Publication Date: 2011-09-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ransohoff, Richard M -- England -- Nature. 2011 Aug 31;477(7362):41-2. doi: 10.1038/477041a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21886154" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/blood/metabolism/*physiology ; Animals ; Chemokine CCL11/blood/metabolism ; Mice ; Neurogenesis/*physiology
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    Hedgehog/Wnt feedback supports regenerative proliferation of epithelial stem cells in bladder (2011)
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    Publication Date: 2011-03-11
    Description: Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676169/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3676169/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shin, Kunyoo -- Lee, John -- Guo, Nini -- Kim, James -- Lim, Agnes -- Qu, Lishu -- Mysorekar, Indira U -- Beachy, Philip A -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Apr 7;472(7341):110-4. doi: 10.1038/nature09851. Epub 2011 Mar 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Developmental Biology, Institute for Stem Cell Biology and Regenerative Medicine, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305, USA. kunyoos@stanford.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21389986" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Cell Proliferation ; Epithelial Cells/*cytology/metabolism ; Feedback, Physiological ; Female ; Fibroblast Growth Factors/metabolism ; Hedgehog Proteins/*metabolism ; Kruppel-Like Transcription Factors/genetics/metabolism ; Mice ; Organoids/cytology ; Regeneration/*physiology ; Signal Transduction ; Stem Cells/*cytology/metabolism ; Stromal Cells/cytology/metabolism ; Urinary Bladder/*cytology/drug effects/injuries/metabolism ; Urinary Bladder Diseases/chemically induced/metabolism/microbiology/pathology ; Uropathogenic Escherichia coli/physiology ; Urothelium/cytology ; Wnt Proteins/*metabolism
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    Cell biology: Ageing theories unified (2011)
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    Publication Date: 2011-02-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Daniel P -- England -- Nature. 2011 Feb 17;470(7334):342-3. doi: 10.1038/nature09896. Epub 2011 Feb 9.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21307852" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/*metabolism/pathology ; Animals ; Cardiomyopathies/metabolism/pathology/physiopathology ; Cell Aging/*physiology ; Heart/physiopathology ; Liver/metabolism/pathology/physiopathology ; Mice ; Mitochondria/*metabolism/*pathology ; Telomere/genetics/*metabolism/*pathology ; Transcription Factors/metabolism ; Tumor Suppressor Protein p53/metabolism
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    Chemical biology: Catalytic detoxification (2011)
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    Publication Date: 2011-01-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Raushel, Frank M -- England -- Nature. 2011 Jan 20;469(7330):310-1. doi: 10.1038/469310a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248836" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aryldialkylphosphatase/chemistry/genetics/*metabolism ; Biocatalysis ; Butyrylcholinesterase/metabolism ; Chemical Warfare Agents/metabolism/pharmacokinetics/poisoning/toxicity ; Humans ; Inactivation, Metabolic ; Mice ; Organophosphate Poisoning ; Organophosphates/*metabolism/pharmacokinetics/*toxicity ; Organophosphorus Compounds/metabolism/pharmacokinetics/toxicity ; Protein Engineering
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    Developmental biology: Remarkable role for the placenta (2011)
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    Publication Date: 2011-04-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McKay, Ron -- England -- Nature. 2011 Apr 21;472(7343):298-9. doi: 10.1038/472298a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21512563" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Brain/cytology/*embryology/*metabolism ; Female ; Fetus/cytology/embryology/*metabolism ; Humans ; Maternal-Fetal Exchange/*physiology ; Mice ; Placenta/cytology/*metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; Serotonin/*biosynthesis/metabolism
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    A transient placental source of serotonin for the fetal forebrain (2011)
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    Publication Date: 2011-04-23
    Description: Serotonin (5-hydroxytryptamine or 5-HT) is thought to regulate neurodevelopmental processes through maternal-fetal interactions that have long-term mental health implications. It is thought that beyond fetal 5-HT neurons there are significant maternal contributions to fetal 5-HT during pregnancy but this has not been tested empirically. To examine putative central and peripheral sources of embryonic brain 5-HT, we used Pet1(-/-) (also called Fev) mice in which most dorsal raphe neurons lack 5-HT. We detected previously unknown differences in accumulation of 5-HT between the forebrain and hindbrain during early and late fetal stages, through an exogenous source of 5-HT which is not of maternal origin. Using additional genetic strategies, a new technology for studying placental biology ex vivo and direct manipulation of placental neosynthesis, we investigated the nature of this exogenous source. We uncovered a placental 5-HT synthetic pathway from a maternal tryptophan precursor in both mice and humans. This study reveals a new, direct role for placental metabolic pathways in modulating fetal brain development and indicates that maternal-placental-fetal interactions could underlie the pronounced impact of 5-HT on long-lasting mental health outcomes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084180/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3084180/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bonnin, Alexandre -- Goeden, Nick -- Chen, Kevin -- Wilson, Melissa L -- King, Jennifer -- Shih, Jean C -- Blakely, Randy D -- Deneris, Evan S -- Levitt, Pat -- 1P50MH078280A1/MH/NIMH NIH HHS/ -- 5R21HD065287/HD/NICHD NIH HHS/ -- P50 MH078028/MH/NIMH NIH HHS/ -- P50 MH078028-01A1/MH/NIMH NIH HHS/ -- P50 MH078028-02/MH/NIMH NIH HHS/ -- P50 MH078028-03/MH/NIMH NIH HHS/ -- P50 MH078028-04/MH/NIMH NIH HHS/ -- P50 MH078028-05/MH/NIMH NIH HHS/ -- R01MH39085/MH/NIMH NIH HHS/ -- R21 HD065287/HD/NICHD NIH HHS/ -- R21 HD065287-01/HD/NICHD NIH HHS/ -- R21 HD065287-02/HD/NICHD NIH HHS/ -- England -- Nature. 2011 Apr 21;472(7343):347-50. doi: 10.1038/nature09972.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Zilkha Neurogenetic Institute, Keck School of Medicine of USC, Los Angeles, California 90089, USA. bonnin@usc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21512572" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Embryo, Mammalian/metabolism ; Female ; Fetus/embryology/*metabolism ; Humans ; In Vitro Techniques ; Maternal-Fetal Exchange/*physiology ; Mice ; Placenta/*metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; Prosencephalon/*embryology/*metabolism ; Raphe Nuclei/cytology ; Rhombencephalon/embryology/metabolism ; Serotonin/analysis/*biosynthesis/metabolism ; Time Factors ; Transcription Factors/deficiency/genetics
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Dopamine neurons derived from human ES cells efficiently engraft in animal models of Parkinson's disease (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-11-08
    Description: Human pluripotent stem cells (PSCs) are a promising source of cells for applications in regenerative medicine. Directed differentiation of PSCs into specialized cells such as spinal motoneurons or midbrain dopamine (DA) neurons has been achieved. However, the effective use of PSCs for cell therapy has lagged behind. Whereas mouse PSC-derived DA neurons have shown efficacy in models of Parkinson's disease, DA neurons from human PSCs generally show poor in vivo performance. There are also considerable safety concerns for PSCs related to their potential for teratoma formation or neural overgrowth. Here we present a novel floor-plate-based strategy for the derivation of human DA neurons that efficiently engraft in vivo, suggesting that past failures were due to incomplete specification rather than a specific vulnerability of the cells. Midbrain floor-plate precursors are derived from PSCs 11 days after exposure to small molecule activators of sonic hedgehog (SHH) and canonical WNT signalling. Engraftable midbrain DA neurons are obtained by day 25 and can be maintained in vitro for several months. Extensive molecular profiling, biochemical and electrophysiological data define developmental progression and confirm identity of PSC-derived midbrain DA neurons. In vivo survival and function is demonstrated in Parkinson's disease models using three host species. Long-term engraftment in 6-hydroxy-dopamine-lesioned mice and rats demonstrates robust survival of midbrain DA neurons derived from human embryonic stem (ES) cells, complete restoration of amphetamine-induced rotation behaviour and improvements in tests of forelimb use and akinesia. Finally, scalability is demonstrated by transplantation into parkinsonian monkeys. Excellent DA neuron survival, function and lack of neural overgrowth in the three animal models indicate promise for the development of cell-based therapies in Parkinson's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245796/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245796/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kriks, Sonja -- Shim, Jae-Won -- Piao, Jinghua -- Ganat, Yosif M -- Wakeman, Dustin R -- Xie, Zhong -- Carrillo-Reid, Luis -- Auyeung, Gordon -- Antonacci, Chris -- Buch, Amanda -- Yang, Lichuan -- Beal, M Flint -- Surmeier, D James -- Kordower, Jeffrey H -- Tabar, Viviane -- Studer, Lorenz -- NS052671/NS/NINDS NIH HHS/ -- P50 NS047085/NS/NINDS NIH HHS/ -- P50 NS071669/NS/NINDS NIH HHS/ -- P50 NS071669-03/NS/NINDS NIH HHS/ -- England -- Nature. 2011 Nov 6;480(7378):547-51. doi: 10.1038/nature10648.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Stem Cell Biology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22056989" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Brain Tissue Transplantation ; Cell Differentiation ; Cell Line ; Cell Survival ; Dopaminergic Neurons/*cytology/*transplantation ; Embryonic Stem Cells/*cytology ; Female ; Humans ; Macaca mulatta ; Mesencephalon/cytology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Parkinson Disease/*therapy ; Rats ; Rats, Sprague-Dawley
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    Adult hippocampal neurogenesis buffers stress responses and depressive behaviour (2011)
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    Publication Date: 2011-08-05
    Description: Glucocorticoids are released in response to stressful experiences and serve many beneficial homeostatic functions. However, dysregulation of glucocorticoids is associated with cognitive impairments and depressive illness. In the hippocampus, a brain region densely populated with receptors for stress hormones, stress and glucocorticoids strongly inhibit adult neurogenesis. Decreased neurogenesis has been implicated in the pathogenesis of anxiety and depression, but direct evidence for this role is lacking. Here we show that adult-born hippocampal neurons are required for normal expression of the endocrine and behavioural components of the stress response. Using either transgenic or radiation methods to inhibit adult neurogenesis specifically, we find that glucocorticoid levels are slower to recover after moderate stress and are less suppressed by dexamethasone in neurogenesis-deficient mice than intact mice, consistent with a role for the hippocampus in regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Relative to controls, neurogenesis-deficient mice also showed increased food avoidance in a novel environment after acute stress, increased behavioural despair in the forced swim test, and decreased sucrose preference, a measure of anhedonia. These findings identify a small subset of neurons within the dentate gyrus that are critical for hippocampal negative control of the HPA axis and support a direct role for adult neurogenesis in depressive illness.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162077/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3162077/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Snyder, Jason S -- Soumier, Amelie -- Brewer, Michelle -- Pickel, James -- Cameron, Heather A -- ZIA MH002784-09/Intramural NIH HHS/ -- England -- Nature. 2011 Aug 3;476(7361):458-61. doi: 10.1038/nature10287.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21814201" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Behavior, Animal/drug effects/physiology ; Corticosterone/analysis/metabolism/secretion ; Dentate Gyrus/cytology/drug effects/physiology ; Depression/drug therapy/*physiopathology ; Dexamethasone/pharmacology ; Glucocorticoids/metabolism/pharmacology/secretion ; Hippocampus/*cytology/drug effects/*physiology ; Hypothalamo-Hypophyseal System/drug effects/physiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neurogenesis/drug effects/*physiology/radiation effects ; Pituitary-Adrenal System/drug effects/physiology ; Receptors, Glucocorticoid/analysis/metabolism ; Restraint, Physical/physiology/psychology ; Stress, Physiological/drug effects/*physiology ; Swimming
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Human-specific loss of regulatory DNA and the evolution of human-specific traits (2011)
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    Publication Date: 2011-03-11
    Description: Humans differ from other animals in many aspects of anatomy, physiology, and behaviour; however, the genotypic basis of most human-specific traits remains unknown. Recent whole-genome comparisons have made it possible to identify genes with elevated rates of amino acid change or divergent expression in humans, and non-coding sequences with accelerated base pair changes. Regulatory alterations may be particularly likely to produce phenotypic effects while preserving viability, and are known to underlie interesting evolutionary differences in other species. Here we identify molecular events particularly likely to produce significant regulatory changes in humans: complete deletion of sequences otherwise highly conserved between chimpanzees and other mammals. We confirm 510 such deletions in humans, which fall almost exclusively in non-coding regions and are enriched near genes involved in steroid hormone signalling and neural function. One deletion removes a sensory vibrissae and penile spine enhancer from the human androgen receptor (AR) gene, a molecular change correlated with anatomical loss of androgen-dependent sensory vibrissae and penile spines in the human lineage. Another deletion removes a forebrain subventricular zone enhancer near the tumour suppressor gene growth arrest and DNA-damage-inducible, gamma (GADD45G), a loss correlated with expansion of specific brain regions in humans. Deletions of tissue-specific enhancers may thus accompany both loss and gain traits in the human lineage, and provide specific examples of the kinds of regulatory alterations and inactivation events long proposed to have an important role in human evolutionary divergence.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071156/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3071156/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McLean, Cory Y -- Reno, Philip L -- Pollen, Alex A -- Bassan, Abraham I -- Capellini, Terence D -- Guenther, Catherine -- Indjeian, Vahan B -- Lim, Xinhong -- Menke, Douglas B -- Schaar, Bruce T -- Wenger, Aaron M -- Bejerano, Gill -- Kingsley, David M -- 1 F32 HD062137-01/HD/NICHD NIH HHS/ -- P50 HG002568/HG/NHGRI NIH HHS/ -- P50 HG002568-10/HG/NHGRI NIH HHS/ -- R01 HD059862/HD/NICHD NIH HHS/ -- R01 HD059862-03/HD/NICHD NIH HHS/ -- R01 HG005058/HG/NHGRI NIH HHS/ -- R01 HG005058-03/HG/NHGRI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 10;471(7337):216-9. doi: 10.1038/nature09774.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Computer Science, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390129" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Evolution ; Brain/anatomy & histology/metabolism ; Chromosomes, Mammalian/genetics ; Conserved Sequence/genetics ; DNA/*genetics ; DNA, Intergenic/genetics ; Enhancer Elements, Genetic/genetics ; Evolution, Molecular ; Genes, Tumor Suppressor ; Genome, Human/*genetics ; *Human Characteristics ; Humans ; Male ; Mice ; Organ Specificity ; Pan troglodytes/genetics ; Penis/anatomy & histology/metabolism ; Regulatory Sequences, Nucleic Acid/*genetics ; Sequence Deletion/*genetics ; Species Specificity ; Transgenes/genetics
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    Oxysterols direct immune cell migration via EBI2 (2011)
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    Publication Date: 2011-07-29
    Description: Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7alpha,25-dihydroxycholesterol (also called 7alpha,25-OHC or 5-cholesten-3beta,7alpha,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7alpha,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7alpha,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7alpha,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297623/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297623/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hannedouche, Sebastien -- Zhang, Juan -- Yi, Tangsheng -- Shen, Weijun -- Nguyen, Deborah -- Pereira, Joao P -- Guerini, Danilo -- Baumgarten, Birgit U -- Roggo, Silvio -- Wen, Ben -- Knochenmuss, Richard -- Noel, Sophie -- Gessier, Francois -- Kelly, Lisa M -- Vanek, Mirka -- Laurent, Stephane -- Preuss, Inga -- Miault, Charlotte -- Christen, Isabelle -- Karuna, Ratna -- Li, Wei -- Koo, Dong-In -- Suply, Thomas -- Schmedt, Christian -- Peters, Eric C -- Falchetto, Rocco -- Katopodis, Andreas -- Spanka, Carsten -- Roy, Marie-Odile -- Detheux, Michel -- Chen, Yu Alice -- Schultz, Peter G -- Cho, Charles Y -- Seuwen, Klaus -- Cyster, Jason G -- Sailer, Andreas W -- R01 AI040098/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 27;475(7357):524-7. doi: 10.1038/nature10280.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Euroscreen S.A., 6041 Gosselies, Belgium.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21796212" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Formation/immunology ; B-Lymphocytes ; Cell Line ; Cell Movement/drug effects ; Gene Expression Profiling ; Gene Expression Regulation/drug effects/immunology ; Humans ; Hydroxycholesterols/chemistry/*pharmacology ; Liver/chemistry ; Mice ; Mice, Knockout ; Receptors, Cell Surface/*immunology ; Receptors, G-Protein-Coupled ; Sheep ; T-Lymphocytes/immunology
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    Taken for a ride (2011)
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    Publication Date: 2011-07-08
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2011 Jul 6;475(7354):5. doi: 10.1038/475005a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21734663" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Expert Testimony ; *Federal Government ; Humans ; *Policy Making ; Public Policy/*legislation & jurisprudence ; Research ; United States
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    SUMO1-dependent modulation of SERCA2a in heart failure (2011)
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    Publication Date: 2011-09-09
    Description: The calcium-transporting ATPase ATP2A2, also known as SERCA2a, is a critical ATPase responsible for Ca(2+) re-uptake during excitation-contraction coupling. Impaired Ca(2+) uptake resulting from decreased expression and reduced activity of SERCA2a is a hallmark of heart failure. Accordingly, restoration of SERCA2a expression by gene transfer has proved to be effective in improving cardiac function in heart-failure patients, as well as in animal models. The small ubiquitin-related modifier (SUMO) can be conjugated to lysine residues of target proteins, and is involved in many cellular processes. Here we show that SERCA2a is SUMOylated at lysines 480 and 585 and that this SUMOylation is essential for preserving SERCA2a ATPase activity and stability in mouse and human cells. The levels of SUMO1 and the SUMOylation of SERCA2a itself were greatly reduced in failing hearts. SUMO1 restitution by adeno-associated-virus-mediated gene delivery maintained the protein abundance of SERCA2a and markedly improved cardiac function in mice with heart failure. This effect was comparable to SERCA2A gene delivery. Moreover, SUMO1 overexpression in isolated cardiomyocytes augmented contractility and accelerated Ca(2+) decay. Transgene-mediated SUMO1 overexpression rescued cardiac dysfunction induced by pressure overload concomitantly with increased SERCA2a function. By contrast, downregulation of SUMO1 using small hairpin RNA (shRNA) accelerated pressure-overload-induced deterioration of cardiac function and was accompanied by decreased SERCA2a function. However, knockdown of SERCA2a resulted in severe contractile dysfunction both in vitro and in vivo, which was not rescued by overexpression of SUMO1. Taken together, our data show that SUMOylation is a critical post-translational modification that regulates SERCA2a function, and provide a platform for the design of novel therapeutic strategies for heart failure.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443490/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3443490/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kho, Changwon -- Lee, Ahyoung -- Jeong, Dongtak -- Oh, Jae Gyun -- Chaanine, Antoine H -- Kizana, Eddy -- Park, Woo Jin -- Hajjar, Roger J -- HL080498/HL/NHLBI NIH HHS/ -- HL093183/HL/NHLBI NIH HHS/ -- P20 HL100396/HL/NHLBI NIH HHS/ -- P20 HL100396-02/HL/NHLBI NIH HHS/ -- P20HL100396/HL/NHLBI NIH HHS/ -- R01 HL078731/HL/NHLBI NIH HHS/ -- R01 HL078731-04/HL/NHLBI NIH HHS/ -- R01 HL080498/HL/NHLBI NIH HHS/ -- R01 HL080498-05/HL/NHLBI NIH HHS/ -- R01 HL083156/HL/NHLBI NIH HHS/ -- R01 HL083156-05/HL/NHLBI NIH HHS/ -- R01 HL088434/HL/NHLBI NIH HHS/ -- R01 HL088434-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Sep 7;477(7366):601-5. doi: 10.1038/nature10407.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cardiovascular Research Center, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1030, New York, New York 10029, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21900893" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; HEK293 Cells ; Heart Failure/*metabolism/physiopathology ; Humans ; Lysine/metabolism ; Mice ; Rats ; Rats, Sprague-Dawley ; SUMO-1 Protein/genetics/*metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases/*metabolism ; *Sumoylation ; Sus scrofa
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    US budget a taste of battles to come (2011)
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    Publication Date: 2011-04-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reich, Eugenie Samuel -- Semeniuk, Ivan -- Tollefson, Jeff -- Wadman, Meredith -- England -- Nature. 2011 Apr 21;472(7343):267-9. doi: 10.1038/472267a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21512542" target="_blank"〉PubMed〈/a〉
    Keywords: Budgets/*legislation & jurisprudence/*trends ; *Federal Government ; Humans ; Science/*economics/trends ; United States ; United States Government Agencies/*economics/legislation & jurisprudence/trends
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    Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor (2011)
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    Publication Date: 2011-02-26
    Description: Pituitary adenylate cyclase-activating polypeptide (PACAP) is known to broadly regulate the cellular stress response. In contrast, it is unclear if the PACAP-PAC1 receptor pathway has a role in human psychological stress responses, such as post-traumatic stress disorder (PTSD). Here we find, in heavily traumatized subjects, a sex-specific association of PACAP blood levels with fear physiology, PTSD diagnosis and symptoms in females. We examined 44 single nucleotide polymorphisms (SNPs) spanning the PACAP (encoded by ADCYAP1) and PAC1 (encoded by ADCYAP1R1) genes, demonstrating a sex-specific association with PTSD. A single SNP in a putative oestrogen response element within ADCYAP1R1, rs2267735, predicts PTSD diagnosis and symptoms in females only. This SNP also associates with fear discrimination and with ADCYAP1R1 messenger RNA expression in human brain. Methylation of ADCYAP1R1 in peripheral blood is also associated with PTSD. Complementing these human data, ADCYAP1R1 mRNA is induced with fear conditioning or oestrogen replacement in rodent models. These data suggest that perturbations in the PACAP-PAC1 pathway are involved in abnormal stress responses underlying PTSD. These sex-specific effects may occur via oestrogen regulation of ADCYAP1R1. PACAP levels and ADCYAP1R1 SNPs may serve as useful biomarkers to further our mechanistic understanding of PTSD.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046811/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046811/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ressler, Kerry J -- Mercer, Kristina B -- Bradley, Bekh -- Jovanovic, Tanja -- Mahan, Amy -- Kerley, Kimberly -- Norrholm, Seth D -- Kilaru, Varun -- Smith, Alicia K -- Myers, Amanda J -- Ramirez, Manuel -- Engel, Anzhelika -- Hammack, Sayamwong E -- Toufexis, Donna -- Braas, Karen M -- Binder, Elisabeth B -- May, Victor -- AG034504/AG/NIA NIH HHS/ -- DA019624/DA/NIDA NIH HHS/ -- HD27468/HD/NICHD NIH HHS/ -- M01RR00039/RR/NCRR NIH HHS/ -- MH071537/MH/NIMH NIH HHS/ -- P20RR16435/RR/NCRR NIH HHS/ -- R01 AG034504/AG/NIA NIH HHS/ -- R01 HD027468/HD/NICHD NIH HHS/ -- R01 HD027468-13/HD/NICHD NIH HHS/ -- UL1 TR000454/TR/NCATS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 24;470(7335):492-7. doi: 10.1038/nature09856.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA. kressle@emory.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350482" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/metabolism ; Animals ; Conditioning, Classical/physiology ; CpG Islands/genetics ; DNA Methylation ; Estrogens/metabolism/pharmacology ; Fear/physiology ; Female ; Gene Expression Regulation/drug effects ; Genetic Association Studies ; Genetic Predisposition to Disease/*genetics ; Humans ; Male ; Mice ; Pituitary Adenylate Cyclase-Activating Polypeptide/*blood/chemistry ; Polymorphism, Single Nucleotide/genetics ; RNA, Messenger/analysis/biosynthesis/genetics ; Rats ; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I/*genetics ; Response Elements/genetics ; Septal Nuclei/drug effects/metabolism ; Sex Characteristics ; Stress Disorders, Post-Traumatic/*blood/*genetics/physiopathology/psychology
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    DHODH modulates transcriptional elongation in the neural crest and melanoma (2011)
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    Publication Date: 2011-03-25
    Description: Melanoma is a tumour of transformed melanocytes, which are originally derived from the embryonic neural crest. It is unknown to what extent the programs that regulate neural crest development interact with mutations in the BRAF oncogene, which is the most commonly mutated gene in human melanoma. We have used zebrafish embryos to identify the initiating transcriptional events that occur on activation of human BRAF(V600E) (which encodes an amino acid substitution mutant of BRAF) in the neural crest lineage. Zebrafish embryos that are transgenic for mitfa:BRAF(V600E) and lack p53 (also known as tp53) have a gene signature that is enriched for markers of multipotent neural crest cells, and neural crest progenitors from these embryos fail to terminally differentiate. To determine whether these early transcriptional events are important for melanoma pathogenesis, we performed a chemical genetic screen to identify small-molecule suppressors of the neural crest lineage, which were then tested for their effects on melanoma. One class of compound, inhibitors of dihydroorotate dehydrogenase (DHODH), for example leflunomide, led to an almost complete abrogation of neural crest development in zebrafish and to a reduction in the self-renewal of mammalian neural crest stem cells. Leflunomide exerts these effects by inhibiting the transcriptional elongation of genes that are required for neural crest development and melanoma growth. When used alone or in combination with a specific inhibitor of the BRAF(V600E) oncogene, DHODH inhibition led to a marked decrease in melanoma growth both in vitro and in mouse xenograft studies. Taken together, these studies highlight developmental pathways in neural crest cells that have a direct bearing on melanoma formation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759979/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3759979/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉White, Richard Mark -- Cech, Jennifer -- Ratanasirintrawoot, Sutheera -- Lin, Charles Y -- Rahl, Peter B -- Burke, Christopher J -- Langdon, Erin -- Tomlinson, Matthew L -- Mosher, Jack -- Kaufman, Charles -- Chen, Frank -- Long, Hannah K -- Kramer, Martin -- Datta, Sumon -- Neuberg, Donna -- Granter, Scott -- Young, Richard A -- Morrison, Sean -- Wheeler, Grant N -- Zon, Leonard I -- K08 AR055368/AR/NIAMS NIH HHS/ -- R01 CA103846/CA/NCI NIH HHS/ -- R01 HG002668/HG/NHGRI NIH HHS/ -- R01 HG002668-08/HG/NHGRI NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Biotechnology and Biological Sciences Research Council/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Mar 24;471(7339):518-22. doi: 10.1038/nature09882.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stem Cell Program and Hematology/Oncology, Children's Hospital Boston, Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21430780" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Substitution ; Animals ; Animals, Genetically Modified ; Cell Differentiation/drug effects ; Cell Line, Tumor ; Cell Lineage/drug effects ; Disease Models, Animal ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics ; Humans ; Isoxazoles/pharmacology/therapeutic use ; Melanoma/drug therapy/enzymology/*genetics/*pathology ; Mice ; Neural Crest/drug effects/*enzymology/metabolism/pathology ; Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors/*metabolism ; Proto-Oncogene Proteins B-raf/antagonists & ; inhibitors/chemistry/genetics/metabolism ; Rats ; Stem Cells/cytology/drug effects/pathology ; *Transcription, Genetic/drug effects/physiology ; Xenograft Model Antitumor Assays ; Zebrafish/embryology/genetics
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    Developmental biology: a hair-raising tale (2011)
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    Publication Date: 2011-04-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Morgan, Bruce A -- R01 AR055256/AR/NIAMS NIH HHS/ -- England -- Nature. 2011 Mar 31;471(7340):586-7. doi: 10.1038/471586a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21455169" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Proliferation ; Hair Follicle/anatomy & histology/*cytology/*physiology ; Keratinocytes/cytology ; Mesoderm/cytology ; Mice ; Muscle, Smooth/*cytology ; Stem Cell Niche/cytology ; Stem Cells/*cytology
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    Prion diseases: Infectivity versus toxicity (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wickner, Reed B -- England -- Nature. 2011 Feb 24;470(7335):470-1. doi: 10.1038/470470a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350474" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Assay ; Gene Expression ; Humans ; Mice ; Models, Biological ; PrPC Proteins/analysis/biosynthesis/genetics/metabolism ; PrPSc Proteins/biosynthesis/*metabolism/*pathogenicity/toxicity ; Prion Diseases/*metabolism/pathology/physiopathology/*transmission ; Survival Rate ; Time Factors ; Toxicity Tests
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    A genetically humanized mouse model for hepatitis C virus infection (2011)
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    Publication Date: 2011-06-10
    Description: Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159410/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3159410/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dorner, Marcus -- Horwitz, Joshua A -- Robbins, Justin B -- Barry, Walter T -- Feng, Qian -- Mu, Kathy -- Jones, Christopher T -- Schoggins, John W -- Catanese, Maria Teresa -- Burton, Dennis R -- Law, Mansun -- Rice, Charles M -- Ploss, Alexander -- F32DK081193/DK/NIDDK NIH HHS/ -- F32DK082155/DK/NIDDK NIH HHS/ -- R01 AI071084/AI/NIAID NIH HHS/ -- R01 AI071084-04/AI/NIAID NIH HHS/ -- R01 AI072613/AI/NIAID NIH HHS/ -- R01 AI072613-05/AI/NIAID NIH HHS/ -- R01 AI079031/AI/NIAID NIH HHS/ -- R01 AI079031-04/AI/NIAID NIH HHS/ -- R01 DK085713/DK/NIDDK NIH HHS/ -- R01 DK085713-03/DK/NIDDK NIH HHS/ -- R01AI071084/AI/NIAID NIH HHS/ -- R01AI072613/AI/NIAID NIH HHS/ -- R01AI079031/AI/NIAID NIH HHS/ -- RC1 DK087193/DK/NIDDK NIH HHS/ -- RC1 DK087193-02/DK/NIDDK NIH HHS/ -- RC1DK087193/DK/NIDDK NIH HHS/ -- England -- Nature. 2011 Jun 8;474(7350):208-11. doi: 10.1038/nature10168.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654804" target="_blank"〉PubMed〈/a〉
    Keywords: Adenoviridae/genetics/physiology ; Animals ; Antibodies, Blocking/immunology ; Antigens, CD/genetics/metabolism ; Antigens, CD81 ; Cells, Cultured ; Claudin-1 ; *Disease Models, Animal ; Genotype ; Hepacivirus/genetics/metabolism/*physiology ; Hepatitis C/*genetics/*virology ; Hepatocytes/cytology/*metabolism/*virology ; Humans ; Immunization, Passive ; Membrane Proteins/genetics/metabolism ; Mice ; Receptors, Virus/genetics/metabolism ; Scavenger Receptors, Class B/genetics/metabolism ; Transfection ; Viral Tropism
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    Glutamate induces de novo growth of functional spines in developing cortex (2011)
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    Publication Date: 2011-05-10
    Description: Mature cortical pyramidal neurons receive excitatory inputs onto small protrusions emanating from their dendrites called spines. Spines undergo activity-dependent remodelling, stabilization and pruning during development, and similar structural changes can be triggered by learning and changes in sensory experiences. However, the biochemical triggers and mechanisms of de novo spine formation in the developing brain and the functional significance of new spines to neuronal connectivity are largely unknown. Here we develop an approach to induce and monitor de novo spine formation in real time using combined two-photon laser-scanning microscopy and two-photon laser uncaging of glutamate. Our data demonstrate that, in mouse cortical layer 2/3 pyramidal neurons, glutamate is sufficient to trigger de novo spine growth from the dendrite shaft in a location-specific manner. We find that glutamate-induced spinogenesis requires opening of NMDARs (N-methyl-D-aspartate-type glutamate receptors) and activation of protein kinase A (PKA) but is independent of calcium-calmodulin-dependent kinase II (CaMKII) and tyrosine kinase receptor B (TrkB) receptors. Furthermore, newly formed spines express glutamate receptors and are rapidly functional such that they transduce presynaptic activity into postsynaptic signals. Together, our data demonstrate that early neural connectivity is shaped by activity in a spatially precise manner and that nascent dendrite spines are rapidly functionally incorporated into cortical circuits.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107907/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107907/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kwon, Hyung-Bae -- Sabatini, Bernardo L -- NS046579/NS/NINDS NIH HHS/ -- R01 NS046579/NS/NINDS NIH HHS/ -- R01 NS046579-06A1/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 2;474(7349):100-4. doi: 10.1038/nature09986. Epub 2011 May 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21552280" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Cerebral Cortex/*drug effects/*embryology ; Dendritic Spines/drug effects ; Electric Stimulation ; Glutamic Acid/*pharmacology ; Mice ; Mice, Inbred C57BL ; Neurotransmitter Agents/*pharmacology ; Pyramidal Cells/drug effects/embryology
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    Multiple sclerosis: One protein, two healing properties (2011)
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    Publication Date: 2011-09-17
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Metcalfe, Su M -- FSH001/Department of Health/United Kingdom -- II-AR-1109-11037/Department of Health/United Kingdom -- England -- Nature. 2011 Sep 14;477(7364):287-8. doi: 10.1038/477287a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21921909" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Culture Media, Conditioned/pharmacology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology/pathology/therapy ; Humans ; Immune Tolerance/drug effects/immunology ; Interleukin-6/immunology/pharmacology ; Leukemia Inhibitory Factor/immunology/*pharmacology/*therapeutic use ; Mice ; Multiple Sclerosis/immunology/pathology/*therapy ; Neural Stem Cells/transplantation ; T-Lymphocytes, Regulatory/cytology/drug effects/immunology ; Th17 Cells/cytology/drug effects/immunology
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    Into ignorance (2011)
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    Publication Date: 2011-03-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2011 Mar 17;471(7338):265-6. doi: 10.1038/471265b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21412287" target="_blank"〉PubMed〈/a〉
    Keywords: Conservation of Energy Resources/legislation & jurisprudence ; *Federal Government ; Global Warming/*legislation & jurisprudence/prevention & control/statistics & ; numerical data ; United States
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    Notes on a scandal (2011)
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    Publication Date: 2011-03-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2011 Mar 10;471(7337):135-6. doi: 10.1038/471135b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21390084" target="_blank"〉PubMed〈/a〉
    Keywords: Cultural Diversity ; *Federal Government ; Germany ; Italy ; Morals ; *Plagiarism ; *Politics ; Research Personnel/*ethics/standards
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    A stress response pathway regulates DNA damage through beta2-adrenoreceptors and beta-arrestin-1 (2011)
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    Publication Date: 2011-08-23
    Description: The human mind and body respond to stress, a state of perceived threat to homeostasis, by activating the sympathetic nervous system and secreting the catecholamines adrenaline and noradrenaline in the 'fight-or-flight' response. The stress response is generally transient because its accompanying effects (for example, immunosuppression, growth inhibition and enhanced catabolism) can be harmful in the long term. When chronic, the stress response can be associated with disease symptoms such as peptic ulcers or cardiovascular disorders, and epidemiological studies strongly indicate that chronic stress leads to DNA damage. This stress-induced DNA damage may promote ageing, tumorigenesis, neuropsychiatric conditions and miscarriages. However, the mechanisms by which these DNA-damage events occur in response to stress are unknown. The stress hormone adrenaline stimulates beta(2)-adrenoreceptors that are expressed throughout the body, including in germline cells and zygotic embryos. Activated beta(2)-adrenoreceptors promote Gs-protein-dependent activation of protein kinase A (PKA), followed by the recruitment of beta-arrestins, which desensitize G-protein signalling and function as signal transducers in their own right. Here we elucidate a molecular mechanism by which beta-adrenergic catecholamines, acting through both Gs-PKA and beta-arrestin-mediated signalling pathways, trigger DNA damage and suppress p53 levels respectively, thus synergistically leading to the accumulation of DNA damage. In mice and in human cell lines, beta-arrestin-1 (ARRB1), activated via beta(2)-adrenoreceptors, facilitates AKT-mediated activation of MDM2 and also promotes MDM2 binding to, and degradation of, p53, by acting as a molecular scaffold. Catecholamine-induced DNA damage is abrogated in Arrb1-knockout (Arrb1(-/-)) mice, which show preserved p53 levels in both the thymus, an organ that responds prominently to acute or chronic stress, and in the testes, in which paternal stress may affect the offspring's genome. Our results highlight the emerging role of ARRB1 as an E3-ligase adaptor in the nucleus, and reveal how DNA damage may accumulate in response to chronic stress.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628753/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628753/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hara, Makoto R -- Kovacs, Jeffrey J -- Whalen, Erin J -- Rajagopal, Sudarshan -- Strachan, Ryan T -- Grant, Wayne -- Towers, Aaron J -- Williams, Barbara -- Lam, Christopher M -- Xiao, Kunhong -- Shenoy, Sudha K -- Gregory, Simon G -- Ahn, Seungkirl -- Duckett, Derek R -- Lefkowitz, Robert J -- HL16037/HL/NHLBI NIH HHS/ -- HL70631/HL/NHLBI NIH HHS/ -- R01 HL016037/HL/NHLBI NIH HHS/ -- R01 HL070631/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Aug 21;477(7364):349-53. doi: 10.1038/nature10368.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21857681" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Arrestins/deficiency/genetics/*metabolism ; Catecholamines/pharmacology ; Cell Line ; Cell Nucleus/enzymology/metabolism ; Cyclic AMP-Dependent Protein Kinases/metabolism ; *DNA Damage ; Fibroblasts ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Protein Processing, Post-Translational/drug effects ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-mdm2/metabolism ; Receptors, Adrenergic, beta-2/*metabolism ; Signal Transduction/drug effects ; Stress, Physiological/*physiology ; Testis/metabolism ; Thymus Gland/metabolism ; Tumor Suppressor Protein p53/chemistry/metabolism
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    Dampening of death pathways by schnurri-2 is essential for T-cell development (2011)
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    Details
    Publication Date: 2011-04-09
    Description: Generation of a diverse and self-tolerant T-cell repertoire requires appropriate interpretation of T-cell antigen receptor (TCR) signals by CD4(+ ) CD8(+) double-positive thymocytes. Thymocyte cell fate is dictated by the nature of TCR-major-histocompatibility-complex (MHC)-peptide interactions, with signals of higher strength leading to death (negative selection) and signals of intermediate strength leading to differentiation (positive selection). Molecules that regulate T-cell development by modulating TCR signal strength have been described but components that specifically define the boundaries between positive and negative selection remain unknown. Here we show in mice that repression of TCR-induced death pathways is critical for proper interpretation of positive selecting signals in vivo, and identify schnurri-2 (Shn2; also known as Hivep2) as a crucial death dampener. Our results indicate that Shn2(-/-) double-positive thymocytes inappropriately undergo negative selection in response to positive selecting signals, thus leading to disrupted T-cell development. Shn2(-/-) double-positive thymocytes are more sensitive to TCR-induced death in vitro and die in response to positive selection interactions in vivo. However, Shn2-deficient thymocytes can be positively selected when TCR-induced death is genetically ablated. Shn2 levels increase after TCR stimulation, indicating that integration of multiple TCR-MHC-peptide interactions may fine-tune the death threshold. Mechanistically, Shn2 functions downstream of TCR proximal signalling compenents to dampen Bax activation and the mitochondrial death pathway. Our findings uncover a critical regulator of T-cell development that controls the balance between death and differentiation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077958/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Staton, Tracy L -- Lazarevic, Vanja -- Jones, Dallas C -- Lanser, Amanda J -- Takagi, Tsuyoshi -- Ishii, Shunsuke -- Glimcher, Laurie H -- AI29673/AI/NIAID NIH HHS/ -- K99AR055668/AR/NIAMS NIH HHS/ -- P30 AI060354/AI/NIAID NIH HHS/ -- R01 AI029673/AI/NIAID NIH HHS/ -- R01 AI029673-22/AI/NIAID NIH HHS/ -- T32 AI007290/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Apr 7;472(7341):105-9. doi: 10.1038/nature09848.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21475200" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis Regulatory Proteins/deficiency/genetics ; Cell Death ; Cell Differentiation ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Membrane Proteins/deficiency/genetics ; Mice ; Mice, Inbred BALB C ; Mitochondria/metabolism/pathology ; Proto-Oncogene Proteins/deficiency/genetics ; Receptors, Antigen, T-Cell/immunology/metabolism ; Signal Transduction ; T-Lymphocytes/*cytology/immunology/metabolism ; Thymus Gland/cytology/immunology
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    Regulation of angiogenesis by a non-canonical Wnt-Flt1 pathway in myeloid cells (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-05-31
    Description: Myeloid cells are a feature of most tissues. Here we show that during development, retinal myeloid cells (RMCs) produce Wnt ligands to regulate blood vessel branching. In the mouse retina, where angiogenesis occurs postnatally, somatic deletion in RMCs of the Wnt ligand transporter Wntless results in increased angiogenesis in the deeper layers. We also show that mutation of Wnt5a and Wnt11 results in increased angiogenesis and that these ligands elicit RMC responses via a non-canonical Wnt pathway. Using cultured myeloid-like cells and RMC somatic deletion of Flt1, we show that an effector of Wnt-dependent suppression of angiogenesis by RMCs is Flt1, a naturally occurring inhibitor of vascular endothelial growth factor (VEGF). These findings indicate that resident myeloid cells can use a non-canonical, Wnt-Flt1 pathway to suppress angiogenic branching.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214992/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3214992/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stefater, James A 3rd -- Lewkowich, Ian -- Rao, Sujata -- Mariggi, Giovanni -- Carpenter, April C -- Burr, Adam R -- Fan, Jieqing -- Ajima, Rieko -- Molkentin, Jeffery D -- Williams, Bart O -- Wills-Karp, Marsha -- Pollard, Jeffrey W -- Yamaguchi, Terry -- Ferrara, Napoleone -- Gerhardt, Holger -- Lang, Richard A -- G1002033/Medical Research Council/United Kingdom -- R01 AR053293/AR/NIAMS NIH HHS/ -- R01 EY015766/EY/NEI NIH HHS/ -- R01 EY015766-05/EY/NEI NIH HHS/ -- Cancer Research UK/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 May 29;474(7352):511-5. doi: 10.1038/nature10085.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Visual Systems Group, Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21623369" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Vessels/growth & development ; Endothelial Cells/metabolism ; Fibroblasts ; Intracellular Signaling Peptides and Proteins/genetics/metabolism ; LDL-Receptor Related Proteins/genetics/metabolism ; Ligands ; Low Density Lipoprotein Receptor-Related Protein-5 ; Mice ; Myeloid Cells/*metabolism ; Neovascularization, Physiologic/*physiology ; Receptors, G-Protein-Coupled ; Retina/*cytology ; *Signal Transduction ; Vascular Endothelial Growth Factor A/antagonists & inhibitors ; Vascular Endothelial Growth Factor ; Receptor-1/deficiency/genetics/*metabolism/secretion ; Wnt Proteins/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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    Asymmetric cell divisions promote Notch-dependent epidermal differentiation (2011)
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    Publication Date: 2011-02-19
    Description: Stem and progenitor cells use asymmetric cell divisions to balance proliferation and differentiation. Evidence from invertebrates shows that this process is regulated by proteins asymmetrically distributed at the cell cortex during mitosis: Par3-Par6-aPKC, which confer polarity, and Galpha(i)-LGN/AGS3-NuMA-dynein/dynactin, which govern spindle positioning. Here we focus on developing mouse skin, where progenitor cells execute a switch from symmetric to predominantly asymmetric divisions concomitant with stratification. Using in vivo skin-specific lentiviral RNA interference, we investigate spindle orientation regulation and provide direct evidence that LGN (also called Gpsm2), NuMA and dynactin (Dctn1) are involved. In compromising asymmetric cell divisions, we uncover profound defects in stratification, differentiation and barrier formation, and implicate Notch signalling as an important effector. Our study demonstrates the efficacy of applying RNA interference in vivo to mammalian systems, and the ease of uncovering complex genetic interactions, here to gain insights into how changes in spindle orientation are coupled to establishing proper tissue architecture during skin development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077085/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3077085/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Williams, Scott E -- Beronja, Slobodan -- Pasolli, H Amalia -- Fuchs, Elaine -- R01 AR050452/AR/NIAMS NIH HHS/ -- R01 AR050452-07/AR/NIAMS NIH HHS/ -- R01AR27883/AR/NIAMS NIH HHS/ -- R37 AR027883/AR/NIAMS NIH HHS/ -- R37 AR027883-30/AR/NIAMS NIH HHS/ -- R37 AR027883-30S1/AR/NIAMS NIH HHS/ -- R37 AR027883-31/AR/NIAMS NIH HHS/ -- R37 AR027883-32/AR/NIAMS NIH HHS/ -- R37 AR027883-33/AR/NIAMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Feb 17;470(7334):353-8. doi: 10.1038/nature09793.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331036" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/genetics/metabolism ; *Cell Differentiation ; *Cell Division ; Cells, Cultured ; Epidermis/*cytology ; Female ; Gene Knockdown Techniques ; Keratinocytes/cytology ; Male ; Mice ; Microtubule-Associated Proteins/deficiency/genetics/metabolism ; Nuclear Proteins/deficiency/genetics/metabolism ; Receptors, Notch/genetics/*metabolism ; Signal Transduction ; Skin/cytology/embryology ; Spindle Apparatus/metabolism
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    BCL6 enables Ph+ acute lymphoblastic leukaemia cells to survive BCR-ABL1 kinase inhibition (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-05-20
    Description: Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with leukaemia driven by BCR-ABL1 (ref. 1) and other oncogenic tyrosine kinases. Recent efforts have focused on developing more potent TKIs that also inhibit mutant tyrosine kinases. However, even effective TKIs typically fail to eradicate leukaemia-initiating cells (LICs), which often cause recurrence of leukaemia after initially successful treatment. Here we report the discovery of a novel mechanism of drug resistance, which is based on protective feedback signalling of leukaemia cells in response to treatment with TKI. We identify BCL6 as a central component of this drug-resistance pathway and demonstrate that targeted inhibition of BCL6 leads to eradication of drug-resistant and leukaemia-initiating subclones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597744/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597744/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Duy, Cihangir -- Hurtz, Christian -- Shojaee, Seyedmehdi -- Cerchietti, Leandro -- Geng, Huimin -- Swaminathan, Srividya -- Klemm, Lars -- Kweon, Soo-mi -- Nahar, Rahul -- Braig, Melanie -- Park, Eugene -- Kim, Yong-mi -- Hofmann, Wolf-Karsten -- Herzog, Sebastian -- Jumaa, Hassan -- Koeffler, H Phillip -- Yu, J Jessica -- Heisterkamp, Nora -- Graeber, Thomas G -- Wu, Hong -- Ye, B Hilda -- Melnick, Ari -- Muschen, Markus -- R01 CA026038/CA/NCI NIH HHS/ -- R01 CA085573/CA/NCI NIH HHS/ -- R01 CA137060/CA/NCI NIH HHS/ -- R01 CA137060-01A1/CA/NCI NIH HHS/ -- R01 CA137060-02/CA/NCI NIH HHS/ -- R01 CA137060-03/CA/NCI NIH HHS/ -- R01 CA137060-04/CA/NCI NIH HHS/ -- R01 CA139032/CA/NCI NIH HHS/ -- R01 CA139032-01/CA/NCI NIH HHS/ -- R01 CA139032-02/CA/NCI NIH HHS/ -- R01 CA139032-03/CA/NCI NIH HHS/ -- R01 CA157644/CA/NCI NIH HHS/ -- R01CA026038/CA/NCI NIH HHS/ -- R01CA085573/CA/NCI NIH HHS/ -- R01CA090321/CA/NCI NIH HHS/ -- R01CA104348/CA/NCI NIH HHS/ -- R01CA137060/CA/NCI NIH HHS/ -- R01CA139032/CA/NCI NIH HHS/ -- R01CA157664/CA/NCI NIH HHS/ -- R21 CA152497/CA/NCI NIH HHS/ -- R21 CA152497-01/CA/NCI NIH HHS/ -- R21 CA152497-02/CA/NCI NIH HHS/ -- R21CA152497/CA/NCI NIH HHS/ -- England -- Nature. 2011 May 19;473(7347):384-8. doi: 10.1038/nature09883.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Laboratory Medicine, University of California San Francisco, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21593872" target="_blank"〉PubMed〈/a〉
    Keywords: ADP-Ribosylation Factor 1/metabolism ; Animals ; Cell Survival/drug effects ; DNA-Binding Proteins/biosynthesis/deficiency/genetics/*metabolism ; *Drug Resistance, Neoplasm ; Fusion Proteins, bcr-abl/*antagonists & inhibitors ; Gene Expression Regulation, Neoplastic/drug effects ; Humans ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/*drug ; therapy/genetics/metabolism/*pathology ; Protein Kinase Inhibitors/*pharmacology/therapeutic use ; Transcription, Genetic ; Tumor Suppressor Protein p53/metabolism
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    Rights for all (2011)
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    Publication Date: 2011-02-26
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉England -- Nature. 2011 Feb 24;470(7335):436. doi: 10.1038/470436a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21350442" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; *Human Rights/legislation & jurisprudence/standards ; Politics ; Research Personnel/*legislation & jurisprudence ; Terrorism/legislation & jurisprudence ; Turkey
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    Cryptochromes mediate rhythmic repression of the glucocorticoid receptor (2011)
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    Publication Date: 2011-12-16
    Description: Mammalian metabolism is highly circadian and major hormonal circuits involving nuclear hormone receptors display interlinked diurnal cycling. However, mechanisms that logically explain the coordination of nuclear hormone receptors and the clock are poorly understood. Here we show that two circadian co-regulators, cryptochromes 1 and 2, interact with the glucocorticoid receptor in a ligand-dependent fashion and globally alter the transcriptional response to glucocorticoids in mouse embryonic fibroblasts: cryptochrome deficiency vastly decreases gene repression and approximately doubles the number of dexamethasone-induced genes, suggesting that cryptochromes broadly oppose glucocorticoid receptor activation and promote repression. In mice, genetic loss of cryptochrome 1 and/or 2 results in glucose intolerance and constitutively high levels of circulating corticosterone, suggesting reduced suppression of the hypothalamic-pituitary-adrenal axis coupled with increased glucocorticoid transactivation in the liver. Genomically, cryptochromes 1 and 2 associate with a glucocorticoid response element in the phosphoenolpyruvate carboxykinase 1 promoter in a hormone-dependent manner, and dexamethasone-induced transcription of the phosphoenolpyruvate carboxykinase 1 gene was strikingly increased in cryptochrome-deficient livers. These results reveal a specific mechanism through which cryptochromes couple the activity of clock and receptor target genes to complex genomic circuits underpinning normal metabolic homeostasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245818/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3245818/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lamia, Katja A -- Papp, Stephanie J -- Yu, Ruth T -- Barish, Grant D -- Uhlenhaut, N Henriette -- Jonker, Johan W -- Downes, Michael -- Evans, Ronald M -- DK057978/DK/NIDDK NIH HHS/ -- DK062434/DK/NIDDK NIH HHS/ -- DK090188/DK/NIDDK NIH HHS/ -- K01 DK090188/DK/NIDDK NIH HHS/ -- K01 DK090188-01/DK/NIDDK NIH HHS/ -- K01 DK090188-02/DK/NIDDK NIH HHS/ -- P30 CA014195/CA/NCI NIH HHS/ -- R37 DK057978/DK/NIDDK NIH HHS/ -- R37 DK057978-22/DK/NIDDK NIH HHS/ -- U19 DK062434/DK/NIDDK NIH HHS/ -- U19 DK062434-01/DK/NIDDK NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Dec 14;480(7378):552-6. doi: 10.1038/nature10700.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. klamia@scripps.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22170608" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Circadian Rhythm ; Corticosterone/blood ; Cryptochromes/genetics/*metabolism ; Dexamethasone/pharmacology ; Female ; *Gene Expression Regulation/drug effects ; Glucocorticoids/pharmacology ; Glucose Intolerance/genetics ; HEK293 Cells ; Humans ; Liver/enzymology/metabolism ; Mice ; Phosphoenolpyruvate Carboxykinase (GTP)/blood/metabolism ; Receptors, Glucocorticoid/*metabolism
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    Fancd2 counteracts the toxic effects of naturally produced aldehydes in mice (2011)
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    Publication Date: 2011-07-08
    Description: Reactive aldehydes are common carcinogens. They are also by-products of several metabolic pathways and, without enzymatic catabolism, may accumulate and cause DNA damage. Ethanol, which is metabolised to acetaldehyde, is both carcinogenic and teratogenic in humans. Here we find that the Fanconi anaemia DNA repair pathway counteracts acetaldehyde-induced genotoxicity in mice. Our results show that the acetaldehyde-catabolising enzyme Aldh2 is essential for the development of Fancd2(-/-) embryos. Nevertheless, acetaldehyde-catabolism-competent mothers (Aldh2(+/-)) can support the development of double-mutant (Aldh2(-/-)Fancd2(-/-)) mice. However, these embryos are unusually sensitive to ethanol exposure in utero, and ethanol consumption by postnatal double-deficient mice rapidly precipitates bone marrow failure. Lastly, Aldh2(-/-)Fancd2(-/-) mice spontaneously develop acute leukaemia. Acetaldehyde-mediated DNA damage may critically contribute to the genesis of fetal alcohol syndrome in fetuses, as well as to abnormal development, haematopoietic failure and cancer predisposition in Fanconi anaemia patients.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Langevin, Frederic -- Crossan, Gerry P -- Rosado, Ivan V -- Arends, Mark J -- Patel, Ketan J -- MC_U105178811/Medical Research Council/United Kingdom -- England -- Nature. 2011 Jul 6;475(7354):53-8. doi: 10.1038/nature10192.〈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/21734703" target="_blank"〉PubMed〈/a〉
    Keywords: Acetaldehyde/metabolism/toxicity ; Aldehyde Dehydrogenase/deficiency/genetics/metabolism ; Aldehydes/*antagonists & inhibitors/metabolism/*toxicity ; Alleles ; Animals ; B-Lymphocytes/drug effects/metabolism ; Bone Marrow/drug effects/pathology/physiopathology ; Cell Line ; Cell Survival/drug effects ; Chickens ; Clone Cells/drug effects ; DNA Damage/genetics ; DNA Repair/genetics ; Embryo Loss/chemically induced/etiology ; Embryo, Mammalian/abnormalities/drug effects/embryology ; Ethanol/metabolism/toxicity ; Fanconi Anemia/genetics/pathology ; Fanconi Anemia Complementation Group D2 Protein/deficiency/genetics/*metabolism ; Female ; Fetal Alcohol Spectrum Disorders/etiology ; Gene Deletion ; Genes, Essential ; Hematopoiesis/drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/chemically induced/etiology ; Pregnancy ; Teratogens/metabolism/toxicity ; Weaning
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    Neuroscience: Seeing into the future (2011)
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    Publication Date: 2011-01-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moser, Edvard I -- Moser, May-Britt -- England -- Nature. 2011 Jan 20;469(7330):303-4. doi: 10.1038/469303a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248830" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/physiology ; Animals ; Eating ; Food ; Hippocampus/*cytology/*physiology ; Memory/physiology ; Mice ; *Models, Neurological ; Neurons/*physiology ; Orientation/physiology ; Rest/physiology ; Space Perception/physiology ; Time Factors
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    Stem cells: The cell division (2011)
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    Publication Date: 2011-12-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2011 Dec 15;480(7377):310-2. doi: 10.1038/480310a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22170661" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Embryo Research/economics/*ethics/legislation & jurisprudence ; *Embryonic Stem Cells/cytology ; Germany ; Humans ; Mice ; Morals ; Patents as Topic/*ethics/*legislation & jurisprudence
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    Licence rules hinder work on rare disease (2011)
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    Publication Date: 2011-02-19
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayden, Erika Check -- England -- Nature. 2011 Feb 17;470(7334):318-9. doi: 10.1038/470318a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21331016" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomedical Research/economics/*legislation & jurisprudence ; *Disease Models, Animal ; Female ; Humans ; Internationality ; Licensure/*legislation & jurisprudence ; Methyl-CpG-Binding Protein 2/genetics/immunology ; Mice ; Models, Immunological ; National Institutes of Health (U.S.) ; *Rare Diseases ; *Rett Syndrome/genetics/immunology/therapy ; Time Factors ; United States
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    Innovation: lessons from UK policy (2011)
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    Publication Date: 2011-01-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stevens, Ashley J -- England -- Nature. 2011 Jan 13;469(7329):162. doi: 10.1038/469162b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21228860" target="_blank"〉PubMed〈/a〉
    Keywords: *Federal Government ; Great Britain ; Licensure/economics/*legislation & jurisprudence ; Patents as Topic/*legislation & jurisprudence ; *Policy ; Research Support as Topic/*legislation & jurisprudence ; United States ; Universities/*economics
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    Translational research: 4 ways to fix the clinical trial (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-10-01
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ledford, Heidi -- England -- Nature. 2011 Sep 28;477(7366):526-8. doi: 10.1038/477526a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21956311" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Clinical Trials as Topic/economics/*methods/*trends ; Database Management Systems ; Disease Models, Animal ; Drug Evaluation, Preclinical/methods ; Female ; Humans ; Male ; Mice ; Multicenter Studies as Topic/methods ; Precision Medicine/economics/methods/trends ; Translational Medical Research/economics/methods/trends ; United States ; United States Food and Drug Administration/legislation & jurisprudence
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    Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-11-15
    Description: While patrolling the body in search of foreign antigens, naive lymphocytes continuously circulate from the blood, through the lymph nodes, into the lymphatic vessels and back to the blood. This process, called lymphocyte recirculation, provides the body with effective immune surveillance for foreign invaders and for alterations to the body's own cells. However, the mechanisms that regulate lymphocyte recirculation during homeostasis remain incompletely characterized. Here we show that dendritic cells (DCs), which are well known for their role in antigen presentation to T lymphocytes, control the entry of naive lymphocytes to lymph nodes by modulating the phenotype of high endothelial venules (HEVs), which are blood vessels specialized in lymphocyte recruitment. We found that in vivo depletion of CD11c(+) DCs in adult mice over a 1-week period induces a reduction in the size and cellularity of the peripheral and mucosal lymph nodes. In the absence of DCs, the mature adult HEV phenotype reverts to an immature neonatal phenotype, and HEV-mediated lymphocyte recruitment to lymph nodes is inhibited. Co-culture experiments showed that the effect of DCs on HEV endothelial cells is direct and requires lymphotoxin-beta-receptor-dependent signalling. DCs express lymphotoxin, and DC-derived lymphotoxin is important for lymphocyte homing to lymph nodes in vivo. Together, our results reveal a previously unsuspected role for DCs in the regulation of lymphocyte recirculation during immune surveillance.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moussion, Christine -- Girard, Jean-Philippe -- England -- Nature. 2011 Nov 13;479(7374):542-6. doi: 10.1038/nature10540.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CNRS, Institut de Pharmacologie et de Biologie Structurale, 205 route de Narbonne, F-31077 Toulouse, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22080953" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD11c/metabolism ; Cell Adhesion ; *Cell Movement ; Dendritic Cells/*immunology/metabolism ; Endothelial Cells/*physiology ; Homeostasis/immunology ; Immunologic Surveillance/immunology ; Leukocyte Rolling ; Lymph Nodes/*cytology/immunology ; Lymphatic System/*cytology/*immunology ; Lymphocytes/*cytology/immunology ; Lymphotoxin-alpha/immunology/metabolism ; Mice ; Mice, Inbred C57BL ; Phenotype ; Receptors, Lymphocyte Homing
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    Control of TH17 cells occurs in the small intestine (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-07-19
    Description: Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified CD4(+) T cell subset distinct from T helper type 1 (T(H)1) and T helper type 2 (T(H)2) cells. T(H)17 cells can drive antigen-specific autoimmune diseases and are considered the main population of pathogenic T cells driving experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. The factors that are needed for the generation of T(H)17 cells have been well characterized. However, where and how the immune system controls T(H)17 cells in vivo remains unclear. Here, by using a model of tolerance induced by CD3-specific antibody, a model of sepsis and influenza A viral infection (H1N1), we show that pro-inflammatory T(H)17 cells can be redirected to and controlled in the small intestine. T(H)17-specific IL-17A secretion induced expression of the chemokine CCL20 in the small intestine, facilitating the migration of these cells specifically to the small intestine via the CCR6/CCL20 axis. Moreover, we found that T(H)17 cells are controlled by two different mechanisms in the small intestine: first, they are eliminated via the intestinal lumen; second, pro-inflammatory T(H)17 cells simultaneously acquire a regulatory phenotype with in vitro and in vivo immune-suppressive properties (rT(H)17). These results identify mechanisms limiting T(H)17 cell pathogenicity and implicate the gastrointestinal tract as a site for control of T(H)17 cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148838/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3148838/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Esplugues, Enric -- Huber, Samuel -- Gagliani, Nicola -- Hauser, Anja E -- Town, Terrence -- Wan, Yisong Y -- O'Connor, William Jr -- Rongvaux, Anthony -- Van Rooijen, Nico -- Haberman, Ann M -- Iwakura, Yoichiro -- Kuchroo, Vijay K -- Kolls, Jay K -- Bluestone, Jeffrey A -- Herold, Kevan C -- Flavell, Richard A -- DK45735/DK/NIDDK NIH HHS/ -- P30 DK045735/DK/NIDDK NIH HHS/ -- P30 DK045735-20/DK/NIDDK NIH HHS/ -- R01 HL061271/HL/NHLBI NIH HHS/ -- R01 HL062052/HL/NHLBI NIH HHS/ -- R21 HL104601/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jul 17;475(7357):514-8. doi: 10.1038/nature10228.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA. enric.esplugues@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21765430" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies/immunology/pharmacology ; Antigens, CD3/immunology ; CD4-Positive T-Lymphocytes/immunology/transplantation ; Cell Movement/drug effects ; Chemokine CCL20/immunology ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Female ; Gene Expression Profiling ; Gene Expression Regulation/immunology ; Influenza A virus/immunology ; Interleukin-17/immunology ; Intestine, Small/cytology/*immunology ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Mice, Transgenic ; Orthomyxoviridae Infections/immunology ; Receptors, CCR6/immunology ; Sepsis/immunology ; Staphylococcal Infections/immunology ; Th17 Cells/*immunology
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    Miwi catalysis is required for piRNA amplification-independent LINE1 transposon silencing (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-11-29
    Description: Repetitive-element-derived Piwi-interacting RNAs (piRNAs) act together with Piwi proteins Mili (also known as Piwil2) and Miwi2 (also known as Piwil4) in a genome defence mechanism that initiates transposon silencing via DNA methylation in the mouse male embryonic germ line. This silencing depends on the participation of the Piwi proteins in a slicer-dependent piRNA amplification pathway and is essential for male fertility. A third Piwi family member, Miwi (also known as Piwil1), is expressed in specific postnatal germ cells and associates with a unique set of piRNAs of unknown function. Here we show that Miwi is a small RNA-guided RNase (slicer) that requires extensive complementarity for target cleavage in vitro. Disruption of its catalytic activity in mice by a single point mutation causes male infertility, and mutant germ cells show increased accumulation of LINE1 retrotransposon transcripts. We provide evidence for Miwi slicer activity directly cleaving transposon messenger RNAs, offering an explanation for the continued maintenance of repeat-derived piRNAs long after transposon silencing is established in germline stem cells. Furthermore, our study supports a slicer-dependent silencing mechanism that functions without piRNA amplification. Thus, Piwi proteins seem to act in a two-pronged mammalian transposon silencing strategy: one promotes transcriptional repression in the embryo, the other reinforces silencing at the post-transcriptional level after birth.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Reuter, Michael -- Berninger, Philipp -- Chuma, Shinichiro -- Shah, Hardik -- Hosokawa, Mihoko -- Funaya, Charlotta -- Antony, Claude -- Sachidanandam, Ravi -- Pillai, Ramesh S -- England -- Nature. 2011 Nov 27;480(7376):264-7. doi: 10.1038/nature10672.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, 6 Rue Jules Horowitz, BP 181, 38042 Grenoble, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22121019" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins/deficiency/genetics/*metabolism ; *Biocatalysis ; DNA Transposable Elements/*genetics ; *Gene Silencing ; Infertility, Male/genetics ; Long Interspersed Nucleotide Elements/*genetics ; Male ; Mice ; Mutation/genetics ; RNA, Messenger/genetics/metabolism ; RNA, Small Interfering/*biosynthesis/genetics ; Spermatogenesis/genetics ; Substrate Specificity
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    Day of reckoning for Ecuador's biodiversity (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-01-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Swing, Kelly -- England -- Nature. 2011 Jan 20;469(7330):267. doi: 10.1038/469267a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tiputini Biodiversity Station, University of San Francisco de Quito, Ecuador. kswing@usfq.edu.ec〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21248795" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biodiversity ; Conservation of Natural Resources/*economics/methods/*trends ; Ecuador ; *Federal Government ; Forestry/economics/trends ; Petroleum/economics/supply & distribution ; Trust ; *Wilderness
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    Melanopsin signalling in mammalian iris and retina (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-11-05
    Description: Non-mammalian vertebrates have an intrinsically photosensitive iris and thus a local pupillary light reflex (PLR). In contrast, it is thought that the PLR in mammals generally requires neuronal circuitry connecting the eye and the brain. Here we report that an intrinsic component of the PLR is in fact widespread in nocturnal and crepuscular mammals. In mouse, this intrinsic PLR requires the visual pigment melanopsin; it also requires PLCbeta4, a vertebrate homologue of the Drosophila NorpA phospholipase C which mediates rhabdomeric phototransduction. The Plcb4(-/-) genotype, in addition to removing the intrinsic PLR, also essentially eliminates the intrinsic light response of the M1 subtype of melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (M1-ipRGCs), which are by far the most photosensitive ipRGC subtype and also have the largest response to light. Ablating in mouse the expression of both TRPC6 and TRPC7, members of the TRP channel superfamily, also essentially eliminated the M1-ipRGC light response but the intrinsic PLR was not affected. Thus, melanopsin signalling exists in both iris and retina, involving a PLCbeta4-mediated pathway that nonetheless diverges in the two locations.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270891/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3270891/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xue, T -- Do, M T H -- Riccio, A -- Jiang, Z -- Hsieh, J -- Wang, H C -- Merbs, S L -- Welsbie, D S -- Yoshioka, T -- Weissgerber, P -- Stolz, S -- Flockerzi, V -- Freichel, M -- Simon, M I -- Clapham, D E -- Yau, K-W -- EY14596/EY/NEI NIH HHS/ -- R01 DC006904/DC/NIDCD NIH HHS/ -- R01 DC006904-07/DC/NIDCD NIH HHS/ -- R01 DC006904-08/DC/NIDCD NIH HHS/ -- R01 DC006904-09/DC/NIDCD NIH HHS/ -- R01 EY006837/EY/NEI NIH HHS/ -- R01 EY006837-22/EY/NEI NIH HHS/ -- R01 EY006837-23/EY/NEI NIH HHS/ -- R01 EY006837-24/EY/NEI NIH HHS/ -- R37 EY006837/EY/NEI NIH HHS/ -- R37 EY006837-13/EY/NEI NIH HHS/ -- R37 EY006837-14/EY/NEI NIH HHS/ -- R37 EY006837-15/EY/NEI NIH HHS/ -- R37 EY006837-15S1/EY/NEI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Nov 2;479(7371):67-73. doi: 10.1038/nature10567.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. txue77@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22051675" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Iris/anatomy & histology/cytology/*metabolism/*radiation effects ; Light Signal Transduction/physiology/*radiation effects ; Mammals/*physiology ; Mice ; Phospholipase C beta/metabolism ; Photic Stimulation ; Primates/physiology ; Reflex, Pupillary/physiology/radiation effects ; Retina/cytology/*metabolism/*radiation effects ; Retinal Ganglion Cells/metabolism/radiation effects ; Rod Opsins/*metabolism
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    Nuclear energy: Nationalize the Fukushima Daiichi atomic plant (2011)
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    Publication Date: 2011-12-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Taira, Tomoyuki -- Hatoyama, Yukio -- England -- Nature. 2011 Dec 14;480(7377):313-4. doi: 10.1038/480313a.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉g11426@shugiin.go.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22170662" target="_blank"〉PubMed〈/a〉
    Keywords: Disasters ; Earthquakes ; Environmental Monitoring ; Explosions/statistics & numerical data ; *Federal Government ; Japan ; Nuclear Energy ; Nuclear Power Plants/*legislation & jurisprudence/standards/statistics & ; numerical data ; Public Sector/*legislation & jurisprudence ; Radioactive Fallout/analysis/statistics & numerical data ; Radioactive Hazard Release/*statistics & numerical data ; Tsunamis ; Xenon Radioisotopes/analysis/chemistry
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    Stem cells: The growing pains of pluripotency (2011)
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    Publication Date: 2011-05-20
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hayden, Erika Check -- England -- Nature. 2011 May 19;473(7347):272-4. doi: 10.1038/473272a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21593837" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/cytology/metabolism ; Animals ; Cellular Reprogramming/genetics ; Epistasis, Genetic/genetics ; Humans ; Induced Pluripotent Stem Cells/*cytology/metabolism ; Insulin-Secreting Cells/cytology/transplantation ; Mice ; Models, Biological ; Mutation ; Precision Medicine/trends ; Regenerative Medicine/*trends ; *Stem Cell Research
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    Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking (2011)
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    Publication Date: 2011-07-01
    Description: The basolateral amygdala (BLA) has a crucial role in emotional learning irrespective of valence. The BLA projection to the nucleus accumbens (NAc) is thought to modulate cue-triggered motivated behaviours, but our understanding of the interaction between these two brain regions has been limited by the inability to manipulate neural-circuit elements of this pathway selectively during behaviour. To circumvent this limitation, we used in vivo optogenetic stimulation or inhibition of glutamatergic fibres from the BLA to the NAc, coupled with intracranial pharmacology and ex vivo electrophysiology. Here we show that optical stimulation of the pathway from the BLA to the NAc in mice reinforces behavioural responding to earn additional optical stimulation of these synaptic inputs. Optical stimulation of these glutamatergic fibres required intra-NAc dopamine D1-type receptor signalling, but not D2-type receptor signalling. Brief optical inhibition of fibres from the BLA to the NAc reduced cue-evoked intake of sucrose, demonstrating an important role of this specific pathway in controlling naturally occurring reward-related behaviour. Moreover, although optical stimulation of glutamatergic fibres from the medial prefrontal cortex to the NAc also elicited reliable excitatory synaptic responses, optical self-stimulation behaviour was not observed by activation of this pathway. These data indicate that whereas the BLA is important for processing both positive and negative affect, the glutamatergic pathway from the BLA to the NAc, in conjunction with dopamine signalling in the NAc, promotes motivated behavioural responding. Thus, optogenetic manipulation of anatomically distinct synaptic inputs to the NAc reveals functionally distinct properties of these inputs in controlling reward-seeking behaviours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775282/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3775282/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Stuber, Garret D -- Sparta, Dennis R -- Stamatakis, Alice M -- van Leeuwen, Wieke A -- Hardjoprajitno, Juanita E -- Cho, Saemi -- Tye, Kay M -- Kempadoo, Kimberly A -- Zhang, Feng -- Deisseroth, Karl -- Bonci, Antonello -- DA029325/DA/NIDA NIH HHS/ -- F32AA018610/AA/NIAAA NIH HHS/ -- R01 DA032750/DA/NIDA NIH HHS/ -- R21 DA029325/DA/NIDA NIH HHS/ -- England -- Nature. 2011 Jun 29;475(7356):377-80. doi: 10.1038/nature10194.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Psychiatry, UNC Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA. gstuber@med.unc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21716290" target="_blank"〉PubMed〈/a〉
    Keywords: Amygdala/cytology/*physiology ; Animals ; Behavior, Addictive/physiopathology ; Cues ; Dopamine/metabolism ; Drinking ; Excitatory Postsynaptic Potentials/*physiology ; Glutamic Acid/metabolism ; Light ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Fibers/physiology ; Neural Pathways/*physiology ; Neurons/metabolism ; Nucleus Accumbens/cytology/*physiology ; Patch-Clamp Techniques ; Photic Stimulation ; Receptors, Dopamine D1/antagonists & inhibitors/metabolism ; *Reward ; Rhodopsin/genetics/metabolism ; Sucrose/metabolism/pharmacology
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    DCC constrains tumour progression via its dependence receptor activity (2011)
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    Publication Date: 2011-12-14
    Description: The role of deleted in colorectal carcinoma (DCC) as a tumour suppressor has been a matter of debate for the past 15 years. DCC gene expression is lost or markedly reduced in the majority of advanced colorectal cancers and, by functioning as a dependence receptor, DCC has been shown to induce apoptosis unless engaged by its ligand, netrin-1 (ref. 2). However, so far no animal model has supported the view that the DCC loss-of-function is causally implicated as predisposing to aggressive cancer development. To investigate the role of DCC-induced apoptosis in the control of tumour progression, here we created a mouse model in which the pro-apoptotic activity of DCC is genetically silenced. Although the loss of DCC-induced apoptosis in this mouse model is not associated with a major disorganization of the intestines, it leads to spontaneous intestinal neoplasia at a relatively low frequency. Loss of DCC-induced apoptosis is also associated with an increase in the number and aggressiveness of intestinal tumours in a predisposing APC mutant context, resulting in the development of highly invasive adenocarcinomas. These results demonstrate that DCC functions as a tumour suppressor via its ability to trigger tumour cell apoptosis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Castets, Marie -- Broutier, Laura -- Molin, Yann -- Brevet, Marie -- Chazot, Guillaume -- Gadot, Nicolas -- Paquet, Armelle -- Mazelin, Laetitia -- Jarrosson-Wuilleme, Loraine -- Scoazec, Jean-Yves -- Bernet, Agnes -- Mehlen, Patrick -- England -- Nature. 2011 Dec 11;482(7386):534-7. doi: 10.1038/nature10708.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Apoptosis, Cancer and Development Laboratory - Equipe labellisee La Ligue, LabEx DEVweCAN, Centre de Cancerologie de Lyon, INSERM U1052-CNRS UMR5286, Universite de Lyon, Centre Leon Berard, 69008 Lyon, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158121" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/genetics/pathology ; Animals ; Apoptosis/genetics ; Caspases/metabolism ; Cells, Cultured ; Disease Models, Animal ; *Disease Progression ; Fibroblasts ; Gene Silencing ; Genes, APC ; HEK293 Cells ; Humans ; Intestinal Neoplasms/*genetics/metabolism/*pathology ; Mice ; Mutant Proteins/genetics/metabolism ; Mutation ; Nerve Growth Factors/deficiency/genetics ; Receptors, Cell Surface/deficiency/genetics/*metabolism ; Tumor Suppressor Proteins/deficiency/genetics/*metabolism
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    Reductive carboxylation supports growth in tumour cells with defective mitochondria (2011)
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    Publication Date: 2011-11-22
    Description: Mitochondrial metabolism provides precursors to build macromolecules in growing cancer cells. In normally functioning tumour cell mitochondria, oxidative metabolism of glucose- and glutamine-derived carbon produces citrate and acetyl-coenzyme A for lipid synthesis, which is required for tumorigenesis. Yet some tumours harbour mutations in the citric acid cycle (CAC) or electron transport chain (ETC) that disable normal oxidative mitochondrial function, and it is unknown how cells from such tumours generate precursors for macromolecular synthesis. Here we show that tumour cells with defective mitochondria use glutamine-dependent reductive carboxylation rather than oxidative metabolism as the major pathway of citrate formation. This pathway uses mitochondrial and cytosolic isoforms of NADP(+)/NADPH-dependent isocitrate dehydrogenase, and subsequent metabolism of glutamine-derived citrate provides both the acetyl-coenzyme A for lipid synthesis and the four-carbon intermediates needed to produce the remaining CAC metabolites and related macromolecular precursors. This reductive, glutamine-dependent pathway is the dominant mode of metabolism in rapidly growing malignant cells containing mutations in complex I or complex III of the ETC, in patient-derived renal carcinoma cells with mutations in fumarate hydratase, and in cells with normal mitochondria subjected to acute pharmacological ETC inhibition. Our findings reveal the novel induction of a versatile glutamine-dependent pathway that reverses many of the reactions of the canonical CAC, supports tumour cell growth, and explains how cells generate pools of CAC intermediates in the face of impaired mitochondrial metabolism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262117/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3262117/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mullen, Andrew R -- Wheaton, William W -- Jin, Eunsook S -- Chen, Pei-Hsuan -- Sullivan, Lucas B -- Cheng, Tzuling -- Yang, Youfeng -- Linehan, W Marston -- Chandel, Navdeep S -- DeBerardinis, Ralph J -- 5T32GM083831/GM/NIGMS NIH HHS/ -- DK078933/DK/NIDDK NIH HHS/ -- K01 DK078933/DK/NIDDK NIH HHS/ -- K01 DK078933-03/DK/NIDDK NIH HHS/ -- K08 DK072565/DK/NIDDK NIH HHS/ -- K08 DK072565-06/DK/NIDDK NIH HHS/ -- K08DK072565/DK/NIDDK NIH HHS/ -- P41 RR002584/RR/NCRR NIH HHS/ -- P41 RR002584-22/RR/NCRR NIH HHS/ -- R01 CA123067/CA/NCI NIH HHS/ -- R01 CA123067-05/CA/NCI NIH HHS/ -- R01 CA157996/CA/NCI NIH HHS/ -- R01 CA157996-01/CA/NCI NIH HHS/ -- R01CA123067/CA/NCI NIH HHS/ -- R01CA157996/CA/NCI NIH HHS/ -- RR02584/RR/NCRR NIH HHS/ -- T32 CA009560/CA/NCI NIH HHS/ -- T32 CA009560-20/CA/NCI NIH HHS/ -- T32 GM008061/GM/NIGMS NIH HHS/ -- T32 GM008061-30/GM/NIGMS NIH HHS/ -- T32 GM083831/GM/NIGMS NIH HHS/ -- T32 GM083831-04/GM/NIGMS NIH HHS/ -- T32CA009560/CA/NCI NIH HHS/ -- T32GM008061/GM/NIGMS NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2011 Nov 20;481(7381):385-8. doi: 10.1038/nature10642.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, University of Texas - Southwestern Medical Center at Dallas, Dallas, Texas 75390-9063, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22101431" target="_blank"〉PubMed〈/a〉
    Keywords: Acetyl Coenzyme A/metabolism ; Animals ; Carcinoma, Renal Cell/genetics/metabolism/pathology ; Cell Hypoxia ; Cell Line, Tumor ; Citric Acid/metabolism ; Electron Transport ; Electron Transport Complex I/metabolism ; Electron Transport Complex III/metabolism ; Fumarate Hydratase/genetics/metabolism ; Glucose/metabolism ; Glutamine/metabolism ; Humans ; Isocitrate Dehydrogenase/metabolism ; Kidney Neoplasms/genetics/metabolism/pathology ; Mice ; Mitochondria/*metabolism/*pathology ; NADP/metabolism ; Neoplasms/*metabolism/*pathology
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-12-14
    Description: The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-alpha (TNF-alpha) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-alpha and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487691/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3487691/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fritz, Jorg H -- Rojas, Olga Lucia -- Simard, Nathalie -- McCarthy, Douglas D -- Hapfelmeier, Siegfried -- Rubino, Stephen -- Robertson, Susan J -- Larijani, Mani -- Gosselin, Jean -- Ivanov, Ivaylo I -- Martin, Alberto -- Casellas, Rafael -- Philpott, Dana J -- Girardin, Stephen E -- McCoy, Kathy D -- Macpherson, Andrew J -- Paige, Christopher J -- Gommerman, Jennifer L -- 67157-3/Canadian Institutes of Health Research/Canada -- 89783-2/Canadian Institutes of Health Research/Canada -- MOP 114972/Canadian Institutes of Health Research/Canada -- MOP 67157/Canadian Institutes of Health Research/Canada -- MOP 89783/Canadian Institutes of Health Research/Canada -- MOP 9862/Canadian Institutes of Health Research/Canada -- R00 DK085329/DK/NIDDK NIH HHS/ -- R00 DK085329-02/DK/NIDDK NIH HHS/ -- Z01 AR041148-03/Intramural NIH HHS/ -- ZIA AR041148-08/Intramural NIH HHS/ -- England -- Nature. 2011 Dec 11;481(7380):199-203. doi: 10.1038/nature10698.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Toronto, Toronto M5S 1A8, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158124" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Lineage ; Cells, Cultured ; Chimera/immunology ; Citrobacter rodentium/immunology ; Coculture Techniques ; Female ; Germ-Free Life ; Granulocytes/cytology/metabolism ; Immunity, Innate/immunology ; Immunoglobulin A/biosynthesis/*immunology ; Intestinal Mucosa/cytology/immunology ; Intestine, Small/*cytology/*immunology/microbiology ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Monocytes/cytology/metabolism ; Nitric Oxide Synthase Type II/biosynthesis/deficiency/metabolism ; Phenotype ; Plasma Cells/*cytology/*immunology/metabolism ; Spleen/cytology ; Stromal Cells/cytology ; Tumor Necrosis Factor-alpha/biosynthesis/deficiency/immunology/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Reversal of cocaine-evoked synaptic potentiation resets drug-induced adaptive behaviour (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-12-14
    Description: Drug-evoked synaptic plasticity is observed at many synapses and may underlie behavioural adaptations in addiction. Mechanistic investigations start with the identification of the molecular drug targets. Cocaine, for example, exerts its reinforcing and early neuroadaptive effects by inhibiting the dopamine transporter, thus causing a strong increase in mesolimbic dopamine. Among the many signalling pathways subsequently engaged, phosphorylation of the extracellular signal-regulated kinase (ERK) in the nucleus accumbens is of particular interest because it has been implicated in NMDA-receptor and type 1 dopamine (D1)-receptor-dependent synaptic potentiation as well as in several behavioural adaptations. A causal link between drug-evoked plasticity at identified synapses and behavioural adaptations, however, is missing, and the benefits of restoring baseline transmission have yet to be demonstrated. Here we find that cocaine potentiates excitatory transmission in D1-receptor-expressing medium-sized spiny neurons (D1R-MSNs) in mice via ERK signalling with a time course that parallels locomotor sensitization. Depotentiation of cortical nucleus accumbens inputs by optogenetic stimulation in vivo efficiently restored normal transmission and abolished cocaine-induced locomotor sensitization. These findings establish synaptic potentiation selectively in D1R-MSNs as a mechanism underlying a core component of addiction, probably by creating an imbalance between distinct populations of MSNs in the nucleus accumbens. Our data also provide proof of principle that reversal of cocaine-evoked synaptic plasticity can treat behavioural alterations caused by addictive drugs and may inspire novel therapeutic approaches involving deep brain stimulation or transcranial magnetic stimulation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pascoli, Vincent -- Turiault, Marc -- Luscher, Christian -- England -- Nature. 2011 Dec 7;481(7379):71-5. doi: 10.1038/nature10709.〈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/22158102" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptation, Physiological/drug effects ; Animals ; Cocaine/administration & dosage/*pharmacology ; Cocaine-Related Disorders/metabolism/pathology ; Dopaminergic Neurons/drug effects/metabolism ; Electric Stimulation ; Enzyme Activation ; Excitatory Postsynaptic Potentials/drug effects ; Extracellular Signal-Regulated MAP Kinases/metabolism ; Injections ; Long-Term Potentiation/drug effects ; MAP Kinase Signaling System/drug effects ; Mice ; Mice, Inbred C57BL ; Motor Activity/drug effects ; Neuronal Plasticity/drug effects ; Nucleus Accumbens/cytology/drug effects ; Phenotype ; Receptors, Dopamine D1/metabolism ; Synapses/drug effects/metabolism ; Synaptic Transmission/drug effects
    Print ISSN: 0028-0836
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    Interactions between cancer stem cells and their niche govern metastatic colonization (2011)
    Nature Publishing Group (NPG)
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    Publication Date: 2011-12-14
    Description: Metastatic growth in distant organs is the major cause of cancer mortality. The development of metastasis is a multistage process with several rate-limiting steps. Although dissemination of tumour cells seems to be an early and frequent event, the successful initiation of metastatic growth, a process termed 'metastatic colonization', is inefficient for many cancer types and is accomplished only by a minority of cancer cells that reach distant sites. Prevalent target sites are characteristic of many tumour entities, suggesting that inadequate support by distant tissues contributes to the inefficiency of the metastatic process. Here we show that a small population of cancer stem cells is critical for metastatic colonization, that is, the initial expansion of cancer cells at the secondary site, and that stromal niche signals are crucial to this expansion process. We find that periostin (POSTN), a component of the extracellular matrix, is expressed by fibroblasts in the normal tissue and in the stroma of the primary tumour. Infiltrating tumour cells need to induce stromal POSTN expression in the secondary target organ (in this case lung) to initiate colonization. POSTN is required to allow cancer stem cell maintenance, and blocking its function prevents metastasis. POSTN recruits Wnt ligands and thereby increases Wnt signalling in cancer stem cells. We suggest that the education of stromal cells by infiltrating tumour cells is an important step in metastatic colonization and that preventing de novo niche formation may be a novel strategy for the treatment of metastatic disease.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Malanchi, Ilaria -- Santamaria-Martinez, Albert -- Susanto, Evelyn -- Peng, Hong -- Lehr, Hans-Anton -- Delaloye, Jean-Francois -- Huelsken, Joerg -- England -- Nature. 2011 Dec 7;481(7379):85-9. doi: 10.1038/nature10694.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Ecole Polytechnique Federale de Lausanne, Swiss Institute for Experimental Cancer Research and National Center of Competence in Research Molecular Oncology, 1015 Lausanne, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22158103" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/pathology ; Cell Adhesion Molecules/genetics/metabolism ; Female ; Lung Neoplasms/secondary ; Mice ; Mice, Inbred C57BL ; Neoplasm Metastasis/*pathology ; Neoplastic Stem Cells/metabolism/*pathology ; Stem Cell Niche/*physiology ; Stromal Cells/metabolism ; Wnt Signaling Pathway
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-10-25
    Description: Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923348/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3923348/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Han, Kihoon -- Holder, J Lloyd Jr -- Schaaf, Christian P -- Lu, Hui -- Chen, Hongmei -- Kang, Hyojin -- Tang, Jianrong -- Wu, Zhenyu -- Hao, Shuang -- Cheung, Sau Wai -- Yu, Peng -- Sun, Hao -- Breman, Amy M -- Patel, Ankita -- Lu, Hui-Chen -- Zoghbi, Huda Y -- 1R01NS070302/NS/NINDS NIH HHS/ -- 2T32NS043124/NS/NINDS NIH HHS/ -- P30HD024064/HD/NICHD NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA [3] Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24153177" target="_blank"〉PubMed〈/a〉
    Keywords: Actin-Related Protein 2-3 Complex/metabolism ; Actins/metabolism ; Adult ; Animals ; Behavior, Animal ; Bipolar Disorder/*drug therapy/genetics/*physiopathology ; Chromosomes, Human, Pair 22/genetics ; Disease Models, Animal ; Excitatory Postsynaptic Potentials ; Female ; Gene Dosage/genetics ; Gene Expression/genetics ; Genes, Duplicate/genetics ; Humans ; Hyperkinesis/genetics/physiopathology ; Inhibitory Postsynaptic Potentials ; Lithium/pharmacology ; Male ; Mice ; Mice, Transgenic ; Nerve Tissue Proteins/*genetics/*metabolism ; Seizures/genetics ; Valproic Acid/pharmacology/therapeutic use
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    CLP1 links tRNA metabolism to progressive motor-neuron loss (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-12
    Description: CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clp1 (Clp1(K/K)) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues Clp1(K/K) mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674495/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Toshikatsu -- Weitzer, Stefan -- Mair, Barbara -- Bernreuther, Christian -- Wainger, Brian J -- Ichida, Justin -- Hanada, Reiko -- Orthofer, Michael -- Cronin, Shane J -- Komnenovic, Vukoslav -- Minis, Adi -- Sato, Fuminori -- Mimata, Hiromitsu -- Yoshimura, Akihiko -- Tamir, Ido -- Rainer, Johannes -- Kofler, Reinhard -- Yaron, Avraham -- Eggan, Kevin C -- Woolf, Clifford J -- Glatzel, Markus -- Herbst, Ruth -- Martinez, Javier -- Penninger, Josef M -- K99NS077435-01A1/NS/NINDS NIH HHS/ -- NS038253/NS/NINDS NIH HHS/ -- P 19223/Austrian Science Fund FWF/Austria -- P 21667/Austrian Science Fund FWF/Austria -- R00 NS077435/NS/NINDS NIH HHS/ -- R01 NS038253/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Mar 28;495(7442):474-80. doi: 10.1038/nature11923. Epub 2013 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna 1030, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23474986" target="_blank"〉PubMed〈/a〉
    Keywords: Amyotrophic Lateral Sclerosis ; Animals ; Animals, Newborn ; Axons/metabolism/pathology ; Cell Death ; Diaphragm/innervation ; Embryo Loss ; Embryo, Mammalian/metabolism/pathology ; Exons/genetics ; Female ; Fibroblasts ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Motor Neurons/*metabolism/*pathology ; Muscular Atrophy, Spinal ; Neuromuscular Diseases/metabolism/pathology ; Oxidative Stress ; RNA Processing, Post-Transcriptional ; RNA, Transfer, Tyr/genetics/*metabolism ; Respiration ; Spinal Nerves/cytology ; Transcription Factors/deficiency/*metabolism ; Tumor Suppressor Protein p53/metabolism ; Tyrosine/genetics/metabolism
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    Microbial colonization influences early B-lineage development in the gut lamina propria (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-24
    Description: The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH mu and IgL (Igkappa or Iglambda) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igkappa V(D)J recombination that replaces the initial VkappaJkappa exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Iglambda V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vkappa repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Iglambda-expressing versus Igkappa-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807868/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3807868/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wesemann, Duane R -- Portuguese, Andrew J -- Meyers, Robin M -- Gallagher, Michael P -- Cluff-Jones, Kendra -- Magee, Jennifer M -- Panchakshari, Rohit A -- Rodig, Scott J -- Kepler, Thomas B -- Alt, Frederick W -- AI020047/AI/NIAID NIH HHS/ -- AI89972/AI/NIAID NIH HHS/ -- HHSN272201000053C/PHS HHS/ -- K08 AI089972/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 5;501(7465):112-5. doi: 10.1038/nature12496. Epub 2013 Aug 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program in Cellular and Molecular Medicine and Department of Medicine, Children's Hospital Boston, Boston, Massachusetts 02115, USA. dwesemann@research.bwh.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23965619" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*cytology/*immunology/metabolism ; Bone Marrow Cells/cytology/immunology ; *Cell Lineage ; DNA-Binding Proteins/genetics/metabolism ; Gene Rearrangement, B-Lymphocyte/genetics ; Germ-Free Life ; Immunoglobulins/genetics/immunology ; Intestinal Mucosa/*cytology/*immunology ; Mice ; Precursor Cells, B-Lymphoid/cytology/metabolism ; Symbiosis ; Weaning
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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