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  • Mice  (114)
  • Nature Publishing Group (NPG)  (114)
  • Institute of Physics
  • 2010-2014  (114)
  • 1955-1959
  • 2013  (114)
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  • 2010-2014  (114)
  • 1955-1959
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  • 1
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    The African coelacanth genome provides insights into tetrapod evolution (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-20
    Description: The discovery of a living coelacanth specimen in 1938 was remarkable, as this lineage of lobe-finned fish was thought to have become extinct 70 million years ago. The modern coelacanth looks remarkably similar to many of its ancient relatives, and its evolutionary proximity to our own fish ancestors provides a glimpse of the fish that first walked on land. Here we report the genome sequence of the African coelacanth, Latimeria chalumnae. Through a phylogenomic analysis, we conclude that the lungfish, and not the coelacanth, is the closest living relative of tetrapods. Coelacanth protein-coding genes are significantly more slowly evolving than those of tetrapods, unlike other genomic features. Analyses of changes in genes and regulatory elements during the vertebrate adaptation to land highlight genes involved in immunity, nitrogen excretion and the development of fins, tail, ear, eye, brain and olfaction. Functional assays of enhancers involved in the fin-to-limb transition and in the emergence of extra-embryonic tissues show the importance of the coelacanth genome as a blueprint for understanding tetrapod evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633110/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3633110/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Amemiya, Chris T -- Alfoldi, Jessica -- Lee, Alison P -- Fan, Shaohua -- Philippe, Herve -- Maccallum, Iain -- Braasch, Ingo -- Manousaki, Tereza -- Schneider, Igor -- Rohner, Nicolas -- Organ, Chris -- Chalopin, Domitille -- Smith, Jeramiah J -- Robinson, Mark -- Dorrington, Rosemary A -- Gerdol, Marco -- Aken, Bronwen -- Biscotti, Maria Assunta -- Barucca, Marco -- Baurain, Denis -- Berlin, Aaron M -- Blatch, Gregory L -- Buonocore, Francesco -- Burmester, Thorsten -- Campbell, Michael S -- Canapa, Adriana -- Cannon, John P -- Christoffels, Alan -- De Moro, Gianluca -- Edkins, Adrienne L -- Fan, Lin -- Fausto, Anna Maria -- Feiner, Nathalie -- Forconi, Mariko -- Gamieldien, Junaid -- Gnerre, Sante -- Gnirke, Andreas -- Goldstone, Jared V -- Haerty, Wilfried -- Hahn, Mark E -- Hesse, Uljana -- Hoffmann, Steve -- Johnson, Jeremy -- Karchner, Sibel I -- Kuraku, Shigehiro -- Lara, Marcia -- Levin, Joshua Z -- Litman, Gary W -- Mauceli, Evan -- Miyake, Tsutomu -- Mueller, M Gail -- Nelson, David R -- Nitsche, Anne -- Olmo, Ettore -- Ota, Tatsuya -- Pallavicini, Alberto -- Panji, Sumir -- Picone, Barbara -- Ponting, Chris P -- Prohaska, Sonja J -- Przybylski, Dariusz -- Saha, Nil Ratan -- Ravi, Vydianathan -- Ribeiro, Filipe J -- Sauka-Spengler, Tatjana -- Scapigliati, Giuseppe -- Searle, Stephen M J -- Sharpe, Ted -- Simakov, Oleg -- Stadler, Peter F -- Stegeman, John J -- Sumiyama, Kenta -- Tabbaa, Diana -- Tafer, Hakim -- Turner-Maier, Jason -- van Heusden, Peter -- White, Simon -- Williams, Louise -- Yandell, Mark -- Brinkmann, Henner -- Volff, Jean-Nicolas -- Tabin, Clifford J -- Shubin, Neil -- Schartl, Manfred -- Jaffe, David B -- Postlethwait, John H -- Venkatesh, Byrappa -- Di Palma, Federica -- Lander, Eric S -- Meyer, Axel -- Lindblad-Toh, Kerstin -- 095908/Wellcome Trust/United Kingdom -- MC_U137761446/Medical Research Council/United Kingdom -- P42 ES007381/ES/NIEHS NIH HHS/ -- R01 ES006272/ES/NIEHS NIH HHS/ -- R01 HG003474/HG/NHGRI NIH HHS/ -- R01 OD011116/OD/NIH HHS/ -- R24 OD011199/OD/NIH HHS/ -- R24 RR032670/RR/NCRR NIH HHS/ -- R37 HD032443/HD/NICHD NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- England -- Nature. 2013 Apr 18;496(7445):311-6. doi: 10.1038/nature12027.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Genetics Program, Benaroya Research Institute, Seattle, Washington 98101, USA. camemiya@benaroyaresearch.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23598338" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; *Biological Evolution ; Chick Embryo ; Conserved Sequence/genetics ; Enhancer Elements, Genetic/genetics ; Evolution, Molecular ; Extremities/anatomy & histology/growth & development ; Fishes/anatomy & histology/*classification/*genetics/physiology ; Genes, Homeobox/genetics ; Genome/*genetics ; Genomics ; Immunoglobulin M/genetics ; Mice ; Molecular Sequence Annotation ; Molecular Sequence Data ; Phylogeny ; Sequence Alignment ; Sequence Analysis, DNA ; Vertebrates/anatomy & histology/genetics/physiology
    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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    Maternal imprinting at the H19-Igf2 locus maintains adult haematopoietic stem cell quiescence (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-07-19
    Description: The epigenetic regulation of imprinted genes by monoallelic DNA methylation of either maternal or paternal alleles is critical for embryonic growth and development. Imprinted genes were recently shown to be expressed in mammalian adult stem cells to support self-renewal of neural and lung stem cells; however, a role for imprinting per se in adult stem cells remains elusive. Here we show upregulation of growth-restricting imprinted genes, including in the H19-Igf2 locus, in long-term haematopoietic stem cells and their downregulation upon haematopoietic stem cell activation and proliferation. A differentially methylated region upstream of H19 (H19-DMR), serving as the imprinting control region, determines the reciprocal expression of H19 from the maternal allele and Igf2 from the paternal allele. In addition, H19 serves as a source of miR-675, which restricts Igf1r expression. We demonstrate that conditional deletion of the maternal but not the paternal H19-DMR reduces adult haematopoietic stem cell quiescence, a state required for long-term maintenance of haematopoietic stem cells, and compromises haematopoietic stem cell function. Maternal-specific H19-DMR deletion results in activation of the Igf2-Igfr1 pathway, as shown by the translocation of phosphorylated FoxO3 (an inactive form) from nucleus to cytoplasm and the release of FoxO3-mediated cell cycle arrest, thus leading to increased activation, proliferation and eventual exhaustion of haematopoietic stem cells. Mechanistically, maternal-specific H19-DMR deletion leads to Igf2 upregulation and increased translation of Igf1r, which is normally suppressed by H19-derived miR-675. Similarly, genetic inactivation of Igf1r partly rescues the H19-DMR deletion phenotype. Our work establishes a new role for this unique form of epigenetic control at the H19-Igf2 locus in maintaining adult stem cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896866/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3896866/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Venkatraman, Aparna -- He, Xi C -- Thorvaldsen, Joanne L -- Sugimura, Ryohichi -- Perry, John M -- Tao, Fang -- Zhao, Meng -- Christenson, Matthew K -- Sanchez, Rebeca -- Yu, Jaclyn Y -- Peng, Lai -- Haug, Jeffrey S -- Paulson, Ariel -- Li, Hua -- Zhong, Xiao-bo -- Clemens, Thomas L -- Bartolomei, Marisa S -- Li, Linheng -- GM51279/GM/NIGMS NIH HHS/ -- R01 GM087376/GM/NIGMS NIH HHS/ -- R37 GM051279/GM/NIGMS NIH HHS/ -- England -- Nature. 2013 Aug 15;500(7462):345-9. doi: 10.1038/nature12303. Epub 2013 Jul 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Stowers Institute for Medical Research, Kansas City, Missouri 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23863936" target="_blank"〉PubMed〈/a〉
    Keywords: Adult Stem Cells/*cytology/*physiology ; Animals ; Epigenesis, Genetic/genetics ; Gene Expression Regulation, Developmental ; *Genomic Imprinting ; Insulin-Like Growth Factor II/*genetics/*metabolism ; Mice ; RNA, Long Noncoding/*genetics/*metabolism ; Receptor, IGF Type 1/genetics ; Signal Transduction ; Transcriptional Activation
    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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    Differential stem- and progenitor-cell trafficking by prostaglandin E2 (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-15
    Description: To maintain lifelong production of blood cells, haematopoietic stem cells (HSCs) are tightly regulated by inherent programs and extrinsic regulatory signals received from their microenvironmental niche. Long-term repopulating HSCs reside in several, perhaps overlapping, niches that produce regulatory molecules and signals necessary for homeostasis and for increased output after stress or injury. Despite considerable advances in the specific cellular or molecular mechanisms governing HSC-niche interactions, little is known about the regulatory function in the intact mammalian haematopoietic niche. Recently, we and others described a positive regulatory role for prostaglandin E2 (PGE2) on HSC function ex vivo. Here we show that inhibition of endogenous PGE2 by non-steroidal anti-inflammatory drug (NSAID) treatment in mice results in modest HSC egress from the bone marrow. Surprisingly, this was independent of the SDF-1-CXCR4 axis implicated in stem-cell migration. Stem and progenitor cells were found to have differing mechanisms of egress, with HSC transit to the periphery dependent on niche attenuation and reduction in the retentive molecule osteopontin. Haematopoietic grafts mobilized with NSAIDs had superior repopulating ability and long-term engraftment. Treatment of non-human primates and healthy human volunteers confirmed NSAID-mediated egress in other species. PGE2 receptor knockout mice demonstrated that progenitor expansion and stem/progenitor egress resulted from reduced E-prostanoid 4 (EP4) receptor signalling. These results not only uncover unique regulatory roles for EP4 signalling in HSC retention in the niche, but also define a rapidly translatable strategy to enhance transplantation therapeutically.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606692/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3606692/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hoggatt, Jonathan -- Mohammad, Khalid S -- Singh, Pratibha -- Hoggatt, Amber F -- Chitteti, Brahmananda R -- Speth, Jennifer M -- Hu, Peirong -- Poteat, Bradley A -- Stilger, Kayla N -- Ferraro, Francesca -- Silberstein, Lev -- Wong, Frankie K -- Farag, Sherif S -- Czader, Magdalena -- Milne, Ginger L -- Breyer, Richard M -- Serezani, Carlos H -- Scadden, David T -- Guise, Theresa A -- Srour, Edward F -- Pelus, Louis M -- CA069158/CA/NCI NIH HHS/ -- CA143057/CA/NCI NIH HHS/ -- DK07519/DK/NIDDK NIH HHS/ -- DK37097/DK/NIDDK NIH HHS/ -- HL07910/HL/NHLBI NIH HHS/ -- HL087735/HL/NHLBI NIH HHS/ -- HL096305/HL/NHLBI NIH HHS/ -- HL100402/HL/NHLBI NIH HHS/ -- P01 DK090948/DK/NIDDK NIH HHS/ -- P30 CA082709/CA/NCI NIH HHS/ -- R01 HL044851/HL/NHLBI NIH HHS/ -- R01 HL096305/HL/NHLBI NIH HHS/ -- England -- Nature. 2013 Mar 21;495(7441):365-9. doi: 10.1038/nature11929. Epub 2013 Mar 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23485965" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Cell Count ; Cell Movement/physiology ; Cells, Cultured ; Dinoprostone/*metabolism ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/*cytology/drug effects ; Heterocyclic Compounds/pharmacology ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Osteopontin/genetics ; Papio ; Receptors, Prostaglandin E, EP4 Subtype/genetics/metabolism ; Stem Cells/*cytology/drug effects ; Thiazines/pharmacology ; Thiazoles/pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-03-29
    Description: Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1beta but not tumour-necrosis factor-alpha in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (gamma-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1alpha, an effect that is inhibited by 2-deoxyglucose, with interleukin-1beta as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1beta production during inflammation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031686/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tannahill, G M -- Curtis, A M -- Adamik, J -- Palsson-McDermott, E M -- McGettrick, A F -- Goel, G -- Frezza, C -- Bernard, N J -- Kelly, B -- Foley, N H -- Zheng, L -- Gardet, A -- Tong, Z -- Jany, S S -- Corr, S C -- Haneklaus, M -- Caffrey, B E -- Pierce, K -- Walmsley, S -- Beasley, F C -- Cummins, E -- Nizet, V -- Whyte, M -- Taylor, C T -- Lin, H -- Masters, S L -- Gottlieb, E -- Kelly, V P -- Clish, C -- Auron, P E -- Xavier, R J -- O'Neill, L A J -- 098516/Wellcome Trust/United Kingdom -- R01 AI093451/AI/NIAID NIH HHS/ -- R56 AI090863/AI/NIAID NIH HHS/ -- U54 AI057153/AI/NIAID NIH HHS/ -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Apr 11;496(7444):238-42. doi: 10.1038/nature11986. Epub 2013 Mar 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23535595" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Citric Acid Cycle/drug effects ; Deoxyglucose/pharmacology ; Down-Regulation/drug effects ; Genes, Mitochondrial/drug effects/genetics ; Glutamine/metabolism ; Glycolysis/drug effects/genetics ; Humans ; Hypoxia-Inducible Factor 1, alpha Subunit/*metabolism ; Immunity, Innate/drug effects ; Inflammation/metabolism ; Interleukin-1beta/*biosynthesis/genetics ; Lipopolysaccharides/pharmacology ; Macrophages/cytology/drug effects/metabolism ; Mice ; *Signal Transduction ; Succinic Acid/*metabolism ; Up-Regulation/drug effects ; gamma-Aminobutyric Acid/metabolism
    Print ISSN: 0028-0836
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Pathogen blocks host death receptor signalling by arginine GlcNAcylation of death domains (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-08-21
    Description: The tumour necrosis factor (TNF) family is crucial for immune homeostasis, cell death and inflammation. These cytokines are recognized by members of the TNF receptor (TNFR) family of death receptors, including TNFR1 and TNFR2, and FAS and TNF-related apoptosis-inducing ligand (TRAIL) receptors. Death receptor signalling requires death-domain-mediated homotypic/heterotypic interactions between the receptor and its downstream adaptors, including TNFR1-associated death domain protein (TRADD) and FAS-associated death domain protein (FADD). Here we discover that death domains in several proteins, including TRADD, FADD, RIPK1 and TNFR1, were directly inactivated by NleB, an enteropathogenic Escherichia coli (EPEC) type III secretion system effector known to inhibit host nuclear factor-kappaB (NF-kappaB) signalling. NleB contained an unprecedented N-acetylglucosamine (GlcNAc) transferase activity that specifically modified a conserved arginine in these death domains (Arg 235 in the TRADD death domain). NleB GlcNAcylation (the addition of GlcNAc onto a protein side chain) of death domains blocked homotypic/heterotypic death domain interactions and assembly of the oligomeric TNFR1 complex, thereby disrupting TNF signalling in EPEC-infected cells, including NF-kappaB signalling, apoptosis and necroptosis. Type-III-delivered NleB also blocked FAS ligand and TRAIL-induced cell death by preventing formation of a FADD-mediated death-inducing signalling complex (DISC). The arginine GlcNAc transferase activity of NleB was required for bacterial colonization in the mouse model of EPEC infection. The mechanism of action of NleB represents a new model by which bacteria counteract host defences, and also a previously unappreciated post-translational modification.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Shan -- Zhang, Li -- Yao, Qing -- Li, Lin -- Dong, Na -- Rong, Jie -- Gao, Wenqing -- Ding, Xiaojun -- Sun, Liming -- Chen, Xing -- Chen, She -- Shao, Feng -- Howard Hughes Medical Institute/ -- England -- Nature. 2013 Sep 12;501(7466):242-6. doi: 10.1038/nature12436. Epub 2013 Aug 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉College of Biological Sciences, China Agricultural University, Beijing 100094, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23955153" target="_blank"〉PubMed〈/a〉
    Keywords: Acylation ; Animals ; Antigens, CD95/metabolism ; Apoptosis ; Arginine/*metabolism ; Death Domain Receptor Signaling Adaptor Proteins/metabolism ; Disease Models, Animal ; Enteropathogenic Escherichia coli/*metabolism/pathogenicity ; Escherichia coli Infections/metabolism/microbiology/pathology ; Escherichia coli Proteins/*metabolism ; Fas-Associated Death Domain Protein/chemistry/metabolism ; HeLa Cells ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Multiprotein Complexes/chemistry/metabolism ; N-Acetylglucosaminyltransferases/*metabolism ; NF-kappa B/metabolism ; Protein Biosynthesis ; Protein Structure, Tertiary ; Receptor-Interacting Protein Serine-Threonine Kinases/chemistry/metabolism ; Receptors, Tumor Necrosis Factor, Type I/chemistry/metabolism ; *Signal Transduction ; TNF Receptor-Associated Death Domain Protein/*chemistry/*metabolism ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Tumor Necrosis Factor-alpha/metabolism ; Virulence ; Virulence Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    EndMT contributes to the onset and progression of cerebral cavernous malformations (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-06-12
    Description: Cerebral cavernous malformation (CCM) is a vascular dysplasia, mainly localized within the brain and affecting up to 0.5% of the human population. CCM lesions are formed by enlarged and irregular blood vessels that often result in cerebral haemorrhages. CCM is caused by loss-of-function mutations in one of three genes, namely CCM1 (also known as KRIT1), CCM2 (OSM) and CCM3 (PDCD10), and occurs in both sporadic and familial forms. Recent studies have investigated the cause of vascular dysplasia and fragility in CCM, but the in vivo functions of this ternary complex remain unclear. Postnatal deletion of any of the three Ccm genes in mouse endothelium results in a severe phenotype, characterized by multiple brain vascular malformations that are markedly similar to human CCM lesions. Endothelial-to-mesenchymal transition (EndMT) has been described in different pathologies, and it is defined as the acquisition of mesenchymal- and stem-cell-like characteristics by the endothelium. Here we show that endothelial-specific disruption of the Ccm1 gene in mice induces EndMT, which contributes to the development of vascular malformations. EndMT in CCM1-ablated endothelial cells is mediated by the upregulation of endogenous BMP6 that, in turn, activates the transforming growth factor-beta (TGF-beta) and bone morphogenetic protein (BMP) signalling pathway. Inhibitors of the TGF-beta and BMP pathway prevent EndMT both in vitro and in vivo and reduce the number and size of vascular lesions in CCM1-deficient mice. Thus, increased TGF-beta and BMP signalling, and the consequent EndMT of CCM1-null endothelial cells, are crucial events in the onset and progression of CCM disease. These studies offer novel therapeutic opportunities for this severe, and so far incurable, pathology.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Maddaluno, Luigi -- Rudini, Noemi -- Cuttano, Roberto -- Bravi, Luca -- Giampietro, Costanza -- Corada, Monica -- Ferrarini, Luca -- Orsenigo, Fabrizio -- Papa, Eleanna -- Boulday, Gwenola -- Tournier-Lasserve, Elisabeth -- Chapon, Francoise -- Richichi, Cristina -- Retta, Saverio Francesco -- Lampugnani, Maria Grazia -- Dejana, Elisabetta -- England -- Nature. 2013 Jun 27;498(7455):492-6. doi: 10.1038/nature12207. Epub 2013 Jun 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IFOM Fondazione, FIRC Institute of Molecular Oncology, 20139 Milan, Italy. uigi.maddaluno@ifom.eu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23748444" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Morphogenetic Protein 6/antagonists & inhibitors/metabolism/pharmacology ; Disease Models, Animal ; *Disease Progression ; *Epithelial-Mesenchymal Transition/drug effects/genetics ; Hemangioma, Cavernous, Central Nervous System/genetics/*pathology ; Humans ; Mice ; Microtubule-Associated Proteins/deficiency/genetics/metabolism ; Proto-Oncogene Proteins/deficiency/genetics/metabolism ; Signal Transduction/drug effects/genetics ; Transforming Growth Factor beta/antagonists & inhibitors/metabolism ; Up-Regulation
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    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    The TLR4 antagonist Eritoran protects mice from lethal influenza infection (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-05-03
    Description: There is a pressing need to develop alternatives to annual influenza vaccines and antiviral agents licensed for mitigating influenza infection. Previous studies reported that acute lung injury caused by chemical or microbial insults is secondary to the generation of host-derived, oxidized phospholipid that potently stimulates Toll-like receptor 4 (TLR4)-dependent inflammation. Subsequently, we reported that Tlr4(-/-) mice are highly refractory to influenza-induced lethality, and proposed that therapeutic antagonism of TLR4 signalling would protect against influenza-induced acute lung injury. Here we report that therapeutic administration of Eritoran (also known as E5564)-a potent, well-tolerated, synthetic TLR4 antagonist-blocks influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreases viral titres. CD14 and TLR2 are also required for Eritoran-mediated protection, and CD14 directly binds Eritoran and inhibits ligand binding to MD2. Thus, Eritoran blockade of TLR signalling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725830/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725830/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shirey, Kari Ann -- Lai, Wendy -- Scott, Alison J -- Lipsky, Michael -- Mistry, Pragnesh -- Pletneva, Lioubov M -- Karp, Christopher L -- McAlees, Jaclyn -- Gioannini, Theresa L -- Weiss, Jerrold -- Chen, Wilbur H -- Ernst, Robert K -- Rossignol, Daniel P -- Gusovsky, Fabian -- Blanco, Jorge C G -- Vogel, Stefanie N -- AI018797/AI/NIAID NIH HHS/ -- AI057575/AI/NIAID NIH HHS/ -- AI059372/AI/NIAID NIH HHS/ -- NCRR K12-RR-023250/PHS HHS/ -- R01 AI018797/AI/NIAID NIH HHS/ -- R01 AI057575/AI/NIAID NIH HHS/ -- R01 AI059372/AI/NIAID NIH HHS/ -- T32 AI007540/AI/NIAID NIH HHS/ -- England -- Nature. 2013 May 23;497(7450):498-502. doi: 10.1038/nature12118. Epub 2013 May 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland 21201, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23636320" target="_blank"〉PubMed〈/a〉
    Keywords: Acute Lung Injury/complications/drug therapy/pathology/prevention & control ; Animals ; Antigens, CD14/metabolism ; Antiviral Agents/*pharmacology/therapeutic use ; Cytokines/genetics/immunology ; Disaccharides/metabolism/*pharmacology/*therapeutic use ; Female ; Influenza A Virus, H1N1 Subtype/*drug effects/*pathogenicity ; Ligands ; Lymphocyte Antigen 96/metabolism ; Mice ; Mice, Inbred C57BL ; Orthomyxoviridae Infections/*drug therapy/immunology/pathology/virology ; Sugar Phosphates/metabolism/*pharmacology/*therapeutic use ; Survival Analysis ; Time Factors ; Toll-Like Receptor 2/immunology/metabolism ; Toll-Like Receptor 4/*antagonists & inhibitors/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Thymus-derived regulatory T cells contribute to tolerance to commensal microbiota (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-04-30
    Description: Peripheral mechanisms preventing autoimmunity and maintaining tolerance to commensal microbiota involve CD4(+) Foxp3(+) regulatory T (Treg) cells generated in the thymus or extrathymically by induction of naive CD4(+) Foxp3(-) T cells. Previous studies suggested that the T-cell receptor repertoires of thymic Treg cells and induced Treg cells are biased towards self and non-self antigens, respectively, but their relative contribution in controlling immunopathology, such as colitis and other untoward inflammatory responses triggered by different types of antigens, remains unresolved. The intestine, and especially the colon, is a particularly suitable organ to study this question, given the variety of self-, microbiota- and food-derived antigens to which Treg cells and other T-cell populations are exposed. Intestinal environments can enhance conversion to a regulatory lineage and favour tolerogenic presentation of antigens to naive CD4(+) T cells, suggesting that intestinal homeostasis depends on microbiota-specific induced Treg cells. Here, to identify the origin and antigen-specificity of intestinal Treg cells, we performed single-cell and high-throughput sequencing of the T-cell receptor repertoires of CD4(+) Foxp3(+) and CD4(+) Foxp3(-) T cells, and analysed their reactivity against specific commensal species. We show that thymus-derived Treg cells constitute most Treg cells in all lymphoid and intestinal organs, including the colon, where their repertoire is heavily influenced by the composition of the microbiota. Our results suggest that thymic Treg cells, and not induced Treg cells, dominantly mediate tolerance to antigens produced by intestinal commensals.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711137/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711137/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cebula, Anna -- Seweryn, Michal -- Rempala, Grzegorz A -- Pabla, Simarjot Singh -- McIndoe, Richard A -- Denning, Timothy L -- Bry, Lynn -- Kraj, Piotr -- Kisielow, Pawel -- Ignatowicz, Leszek -- 5R01AI079277/AI/NIAID NIH HHS/ -- P30 DK034854/DK/NIDDK NIH HHS/ -- P30-DK034854/DK/NIDDK NIH HHS/ -- R01 CA152158/CA/NCI NIH HHS/ -- R01 HD061916/HD/NICHD NIH HHS/ -- R01CA152158/CA/NCI NIH HHS/ -- England -- Nature. 2013 May 9;497(7448):258-62. doi: 10.1038/nature12079. Epub 2013 Apr 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, Gerogia 30912, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23624374" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Anti-Bacterial Agents/pharmacology ; Antigens, Bacterial/immunology ; Colon/drug effects/immunology/*microbiology ; Female ; Forkhead Transcription Factors/metabolism ; High-Throughput Nucleotide Sequencing ; Homeostasis/drug effects/immunology ; Immune Tolerance/drug effects/*immunology ; Lymphoid Tissue/cytology/immunology ; Male ; Mice ; Mice, Transgenic ; Receptors, Antigen, T-Cell/genetics/metabolism ; Single-Cell Analysis ; Symbiosis/drug effects/*immunology ; T-Lymphocytes, Regulatory/cytology/drug effects/*immunology/metabolism ; Thymocytes/cytology/drug effects/immunology/metabolism ; Thymus Gland/cytology/*immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    Two replication fork maintenance pathways fuse inverted repeats to rearrange chromosomes (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-10
    Description: Replication fork maintenance pathways preserve chromosomes, but their faulty application at nonallelic repeats could generate rearrangements causing cancer, genomic disorders and speciation. Potential causal mechanisms are homologous recombination and error-free postreplication repair (EF-PRR). Homologous recombination repairs damage-induced DNA double-strand breaks (DSBs) and single-ended DSBs within replication. To facilitate homologous recombination, the recombinase RAD51 and mediator BRCA2 form a filament on the 3' DNA strand at a break to enable annealing to the complementary sister chromatid while the RecQ helicase, BLM (Bloom syndrome mutated) suppresses crossing over to prevent recombination. Homologous recombination also stabilizes and restarts replication forks without a DSB. EF-PRR bypasses DNA incongruities that impede replication by ubiquitinating PCNA (proliferating cell nuclear antigen) using the RAD6-RAD18 and UBC13-MMS2-RAD5 ubiquitin ligase complexes. Some components are common to both homologous recombination and EF-PRR such as RAD51 and RAD18. Here we delineate two pathways that spontaneously fuse inverted repeats to generate unstable chromosomal rearrangements in wild-type mouse embryonic stem (ES) cells. Gamma-radiation induced a BLM-regulated pathway that selectively fused identical, but not mismatched, repeats. By contrast, ultraviolet light induced a RAD18-dependent pathway that efficiently fused mismatched repeats. Furthermore, TREX2 (a 3'--〉5' exonuclease) suppressed identical repeat fusion but enhanced mismatched repeat fusion, clearly separating these pathways. TREX2 associated with UBC13 and enhanced PCNA ubiquitination in response to ultraviolet light, consistent with it being a novel member of EF-PRR. RAD18 and TREX2 also suppressed replication fork stalling in response to nucleotide depletion. Interestingly, replication fork stalling induced fusion for identical and mismatched repeats, implicating faulty replication as a causal mechanism for both pathways.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805358/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805358/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hu, Lingchuan -- Kim, Tae Moon -- Son, Mi Young -- Kim, Sung-A -- Holland, Cory L -- Tateishi, Satoshi -- Kim, Dong Hyun -- Yew, P Renee -- Montagna, Cristina -- Dumitrache, Lavinia C -- Hasty, Paul -- 1 R01 CA123203-01A1/CA/NCI NIH HHS/ -- 2P01AG017242-12/AG/NIA NIH HHS/ -- P30 CA054174/CA/NCI NIH HHS/ -- P30CA013330/CA/NCI NIH HHS/ -- R01 CA123203/CA/NCI NIH HHS/ -- England -- Nature. 2013 Sep 26;501(7468):569-72. doi: 10.1038/nature12500. Epub 2013 Sep 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Medicine/Institute of Biotechnology, The Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245-3207, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24013173" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Chromosomal Instability/*genetics ; Chromosome Breakage ; Chromosomes, Mammalian/*genetics ; DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; DNA Replication/*genetics ; DNA-Binding Proteins/metabolism ; Embryonic Stem Cells/metabolism ; Exodeoxyribonucleases/metabolism ; Homologous Recombination/*genetics ; Hydroxyurea/pharmacology ; Inverted Repeat Sequences/*genetics ; Mice ; Nucleotides/deficiency/metabolism ; Proliferating Cell Nuclear Antigen/metabolism ; Rad51 Recombinase/metabolism ; RecQ Helicases/metabolism ; Ubiquitin-Conjugating Enzymes/metabolism ; Ubiquitination/radiation effects ; Ultraviolet Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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    A type III effector antagonizes death receptor signalling during bacterial gut infection (2013)
    Nature Publishing Group (NPG)
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    Publication Date: 2013-09-13
    Description: Successful infection by enteric bacterial pathogens depends on the ability of the bacteria to colonize the gut, replicate in host tissues and disseminate to other hosts. Pathogens such as Salmonella, Shigella and enteropathogenic and enterohaemorrhagic (EPEC and EHEC, respectively) Escherichia coli use a type III secretion system (T3SS) to deliver virulence effector proteins into host cells during infection that promote colonization and interfere with antimicrobial host responses. Here we report that the T3SS effector NleB1 from EPEC binds to host cell death-domain-containing proteins and thereby inhibits death receptor signalling. Protein interaction studies identified FADD, TRADD and RIPK1 as binding partners of NleB1. NleB1 expressed ectopically or injected by the bacterial T3SS prevented Fas ligand or TNF-induced formation of the canonical death-inducing signalling complex (DISC) and proteolytic activation of caspase-8, an essential step in death-receptor-induced apoptosis. This inhibition depended on the N-acetylglucosamine transferase activity of NleB1, which specifically modified Arg 117 in the death domain of FADD. The importance of the death receptor apoptotic pathway to host defence was demonstrated using mice deficient in the FAS signalling pathway, which showed delayed clearance of the EPEC-like mouse pathogen Citrobacter rodentium and reversion to virulence of an nleB mutant. The activity of NleB suggests that EPEC and other attaching and effacing pathogens antagonize death-receptor-induced apoptosis of infected cells, thereby blocking a major antimicrobial host response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836246/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3836246/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pearson, Jaclyn S -- Giogha, Cristina -- Ong, Sze Ying -- Kennedy, Catherine L -- Kelly, Michelle -- Robinson, Keith S -- Lung, Tania Wong Fok -- Mansell, Ashley -- Riedmaier, Patrice -- Oates, Clare V L -- Zaid, Ali -- Muhlen, Sabrina -- Crepin, Valerie F -- Marches, Olivier -- Ang, Ching-Seng -- Williamson, Nicholas A -- O'Reilly, Lorraine A -- Bankovacki, Aleksandra -- Nachbur, Ueli -- Infusini, Giuseppe -- Webb, Andrew I -- Silke, John -- Strasser, Andreas -- Frankel, Gad -- Hartland, Elizabeth L -- 090325/Wellcome Trust/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2013 Sep 12;501(7466):247-51. doi: 10.1038/nature12524.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology, University of Melbourne, Victoria 3010, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24025841" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD95/deficiency/metabolism ; Caspase 8/metabolism ; Cell Death ; Citrobacter rodentium/pathogenicity/physiology ; Enteropathogenic Escherichia coli/*metabolism/pathogenicity ; Enzyme Activation ; Escherichia coli Infections/*metabolism/*microbiology/pathology ; Escherichia coli Proteins/*metabolism ; Fas Ligand Protein/antagonists & inhibitors/metabolism ; Fas-Associated Death Domain Protein/chemistry/metabolism ; Female ; Gastrointestinal Tract/*microbiology ; HEK293 Cells ; HeLa Cells ; Humans ; Male ; Mice ; N-Acetylglucosaminyltransferases/metabolism ; Protein Structure, Tertiary ; Receptor-Interacting Protein Serine-Threonine Kinases/chemistry/metabolism ; *Signal Transduction ; TNF Receptor-Associated Death Domain Protein/chemistry/metabolism ; Virulence Factors/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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