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  • Inorganic Chemistry  (1,627)
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  • 1
    Publication Date: 2009-12-23
    Description: Reprogramming of somatic cell nuclei to yield induced pluripotent stem (iPS) cells makes possible derivation of patient-specific stem cells for regenerative medicine. However, iPS cell generation is asynchronous and slow (2-3 weeks), the frequency is low (〈0.1%), and DNA demethylation constitutes a bottleneck. To determine regulatory mechanisms involved in reprogramming, we generated interspecies heterokaryons (fused mouse embryonic stem (ES) cells and human fibroblasts) that induce reprogramming synchronously, frequently and fast. Here we show that reprogramming towards pluripotency in single heterokaryons is initiated without cell division or DNA replication, rapidly (1 day) and efficiently (70%). Short interfering RNA (siRNA)-mediated knockdown showed that activation-induced cytidine deaminase (AID, also known as AICDA) is required for promoter demethylation and induction of OCT4 (also known as POU5F1) and NANOG gene expression. AID protein bound silent methylated OCT4 and NANOG promoters in fibroblasts, but not active demethylated promoters in ES cells. These data provide new evidence that mammalian AID is required for active DNA demethylation and initiation of nuclear reprogramming towards pluripotency in human somatic cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2906123/" 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/PMC2906123/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Bhutani, Nidhi -- Brady, Jennifer J -- Damian, Mara -- Sacco, Alessandra -- Corbel, Stephane Y -- Blau, Helen M -- AG009521/AG/NIA NIH HHS/ -- AG024987/AG/NIA NIH HHS/ -- AI007328/AI/NIAID NIH HHS/ -- R01 AG009521/AG/NIA NIH HHS/ -- R01 AG009521-25/AG/NIA NIH HHS/ -- R01 AG024987/AG/NIA NIH HHS/ -- R01 AG024987-05/AG/NIA NIH HHS/ -- T32 AI007328/AI/NIAID NIH HHS/ -- U01 HL100397/HL/NHLBI NIH HHS/ -- England -- Nature. 2010 Feb 25;463(7284):1042-7. doi: 10.1038/nature08752.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Baxter Laboratory for Stem Cell Biology, Institute for Stem Cell Biology and Regenerative Medicine, Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California 94305-5175, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20027182" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Division ; Cell Fusion ; Cell Line ; Cells, Cultured ; Cellular Reprogramming/genetics/*physiology ; Chromatin Immunoprecipitation ; Cytidine Deaminase/deficiency/genetics/*metabolism ; DNA/chemistry/genetics/metabolism ; *DNA Methylation ; DNA Replication ; Embryonic Stem Cells/cytology/metabolism ; Fibroblasts/cytology/metabolism ; Gene Expression Regulation ; Gene Knockdown Techniques ; Homeodomain Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells/*cytology/enzymology/*metabolism ; Lung/cytology/embryology ; Mice ; Models, Biological ; Octamer Transcription Factor-3/genetics ; Promoter Regions, Genetic/genetics ; Time Factors
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  • 2
    Publication Date: 2009-01-14
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4340503/" 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/PMC4340503/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kelly, Bernard T -- McCoy, Airlie J -- Spate, Kira -- Miller, Sharon E -- Evans, Philip R -- Honing, Stefan -- Owen, David J -- 090909/Wellcome Trust/United Kingdom -- MC_U105178845/Medical Research Council/United Kingdom -- England -- Nature. 2008 Dec 18;456(7224):976-79. doi: 10.1038/nature07422.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19140243" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Protein Complex 2/*chemistry/genetics/*metabolism ; Amino Acid Motifs ; Animals ; Antigens, CD4/*chemistry/*metabolism ; Binding Sites ; Conserved Sequence ; *Endocytosis ; Humans ; Leucine/*metabolism ; Mice ; Models, Molecular ; Protein Binding ; Protein Conformation ; Protein Subunits/chemistry/genetics/metabolism ; Rats
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  • 3
    Publication Date: 2009-05-05
    Description: A20 is a negative regulator of the NF-kappaB pathway and was initially identified as being rapidly induced after tumour-necrosis factor-alpha stimulation. It has a pivotal role in regulation of the immune response and prevents excessive activation of NF-kappaB in response to a variety of external stimuli; recent genetic studies have disclosed putative associations of polymorphic A20 (also called TNFAIP3) alleles with autoimmune disease risk. However, the involvement of A20 in the development of human cancers is unknown. Here we show, using a genome-wide analysis of genetic lesions in 238 B-cell lymphomas, that A20 is a common genetic target in B-lineage lymphomas. A20 is frequently inactivated by somatic mutations and/or deletions in mucosa-associated tissue lymphoma (18 out of 87; 21.8%) and Hodgkin's lymphoma of nodular sclerosis histology (5 out of 15; 33.3%), and, to a lesser extent, in other B-lineage lymphomas. When re-expressed in a lymphoma-derived cell line with no functional A20 alleles, wild-type A20, but not mutant A20, resulted in suppression of cell growth and induction of apoptosis, accompanied by downregulation of NF-kappaB activation. The A20-deficient cells stably generated tumours in immunodeficient mice, whereas the tumorigenicity was effectively suppressed by re-expression of A20. In A20-deficient cells, suppression of both cell growth and NF-kappaB activity due to re-expression of A20 depended, at least partly, on cell-surface-receptor signalling, including the tumour-necrosis factor receptor. Considering the physiological function of A20 in the negative modulation of NF-kappaB activation induced by multiple upstream stimuli, our findings indicate that uncontrolled signalling of NF-kappaB caused by loss of A20 function is involved in the pathogenesis of subsets of B-lineage lymphomas.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kato, Motohiro -- Sanada, Masashi -- Kato, Itaru -- Sato, Yasuharu -- Takita, Junko -- Takeuchi, Kengo -- Niwa, Akira -- Chen, Yuyan -- Nakazaki, Kumi -- Nomoto, Junko -- Asakura, Yoshitaka -- Muto, Satsuki -- Tamura, Azusa -- Iio, Mitsuru -- Akatsuka, Yoshiki -- Hayashi, Yasuhide -- Mori, Hiraku -- Igarashi, Takashi -- Kurokawa, Mineo -- Chiba, Shigeru -- Mori, Shigeo -- Ishikawa, Yuichi -- Okamoto, Koji -- Tobinai, Kensei -- Nakagama, Hitoshi -- Nakahata, Tatsutoshi -- Yoshino, Tadashi -- Kobayashi, Yukio -- Ogawa, Seishi -- England -- Nature. 2009 Jun 4;459(7247):712-6. doi: 10.1038/nature07969. Epub 2009 May 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, Department of Pediatrics, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19412163" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis/physiology ; Cell Line ; Cysteine Endopeptidases/*genetics/*metabolism ; DNA-Binding Proteins ; Gene Expression ; *Gene Silencing ; Genome/genetics ; Humans ; Intracellular Signaling Peptides and Proteins/*genetics/*metabolism ; Lymphoma, B-Cell/*genetics/*physiopathology ; Mice ; NF-kappa B/genetics/metabolism ; Nuclear Proteins/*genetics/*metabolism
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  • 4
    Publication Date: 2009-03-27
    Description: Toll-like receptors (TLRs) recognize microbial components, and evoke inflammation and immune responses. TLR stimulation activates complex gene expression networks that regulate the magnitude and duration of the immune reaction. Here we identify the TLR-inducible gene Zc3h12a as an immune response modifier that has an essential role in preventing immune disorders. Zc3h12a-deficient mice suffered from severe anaemia, and most died within 12 weeks. Zc3h12a(-/-) mice also showed augmented serum immunoglobulin levels and autoantibody production, together with a greatly increased number of plasma cells, as well as infiltration of plasma cells to the lung. Most Zc3h12a(-/-) splenic T cells showed effector/memory characteristics and produced interferon-gamma in response to T-cell receptor stimulation. Macrophages from Zc3h12a(-/-) mice showed highly increased production of interleukin (IL)-6 and IL-12p40 (also known as IL12b), but not TNF, in response to TLR ligands. Although the activation of TLR signalling pathways was normal, Il6 messenger RNA decay was severely impaired in Zc3h12a(-/-) macrophages. Overexpression of Zc3h12a accelerated Il6 mRNA degradation via its 3'-untranslated region (UTR), and destabilized RNAs with 3'-UTRs for genes including Il6, Il12p40 and the calcitonin receptor gene Calcr. Zc3h12a contains a putative amino-terminal nuclease domain, and the expressed protein had RNase activity, consistent with a role in the decay of Il6 mRNA. Together, these results indicate that Zc3h12a is an essential RNase that prevents immune disorders by directly controlling the stability of a set of inflammatory genes.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Matsushita, Kazufumi -- Takeuchi, Osamu -- Standley, Daron M -- Kumagai, Yutaro -- Kawagoe, Tatsukata -- Miyake, Tohru -- Satoh, Takashi -- Kato, Hiroki -- Tsujimura, Tohru -- Nakamura, Haruki -- Akira, Shizuo -- P01 AI070167/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Apr 30;458(7242):1185-90. doi: 10.1038/nature07924. Epub 2009 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory of Host Defense, WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19322177" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/genetics/metabolism ; Anemia/complications/genetics ; Animals ; Autoantibodies/blood/immunology ; Autoimmune Diseases/complications/immunology ; Cell Line ; Cytokines/biosynthesis/genetics ; Fetal Diseases/immunology ; Humans ; Immunity/*genetics/*immunology ; Inflammation Mediators/metabolism ; Interleukin-6/genetics ; Macrophages, Peritoneal/immunology/metabolism ; Mice ; Plasma Cells/cytology ; *RNA Stability ; Ribonucleases/deficiency/genetics/*metabolism ; T-Lymphocytes/immunology
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  • 5
    Publication Date: 2009-08-12
    Description: Reprogramming somatic cells to induced pluripotent stem (iPS) cells has been accomplished by expressing pluripotency factors and oncogenes, but the low frequency and tendency to induce malignant transformation compromise the clinical utility of this powerful approach. We address both issues by investigating the mechanisms limiting reprogramming efficiency in somatic cells. Here we show that reprogramming factors can activate the p53 (also known as Trp53 in mice, TP53 in humans) pathway. Reducing signalling to p53 by expressing a mutated version of one of its negative regulators, by deleting or knocking down p53 or its target gene, p21 (also known as Cdkn1a), or by antagonizing reprogramming-induced apoptosis in mouse fibroblasts increases reprogramming efficiency. Notably, decreasing p53 protein levels enabled fibroblasts to give rise to iPS cells capable of generating germline-transmitting chimaeric mice using only Oct4 (also known as Pou5f1) and Sox2. Furthermore, silencing of p53 significantly increased the reprogramming efficiency of human somatic cells. These results provide insights into reprogramming mechanisms and suggest new routes to more efficient reprogramming while minimizing the use of oncogenes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735889/" 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/PMC2735889/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kawamura, Teruhisa -- Suzuki, Jotaro -- Wang, Yunyuan V -- Menendez, Sergio -- Morera, Laura Batlle -- Raya, Angel -- Wahl, Geoffrey M -- Izpisua Belmonte, Juan Carlos -- 5 R01 CA061449/CA/NCI NIH HHS/ -- 5 R01 CA100845/CA/NCI NIH HHS/ -- R01 CA061449/CA/NCI NIH HHS/ -- R01 CA061449-30/CA/NCI NIH HHS/ -- R01 CA100845/CA/NCI NIH HHS/ -- R01 CA100845-05/CA/NCI NIH HHS/ -- R33 HL088293/HL/NHLBI NIH HHS/ -- R33 HL088293-03/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Aug 27;460(7259):1140-4. doi: 10.1038/nature08311. Epub 2009 Aug 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19668186" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cellular Reprogramming/*physiology ; Cyclin-Dependent Kinase Inhibitor p21/deficiency/genetics/metabolism ; Down-Regulation ; Embryo, Mammalian/cytology ; Female ; Fibroblasts/cytology/metabolism ; Humans ; Keratinocytes ; Male ; Mice ; Mice, Inbred C57BL ; Pluripotent Stem Cells/*cytology/*metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/*metabolism
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  • 6
    Publication Date: 2009-01-13
    Description: In an adaptive immune response, naive T cells proliferate during infection and generate long-lived memory cells that undergo secondary expansion after a repeat encounter with the same pathogen. Although natural killer (NK) cells have traditionally been classified as cells of the innate immune system, they share many similarities with cytotoxic T lymphocytes. We use a mouse model of cytomegalovirus infection to show that, like T cells, NK cells bearing the virus-specific Ly49H receptor proliferate 100-fold in the spleen and 1,000-fold in the liver after infection. After a contraction phase, Ly49H-positive NK cells reside in lymphoid and non-lymphoid organs for several months. These self-renewing 'memory' NK cells rapidly degranulate and produce cytokines on reactivation. Adoptive transfer of these NK cells into naive animals followed by viral challenge results in a robust secondary expansion and protective immunity. These findings reveal properties of NK cells that were previously attributed only to cells of the adaptive immune system.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674434/" 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/PMC2674434/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sun, Joseph C -- Beilke, Joshua N -- Lanier, Lewis L -- AI068129/AI/NIAID NIH HHS/ -- R01 AI068129/AI/NIAID NIH HHS/ -- R01 AI068129-09/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jan 29;457(7229):557-61. doi: 10.1038/nature07665. Epub 2009 Jan 11.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Microbiology and Immunology and the Cancer Research Institute, University of California, San Francisco, California 94143, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19136945" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/deficiency/genetics ; Adoptive Transfer ; Animals ; Cell Proliferation ; Immunologic Memory/*immunology ; Killer Cells, Natural/*cytology/*immunology ; Lymphoid Tissue/immunology ; Mice ; Mice, Congenic ; Mice, Inbred C57BL ; *Models, Immunological ; Muromegalovirus/immunology/physiology ; Phenotype ; T-Lymphocytes, Cytotoxic/immunology
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  • 7
    Publication Date: 2009-07-03
    Description: Induced pluripotent stem cells offer unprecedented potential for disease research, drug screening, toxicology and regenerative medicine. However, the process of reprogramming is inefficient and often incomplete. Here I consider reasons for bottlenecks in induced pluripotent stem cell generation, and propose a model in which most or all cells have the potential to become pluripotent.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yamanaka, Shinya -- England -- Nature. 2009 Jul 2;460(7251):49-52. doi: 10.1038/nature08180.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan. yamanaka@cira.kyoto-u.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19571877" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Differentiation ; Cell Lineage ; *Cellular Reprogramming/genetics ; Epigenesis, Genetic ; Humans ; Mice ; *Models, Biological ; Pluripotent Stem Cells/*cytology/metabolism ; Stochastic Processes ; Transduction, Genetic
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  • 8
    Publication Date: 2009-11-06
    Description: The activation of innate immune responses by nucleic acids is crucial to protective and pathological immunities and is mediated by the transmembrane Toll-like receptors (TLRs) and cytosolic receptors. However, it remains unknown whether a mechanism exists that integrates these nucleic-acid-sensing systems. Here we show that high-mobility group box (HMGB) proteins 1, 2 and 3 function as universal sentinels for nucleic acids. HMGBs bind to all immunogenic nucleic acids examined with a correlation between affinity and immunogenic potential. Hmgb1(-/-) and Hmgb2(-/-) mouse cells are defective in type-I interferon and inflammatory cytokine induction by DNA or RNA targeted to activate the cytosolic nucleic-acid-sensing receptors; cells in which the expression of all three HMGBs is suppressed show a more profound defect, accompanied by impaired activation of the transcription factors interferon regulatory factor 3 (IRF3) and nuclear factor (NF)-kappaB. The absence of HMGBs also severely impairs the activation of TLR3, TLR7 and TLR9 by their cognate nucleic acids. Our results therefore indicate a hierarchy in the nucleic-acid-mediated activation of immune responses, wherein the selective activation of nucleic-acid-sensing receptors is contingent on the more promiscuous sensing of nucleic acids by HMGBs. These findings may have implications for understanding the evolution of the innate immune system and for the treatment of immunological disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yanai, Hideyuki -- Ban, Tatsuma -- Wang, ZhiChao -- Choi, Myoung Kwon -- Kawamura, Takeshi -- Negishi, Hideo -- Nakasato, Makoto -- Lu, Yan -- Hangai, Sho -- Koshiba, Ryuji -- Savitsky, David -- Ronfani, Lorenza -- Akira, Shizuo -- Bianchi, Marco E -- Honda, Kenya -- Tamura, Tomohiko -- Kodama, Tatsuhiko -- Taniguchi, Tadatsugu -- England -- Nature. 2009 Nov 5;462(7269):99-103. doi: 10.1038/nature08512.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890330" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytosol/immunology ; DNA/immunology ; HMGB Proteins/deficiency/genetics/*immunology/*metabolism ; HMGB1 Protein/deficiency/genetics/immunology/metabolism ; HMGB2 Protein/deficiency/genetics/immunology/metabolism ; Immunity, Innate/*immunology ; Interferon Regulatory Factor-3/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; NF-kappa B/metabolism ; Nucleic Acids/*immunology ; Nucleotides/chemistry/immunology/metabolism ; RNA/immunology ; Signal Transduction ; Toll-Like Receptors/immunology ; Virus Diseases/immunology/virology
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  • 9
    Publication Date: 2009-12-17
    Description: B-cell malignancies, such as human Burkitt's lymphoma, often contain translocations that link c-myc or other proto-oncogenes to the immunoglobulin heavy chain locus (IgH, encoded by Igh). The nature of elements that activate oncogenes within such translocations has been a long-standing question. Translocations within Igh involve DNA double-strand breaks initiated either by the RAG1/2 endonuclease during variable, diversity and joining gene segment (V(D)J) recombination, or by activation-induced cytidine deaminase (AID, also known as AICDA) during class switch recombination (CSR). V(D)J recombination in progenitor B (pro-B) cells assembles Igh variable region exons upstream of mu constant region (Cmu) exons, which are the first of several sets of C(H) exons ('C(H) genes') within a C(H) locus that span several hundred kilobases (kb). In mature B cells, CSR deletes Cmu and replaces it with a downstream C(H) gene. An intronic enhancer (iEmu) between the variable region exons and Cmu promotes V(D)J recombination in developing B cells. Furthermore, the Igh 3' regulatory region (Igh3'RR) lies downstream of the C(H) locus and modulates CSR by long-range transcriptional enhancement of C(H) genes. Transgenic mice bearing iEmu or Igh3'RR sequences fused to c-myc are predisposed to B lymphomas, demonstrating that such elements can confer oncogenic c-myc expression. However, in many B-cell lymphomas, Igh-c-myc translocations delete iEmu and place c-myc up to 200 kb upstream of the Igh3'RR. Here we address the oncogenic role of the Igh3'RR by inactivating it in two distinct mouse models for B-cell lymphoma with Igh-c-myc translocations. We show that the Igh3'RR is dispensable for pro-B-cell lymphomas with V(D)J recombination-initiated translocations, but is required for peripheral B-cell lymphomas with CSR-associated translocations. As the Igh3'RR is not required for CSR-associated Igh breaks or Igh-c-myc translocations in peripheral B-cell lymphoma progenitors, we conclude that this regulatory region confers oncogenic activity by long-range and developmental stage-specific activation of translocated c-myc genes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802177/" 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/PMC2802177/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gostissa, Monica -- Yan, Catherine T -- Bianco, Julia M -- Cogne, Michel -- Pinaud, Eric -- Alt, Frederick W -- CA92625/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 10;462(7274):803-7. doi: 10.1038/nature08633.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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/20010689" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/*genetics ; Alleles ; Animals ; Cells, Cultured ; Chromosome Breakpoints ; Gene Rearrangement, B-Lymphocyte/*genetics ; Genes, Immunoglobulin Heavy Chain/*genetics ; Genes, myc/*genetics ; Immunoglobulin Class Switching/genetics ; Lymphoma, B-Cell/*genetics/pathology ; Mice ; Mice, Transgenic ; Regulatory Sequences, Nucleic Acid/*genetics ; Translocation, Genetic/*genetics
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  • 10
    Publication Date: 2009-12-01
    Description: Changes in synaptic connections are considered essential for learning and memory formation. However, it is unknown how neural circuits undergo continuous synaptic changes during learning while maintaining lifelong memories. Here we show, by following postsynaptic dendritic spines over time in the mouse cortex, that learning and novel sensory experience lead to spine formation and elimination by a protracted process. The extent of spine remodelling correlates with behavioural improvement after learning, suggesting a crucial role of synaptic structural plasticity in memory formation. Importantly, a small fraction of new spines induced by novel experience, together with most spines formed early during development and surviving experience-dependent elimination, are preserved and provide a structural basis for memory retention throughout the entire life of an animal. These studies indicate that learning and daily sensory experience leave minute but permanent marks on cortical connections and suggest that lifelong memories are stored in largely stably connected synaptic networks.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724802/" 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/PMC4724802/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Guang -- Pan, Feng -- Gan, Wen-Biao -- R01 NS047325/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Dec 17;462(7275):920-4. doi: 10.1038/nature08577. Epub 2009 Nov 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Neurobiology Program, The Helen and Martin Kimmel Center for Biology and Medicine at the Skirball Institute of Biomolecular Medicine, Department of Physiology and Neuroscience, New York University School of Medicine, New York, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19946265" target="_blank"〉PubMed〈/a〉
    Keywords: Aging/physiology ; Animals ; Dendritic Spines/metabolism/*physiology ; Forelimb/physiology ; Memory/*physiology ; Mice ; Motor Cortex/cytology/physiology ; Motor Skills/physiology ; Neuronal Plasticity/physiology ; Pyramidal Cells/metabolism ; Synapses/*metabolism ; Time Factors
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  • 11
    Publication Date: 2009-11-13
    Description: Experience-dependent plasticity in the brain requires balanced excitation-inhibition. How individual circuit elements contribute to plasticity outcome in complex neocortical networks remains unknown. Here we report an intracellular analysis of ocular dominance plasticity-the loss of acuity and cortical responsiveness for an eye deprived of vision in early life. Unlike the typical progressive loss of pyramidal-cell bias, direct recording from fast-spiking cells in vivo reveals a counterintuitive initial shift towards the occluded eye followed by a late preference for the open eye, consistent with a spike-timing-dependent plasticity rule for these inhibitory neurons. Intracellular pharmacology confirms a dynamic switch of GABA (gamma-aminobutyric acid) impact to pyramidal cells following deprivation in juvenile mice only. Together these results suggest that the bidirectional recruitment of an initially binocular GABA circuit may contribute to experience-dependent plasticity in the developing visual cortex.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yazaki-Sugiyama, Yoko -- Kang, Siu -- Cateau, Hideyuki -- Fukai, Tomoki -- Hensch, Takao K -- England -- Nature. 2009 Nov 12;462(7270):218-21. doi: 10.1038/nature08485.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉CREST, JST, Toyonaka, Osaka 560-0082, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907494" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/*physiology ; Aging/physiology ; Animals ; Dominance, Ocular/*physiology ; Interneurons/metabolism ; Mice ; Mice, Inbred C57BL ; Models, Neurological ; Neuronal Plasticity/*physiology ; Neurons/*metabolism ; Photic Stimulation ; Pyramidal Cells/metabolism ; Receptors, GABA/metabolism ; Visual Cortex/cytology/physiology ; Visual Pathways/physiology ; Visual Perception/*physiology ; gamma-Aminobutyric Acid/*metabolism
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  • 12
    Publication Date: 2009-07-31
    Description: Reactive oxygen species (ROS) produced by NADPH oxidase function as defence and signalling molecules related to innate immunity and various cellular responses. The activation of NADPH oxidase in response to plasma membrane receptor activation depends on the phosphorylation of cytoplasmic oxidase subunits, their translocation to membranes and the assembly of all NADPH oxidase components. Tumour necrosis factor (TNF) is a prominent stimulus of ROS production, but the molecular mechanisms by which TNF activates NADPH oxidase are poorly understood. Here we identify riboflavin kinase (RFK, formerly known as flavokinase) as a previously unrecognized TNF-receptor-1 (TNFR1)-binding protein that physically and functionally couples TNFR1 to NADPH oxidase. In mouse and human cells, RFK binds to both the TNFR1-death domain and to p22(phox), the common subunit of NADPH oxidase isoforms. RFK-mediated bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but not for Toll-like-receptor-induced ROS production. Exogenous flavin mononucleotide or FAD was able to substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient cells. RFK is rate-limiting in the synthesis of FAD, an essential prosthetic group of NADPH oxidase. The results suggest that TNF, through the activation of RFK, enhances the incorporation of FAD in NADPH oxidase enzymes, a critical step for the assembly and activation of NADPH oxidase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yazdanpanah, Benjamin -- Wiegmann, Katja -- Tchikov, Vladimir -- Krut, Oleg -- Pongratz, Carola -- Schramm, Michael -- Kleinridders, Andre -- Wunderlich, Thomas -- Kashkar, Hamid -- Utermohlen, Olaf -- Bruning, Jens C -- Schutze, Stefan -- Kronke, Martin -- England -- Nature. 2009 Aug 27;460(7259):1159-63. doi: 10.1038/nature08206. Epub 2009 Jul 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Medical Microbiology, Immunology and Hygiene, University of Cologne, Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cytochrome b Group/metabolism ; Enzyme Activation ; Fibroblasts ; Flavin Mononucleotide/metabolism ; Flavin-Adenine Dinucleotide/biosynthesis/metabolism ; HeLa Cells ; Humans ; Isoenzymes/chemistry/metabolism ; Membrane Glycoproteins/metabolism ; Mice ; NADH, NADPH Oxidoreductases/metabolism ; NADPH Oxidase/chemistry/*metabolism ; Phosphotransferases (Alcohol Group Acceptor)/deficiency/genetics/*metabolism ; Protein Binding ; Protein Structure, Tertiary ; Reactive Oxygen Species/metabolism ; Receptors, Tumor Necrosis Factor, Type I/chemistry/*metabolism
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  • 13
    Publication Date: 2009-11-03
    Description: Although drugs are intended to be selective, at least some bind to several physiological targets, explaining side effects and efficacy. Because many drug-target combinations exist, it would be useful to explore possible interactions computationally. Here we compared 3,665 US Food and Drug Administration (FDA)-approved and investigational drugs against hundreds of targets, defining each target by its ligands. Chemical similarities between drugs and ligand sets predicted thousands of unanticipated associations. Thirty were tested experimentally, including the antagonism of the beta(1) receptor by the transporter inhibitor Prozac, the inhibition of the 5-hydroxytryptamine (5-HT) transporter by the ion channel drug Vadilex, and antagonism of the histamine H(4) receptor by the enzyme inhibitor Rescriptor. Overall, 23 new drug-target associations were confirmed, five of which were potent (〈100 nM). The physiological relevance of one, the drug N,N-dimethyltryptamine (DMT) on serotonergic receptors, was confirmed in a knockout mouse. The chemical similarity approach is systematic and comprehensive, and may suggest side-effects and new indications for many drugs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784146/" 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/PMC2784146/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Keiser, Michael J -- Setola, Vincent -- Irwin, John J -- Laggner, Christian -- Abbas, Atheir I -- Hufeisen, Sandra J -- Jensen, Niels H -- Kuijer, Michael B -- Matos, Roberto C -- Tran, Thuy B -- Whaley, Ryan -- Glennon, Richard A -- Hert, Jerome -- Thomas, Kelan L H -- Edwards, Douglas D -- Shoichet, Brian K -- Roth, Bryan L -- R01 DA017204/DA/NIDA NIH HHS/ -- R01 DA017204-04/DA/NIDA NIH HHS/ -- R01 DA017204-05/DA/NIDA NIH HHS/ -- R01 MH061887/MH/NIMH NIH HHS/ -- R01 MH061887-09/MH/NIMH NIH HHS/ -- R01 MH061887-10/MH/NIMH NIH HHS/ -- U19 MH082441/MH/NIMH NIH HHS/ -- U19 MH082441-01/MH/NIMH NIH HHS/ -- U19 MH082441-010001/MH/NIMH NIH HHS/ -- U19 MH082441-019002/MH/NIMH NIH HHS/ -- U19 MH082441-019003/MH/NIMH NIH HHS/ -- U19 MH082441-02/MH/NIMH NIH HHS/ -- U19 MH082441-020001/MH/NIMH NIH HHS/ -- U19 MH082441-029002/MH/NIMH NIH HHS/ -- U19 MH082441-03/MH/NIMH NIH HHS/ -- U19 MH082441-030001/MH/NIMH NIH HHS/ -- U19 MH082441-039002/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):175-81. doi: 10.1038/nature08506. Epub 2009 Nov 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmaceutical Chemistry, University of California San Francisco, 1700 4th Street, San Francisco, California 94143-2550, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19881490" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Computational Biology ; Databases, Factual ; Drug Evaluation, Preclinical/*methods ; Drug-Related Side Effects and Adverse Reactions ; Humans ; Ligands ; Mice ; Mice, Knockout ; Off-Label Use ; Pharmaceutical Preparations/*metabolism ; Receptors, Serotonin/metabolism ; *Substrate Specificity ; United States ; United States Food and Drug Administration
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  • 14
    Publication Date: 2009-06-16
    Description: Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2712122/" 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/PMC2712122/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takeda, Atsunobu -- Baffi, Judit Z -- Kleinman, Mark E -- Cho, Won Gil -- Nozaki, Miho -- Yamada, Kiyoshi -- Kaneko, Hiroki -- Albuquerque, Romulo J C -- Dridi, Sami -- Saito, Kuniharu -- Raisler, Brian J -- Budd, Steven J -- Geisen, Pete -- Munitz, Ariel -- Ambati, Balamurali K -- Green, Martha G -- Ishibashi, Tatsuro -- Wright, John D -- Humbles, Alison A -- Gerard, Craig J -- Ogura, Yuichiro -- Pan, Yuzhen -- Smith, Justine R -- Grisanti, Salvatore -- Hartnett, M Elizabeth -- Rothenberg, Marc E -- Ambati, Jayakrishna -- AI039759/AI/NIAID NIH HHS/ -- AI45898/AI/NIAID NIH HHS/ -- DK076893/DK/NIDDK NIH HHS/ -- EY010572/EY/NEI NIH HHS/ -- EY015130/EY/NEI NIH HHS/ -- EY015422/EY/NEI NIH HHS/ -- EY017011/EY/NEI NIH HHS/ -- EY017182/EY/NEI NIH HHS/ -- EY017950/EY/NEI NIH HHS/ -- EY018350/EY/NEI NIH HHS/ -- EY018836/EY/NEI NIH HHS/ -- R01 DK076893/DK/NIDDK NIH HHS/ -- R01 EY015422/EY/NEI NIH HHS/ -- R01 EY015422-04/EY/NEI NIH HHS/ -- R01 EY018350/EY/NEI NIH HHS/ -- R01 EY018350-02/EY/NEI NIH HHS/ -- R01 EY018836/EY/NEI NIH HHS/ -- R01 EY018836-02/EY/NEI NIH HHS/ -- England -- Nature. 2009 Jul 9;460(7252):225-30. doi: 10.1038/nature08151. Epub 2009 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology & Visual Science, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19525930" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Movement ; Cell Proliferation ; Cells, Cultured ; Chemokine CCL11/antagonists & inhibitors/metabolism ; Chemokine CCL24/antagonists & inhibitors/metabolism ; Chemokines, CC/antagonists & inhibitors/metabolism ; Choroid/blood supply/cytology/metabolism ; Choroidal Neovascularization/diagnosis/metabolism ; Disease Models, Animal ; Endothelial Cells/cytology/metabolism ; Humans ; Inflammation ; Leukocytes ; Ligands ; Macular Degeneration/*diagnosis/metabolism/*therapy ; Mice ; Mice, Inbred C57BL ; Quantum Dots ; Receptors, CCR3/analysis/*antagonists & ; inhibitors/genetics/immunology/*metabolism ; Retina/drug effects/pathology ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/immunology
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  • 15
    Publication Date: 2009-06-30
    Description: One of the most distinctive steps in the development of the vertebrate nervous system occurs at mitotic exit when cells lose multipotency and begin to develop stable connections that will persist for a lifetime. This transition is accompanied by a switch in ATP-dependent chromatin-remodelling mechanisms that appears to coincide with the final mitotic division of neurons. This switch involves the exchange of the BAF53a (also known as ACTL6a) and BAF45a (PHF10) subunits within Swi/Snf-like neural-progenitor-specific BAF (npBAF) complexes for the homologous BAF53b (ACTL6b) and BAF45b (DPF1) subunits within neuron-specific BAF (nBAF) complexes in post-mitotic neurons. The subunits of the npBAF complex are essential for neural-progenitor proliferation, and mice with reduced dosage for the genes encoding its subunits have defects in neural-tube closure similar to those in human spina bifida, one of the most serious congenital birth defects. In contrast, BAF53b and the nBAF complex are essential for an evolutionarily conserved program of post-mitotic neural development and dendritic morphogenesis. Here we show that this essential transition is mediated by repression of BAF53a by miR-9* and miR-124. We find that BAF53a repression is mediated by sequences in the 3' untranslated region corresponding to the recognition sites for miR-9* and miR-124, which are selectively expressed in post-mitotic neurons. Mutation of these sites led to persistent expression of BAF53a and defective activity-dependent dendritic outgrowth in neurons. In addition, overexpression of miR-9* and miR-124 in neural progenitors caused reduced proliferation. Previous studies have indicated that miR-9* and miR-124 are repressed by the repressor-element-1-silencing transcription factor (REST, also known as NRSF). Indeed, expression of REST in post-mitotic neurons led to derepression of BAF53a, indicating that REST-mediated repression of microRNAs directs the essential switch of chromatin regulatory complexes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2921580/" 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/PMC2921580/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoo, Andrew S -- Staahl, Brett T -- Chen, Lei -- Crabtree, Gerald R -- 2 T32 HD007249/HD/NICHD NIH HHS/ -- AI060037/AI/NIAID NIH HHS/ -- HD55391/HD/NICHD NIH HHS/ -- NS046789/NS/NINDS NIH HHS/ -- R01 HD055391/HD/NICHD NIH HHS/ -- R01 NS046789/NS/NINDS NIH HHS/ -- R01 NS046789-08/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 30;460(7255):642-6. doi: 10.1038/nature08139. Epub 2009 Jun 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, and Department of Developmental Biology, Stanford University, Stanford, California 94305, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19561591" target="_blank"〉PubMed〈/a〉
    Keywords: 3' Untranslated Regions/metabolism ; Actins/genetics/metabolism ; Animals ; CHO Cells ; Cell Line ; Chromatin Assembly and Disassembly/genetics/*physiology ; Chromosomal Proteins, Non-Histone/genetics/metabolism ; Cricetinae ; Cricetulus ; DNA-Binding Proteins/genetics/metabolism ; Dendrites/physiology ; *Gene Expression Regulation, Developmental ; Mice ; Mice, Transgenic ; MicroRNAs/*metabolism ; Mitosis ; Nervous System/cytology/*embryology ; Neurons/cytology ; Repressor Proteins/metabolism ; Stem Cells/metabolism
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  • 16
    Publication Date: 2009-04-28
    Description: Heart disease is the leading cause of mortality and morbidity in the western world. The heart has little regenerative capacity after damage, leading to much interest in understanding the factors required to produce new cardiac myocytes. Despite a robust understanding of the molecular networks regulating cardiac differentiation, no single transcription factor or combination of factors has been shown to activate the cardiac gene program de novo in mammalian cells or tissues. Here we define the minimal requirements for transdifferentiation of mouse mesoderm to cardiac myocytes. We show that two cardiac transcription factors, Gata4 and Tbx5, and a cardiac-specific subunit of BAF chromatin-remodelling complexes, Baf60c (also called Smarcd3), can direct ectopic differentiation of mouse mesoderm into beating cardiomyocytes, including the normally non-cardiogenic posterior mesoderm and the extraembryonic mesoderm of the amnion. Gata4 with Baf60c initiated ectopic cardiac gene expression. Addition of Tbx5 allowed differentiation into contracting cardiomyocytes and repression of non-cardiac mesodermal genes. Baf60c was essential for the ectopic cardiogenic activity of Gata4 and Tbx5, partly by permitting binding of Gata4 to cardiac genes, indicating a novel instructive role for BAF complexes in tissue-specific regulation. The combined function of these factors establishes a robust mechanism for controlling cellular differentiation, and may allow reprogramming of new cardiomyocytes for regenerative purposes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728356/" 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/PMC2728356/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Takeuchi, Jun K -- Bruneau, Benoit G -- C06 RR018928/RR/NCRR NIH HHS/ -- R01 HL085860/HL/NHLBI NIH HHS/ -- R01 HL085860-01/HL/NHLBI NIH HHS/ -- R01HL085860/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Jun 4;459(7247):708-11. doi: 10.1038/nature08039. Epub 2009 Apr 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA. takeuchi.j.ab@m.titech.ac.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19396158" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Transdifferentiation ; Chromosomal Proteins, Non-Histone ; Embryo, Mammalian ; GATA4 Transcription Factor/metabolism ; Gene Expression Regulation, Developmental ; Heart/*embryology ; Mesoderm/cytology/*embryology ; Mice ; Muscle Proteins ; Myocytes, Cardiac/*cytology/metabolism ; T-Box Domain Proteins/metabolism
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  • 17
    Publication Date: 2009-08-21
    Description: Activity is thought to guide the patterning of synaptic connections in the developing nervous system. Specifically, differences in the activity of converging inputs are thought to cause the elimination of synapses from less active inputs and increase connectivity with more active inputs. Here we present findings that challenge the generality of this notion and offer a new view of the role of activity in synapse development. To imbalance neurotransmission from different sets of inputs in vivo, we generated transgenic mice in which ON but not OFF types of bipolar cells in the retina express tetanus toxin (TeNT). During development, retinal ganglion cells (RGCs) select between ON and OFF bipolar cell inputs (ON or OFF RGCs) or establish a similar number of synapses with both on separate dendritic arborizations (ON-OFF RGCs). In TeNT retinas, ON RGCs correctly selected the silenced ON bipolar cell inputs over the transmitting OFF bipolar cells, but were connected with them through fewer synapses at maturity. Time-lapse imaging revealed that this was caused by a reduced rate of synapse formation rather than an increase in synapse elimination. Similarly, TeNT-expressing ON bipolar cell axons generated fewer presynaptic active zones. The remaining active zones often recruited multiple, instead of single, synaptic ribbons. ON-OFF RGCs in TeNT mice maintained convergence of ON and OFF bipolar cells inputs and had fewer synapses on their ON arbor without changes to OFF arbor synapses. Our results reveal an unexpected and remarkably selective role for activity in circuit development in vivo, regulating synapse formation but not elimination, affecting synapse number but not dendritic or axonal patterning, and mediating independently the refinement of connections from parallel (ON and OFF) processing streams even where they converge onto the same postsynaptic cell.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746695/" 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/PMC2746695/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kerschensteiner, Daniel -- Morgan, Josh L -- Parker, Edward D -- Lewis, Renate M -- Wong, Rachel O L -- EY01730/EY/NEI NIH HHS/ -- EY10699/EY/NEI NIH HHS/ -- R01 EY010699/EY/NEI NIH HHS/ -- R01 EY010699-16/EY/NEI NIH HHS/ -- T32 EY07031/EY/NEI NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1016-20. doi: 10.1038/nature08236.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri 63110, USA. KerschensteinerD@vision.wustl.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19693082" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/metabolism ; Dendrites/metabolism ; Female ; Glutamic Acid/metabolism ; Male ; Mice ; Mice, Transgenic ; Receptors, Kainic Acid/genetics/metabolism ; Retinal Bipolar Cells/cytology/metabolism ; Retinal Ganglion Cells/cytology/metabolism ; Synapses/*metabolism ; Synaptic Transmission/*physiology ; Tetanus Toxin/genetics/metabolism
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  • 18
    Publication Date: 2009-09-11
    Description: Infectious prion diseases-scrapie of sheep and chronic wasting disease (CWD) of several species in the deer family-are transmitted naturally within affected host populations. Although several possible sources of contagion have been identified in excretions and secretions from symptomatic animals, the biological importance of these sources in sustaining epidemics remains unclear. Here we show that asymptomatic CWD-infected mule deer (Odocoileus hemionus) excrete CWD prions in their faeces long before they develop clinical signs of prion disease. Intracerebral inoculation of irradiated deer faeces into transgenic mice overexpressing cervid prion protein (PrP) revealed infectivity in 14 of 15 faecal samples collected from five deer at 7-11 months before the onset of neurological disease. Although prion concentrations in deer faeces were considerably lower than in brain tissue from the same deer collected at the end of the disease, the estimated total infectious dose excreted in faeces by an infected deer over the disease course may approximate the total contained in a brain. Prolonged faecal prion excretion by infected deer provides a plausible natural mechanism that might explain the high incidence and efficient horizontal transmission of CWD within deer herds, as well as prion transmission among other susceptible cervids.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186440/" 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/PMC3186440/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tamguney, Gultekin -- Miller, Michael W -- Wolfe, Lisa L -- Sirochman, Tracey M -- Glidden, David V -- Palmer, Christina -- Lemus, Azucena -- DeArmond, Stephen J -- Prusiner, Stanley B -- AG02132/AG/NIA NIH HHS/ -- P01 AG002132/AG/NIA NIH HHS/ -- P01 AG002132-26/AG/NIA NIH HHS/ -- P01 AG002132-29/AG/NIA NIH HHS/ -- England -- Nature. 2009 Sep 24;461(7263):529-32. doi: 10.1038/nature08289. Epub 2009 Sep 9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute for Neurodegenerative Diseases, University of California, San Francisco, California 94143 USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741608" target="_blank"〉PubMed〈/a〉
    Keywords: Administration, Oral ; Animals ; Biological Assay ; Brain/metabolism ; Deer/*metabolism ; Feces/*chemistry ; Injections, Intraventricular ; Mice ; Mice, Transgenic ; PrPSc Proteins/isolation & purification/*metabolism/*pathogenicity/radiation ; effects ; Time Factors ; Wasting Disease, Chronic/*metabolism/*transmission
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  • 19
    Publication Date: 2009-02-13
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766277/" 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/PMC2766277/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yoshimoto, Momoko -- Yoder, Mervin C -- R01 AI080759/AI/NIAID NIH HHS/ -- R01 AI080759-01/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Feb 12;457(7231):801-3. doi: 10.1038/457801a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212393" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Cells/*cytology ; Embryo, Mammalian/cytology/embryology ; Hemangioblasts/*cytology ; Hematopoietic Stem Cells/cytology ; Mice
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  • 20
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    Nature Publishing Group (NPG)
    Publication Date: 2009-07-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Grant, Maria -- England -- Nature. 2009 Jul 9;460(7252):182-3. doi: 10.1038/460182a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19587753" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chemokine CCL11/antagonists & inhibitors/metabolism ; Chemokine CCL24/antagonists & inhibitors/metabolism ; Chemokines, CC/antagonists & inhibitors/metabolism ; Choroid/blood supply/cytology/metabolism ; Choroidal Neovascularization/diagnosis/metabolism ; Humans ; Hypersensitivity/metabolism ; Inflammation ; Macular Degeneration/diagnosis/*metabolism/therapy ; Mice ; Receptors, CCR3/antagonists & inhibitors/immunology/*metabolism ; Vascular Endothelial Growth Factor A/antagonists & inhibitors/metabolism
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  • 21
    Publication Date: 2009-08-29
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Riley, Paul -- England -- Nature. 2009 Aug 27;460(7259):1061. doi: 10.1038/4601061e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University College London.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19713895" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cardiovascular Diseases/therapy ; Fishes/*physiology ; Mice ; Myocardium/*cytology ; Neuregulin-1/*pharmacology ; Regeneration/*drug effects ; Salamandridae/physiology
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  • 22
    Publication Date: 2009-09-29
    Description: Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies. JAK2 is a non-receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1alpha at the same site. Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3785147/" 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/PMC3785147/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Mark A -- Bannister, Andrew J -- Gottgens, Berthold -- Foster, Samuel D -- Bartke, Till -- Green, Anthony R -- Kouzarides, Tony -- 089957/Wellcome Trust/United Kingdom -- 12765/Cancer Research UK/United Kingdom -- G0800784/Medical Research Council/United Kingdom -- MC_UP_1102/2/Medical Research Council/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- Wellcome Trust/United Kingdom -- England -- Nature. 2009 Oct 8;461(7265):819-22. doi: 10.1038/nature08448. Epub 2009 Sep 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cambridge Institute for Medical Research and Department of Haematology, University of Cambridge, Hills Road, Cambridge CB2 0XY, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19783980" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing ; Animals ; Binding Sites ; Cell Line ; Cell Nucleus/enzymology ; Chromatin/chemistry/*metabolism ; Chromosomal Proteins, Non-Histone/*metabolism ; DNA-Binding Proteins/genetics ; Gene Expression Regulation, Neoplastic ; Hematopoiesis/genetics ; Hematopoietic Stem Cells/cytology/enzymology ; Histones/chemistry/genetics/*metabolism ; Humans ; Janus Kinase 2/antagonists & inhibitors/*metabolism ; LIM Domain Proteins ; Leukemia/enzymology/genetics/metabolism/pathology ; Metalloproteins/genetics ; Mice ; Oncogenes/genetics ; Phosphorylation ; Promoter Regions, Genetic/genetics ; Protein Binding ; Proto-Oncogene Proteins ; Signal Transduction ; Tyrosine/metabolism
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  • 23
    Publication Date: 2009-02-06
    Description: Recent studies indicate that the methylation state of histones can be dynamically regulated by histone methyltransferases and demethylases. The H3K9-specific demethylase Jhdm2a (also known as Jmjd1a and Kdm3a) has an important role in nuclear hormone receptor-mediated gene activation and male germ cell development. Through disruption of the Jhdm2a gene in mice, here we demonstrate that Jhdm2a is critically important in regulating the expression of metabolic genes. The loss of Jhdm2a function results in obesity and hyperlipidemia in mice. We provide evidence that the loss of Jhdm2a function disrupts beta-adrenergic-stimulated glycerol release and oxygen consumption in brown fat, and decreases fat oxidation and glycerol release in skeletal muscles. We show that Jhdm2a expression is induced by beta-adrenergic stimulation, and that Jhdm2a directly regulates peroxisome proliferator-activated receptor alpha (Ppara) and Ucp1 expression. Furthermore, we demonstrate that beta-adrenergic activation-induced binding of Jhdm2a to the PPAR responsive element (PPRE) of the Ucp1 gene not only decreases levels of H3K9me2 (dimethylation of lysine 9 of histone H3) at the PPRE, but also facilitates the recruitment of Ppargamma and Rxralpha and their co-activators Pgc1alpha (also known as Ppargc1a), CBP/p300 (Crebbp) and Src1 (Ncoa1) to the PPRE. Our studies thus demonstrate an essential role for Jhdm2a in regulating metabolic gene expression and normal weight control in mice.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4085783/" 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/PMC4085783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tateishi, Keisuke -- Okada, Yuki -- Kallin, Eric M -- Zhang, Yi -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Apr 9;458(7239):757-61. doi: 10.1038/nature07777. Epub 2009 Feb 4.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19194461" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue, Brown/metabolism ; Animals ; Cells, Cultured ; Energy Metabolism/*physiology ; Gene Expression Profiling ; *Gene Expression Regulation ; Glycerol/metabolism ; Ion Channels/metabolism ; Jumonji Domain-Containing Histone Demethylases ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitochondrial Proteins/metabolism ; Muscle, Skeletal/metabolism ; Obesity/*metabolism ; Oxidation-Reduction ; Oxidoreductases, N-Demethylating/*genetics/*metabolism ; Phenotype ; Receptors, Adrenergic, beta/metabolism
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  • 24
    Publication Date: 2009-04-24
    Description: Mammals rely heavily on olfaction to interact adequately with each other and with their environment. They make use of seven-transmembrane G-protein-coupled receptors to identify odorants and pheromones. These receptors are present on dendrites of olfactory sensory neurons located in the main olfactory or vomeronasal sensory epithelia, and pertain to the odorant, trace amine-associated receptor and vomeronasal type 1 (ref. 4) or 2 (refs 5-7) receptor superfamilies. Whether these four sensor classes represent the complete olfactory molecular repertoire used by mammals to make sense of the outside world is unknown. Here we report the expression of formyl peptide receptor-related genes by vomeronasal sensory neurons, in multiple mammalian species. Similar to the four known olfactory receptor gene classes, these genes encode seven-transmembrane proteins, and are characterized by monogenic transcription and a punctate expression pattern in the sensory neuroepithelium. In vitro expression of mouse formyl peptide receptor-like 1, 3, 4, 6 and 7 provides sensitivity to disease/inflammation-related ligands. Establishing an in situ approach that combines whole-mount vomeronasal preparations with dendritic calcium imaging in the intact neuroepithelium, we show neuronal responses to the same molecules, which therefore represent a new class of vomeronasal agonists. Taken together, these results suggest that formyl peptide receptor-like proteins have an olfactory function associated with the identification of pathogens, or of pathogenic states.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Riviere, Stephane -- Challet, Ludivine -- Fluegge, Daniela -- Spehr, Marc -- Rodriguez, Ivan -- England -- Nature. 2009 May 28;459(7246):574-7. doi: 10.1038/nature08029.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Zoology and Animal Biology, and National Center of Competence Frontiers in Genetics, University of Geneva, 1205 Geneva, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19387439" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium Signaling ; Cell Line ; Dendrites/drug effects/metabolism ; *Disease ; Gene Expression Profiling ; Humans ; Inflammation/pathology ; Ligands ; Mice ; Olfactory Perception/drug effects/*physiology ; Olfactory Receptor Neurons/cytology/drug effects/*metabolism ; Organ Specificity ; Receptors, Formyl Peptide/genetics/*metabolism ; Smell/drug effects/*physiology ; Vomeronasal Organ/*cytology/drug effects/physiology
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  • 25
    Publication Date: 2009-09-18
    Description: Molecules such as vascular endothelial growth factor (VEGF) or placental growth factor-critical regulators of tumour angiogenesis-are also thought to mobilize into blood circulation bone marrow-derived cells (BMDCs), which may subsequently be recruited to tumours and facilitate tumour growth and metastasis. A study has suggested that BMDCs form 'metastatic niches' in lungs before arrival of cancer cells, and showed that pharmacological inhibition of VEGF receptor 1 (VEGFR1, also known as Flt1)-cognate receptor for VEGF and placental growth factor-prevented BMDC infiltration in lungs and 'metastatic niche' formation. Here we report that blockade of VEGFR1 activity does not affect the rate of spontaneous metastasis formation in a clinically relevant and widely used preclinical model. Therefore, alternative pathways probably mediate the priming of tissues for metastasis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3065241/" 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/PMC3065241/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dawson, Michelle R -- Duda, Dan G -- Fukumura, Dai -- Jain, Rakesh K -- P01 CA080124/CA/NCI NIH HHS/ -- P01 CA080124-05/CA/NCI NIH HHS/ -- P01 CA080124-06A2/CA/NCI NIH HHS/ -- P01 CA080124-07/CA/NCI NIH HHS/ -- P01 CA080124-08/CA/NCI NIH HHS/ -- P01 CA080124-09/CA/NCI NIH HHS/ -- R01 CA085140/CA/NCI NIH HHS/ -- R01 CA085140-06/CA/NCI NIH HHS/ -- R01 CA085140-07/CA/NCI NIH HHS/ -- R01 CA085140-08/CA/NCI NIH HHS/ -- R01 CA085140-09/CA/NCI NIH HHS/ -- R01 CA096915/CA/NCI NIH HHS/ -- R01 CA096915-04/CA/NCI NIH HHS/ -- R01 CA096915-05/CA/NCI NIH HHS/ -- R01 CA096915-06A1/CA/NCI NIH HHS/ -- R01 CA096915-07/CA/NCI NIH HHS/ -- R01 CA096915-08/CA/NCI NIH HHS/ -- R01 CA115767/CA/NCI NIH HHS/ -- R01 CA115767-01A1/CA/NCI NIH HHS/ -- R01 CA115767-02/CA/NCI NIH HHS/ -- R01 CA115767-03/CA/NCI NIH HHS/ -- R01 CA115767-04/CA/NCI NIH HHS/ -- R01 CA126642/CA/NCI NIH HHS/ -- R01 CA126642-01A1/CA/NCI NIH HHS/ -- R01 CA126642-02/CA/NCI NIH HHS/ -- R24 CA085140/CA/NCI NIH HHS/ -- R24 CA085140-05/CA/NCI NIH HHS/ -- T32 CA073479/CA/NCI NIH HHS/ -- T32 CA073479-08/CA/NCI NIH HHS/ -- T32 CA073479-09/CA/NCI NIH HHS/ -- T32 CA073479-10/CA/NCI NIH HHS/ -- T32 CA073479-11/CA/NCI NIH HHS/ -- T32 CA073479-12/CA/NCI NIH HHS/ -- England -- Nature. 2009 Sep 17;461(7262):E4; discussion E5. doi: 10.1038/nature08254.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759568" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bone Marrow Cells/cytology ; Cell Movement ; Lung/pathology ; Lung Neoplasms/*secondary ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Neoplasms/*pathology ; Vascular Endothelial Growth Factor Receptor-1/*antagonists & ; inhibitors/deficiency/*metabolism
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  • 26
    Publication Date: 2009-09-01
    Description: Induced pluripotent stem (iPS) cells have been generated from mouse and human somatic cells by ectopic expression of four transcription factors (OCT4 (also called POU5F1), SOX2, c-Myc and KLF4). We previously reported that Oct4 alone is sufficient to reprogram directly adult mouse neural stem cells to iPS cells. Here we report the generation of one-factor human iPS cells from human fetal neural stem cells (one-factor (1F) human NiPS cells) by ectopic expression of OCT4 alone. One-factor human NiPS cells resemble human embryonic stem cells in global gene expression profiles, epigenetic status, as well as pluripotency in vitro and in vivo. These findings demonstrate that the transcription factor OCT4 is sufficient to reprogram human neural stem cells to pluripotency. One-factor iPS cell generation will advance the field further towards understanding reprogramming and generating patient-specific pluripotent stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Jeong Beom -- Greber, Boris -- Arauzo-Bravo, Marcos J -- Meyer, Johann -- Park, Kook In -- Zaehres, Holm -- Scholer, Hans R -- England -- Nature. 2009 Oct 1;461(7264):649-3. doi: 10.1038/nature08436.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Max Planck Institute for Molecular Biomedicine, Department of Cell and Developmental Biology, Rontgenstrasse 20, 48149 Munster, NRW, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19718018" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biomarkers/analysis ; *Cell Dedifferentiation ; Cell Differentiation ; Cell Line ; *Cellular Reprogramming ; DNA Methylation ; Embryonic Stem Cells/cytology/metabolism ; Epigenesis, Genetic ; Fetus/*cytology ; Gene Expression Profiling ; Germ Layers/cytology/metabolism ; Humans ; Mice ; Neurons/*cytology/metabolism ; Octamer Transcription Factor-3/genetics/*metabolism ; Pluripotent Stem Cells/*cytology/*metabolism
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  • 27
    Publication Date: 2009-02-11
    Description: Neurons in the mammalian neocortex are organized into functional columns. Within a column, highly specific synaptic connections are formed to ensure that similar physiological properties are shared by neuron ensembles spanning from the pia to the white matter. Recent studies indicate that synaptic connectivity in the neocortex is sparse and highly specific to allow even adjacent neurons to convey information independently. How this fine-scale microcircuit is constructed to create a functional columnar architecture at the level of individual neurons largely remains a mystery. Here we investigate whether radial clones of excitatory neurons arising from the same mother cell in the developing neocortex serve as a substrate for the formation of this highly specific microcircuit. We labelled ontogenetic radial clones of excitatory neurons in the mouse neocortex by in utero intraventricular injection of enhanced green fluorescent protein (EGFP)-expressing retroviruses around the onset of the peak phase of neocortical neurogenesis. Multiple-electrode whole-cell recordings were performed to probe synapse formation among these EGFP-labelled sister excitatory neurons in radial clones and the adjacent non-siblings during postnatal stages. We found that radially aligned sister excitatory neurons have a propensity for developing unidirectional chemical synapses with each other rather than with neighbouring non-siblings. Moreover, these synaptic connections display the same interlaminar directional preference as those observed in the mature neocortex. These results indicate that specific microcircuits develop preferentially within ontogenetic radial clones of excitatory neurons in the developing neocortex and contribute to the emergence of functional columnar microarchitectures in the mature neocortex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2727717/" 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/PMC2727717/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yu, Yong-Chun -- Bultje, Ronald S -- Wang, Xiaoqun -- Shi, Song-Hai -- AS5274/Autism Speaks/ -- R01 DA024681/DA/NIDA NIH HHS/ -- R01 DA024681-01A1/DA/NIDA NIH HHS/ -- R21 MH083624/MH/NIMH NIH HHS/ -- R21 MH083624-01/MH/NIMH NIH HHS/ -- England -- Nature. 2009 Mar 26;458(7237):501-4. doi: 10.1038/nature07722. Epub 2009 Feb 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Developmental Biology Program, Memorial Sloan Kettering Cancer Centre, 1275 York Avenue, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19204731" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Lineage ; Clone Cells/cytology ; Mice ; Neocortex/anatomy & histology/*cytology ; Neurons/*cytology/*metabolism ; Synapses/*metabolism
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  • 28
    Publication Date: 2009-10-23
    Description: NF-kappaB transcription factors function as crucial regulators of inflammatory and immune responses as well as of cell survival. They have also been implicated in cellular transformation and tumorigenesis. However, despite extensive biochemical characterization of NF-kappaB signalling during the past twenty years, the requirement for NF-kappaB in tumour development in vivo, particularly in solid tumours, is not completely understood. Here we show that the NF-kappaB pathway is required for the development of tumours in a mouse model of lung adenocarcinoma. Concomitant loss of p53 (also known as Trp53) and expression of oncogenic Kras(G12D) resulted in NF-kappaB activation in primary mouse embryonic fibroblasts. Conversely, in lung tumour cell lines expressing Kras(G12D) and lacking p53, p53 restoration led to NF-kappaB inhibition. Furthermore, the inhibition of NF-kappaB signalling induced apoptosis in p53-null lung cancer cell lines. Inhibition of the pathway in lung tumours in vivo, from the time of tumour initiation or after tumour progression, resulted in significantly reduced tumour development. Together, these results indicate a critical function for NF-kappaB signalling in lung tumour development and, further, that this requirement depends on p53 status. These findings also provide support for the development of NF-kappaB inhibitory drugs as targeted therapies for the treatment of patients with defined mutations in Kras and p53.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780341/" 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/PMC2780341/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Meylan, Etienne -- Dooley, Alison L -- Feldser, David M -- Shen, Lynn -- Turk, Erin -- Ouyang, Chensi -- Jacks, Tyler -- P30 CA014051/CA/NCI NIH HHS/ -- P30 CA014051-37/CA/NCI NIH HHS/ -- P30 CA014051-38/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Nov 5;462(7269):104-7. doi: 10.1038/nature08462. Epub 2009 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Koch Institute for Integrative Cancer Research, and Department of Biology, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847165" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*metabolism/*pathology ; Animals ; Apoptosis ; Carcinoma, Non-Small-Cell Lung/metabolism/pathology ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Cells, Cultured ; DNA/metabolism ; *Disease Models, Animal ; Fibroblasts ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*metabolism/*pathology ; Mice ; NF-kappa B/antagonists & inhibitors/*metabolism ; Oncogene Protein p21(ras)/genetics/metabolism ; *Signal Transduction ; Transcription Factor RelA/metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/metabolism
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  • 29
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    Nature Publishing Group (NPG)
    Publication Date: 2009-09-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gregory, Christopher -- England -- Nature. 2009 Sep 10;461(7261):181-2. doi: 10.1038/461181a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741694" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/*metabolism/secretion ; Animals ; Apoptosis/*physiology ; Chemotactic Factors/metabolism/secretion ; Chemotaxis/drug effects ; Culture Media, Conditioned/metabolism/pharmacology ; Humans ; Macrophages/cytology/drug effects/metabolism ; Mice ; Monocytes/cytology/drug effects/metabolism ; Phagocytes/*cytology/drug effects/metabolism ; Phagocytosis/drug effects/*physiology ; Receptors, Purinergic P2/metabolism ; Receptors, Purinergic P2Y2 ; *Signal Transduction/drug effects ; Thymus Gland/*cytology ; Uridine Triphosphate/*metabolism/secretion
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  • 30
    Publication Date: 2009-06-03
    Description: The rapid turnover and exfoliation of mucosal epithelial cells provides an innate defence system against bacterial infection. Nevertheless, many pathogenic bacteria, including Shigella, are able to surmount exfoliation and colonize the epithelium efficiently. Here we show that the Shigella flexneri effector OspE (consisting of OspE1 and OspE2 proteins), which is highly conserved among enteropathogenic Escherichia coli, enterohaemorrhagic E. coli, Citrobacter rodentium and Salmonella strains, reinforces host cell adherence to the basement membrane by interacting with integrin-linked kinase (ILK). The number of focal adhesions was augmented along with membrane fraction ILK by ILK-OspE binding. The interaction between ILK and OspE increased cell surface levels of 1 integrin and suppressed phosphorylation of focal adhesion kinase and paxillin, which are required for rapid turnover of focal adhesion in cell motility. Nocodazole-washout-induced focal adhesion disassembly was blocked by expression of OspE. Polarized epithelial cells infected with a Shigella mutant lacking the ospE gene underwent more rapid cell detachment than cells infected with wild-type Shigella. Infection of guinea pig colons with Shigella corroborated the pivotal role of the OspE-ILK interaction in suppressing epithelial detachment, increasing bacterial cell-to-cell spreading, and promoting bacterial colonization. These results indicate that Shigella sustain their infectious foothold by using special tactics to prevent detachment of infected cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Minsoo -- Ogawa, Michinaga -- Fujita, Yukihiro -- Yoshikawa, Yuko -- Nagai, Takeshi -- Koyama, Tomohiro -- Nagai, Shinya -- Lange, Anika -- Fassler, Reinhard -- Sasakawa, Chihiro -- England -- Nature. 2009 May 28;459(7246):578-82. doi: 10.1038/nature07952.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Infectious Disease Control, International Research Center for Infectious Diseases, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19489119" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD29/metabolism ; Bacterial Outer Membrane Proteins/genetics/metabolism ; Cell Adhesion/drug effects/*physiology ; Cell Polarity ; Colon/microbiology ; Epithelial Cells/cytology/microbiology ; Focal Adhesions/drug effects/*physiology ; Guinea Pigs ; HeLa Cells ; Humans ; Mice ; Nocodazole/pharmacology ; Phosphorylation ; Protein Binding ; Protein-Serine-Threonine Kinases/*metabolism ; Shigella flexneri/pathogenicity/*physiology ; Virulence Factors/deficiency/genetics/metabolism
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  • 31
    Publication Date: 2009-02-27
    Description: Establishment and maintenance of the pluripotent state of ESCs is a key issue in stem cell biology and regenerative medicine, and consequently identification of transcription factors that regulate ESC pluripotency is an important goal. Singh et al. claim that the transcriptional repressor REST is such a regulator and that a 50% reduction of REST in ESCs leads to activation of a specific microRNA, miR-21, and that this subsequently results in loss of pluripotency markers and a reciprocal gain in some lineage-specific differentiation markers. In contrast, we show that, in haplodeficient Rest(+/-) ESCs, we detected no change in pluripotency markers, no precocious expression of differentiated neuronal markers and no interaction of REST with miR-21. It is vital that identification of factors that regulate pluripotency is based on robust, consistent data, and the contrast in data reported here undermines the claim by Singh et al. that REST is such a regulator.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buckley, Noel J -- Johnson, Rory -- Sun, Yuh-Man -- Stanton, Lawrence W -- England -- Nature. 2009 Feb 26;457(7233):E5-6; discussion E7. doi: 10.1038/nature07784.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉King's College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour, James Black Centre, 125 Coldharbour Lane, London SE5 9NU, UK. noel.buckley@iop.kcl.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242418" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Embryonic Stem Cells/*cytology/*metabolism ; Gene Knockdown Techniques ; Mice ; MicroRNAs/genetics/metabolism ; Pluripotent Stem Cells/*cytology/*metabolism ; Polymerase Chain Reaction ; Repressor Proteins/genetics/*metabolism ; Reproducibility of Results
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  • 32
    Publication Date: 2009-10-16
    Description: Epigenetic modifications at the histone level affect gene regulation in response to extracellular signals. However, regulated epigenetic modifications at the DNA level, especially active DNA demethylation, in gene activation are not well understood. Here we report that DNA methylation/demethylation is hormonally switched to control transcription of the cytochrome p450 27B1 (CYP27B1) gene. Reflecting vitamin-D-mediated transrepression of the CYP27B1 gene by the negative vitamin D response element (nVDRE), methylation of CpG sites ((5m)CpG) is induced by vitamin D in this gene promoter. Conversely, treatment with parathyroid hormone, a hormone known to activate the CYP27B1 gene, induces active demethylation of the (5m)CpG sites in this promoter. Biochemical purification of a complex associated with the nVDRE-binding protein (VDIR, also known as TCF3) identified two DNA methyltransferases, DNMT1 and DNMT3B, for methylation of CpG sites, as well as a DNA glycosylase, MBD4 (ref. 10). Protein-kinase-C-phosphorylated MBD4 by parathyroid hormone stimulation promotes incision of methylated DNA through glycosylase activity, and a base-excision repair process seems to complete DNA demethylation in the MBD4-bound promoter. Such parathyroid-hormone-induced DNA demethylation and subsequent transcriptional derepression are impaired in Mbd4(-/-) mice. Thus, the present findings suggest that methylation switching at the DNA level contributes to the hormonal control of transcription.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Mi-Sun -- Kondo, Takeshi -- Takada, Ichiro -- Youn, Min-Young -- Yamamoto, Yoko -- Takahashi, Sayuri -- Matsumoto, Takahiro -- Fujiyama, Sally -- Shirode, Yuko -- Yamaoka, Ikuko -- Kitagawa, Hirochika -- Takeyama, Ken-ichi -- Shibuya, Hiroshi -- Ohtake, Fumiaki -- Kato, Shigeaki -- England -- Nature. 2009 Oct 15;461(7266):1007-12. doi: 10.1038/nature08456.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉ERATO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchisi, Saitama 332-0012, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829383" target="_blank"〉PubMed〈/a〉
    Keywords: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase/genetics ; Animals ; Cell Line ; CpG Islands/genetics ; DNA (Cytosine-5-)-Methyltransferase/metabolism ; DNA Glycosylases/metabolism ; DNA Methylation/*drug effects ; Down-Regulation/drug effects ; Endodeoxyribonucleases/deficiency/genetics ; Mice ; Parathyroid Hormone/*pharmacology ; Phosphorylation ; Protein Kinase C/metabolism ; Response Elements/genetics ; Transcription, Genetic/*drug effects ; Vitamin D/pharmacology
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  • 33
    Publication Date: 2009-01-06
    Description: Metastatic progression depends on genetic alterations intrinsic to cancer cells as well as the inflammatory microenvironment of advanced tumours. To understand how cancer cells affect the inflammatory microenvironment, we conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. Here we show that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL-6) and tumour-necrosis factor-alpha (TNF-alpha) through activation of the Toll-like receptor (TLR) family members TLR2 and TLR6. Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium (LCM) led to identification of the extracellular matrix proteoglycan versican, which is upregulated in many human tumours including lung cancer, as a macrophage activator that acts through TLR2 and its co-receptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. These results explain how advanced cancer cells usurp components of the host innate immune system, including bone-marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2746432/" 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/PMC2746432/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kim, Sunhwa -- Takahashi, Hiroyuki -- Lin, Wan-Wan -- Descargues, Pascal -- Grivennikov, Sergei -- Kim, Youngjun -- Luo, Jun-Li -- Karin, Michael -- R01 CA118165/CA/NCI NIH HHS/ -- R01 CA118165-02/CA/NCI NIH HHS/ -- R01 CA132586/CA/NCI NIH HHS/ -- R01 ES006376/ES/NIEHS NIH HHS/ -- R01 ES006376-14/ES/NIEHS NIH HHS/ -- T32 CA121938/CA/NCI NIH HHS/ -- England -- Nature. 2009 Jan 1;457(7225):102-6. doi: 10.1038/nature07623.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Center, School of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0723, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19122641" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD14/metabolism ; Carcinoma, Lewis Lung/*metabolism/pathology/secretion ; Culture Media, Conditioned/metabolism/pharmacology ; Culture Media, Serum-Free/metabolism ; Interleukin-6/metabolism/secretion ; Liver Neoplasms/secondary ; Lung Neoplasms/metabolism/pathology/secondary ; *Macrophage Activation ; Macrophages/*metabolism/secretion ; Mice ; Mice, Inbred C57BL ; *Neoplasm Metastasis/pathology ; Neoplasm Transplantation ; Toll-Like Receptor 2/agonists/*metabolism ; Toll-Like Receptor 6/metabolism ; Tumor Necrosis Factor-alpha/metabolism/secretion ; Versicans/metabolism/pharmacology
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  • 34
    Publication Date: 2009-10-23
    Description: Fluorescence, that is, spontaneous emission, is generally more sensitive than absorption measurement, and is widely used in optical imaging. However, many chromophores, such as haemoglobin and cytochromes, absorb but have undetectable fluorescence because the spontaneous emission is dominated by their fast non-radiative decay. Yet the detection of their absorption is difficult under a microscope. Here we use stimulated emission, which competes effectively with the nonradiative decay, to make the chromophores detectable, and report a new contrast mechanism for optical microscopy. In a pump-probe experiment, on photoexcitation by a pump pulse, the sample is stimulated down to the ground state by a time-delayed probe pulse, the intensity of which is concurrently increased. We extract the miniscule intensity increase with shot-noise-limited sensitivity by using a lock-in amplifier and intensity modulation of the pump beam at a high megahertz frequency. The signal is generated only at the laser foci owing to the nonlinear dependence on the input intensities, providing intrinsic three-dimensional optical sectioning capability. In contrast, conventional one-beam absorption measurement exhibits low sensitivity, lack of three-dimensional sectioning capability, and complication by linear scattering of heterogeneous samples. We demonstrate a variety of applications of stimulated emission microscopy, such as visualizing chromoproteins, non-fluorescent variants of the green fluorescent protein, monitoring lacZ gene expression with a chromogenic reporter, mapping transdermal drug distributions without histological sectioning, and label-free microvascular imaging based on endogenous contrast of haemoglobin. For all these applications, sensitivity is orders of magnitude higher than for spontaneous emission or absorption contrast, permitting nonfluorescent reporters for molecular imaging.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Min, Wei -- Lu, Sijia -- Chong, Shasha -- Roy, Rahul -- Holtom, Gary R -- Xie, X Sunney -- England -- Nature. 2009 Oct 22;461(7267):1105-9. doi: 10.1038/nature08438.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847261" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Ear ; Escherichia coli/metabolism ; Fluorescence ; Gene Expression Profiling ; Genes, Reporter/genetics ; Hemoglobins/analysis ; Indigo Carmine ; Indoles/metabolism ; Lac Operon/genetics ; Lasers ; Mice ; Microscopy/*methods ; Molecular Imaging/*methods ; Photosensitizing Agents/analysis ; Sensitivity and Specificity
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  • 35
    Publication Date: 2009-04-03
    Description: Fungal infections represent a serious threat, particularly in immunocompromised patients. Interleukin-1beta (IL-1beta) is a key pro-inflammatory factor in innate antifungal immunity. The mechanism by which the mammalian immune system regulates IL-1beta production after fungal recognition is unclear. Two signals are generally required for IL-1beta production: an NF-kappaB-dependent signal that induces the synthesis of pro-IL-1beta (p35), and a second signal that triggers proteolytic pro-IL-1beta processing to produce bioactive IL-1beta (p17) via Caspase-1-containing multiprotein complexes called inflammasomes. Here we demonstrate that the tyrosine kinase Syk, operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL-1beta synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signalling for pro-IL-1beta synthesis selectively uses the Card9 pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmalogical inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 (also known as NALP3) was identified as the critical NOD-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (Pycard) for Caspase-1 (Casp1) activation and pro-IL-1beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, we show that Nlrp3-deficient mice are hypersusceptible to Candida albicans infection. Thus, our results demonstrate the molecular basis for IL-1beta production after fungal infection and identify a crucial function for the Nlrp3 inflammasome in mammalian host defence in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gross, Olaf -- Poeck, Hendrik -- Bscheider, Michael -- Dostert, Catherine -- Hannesschlager, Nicole -- Endres, Stefan -- Hartmann, Gunther -- Tardivel, Aubry -- Schweighoffer, Edina -- Tybulewicz, Victor -- Mocsai, Attila -- Tschopp, Jurg -- Ruland, Jurgen -- MC_U117527252/Medical Research Council/United Kingdom -- England -- Nature. 2009 May 21;459(7245):433-6. doi: 10.1038/nature07965. Epub 2009 Apr 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉III. Medizinische Klinik, Klinikum rechts der Isar, Technische Universitat Munchen, Ismaninger Str. 22, 81675 Munich, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19339971" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Candida albicans/*immunology/physiology ; Carrier Proteins/*immunology/*metabolism ; Caspase 1/metabolism ; Enzyme Activation ; Humans ; Inflammation/immunology ; Interleukin-1beta/biosynthesis/immunology ; Intracellular Signaling Peptides and Proteins/antagonists & ; inhibitors/deficiency/genetics/*metabolism ; Macrophages/metabolism ; Mice ; Monocytes/metabolism ; Nigericin/pharmacology ; Potassium/metabolism ; Protein-Tyrosine Kinases/antagonists & inhibitors/deficiency/genetics/*metabolism ; Reactive Oxygen Species/metabolism ; *Signal Transduction
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  • 36
    Publication Date: 2009-06-19
    Description: T-cell acute lymphoblastic leukaemia (T-ALL) is a blood malignancy afflicting mainly children and adolescents. T-ALL patients present at diagnosis with increased white cell counts and hepatosplenomegaly, and are at an increased risk of central nervous system (CNS) relapse. For that reason, T-ALL patients usually receive cranial irradiation in addition to intensified intrathecal chemotherapy. The marked increase in survival is thought to be worth the considerable side-effects associated with this therapy. Such complications include secondary tumours, neurocognitive deficits, endocrine disorders and growth impairment. Little is known about the mechanism of leukaemic cell infiltration of the CNS, despite its clinical importance. Here we show, using T-ALL animal modelling and gene-expression profiling, that the chemokine receptor CCR7 (ref. 5) is the essential adhesion signal required for the targeting of leukaemic T-cells into the CNS. Ccr7 gene expression is controlled by the activity of the T-ALL oncogene Notch1 and is expressed in human tumours carrying Notch1-activating mutations. Silencing of either CCR7 or its chemokine ligand CCL19 (ref. 6) in an animal model of T-ALL specifically inhibits CNS infiltration. Furthermore, murine CNS-targeting by human T-ALL cells depends on their ability to express CCR7. These studies identify a single chemokine-receptor interaction as a CNS 'entry' signal, and open the way for future pharmacological targeting. Targeted inhibition of CNS involvement in T-ALL could potentially decrease the intensity of CNS-targeted therapy, thus reducing its associated short- and long-term complications.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3750496/" 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/PMC3750496/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Buonamici, Silvia -- Trimarchi, Thomas -- Ruocco, Maria Grazia -- Reavie, Linsey -- Cathelin, Severine -- Mar, Brenton G -- Klinakis, Apostolos -- Lukyanov, Yevgeniy -- Tseng, Jen-Chieh -- Sen, Filiz -- Gehrie, Eric -- Li, Mengling -- Newcomb, Elizabeth -- Zavadil, Jiri -- Meruelo, Daniel -- Lipp, Martin -- Ibrahim, Sherif -- Efstratiadis, Argiris -- Zagzag, David -- Bromberg, Jonathan S -- Dustin, Michael L -- Aifantis, Iannis -- 1 P01 CA97403/CA/NCI NIH HHS/ -- P30CA016087/CA/NCI NIH HHS/ -- R01 AI041428/AI/NIAID NIH HHS/ -- R01 AI062765/AI/NIAID NIH HHS/ -- R01 AI072039/AI/NIAID NIH HHS/ -- R01 CA105129/CA/NCI NIH HHS/ -- R01 CA149655/CA/NCI NIH HHS/ -- R01AI072039/AI/NIAID NIH HHS/ -- R01AI41428/AI/NIAID NIH HHS/ -- R01CA105129/CA/NCI NIH HHS/ -- R01CA133379/CA/NCI NIH HHS/ -- R21 CA141399/CA/NCI NIH HHS/ -- R56AI070310/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Jun 18;459(7249):1000-4. doi: 10.1038/nature08020.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and New York University Cancer Institute, New York 10016, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536265" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Adhesion ; Cell Line, Tumor ; Central Nervous System/*metabolism/*pathology ; Chemokine CCL19/deficiency/metabolism ; Chemokine CCL21/metabolism ; Humans ; Leukemia, T-Cell/*metabolism/*pathology ; Mice ; Mice, Inbred C57BL ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/metabolism/pathology ; Receptor, Notch1/genetics/metabolism ; Receptors, CCR7/deficiency/*metabolism ; *Signal Transduction
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  • 37
    Publication Date: 2009-04-28
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ross, Christopher A -- Margolis, Russell L -- England -- Nature. 2009 Apr 23;458(7241):976-7. doi: 10.1038/458976a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19396131" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Glycogen Synthase Kinase 3/metabolism ; Humans ; Mice ; Nerve Tissue Proteins/genetics/*metabolism ; Schizophrenia/drug therapy/*metabolism/pathology ; *Signal Transduction ; Wnt1 Protein/metabolism ; beta Catenin/metabolism
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  • 38
    Publication Date: 2009-05-02
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zechner, Rudolf -- Madeo, Frank -- England -- Nature. 2009 Apr 30;458(7242):1118-9. doi: 10.1038/4581118a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19407787" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autophagy/*physiology ; Cholesterol/metabolism ; Fatty Acids/*metabolism ; Fatty Liver/metabolism/pathology ; Hepatocytes/cytology/metabolism ; *Lipid Metabolism ; Lipolysis ; Mice ; Rats ; Triglycerides/metabolism
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  • 39
    Publication Date: 2009-08-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Demb, Jonathan B -- Feller, Marla B -- England -- Nature. 2009 Aug 20;460(7258):961-3. doi: 10.1038/460961a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19693075" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Axons/metabolism ; Mice ; Retina/*cytology/*physiology ; Retinal Bipolar Cells/cytology/metabolism ; Retinal Ganglion Cells/cytology/metabolism ; Synapses/*metabolism ; Synaptic Transmission/*physiology
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  • 40
    Publication Date: 2009-06-16
    Description: Toll-like receptors (TLRs) are the best characterized pattern recognition receptors. Individual TLRs recruit diverse combinations of adaptor proteins, triggering signal transduction pathways and leading to the activation of various transcription factors, including nuclear factor kappaB, activation protein 1 and interferon regulatory factors. Interleukin-2 is one of the molecules produced by mouse dendritic cells after stimulation by different pattern recognition receptor agonists. By analogy with the events after T-cell receptor engagement leading to interleukin-2 production, it is therefore plausible that the stimulation of TLRs on dendritic cells may lead to activation of the Ca(2+)/calcineurin and NFAT (nuclear factor of activated T cells) pathway. Here we show that mouse dendritic cell stimulation with lipopolysaccharide (LPS) induces Src-family kinase and phospholipase Cgamma2 activation, influx of extracellular Ca(2+) and calcineurin-dependent nuclear NFAT translocation. The initiation of this pathway is independent of TLR4 engagement, and dependent exclusively on CD14. We also show that LPS-induced NFAT activation via CD14 is necessary to cause the apoptotic death of terminally differentiated dendritic cells, an event that is essential for maintaining self-tolerance and preventing autoimmunity. Consequently, blocking this pathway in vivo causes prolonged dendritic cell survival and an increase in T-cell priming capability. Our findings reveal novel aspects of molecular signalling triggered by LPS in dendritic cells, and identify a new role for CD14: the regulation of the dendritic cell life cycle through NFAT activation. Given the involvement of CD14 in disease, including sepsis and chronic heart failure, the discovery of signal transduction pathways activated exclusively via CD14 is an important step towards the development of potential treatments involving interference with CD14 functions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zanoni, Ivan -- Ostuni, Renato -- Capuano, Giusy -- Collini, Maddalena -- Caccia, Michele -- Ronchi, Antonella Ellena -- Rocchetti, Marcella -- Mingozzi, Francesca -- Foti, Maria -- Chirico, Giuseppe -- Costa, Barbara -- Zaza, Antonio -- Ricciardi-Castagnoli, Paola -- Granucci, Francesca -- England -- Nature. 2009 Jul 9;460(7252):264-8. doi: 10.1038/nature08118. Epub 2009 Jun 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19525933" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD14/*metabolism ; Apoptosis/drug effects ; Bone Marrow Cells/drug effects ; CD4-Positive T-Lymphocytes/drug effects/immunology ; Calcium/metabolism ; Calcium Signaling/drug effects ; Cell Differentiation ; Cell Survival/drug effects ; Dendritic Cells/*cytology/drug effects/*immunology/metabolism ; Lipopolysaccharides/*immunology/pharmacology ; Macrophages/cytology/drug effects/immunology ; Mice ; Mice, Inbred C57BL ; NFATC Transcription Factors/*metabolism ; Phospholipase C gamma/metabolism ; src-Family Kinases/metabolism
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  • 41
    Publication Date: 2009-02-27
    Description: Lung disease is the major cause of morbidity and mortality in cystic fibrosis, an autosomal recessive disease caused by mutations in CFTR. In cystic fibrosis, chronic infection and dysregulated neutrophilic inflammation lead to progressive airway destruction. The severity of cystic fibrosis lung disease has considerable heritability, independent of CFTR genotype. To identify genetic modifiers, here we performed a genome-wide single nucleotide polymorphism scan in one cohort of cystic fibrosis patients, replicating top candidates in an independent cohort. This approach identified IFRD1 as a modifier of cystic fibrosis lung disease severity. IFRD1 is a histone-deacetylase-dependent transcriptional co-regulator expressed during terminal neutrophil differentiation. Neutrophils, but not macrophages, from Ifrd1-deficient mice showed blunted effector function, associated with decreased NF-kappaB p65 transactivation. In vivo, IFRD1 deficiency caused delayed bacterial clearance from the airway, but also less inflammation and disease-a phenotype primarily dependent on haematopoietic cell expression, or lack of expression, of IFRD1. In humans, IFRD1 polymorphisms were significantly associated with variation in neutrophil effector function. These data indicate that IFRD1 modulates the pathogenesis of cystic fibrosis lung disease through the regulation of neutrophil effector function.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2841516/" 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/PMC2841516/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gu, YuanYuan -- Harley, Isaac T W -- Henderson, Lindsay B -- Aronow, Bruce J -- Vietor, Ilja -- Huber, Lukas A -- Harley, John B -- Kilpatrick, Jeffrey R -- Langefeld, Carl D -- Williams, Adrienne H -- Jegga, Anil G -- Chen, Jing -- Wills-Karp, Marsha -- Arshad, S Hasan -- Ewart, Susan L -- Thio, Chloe L -- Flick, Leah M -- Filippi, Marie-Dominique -- Grimes, H Leighton -- Drumm, Mitchell L -- Cutting, Garry R -- Knowles, Michael R -- Karp, Christopher L -- R01 AI024717/AI/NIAID NIH HHS/ -- R01 HL068890/HL/NHLBI NIH HHS/ -- R01 HL068890-01/HL/NHLBI NIH HHS/ -- R01 HL068927/HL/NHLBI NIH HHS/ -- R01 HL068927-01/HL/NHLBI NIH HHS/ -- R01 HL079312/HL/NHLBI NIH HHS/ -- R01 HL079312-01A1/HL/NHLBI NIH HHS/ -- R37 AI024717/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Apr 23;458(7241):1039-42. doi: 10.1038/nature07811. Epub 2009 Feb 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Molecular Immunology, Cincinnati Children's Hospital Research Foundation and the University of Cincinnati College of Medicine, Cincinnati, Ohio 45229, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242412" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cells, Cultured ; Cohort Studies ; Cystic Fibrosis/*genetics/*pathology ; Disease Models, Animal ; Genotype ; Humans ; Immediate-Early Proteins/deficiency/*genetics ; Inflammation/genetics/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/immunology/metabolism ; Polymorphism, Single Nucleotide/genetics ; Pseudomonas aeruginosa/immunology/pathogenicity ; Transcription Factor RelA/metabolism
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  • 42
    Publication Date: 2009-02-03
    Description: After an infection, T cells that carry the CD8 marker are activated and undergo a characteristic kinetic sequence of rapid expansion, subsequent contraction and formation of memory cells. The pool of naive T-cell clones is diverse and contains cells bearing T-cell antigen receptors (TCRs) that differ in their affinity for the same antigen. How these differences in affinity affect the function and the response kinetics of individual T-cell clones was previously unknown. Here we show that during the in vivo response to microbial infection, even very weak TCR-ligand interactions are sufficient to activate naive T cells, induce rapid initial proliferation and generate effector and memory cells. The strength of the TCR-ligand interaction critically affects when expansion stops, when the cells exit lymphoid organs and when contraction begins; that is, strongly stimulated T cells contract and exit lymphoid organs later than weakly stimulated cells. Our data challenge the prevailing view that strong TCR ligation is a prerequisite for CD8(+) T-cell activation. Instead, very weak interactions are sufficient for activation, but strong TCR ligation is required to sustain T-cell expansion. We propose that in response to microbial challenge, T-cell clones with a broad range of avidities for foreign ligands are initially recruited, and that the pool of T cells subsequently matures in affinity owing to the more prolonged expansion of high-affinity T-cell clones.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735344/" 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/PMC2735344/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zehn, Dietmar -- Lee, Sarah Y -- Bevan, Michael J -- R01 AI019335/AI/NIAID NIH HHS/ -- R01 AI019335-27/AI/NIAID NIH HHS/ -- R01 AI019335-28/AI/NIAID NIH HHS/ -- R01 AI019335-29/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Mar 12;458(7235):211-4. doi: 10.1038/nature07657. Epub 2009 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, Howard Hughes Medical Institute, University of Washington, Box 357370, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182777" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibody Affinity/*immunology ; Antigens, Bacterial/*immunology ; CD8-Positive T-Lymphocytes/immunology ; Cell Movement/immunology ; Immunologic Memory/immunology ; Ligands ; Listeria monocytogenes/immunology ; Listeriosis/immunology ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes/*immunology
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  • 43
    Publication Date: 2009-05-09
    Description: Chromatin modifications, especially histone-tail acetylation, have been implicated in memory formation. Increased histone-tail acetylation induced by inhibitors of histone deacetylases (HDACis) facilitates learning and memory in wild-type mice as well as in mouse models of neurodegeneration. Harnessing the therapeutic potential of HDACis requires knowledge of the specific HDAC family member(s) linked to cognitive enhancement. Here we show that neuron-specific overexpression of HDAC2, but not that of HDAC1, decreased dendritic spine density, synapse number, synaptic plasticity and memory formation. Conversely, Hdac2 deficiency resulted in increased synapse number and memory facilitation, similar to chronic treatment with HDACis in mice. Notably, reduced synapse number and learning impairment of HDAC2-overexpressing mice were ameliorated by chronic treatment with HDACis. Correspondingly, treatment with HDACis failed to further facilitate memory formation in Hdac2-deficient mice. Furthermore, analysis of promoter occupancy revealed an association of HDAC2 with the promoters of genes implicated in synaptic plasticity and memory formation. Taken together, our results suggest that HDAC2 functions in modulating synaptic plasticity and long-lasting changes of neural circuits, which in turn negatively regulates learning and memory. These observations encourage the development and testing of HDAC2-selective inhibitors for human diseases associated with memory impairment.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498958/" 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/PMC3498958/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guan, Ji-Song -- Haggarty, Stephen J -- Giacometti, Emanuela -- Dannenberg, Jan-Hermen -- Joseph, Nadine -- Gao, Jun -- Nieland, Thomas J F -- Zhou, Ying -- Wang, Xinyu -- Mazitschek, Ralph -- Bradner, James E -- DePinho, Ronald A -- Jaenisch, Rudolf -- Tsai, Li-Huei -- R01 DA028301/DA/NIDA NIH HHS/ -- R01 DA028301-02/DA/NIDA NIH HHS/ -- R01 NS051874/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 May 7;459(7243):55-60. doi: 10.1038/nature07925.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19424149" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Butyrates/pharmacology ; Dendritic Spines/physiology ; Electrical Synapses/*physiology ; Female ; Gene Expression Regulation ; Hippocampus/metabolism ; Histone Deacetylase 1 ; Histone Deacetylase 2 ; Histone Deacetylase Inhibitors ; Histone Deacetylases/deficiency/genetics/*metabolism ; Hydroxamic Acids/pharmacology ; Learning/drug effects ; Male ; Memory/drug effects/*physiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neurons/metabolism ; Promoter Regions, Genetic/genetics ; Repressor Proteins/antagonists & inhibitors/genetics/*metabolism ; Sodium/pharmacology
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  • 44
    Publication Date: 2009-07-28
    Description: Progressive telomere attrition or uncapping of the shelterin complex elicits a DNA damage response as a result of a cell's inability to distinguish dysfunctional telomeric ends from DNA double-strand breaks. Telomere deprotection activates both ataxia telangiectasia mutated (ATM) and telangiectasia and Rad3-related (ATR) kinase-dependent DNA damage response pathways, and promotes efficient non-homologous end-joining (NHEJ) of dysfunctional telomeres. The mammalian MRE11-RAD50-NBS1 (MRN; NBS1 is also known as NBN) complex interacts with ATM to sense chromosomal double-strand breaks and coordinate global DNA damage responses. Although the MRN complex accumulates at dysfunctional telomeres, it is not known whether mammalian MRN promotes repair at these sites. Here we address this question by using mouse alleles that either inactivate the entire MRN complex or eliminate only the nuclease activities of MRE11 (ref. 8). We show that cells lacking MRN do not activate ATM when telomeric repeat binding factor 2 (TRF2) is removed from telomeres, and ligase 4 (LIG4)-dependent chromosome end-to-end fusions are markedly reduced. Residual chromatid fusions involve only telomeres generated by leading strand synthesis. Notably, although cells deficient for MRE11 nuclease activity efficiently activate ATM and recruit 53BP1 (also known as TP53BP1) to deprotected telomeres, the 3' telomeric overhang persists to prevent NHEJ-mediated chromosomal fusions. Removal of shelterin proteins that protect the 3' overhang in the setting of MRE11 nuclease deficiency restores LIG4-dependent chromosome fusions. Our data indicate a critical role for the MRN complex in sensing dysfunctional telomeres, and show that in the absence of TRF2, MRE11 nuclease activity removes the 3' telomeric overhang to promote chromosome fusions. MRE11 can also protect newly replicated leading strand telomeres from NHEJ by promoting 5' strand resection to generate POT1a-TPP1-bound 3' overhangs.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2760383/" 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/PMC2760383/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Deng, Yibin -- Guo, Xiaolan -- Ferguson, David O -- Chang, Sandy -- K01CA124461/CA/NCI NIH HHS/ -- P30 CA046592/CA/NCI NIH HHS/ -- R01 AG028888/AG/NIA NIH HHS/ -- R01 AG028888-02/AG/NIA NIH HHS/ -- R01 CA129037/CA/NCI NIH HHS/ -- R01 CA129037-02/CA/NCI NIH HHS/ -- R01 HL079118/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Aug 13;460(7257):914-8. doi: 10.1038/nature08196. Epub 2009 Jul 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Box 1010, The M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19633651" target="_blank"〉PubMed〈/a〉
    Keywords: ATP-Binding Cassette Transporters/genetics/metabolism ; Alleles ; Animals ; Ataxia Telangiectasia Mutated Proteins ; Cell Cycle Proteins/genetics/metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone ; Chromosome Aberrations ; DNA Damage ; DNA Ligases/metabolism ; DNA Repair Enzymes/deficiency/genetics/*metabolism ; DNA-Binding Proteins/deficiency/genetics/*metabolism ; Fibroblasts ; Intracellular Signaling Peptides and Proteins/metabolism ; Mice ; Nuclear Proteins/deficiency/genetics/metabolism ; Protein-Serine-Threonine Kinases/metabolism ; Telomere/genetics/*metabolism ; Telomeric Repeat Binding Protein 2/deficiency/metabolism ; Tumor Suppressor Proteins/metabolism
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  • 45
    Publication Date: 2009-06-06
    Description: Inflammation is a protective attempt by the host to remove injurious stimuli and initiate the tissue healing process. The inflammatory response must be actively terminated, however, because failure to do so can result in 'bystander' damage to tissues and diseases such as arthritis or type-2 diabetes. Yet the mechanisms controlling excessive inflammatory responses are still poorly understood. Here we show that mouse effector and memory CD4(+) T cells abolish macrophage inflammasome-mediated caspase-1 activation and subsequent interleukin 1beta release in a cognate manner. Inflammasome inhibition is observed for all tested NLRP1 (commonly called NALP1) and NLRP3 (NALP3 or cryopyrin) activators, whereas NLRC4 (IPAF) inflammasome function and release of other inflammatory mediators such as CXCL2, interleukin 6 and tumour necrosis factor are not affected. Suppression of the NLRP3 inflammasome requires cell-to-cell contact and can be mimicked by macrophage stimulation with selected ligands of the tumour necrosis factor family, such as CD40L (also known as CD40LG). In a NLRP3-dependent peritonitis model, effector CD4(+) T cells are responsible for decreasing neutrophil recruitment in an antigen-dependent manner. Our findings reveal an unexpected mechanism of inflammasome inhibition, whereby effector and memory T cells suppress potentially damaging inflammation, yet leave the primary inflammatory response, crucial for the onset of immunity, intact.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guarda, Greta -- Dostert, Catherine -- Staehli, Francesco -- Cabalzar, Katrin -- Castillo, Rosa -- Tardivel, Aubry -- Schneider, Pascal -- Tschopp, Jurg -- England -- Nature. 2009 Jul 9;460(7252):269-73. doi: 10.1038/nature08100. Epub 2009 Jun 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494813" target="_blank"〉PubMed〈/a〉
    Keywords: Adaptor Proteins, Signal Transducing/*antagonists & inhibitors/metabolism ; Animals ; Antigens/immunology ; Apoptosis Regulatory Proteins/*antagonists & inhibitors/metabolism ; Bone Marrow Cells/cytology ; CD4-Positive T-Lymphocytes/*immunology ; Carrier Proteins/*antagonists & inhibitors/metabolism ; Caspase 1/metabolism ; Cells, Cultured ; Immunity, Innate/*immunology ; Immunologic Memory ; Inflammation/immunology/*metabolism/pathology ; Interleukin-1beta/immunology ; Ligands ; Macrophages/immunology ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Neutrophils/immunology ; Peritoneal Cavity/cytology ; Tumor Necrosis Factors/immunology/metabolism
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  • 46
    Publication Date: 2009-07-31
    Description: Mutations in the presenilin genes are the main cause of familial Alzheimer's disease. Loss of presenilin activity and/or accumulation of amyloid-beta peptides have been proposed to mediate the pathogenesis of Alzheimer's disease by impairing synaptic function. However, the precise site and nature of the synaptic dysfunction remain unknown. Here we use a genetic approach to inactivate presenilins conditionally in either presynaptic (CA3) or postsynaptic (CA1) neurons of the hippocampal Schaeffer-collateral pathway. We show that long-term potentiation induced by theta-burst stimulation is decreased after presynaptic but not postsynaptic deletion of presenilins. Moreover, we found that presynaptic but not postsynaptic inactivation of presenilins alters short-term plasticity and synaptic facilitation. The probability of evoked glutamate release, measured with the open-channel NMDA (N-methyl-D-aspartate) receptor antagonist MK-801, is reduced by presynaptic inactivation of presenilins. Notably, depletion of endoplasmic reticulum Ca(2+) stores by thapsigargin, or blockade of Ca(2+) release from these stores by ryanodine receptor inhibitors, mimics and occludes the effects of presynaptic presenilin inactivation. Collectively, these results indicate a selective role for presenilins in the activity-dependent regulation of neurotransmitter release and long-term potentiation induction by modulation of intracellular Ca(2+) release in presynaptic terminals, and further suggest that presynaptic dysfunction might be an early pathogenic event leading to dementia and neurodegeneration in Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2744588/" 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/PMC2744588/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhang, Chen -- Wu, Bei -- Beglopoulos, Vassilios -- Wines-Samuelson, Mary -- Zhang, Dawei -- Dragatsis, Ioannis -- Sudhof, Thomas C -- Shen, Jie -- R01 NS041783/NS/NINDS NIH HHS/ -- R01 NS041783-04/NS/NINDS NIH HHS/ -- R01 NS041783-08/NS/NINDS NIH HHS/ -- R01NS041783/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Jul 30;460(7255):632-6. doi: 10.1038/nature08177.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19641596" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/metabolism ; Cells, Cultured ; *Gene Expression Regulation ; Glutamic Acid/metabolism ; Hippocampus/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Neurons/*metabolism ; Neurotransmitter Agents/*metabolism ; Presenilins/*genetics/*metabolism ; Presynaptic Terminals/metabolism
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  • 47
    Publication Date: 2009-09-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Denker, Hans-Werner -- England -- Nature. 2009 Sep 17;461(7262):341. doi: 10.1038/461341b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759600" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Dedifferentiation ; Cloning, Organism/*ethics/legislation & jurisprudence/methods/*trends ; Embryo Research/ethics/legislation & jurisprudence ; Fibroblasts/cytology ; Humans ; Mice ; Pluripotent Stem Cells/cytology
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  • 48
    Publication Date: 2009-11-13
    Description: Direct inhibition of transcription factor complexes remains a central challenge in the discipline of ligand discovery. In general, these proteins lack surface involutions suitable for high-affinity binding by small molecules. Here we report the design of synthetic, cell-permeable, stabilized alpha-helical peptides that target a critical protein-protein interface in the NOTCH transactivation complex. We demonstrate that direct, high-affinity binding of the hydrocarbon-stapled peptide SAHM1 prevents assembly of the active transcriptional complex. Inappropriate NOTCH activation is directly implicated in the pathogenesis of several disease states, including T-cell acute lymphoblastic leukaemia (T-ALL). The treatment of leukaemic cells with SAHM1 results in genome-wide suppression of NOTCH-activated genes. Direct antagonism of the NOTCH transcriptional program causes potent, NOTCH-specific anti-proliferative effects in cultured cells and in a mouse model of NOTCH1-driven T-ALL.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2951323/" 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/PMC2951323/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moellering, Raymond E -- Cornejo, Melanie -- Davis, Tina N -- Del Bianco, Cristina -- Aster, Jon C -- Blacklow, Stephen C -- Kung, Andrew L -- Gilliland, D Gary -- Verdine, Gregory L -- Bradner, James E -- 5T32GM007598/GM/NIGMS NIH HHS/ -- N01-CO-12400/CO/NCI NIH HHS/ -- P01 CA119070/CA/NCI NIH HHS/ -- P01 CA119070-049001/CA/NCI NIH HHS/ -- R01 CA092433/CA/NCI NIH HHS/ -- R01 CA092433-06A2/CA/NCI NIH HHS/ -- R56 CA092433/CA/NCI NIH HHS/ -- R56 CA092433-06A1/CA/NCI NIH HHS/ -- T32 GM007598/GM/NIGMS NIH HHS/ -- T32 GM007598-30/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):182-8. doi: 10.1038/nature08543.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry & Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907488" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding, Competitive ; Cell Line, Tumor ; Cell Membrane Permeability ; Cell Proliferation/drug effects ; DNA-Binding Proteins/chemistry/metabolism ; Disease Models, Animal ; Drosophila Proteins/chemistry ; Gene Expression Regulation, Neoplastic/drug effects ; Genome/drug effects/genetics ; Humans ; Immunoglobulin J Recombination Signal Sequence-Binding Protein/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/chemistry ; Peptides/chemical synthesis/chemistry/metabolism/*pharmacology ; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/pathology ; Protein Binding/drug effects ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Receptor, Notch1/*antagonists & inhibitors/chemistry/metabolism ; Signal Transduction/drug effects ; Substrate Specificity ; Transcription Factors/chemistry/metabolism ; Transcriptional Activation/*drug effects
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  • 49
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2009-08-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mitchinson, Andrew -- England -- Nature. 2009 Aug 13;460(7257):805. doi: 10.1038/460805a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19675636" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acids/chemistry/metabolism ; Animals ; Azides/analysis/chemistry ; Coculture Techniques ; Escherichia coli/enzymology/genetics/metabolism ; Fluorescent Dyes/analysis/chemistry ; Macrophages/microbiology ; Methionine-tRNA Ligase/genetics/metabolism ; Mice ; Proteins/*analysis/chemistry/isolation & purification ; Sensitivity and Specificity ; Species Specificity ; Staining and Labeling/*methods
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  • 50
    Publication Date: 2009-01-27
    Description: Although the role of Hedgehog (Hh) signalling in embryonic pattern formation is well established, its functions in adult tissue renewal and maintenance remain unclear, and the relationship of these functions to cancer development has not been determined. Here we show that the loss of Smoothened (Smo), an essential component of the Hh pathway, impairs haematopoietic stem cell renewal and decreases induction of chronic myelogenous leukaemia (CML) by the BCR-ABL1 oncoprotein. Loss of Smo causes depletion of CML stem cells--the cells that propagate the leukaemia--whereas constitutively active Smo augments CML stem cell number and accelerates disease. As a possible mechanism for Smo action, we show that the cell fate determinant Numb, which depletes CML stem cells, is increased in the absence of Smo activity. Furthermore, pharmacological inhibition of Hh signalling impairs not only the propagation of CML driven by wild-type BCR-ABL1, but also the growth of imatinib-resistant mouse and human CML. These data indicate that Hh pathway activity is required for maintenance of normal and neoplastic stem cells of the haematopoietic system and raise the possibility that the drug resistance and disease recurrence associated with imatinib treatment of CML might be avoided by targeting this essential stem cell maintenance pathway.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946231/" 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/PMC2946231/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Chen -- Chen, Alan -- Jamieson, Catriona H -- Fereshteh, Mark -- Abrahamsson, Annelie -- Blum, Jordan -- Kwon, Hyog Young -- Kim, Jynho -- Chute, John P -- Rizzieri, David -- Munchhof, Michael -- VanArsdale, Todd -- Beachy, Philip A -- Reya, Tannishtha -- AI067798/AI/NIAID NIH HHS/ -- DK072234/DK/NIDDK NIH HHS/ -- DK63031/DK/NIDDK NIH HHS/ -- R01 DK063031/DK/NIDDK NIH HHS/ -- R01 DK063031-01/DK/NIDDK NIH HHS/ -- R01 DK063031-01S1/DK/NIDDK NIH HHS/ -- R01 DK063031-02/DK/NIDDK NIH HHS/ -- R01 DK063031-03/DK/NIDDK NIH HHS/ -- R01 DK063031-04/DK/NIDDK NIH HHS/ -- R01 DK063031-05/DK/NIDDK NIH HHS/ -- R01 DK063031-06/DK/NIDDK NIH HHS/ -- R01 DK063031-07/DK/NIDDK NIH HHS/ -- R01 DK063031-07S1/DK/NIDDK NIH HHS/ -- R01 DK063031-08/DK/NIDDK NIH HHS/ -- R01 DK072234/DK/NIDDK NIH HHS/ -- R01 DK072234-01A1/DK/NIDDK NIH HHS/ -- R01 DK072234-02/DK/NIDDK NIH HHS/ -- R01 DK072234-03/DK/NIDDK NIH HHS/ -- R01 DK072234-04/DK/NIDDK NIH HHS/ -- U19 AI067798/AI/NIAID NIH HHS/ -- U19 AI067798-010006/AI/NIAID NIH HHS/ -- U19 AI067798-020006/AI/NIAID NIH HHS/ -- U19 AI067798-030006/AI/NIAID NIH HHS/ -- U19 AI067798-040006/AI/NIAID NIH HHS/ -- U19 AI067798-050006/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):776-9. doi: 10.1038/nature07737.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19169242" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/pharmacology ; Cells, Cultured ; Hedgehog Proteins/*physiology ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/*physiopathology ; Membrane Proteins/metabolism ; Mice ; Neoplastic Stem Cells/*physiology ; Nerve Tissue Proteins/metabolism ; Proto-Oncogene Proteins c-abl/metabolism ; Receptors, G-Protein-Coupled/antagonists & inhibitors/genetics/metabolism ; *Signal Transduction ; Tomatine/analogs & derivatives/pharmacology ; Veratrum Alkaloids/pharmacology
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  • 51
    Publication Date: 2009-08-13
    Description: Since the initial description of induced pluripotent stem (iPS) cells created by forced expression of four transcription factors in mouse fibroblasts, the technique has been used to generate embryonic stem (ES)-cell-like pluripotent cells from a variety of cell types in other species, including primates and rat. It has become a popular means to reprogram somatic genomes into an embryonic-like pluripotent state, and a preferred alternative to somatic-cell nuclear transfer and somatic-cell fusion with ES cells. However, iPS cell reprogramming remains slow and inefficient. Notably, no live animals have been produced by the most stringent tetraploid complementation assay, indicative of a failure to create fully pluripotent cells. Here we report the generation of several iPS cell lines that are capable of generating viable, fertile live-born progeny by tetraploid complementation. These iPS cells maintain a pluripotent potential that is very close to ES cells generated from in vivo or nuclear transfer embryos. We demonstrate the practicality of using iPS cells as useful tools for the characterization of cellular reprogramming and developmental potency, and confirm that iPS cells can attain true pluripotency that is similar to that of ES cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhao, Xiao-yang -- Li, Wei -- Lv, Zhuo -- Liu, Lei -- Tong, Man -- Hai, Tang -- Hao, Jie -- Guo, Chang-long -- Ma, Qing-wen -- Wang, Liu -- Zeng, Fanyi -- Zhou, Qi -- England -- Nature. 2009 Sep 3;461(7260):86-90. doi: 10.1038/nature08267.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672241" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blastocyst/cytology/physiology ; Cell Dedifferentiation/physiology ; Cell Line ; Cell Lineage ; Cellular Reprogramming ; Embryo, Mammalian/cytology/embryology/metabolism ; Embryonic Stem Cells/cytology/physiology ; Female ; Fibroblasts/cytology ; Gene Expression Profiling ; Genetic Complementation Test ; Male ; Mice ; Mice, SCID ; Pluripotent Stem Cells/cytology/*physiology ; *Polyploidy ; Pregnancy ; *Reproductive Techniques ; Survival Rate ; Teratoma
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  • 52
    Publication Date: 2009-02-27
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dholakia, Kishan -- England -- Nature. 2009 Feb 26;457(7233):1061. doi: 10.1038/4571061e.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of St Andrews, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242433" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Fatty Acids, Omega-3/metabolism ; Fluorescent Dyes ; Humans ; *Lasers ; Lung Neoplasms/metabolism ; Mice ; Pharmaceutical Preparations/metabolism ; Pharmacokinetics ; Sensitivity and Specificity ; Skin/metabolism ; Spectrum Analysis, Raman/*instrumentation/*methods
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  • 53
    Publication Date: 2009-02-03
    Description: There is growing recognition that mammalian cells produce many thousands of large intergenic transcripts. However, the functional significance of these transcripts has been particularly controversial. Although there are some well-characterized examples, most (〉95%) show little evidence of evolutionary conservation and have been suggested to represent transcriptional noise. Here we report a new approach to identifying large non-coding RNAs using chromatin-state maps to discover discrete transcriptional units intervening known protein-coding loci. Our approach identified approximately 1,600 large multi-exonic RNAs across four mouse cell types. In sharp contrast to previous collections, these large intervening non-coding RNAs (lincRNAs) show strong purifying selection in their genomic loci, exonic sequences and promoter regions, with greater than 95% showing clear evolutionary conservation. We also developed a functional genomics approach that assigns putative functions to each lincRNA, demonstrating a diverse range of roles for lincRNAs in processes from embryonic stem cell pluripotency to cell proliferation. We obtained independent functional validation for the predictions for over 100 lincRNAs, using cell-based assays. In particular, we demonstrate that specific lincRNAs are transcriptionally regulated by key transcription factors in these processes such as p53, NFkappaB, Sox2, Oct4 (also known as Pou5f1) and Nanog. Together, these results define a unique collection of functional lincRNAs that are highly conserved and implicated in diverse biological processes.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2754849/" 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/PMC2754849/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Guttman, Mitchell -- Amit, Ido -- Garber, Manuel -- French, Courtney -- Lin, Michael F -- Feldser, David -- Huarte, Maite -- Zuk, Or -- Carey, Bryce W -- Cassady, John P -- Cabili, Moran N -- Jaenisch, Rudolf -- Mikkelsen, Tarjei S -- Jacks, Tyler -- Hacohen, Nir -- Bernstein, Bradley E -- Kellis, Manolis -- Regev, Aviv -- Rinn, John L -- Lander, Eric S -- DP1 OD003958/OD/NIH HHS/ -- R01 HG004037/HG/NHGRI NIH HHS/ -- R01 HG004037-02/HG/NHGRI NIH HHS/ -- U54 HG003067/HG/NHGRI NIH HHS/ -- U54 HG003067-05/HG/NHGRI NIH HHS/ -- England -- Nature. 2009 Mar 12;458(7235):223-7. doi: 10.1038/nature07672. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182780" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cells, Cultured ; Chromatin/*genetics ; *Conserved Sequence/genetics ; DNA, Intergenic ; Exons/genetics ; Mammals/*genetics ; Mice ; Promoter Regions, Genetic/genetics ; RNA/*genetics ; Reproducibility of Results ; Transcription Factors/metabolism
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  • 54
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2009-07-25
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toledo, Franck -- Bardot, Boris -- England -- Nature. 2009 Jul 23;460(7254):466-7. doi: 10.1038/460466a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19626103" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Gene Expression Regulation, Neoplastic ; Genes, p53/genetics/*physiology ; Humans ; Mice ; MicroRNAs/*metabolism ; Mutation ; Neoplasms/*metabolism
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  • 55
    Publication Date: 2009-02-03
    Description: In the course of infection or autoimmunity, particular transcription factors orchestrate the differentiation of T(H)1, T(H)2 or T(H)17 effector cells, the responses of which are limited by a distinct lineage of suppressive regulatory T cells (T(reg)). T(reg) cell differentiation and function are guided by the transcription factor Foxp3, and their deficiency due to mutations in Foxp3 results in aggressive fatal autoimmune disease associated with sharply augmented T(H)1 and T(H)2 cytokine production. Recent studies suggested that Foxp3 regulates the bulk of the Foxp3-dependent transcriptional program indirectly through a set of transcriptional regulators serving as direct Foxp3 targets. Here we show that in mouse T(reg) cells, high amounts of interferon regulatory factor-4 (IRF4), a transcription factor essential for T(H)2 effector cell differentiation, is dependent on Foxp3 expression. We proposed that IRF4 expression endows T(reg) cells with the ability to suppress T(H)2 responses. Indeed, ablation of a conditional Irf4 allele in T(reg) cells resulted in selective dysregulation of T(H)2 responses, IL4-dependent immunoglobulin isotype production, and tissue lesions with pronounced plasma cell infiltration, in contrast to the mononuclear-cell-dominated pathology typical of mice lacking T(reg) cells. Our results indicate that T(reg) cells use components of the transcriptional machinery, promoting a particular type of effector CD4(+) T cell differentiation, to efficiently restrain the corresponding type of the immune response.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2864791/" 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/PMC2864791/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zheng, Ye -- Chaudhry, Ashutosh -- Kas, Arnold -- deRoos, Paul -- Kim, Jeong M -- Chu, Tin-Tin -- Corcoran, Lynn -- Treuting, Piper -- Klein, Ulf -- Rudensky, Alexander Y -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Mar 19;458(7236):351-6. doi: 10.1038/nature07674. Epub 2009 Feb 1.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182775" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Autoimmune Diseases/pathology ; CD4 Lymphocyte Count ; Cell Differentiation ; Forkhead Transcription Factors/deficiency/genetics/metabolism ; Immunoglobulin E/blood/immunology ; Immunoglobulin G/blood/immunology ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory/*immunology ; Th2 Cells/cytology/*immunology/metabolism ; Thymus Gland/cytology
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  • 56
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2009-07-10
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diaz, Marilyn -- Daly, Janssen -- England -- Nature. 2009 Jul 9;460(7252):184-6. doi: 10.1038/460184a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19587755" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; B-Lymphocytes/*metabolism/pathology ; Cytidine Deaminase/metabolism ; *DNA Breaks, Double-Stranded ; DNA Repair/genetics ; DNA-Binding Proteins/deficiency/metabolism ; Gene Rearrangement, B-Lymphocyte/*genetics ; Genes, Immunoglobulin/*genetics ; Genes, myc/genetics ; Immunoglobulin Class Switching/genetics ; Immunoglobulin Heavy Chains/genetics ; Immunoglobulin kappa-Chains/genetics ; Immunoglobulin lambda-Chains/genetics ; Mice ; Translocation, Genetic/*genetics
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  • 57
    Publication Date: 2009-05-19
    Description: The bacterium Listeria monocytogenes is ubiquitous in the environment and can lead to severe food-borne infections. It has recently emerged as a multifaceted model in pathogenesis. However, how this bacterium switches from a saprophyte to a pathogen is largely unknown. Here, using tiling arrays and RNAs from wild-type and mutant bacteria grown in vitro, ex vivo and in vivo, we have analysed the transcription of its entire genome. We provide the complete Listeria operon map and have uncovered far more diverse types of RNAs than expected: in addition to 50 small RNAs (〈500 nucleotides), at least two of which are involved in virulence in mice, we have identified antisense RNAs covering several open-reading frames and long overlapping 5' and 3' untranslated regions. We discovered that riboswitches can act as terminators for upstream genes. When Listeria reaches the host intestinal lumen, an extensive transcriptional reshaping occurs with a SigB-mediated activation of virulence genes. In contrast, in the blood, PrfA controls transcription of virulence genes. Remarkably, several non-coding RNAs absent in the non-pathogenic species Listeria innocua exhibit the same expression patterns as the virulence genes. Together, our data unravel successive and coordinated global transcriptional changes during infection and point to previously unknown regulatory mechanisms in bacteria.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Toledo-Arana, Alejandro -- Dussurget, Olivier -- Nikitas, Georgios -- Sesto, Nina -- Guet-Revillet, Helene -- Balestrino, Damien -- Loh, Edmund -- Gripenland, Jonas -- Tiensuu, Teresa -- Vaitkevicius, Karolis -- Barthelemy, Mathieu -- Vergassola, Massimo -- Nahori, Marie-Anne -- Soubigou, Guillaume -- Regnault, Beatrice -- Coppee, Jean-Yves -- Lecuit, Marc -- Johansson, Jorgen -- Cossart, Pascale -- 233348/European Research Council/International -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 18;459(7249):950-6. doi: 10.1038/nature08080. Epub 2009 May 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut Pasteur, Unite des Interactions Bacteries-Cellules, F-75015 Paris, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19448609" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Gene Expression Regulation, Bacterial ; Genes, Bacterial/genetics ; Genome, Bacterial/genetics ; Intestines/microbiology ; Listeria monocytogenes/*genetics/*pathogenicity ; Mice ; Open Reading Frames/genetics ; Operon/genetics ; RNA, Bacterial/analysis/*genetics ; Regulatory Sequences, Ribonucleic Acid/genetics ; Transcription, Genetic/*genetics ; Untranslated Regions/genetics ; Virulence/genetics
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  • 58
    Publication Date: 2009-12-25
    Description: The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2879581/" 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/PMC2879581/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Zhou, Wenjun -- Ercan, Dalia -- Chen, Liang -- Yun, Cai-Hong -- Li, Danan -- Capelletti, Marzia -- Cortot, Alexis B -- Chirieac, Lucian -- Iacob, Roxana E -- Padera, Robert -- Engen, John R -- Wong, Kwok-Kin -- Eck, Michael J -- Gray, Nathanael S -- Janne, Pasi A -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA130876/CA/NCI NIH HHS/ -- R01 CA130876-02/CA/NCI NIH HHS/ -- R01 CA135257/CA/NCI NIH HHS/ -- R01AG2400401/AG/NIA NIH HHS/ -- R01CA080942/CA/NCI NIH HHS/ -- R01CA11446/CA/NCI NIH HHS/ -- R01CA116020/CA/NCI NIH HHS/ -- R01CA130876-02/CA/NCI NIH HHS/ -- R01CA135257/CA/NCI NIH HHS/ -- R01GM070590/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Dec 24;462(7276):1070-4. doi: 10.1038/nature08622.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cancer Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20033049" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/chemistry/*pharmacology/toxicity ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Drug Evaluation, Preclinical ; Drug Resistance, Neoplasm/genetics ; Lung/drug effects ; Mice ; Models, Chemical ; Models, Molecular ; Mutation/*genetics ; NIH 3T3 Cells ; Phosphorylation/drug effects ; Protein Kinase Inhibitors/chemistry/*pharmacology/toxicity ; Receptor, Epidermal Growth Factor/*antagonists & inhibitors/*genetics
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  • 59
    Publication Date: 2009-02-06
    Description: The metabolism of oxygen, although central to life, produces reactive oxygen species (ROS) that have been implicated in processes as diverse as cancer, cardiovascular disease and ageing. It has recently been shown that central nervous system stem cells and haematopoietic stem cells and early progenitors contain lower levels of ROS than their more mature progeny, and that these differences are critical for maintaining stem cell function. We proposed that epithelial tissue stem cells and their cancer stem cell (CSC) counterparts may also share this property. Here we show that normal mammary epithelial stem cells contain lower concentrations of ROS than their more mature progeny cells. Notably, subsets of CSCs in some human and murine breast tumours contain lower ROS levels than corresponding non-tumorigenic cells (NTCs). Consistent with ROS being critical mediators of ionizing-radiation-induced cell killing, CSCs in these tumours develop less DNA damage and are preferentially spared after irradiation compared to NTCs. Lower ROS levels in CSCs are associated with increased expression of free radical scavenging systems. Pharmacological depletion of ROS scavengers in CSCs markedly decreases their clonogenicity and results in radiosensitization. These results indicate that, similar to normal tissue stem cells, subsets of CSCs in some tumours contain lower ROS levels and enhanced ROS defences compared to their non-tumorigenic progeny, which may contribute to tumour radioresistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778612/" 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/PMC2778612/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Diehn, Maximilian -- Cho, Robert W -- Lobo, Neethan A -- Kalisky, Tomer -- Dorie, Mary Jo -- Kulp, Angela N -- Qian, Dalong -- Lam, Jessica S -- Ailles, Laurie E -- Wong, Manzhi -- Joshua, Benzion -- Kaplan, Michael J -- Wapnir, Irene -- Dirbas, Frederick M -- Somlo, George -- Garberoglio, Carlos -- Paz, Benjamin -- Shen, Jeannie -- Lau, Sean K -- Quake, Stephen R -- Brown, J Martin -- Weissman, Irving L -- Clarke, Michael F -- R01 CA100225/CA/NCI NIH HHS/ -- R01 CA100225-05/CA/NCI NIH HHS/ -- U54 CA126524/CA/NCI NIH HHS/ -- U54 CA126524-04/CA/NCI NIH HHS/ -- England -- Nature. 2009 Apr 9;458(7239):780-3. doi: 10.1038/nature07733.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Radiation Oncology, 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/19194462" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/physiopathology ; Cells, Cultured ; DNA Damage/genetics/radiation effects ; Female ; Gene Expression ; Humans ; Mammary Glands, Human/cytology/metabolism ; Mice ; Mice, Inbred C57BL ; Neoplastic Stem Cells/*metabolism/*radiation effects ; Radiation Tolerance/*physiology ; Reactive Oxygen Species/*metabolism
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  • 60
    Publication Date: 2009-05-22
    Description: Cohesin-mediated sister chromatid cohesion is essential for chromosome segregation and post-replicative DNA repair. In addition, evidence from model organisms and from human genetics suggests that cohesin is involved in the control of gene expression. This non-canonical role has recently been rationalized by the findings that mammalian cohesin complexes are recruited to a subset of DNase I hypersensitive sites and to conserved noncoding sequences by the DNA-binding protein CTCF. CTCF functions at insulators (which control interactions between enhancers and promoters) and at boundary elements (which demarcate regions of distinct chromatin structure), and cohesin contributes to its enhancer-blocking activity. The underlying mechanisms remain unknown, and the full spectrum of cohesin functions remains to be determined. Here we show that cohesin forms the topological and mechanistic basis for cell-type-specific long-range chromosomal interactions in cis at the developmentally regulated cytokine locus IFNG. Hence, the ability of cohesin to constrain chromosome topology is used not only for the purpose of sister chromatid cohesion, but also to dynamically define the spatial conformation of specific loci. This new aspect of cohesin function is probably important for normal development and disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2869028/" 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/PMC2869028/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hadjur, Suzana -- Williams, Luke M -- Ryan, Natalie K -- Cobb, Bradley S -- Sexton, Tom -- Fraser, Peter -- Fisher, Amanda G -- Merkenschlager, Matthias -- G0900491/Medical Research Council/United Kingdom -- G117/530/Medical Research Council/United Kingdom -- MC_U120027516/Medical Research Council/United Kingdom -- U.1200(U.1200)/Medical Research Council/United Kingdom -- Medical Research Council/United Kingdom -- England -- Nature. 2009 Jul 16;460(7253):410-3. doi: 10.1038/nature08079. Epub 2009 May 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lymphocyte Development Group, MRC Clinical Sciences Centre, Imperial College London, Du Cane Road, London W12 0NN, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458616" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; CD4-Positive T-Lymphocytes/metabolism ; Cell Cycle Proteins/*metabolism ; Cell Line ; Chromosomal Proteins, Non-Histone/*metabolism ; Chromosomes/*genetics/*metabolism ; *Gene Expression Regulation, Developmental ; Histones/metabolism ; Humans ; Interferon-gamma/*genetics ; Mice ; Nuclear Proteins/genetics/metabolism ; Organ Specificity ; Phosphoproteins/genetics/metabolism ; Repressor Proteins/metabolism
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  • 61
    Publication Date: 2009-01-02
    Description: A subset of retinal ganglion cells has recently been discovered to be intrinsically photosensitive, with melanopsin as the pigment. These cells project primarily to brain centres for non-image-forming visual functions such as the pupillary light reflex and circadian photoentrainment. How well they signal intrinsic light absorption to drive behaviour remains unclear. Here we report fundamental parameters governing their intrinsic light responses and associated spike generation. The membrane density of melanopsin is 10(4)-fold lower than that of rod and cone pigments, resulting in a very low photon catch and a phototransducing role only in relatively bright light. Nonetheless, each captured photon elicits a large and extraordinarily prolonged response, with a unique shape among known photoreceptors. Notably, like rods, these cells are capable of signalling single-photon absorption. A flash causing a few hundred isomerized melanopsin molecules in a retina is sufficient for reaching threshold for the pupillary light reflex.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2794210/" 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/PMC2794210/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Do, Michael Tri H -- Kang, Shin H -- Xue, Tian -- Zhong, Haining -- Liao, Hsi-Wen -- Bergles, Dwight E -- Yau, King-Wai -- F32 EY016959/EY/NEI NIH HHS/ -- F32 EY016959-01/EY/NEI NIH HHS/ -- F32 EY016959-02/EY/NEI NIH HHS/ -- F32 EY016959-03/EY/NEI NIH HHS/ -- R01 DC006904/DC/NIDCD NIH HHS/ -- R01 DC006904-01/DC/NIDCD NIH HHS/ -- R01 DC006904-02/DC/NIDCD NIH HHS/ -- R01 DC006904-03/DC/NIDCD NIH HHS/ -- R01 DC006904-04/DC/NIDCD NIH HHS/ -- R01 DC006904-05/DC/NIDCD NIH HHS/ -- R01 EY006837/EY/NEI NIH HHS/ -- R01 EY006837-16A1/EY/NEI NIH HHS/ -- R01 EY006837-18/EY/NEI NIH HHS/ -- R01 EY006837-20A1/EY/NEI NIH HHS/ -- R01 EY006837-21/EY/NEI NIH HHS/ -- R01 EY006837-22/EY/NEI NIH HHS/ -- R01 EY014596/EY/NEI NIH HHS/ -- R01 EY014596-01/EY/NEI NIH HHS/ -- R01 EY014596-02/EY/NEI NIH HHS/ -- R01 EY014596-03/EY/NEI NIH HHS/ -- R01 EY014596-04/EY/NEI NIH HHS/ -- R01 EY014596-05/EY/NEI NIH HHS/ -- R01 EY014596-06/EY/NEI NIH HHS/ -- R01 EY014596-07/EY/NEI NIH HHS/ -- R01 EY014596-07S1/EY/NEI NIH HHS/ -- R01 NS051509/NS/NINDS NIH HHS/ -- R01 NS051509-01A1/NS/NINDS NIH HHS/ -- R01 NS051509-02/NS/NINDS NIH HHS/ -- R01 NS051509-03/NS/NINDS NIH HHS/ -- R01 NS051509-04/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Jan 15;457(7227):281-7. doi: 10.1038/nature07682. Epub 2008 Dec 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. mdo@jhmi.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19118382" target="_blank"〉PubMed〈/a〉
    Keywords: Action Potentials/radiation effects ; Animals ; Brain/metabolism ; Kinetics ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; *Photons ; Pupil/physiology/radiation effects ; Reflex, Pupillary/radiation effects ; Retinal Ganglion Cells/*metabolism/*radiation effects ; Rod Opsins/*metabolism
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  • 62
    Publication Date: 2009-10-02
    Description: A key step in many chromatin-related processes is the recognition of histone post-translational modifications by effector modules such as bromodomains and chromo-like domains of the Royal family. Whereas effector-mediated recognition of single post-translational modifications is well characterized, how the cell achieves combinatorial readout of histones bearing multiple modifications is poorly understood. One mechanism involves multivalent binding by linked effector modules. For example, the tandem bromodomains of human TATA-binding protein-associated factor-1 (TAF1) bind better to a diacetylated histone H4 tail than to monoacetylated tails, a cooperative effect attributed to each bromodomain engaging one acetyl-lysine mark. Here we report a distinct mechanism of combinatorial readout for the mouse TAF1 homologue Brdt, a testis-specific member of the BET protein family. Brdt associates with hyperacetylated histone H4 (ref. 7) and is implicated in the marked chromatin remodelling that follows histone hyperacetylation during spermiogenesis, the stage of spermatogenesis in which post-meiotic germ cells mature into fully differentiated sperm. Notably, we find that a single bromodomain (BD1) of Brdt is responsible for selectively recognizing histone H4 tails bearing two or more acetylation marks. The crystal structure of BD1 bound to a diacetylated H4 tail shows how two acetyl-lysine residues cooperate to interact with one binding pocket. Structure-based mutagenesis that reduces the selectivity of BD1 towards diacetylated tails destabilizes the association of Brdt with acetylated chromatin in vivo. Structural analysis suggests that other chromatin-associated proteins may be capable of a similar mode of ligand recognition, including yeast Bdf1, human TAF1 and human CBP/p300 (also known as CREBBP and EP300, respectively). Our findings describe a new mechanism for the combinatorial readout of histone modifications in which a single effector module engages two marks on a histone tail as a composite binding epitope.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Moriniere, Jeanne -- Rousseaux, Sophie -- Steuerwald, Ulrich -- Soler-Lopez, Montserrat -- Curtet, Sandrine -- Vitte, Anne-Laure -- Govin, Jerome -- Gaucher, Jonathan -- Sadoul, Karin -- Hart, Darren J -- Krijgsveld, Jeroen -- Khochbin, Saadi -- Muller, Christoph W -- Petosa, Carlo -- England -- Nature. 2009 Oct 1;461(7264):664-8. doi: 10.1038/nature08397.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉European Molecular Biology Laboratory, Grenoble Outstation, 6 rue Jules Horowitz, BP 181, 38042 Grenoble Cedex 9, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794495" target="_blank"〉PubMed〈/a〉
    Keywords: Acetylation ; Allosteric Regulation ; Animals ; Binding Sites ; COS Cells ; Cercopithecus aethiops ; Chromatin/chemistry/metabolism ; Crystallography, X-Ray ; Histones/*chemistry/*metabolism ; Lysine/metabolism ; Mice ; Models, Molecular ; Nuclear Proteins/*chemistry/genetics/*metabolism ; Protein Binding ; Protein Conformation ; Protein Structure, Tertiary ; Substrate Specificity
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  • 63
    Publication Date: 2009-12-18
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ziv, Noam E -- Ahissar, Ehud -- England -- Nature. 2009 Dec 17;462(7275):859-61. doi: 10.1038/462859a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20016588" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dendrites/*metabolism ; Memory/*physiology ; Mice ; Motor Cortex/*cytology/*physiology ; Motor Skills/*physiology ; Neuronal Plasticity/physiology ; Psychomotor Performance ; Pyramidal Cells/metabolism ; Synapses/*metabolism
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  • 64
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2009-10-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dolgin, Elie -- England -- Nature. 2009 Oct 15;461(7266):854-5. doi: 10.1038/461854b.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829337" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Disease Models, Animal ; Homeodomain Proteins/metabolism ; Humans ; Mice ; Microfluidic Analytical Techniques ; Neoplasm Metastasis/diagnosis/drug therapy/*pathology/prevention & control ; Neoplasms/drug therapy/metabolism/mortality/*pathology ; Neoplastic Stem Cells/pathology ; Transcription Factors/metabolism ; rho-Associated Kinases/antagonists & inhibitors/metabolism
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  • 65
    Publication Date: 2009-09-04
    Description: The emergence of terrestrial life witnessed the need for more sophisticated circulatory systems. This has evolved in birds, mammals and crocodilians into complete septation of the heart into left and right sides, allowing separate pulmonary and systemic circulatory systems, a key requirement for the evolution of endothermy. However, the evolution of the amniote heart is poorly understood. Reptilian hearts have been the subject of debate in the context of the evolution of cardiac septation: do they possess a single ventricular chamber or two incompletely septated ventricles? Here we examine heart development in the red-eared slider turtle, Trachemys scripta elegans (a chelonian), and the green anole, Anolis carolinensis (a squamate), focusing on gene expression in the developing ventricles. Both reptiles initially form a ventricular chamber that homogenously expresses the T-box transcription factor gene Tbx5. In contrast, in birds and mammals, Tbx5 is restricted to left ventricle precursors. In later stages, Tbx5 expression in the turtle (but not anole) heart is gradually restricted to a distinct left ventricle, forming a left-right gradient. This suggests that Tbx5 expression was refined during evolution to pattern the ventricles. In support of this hypothesis, we show that loss of Tbx5 in the mouse ventricle results in a single chamber lacking distinct identity, indicating a requirement for Tbx5 in septation. Importantly, misexpression of Tbx5 throughout the developing myocardium to mimic the reptilian expression pattern also results in a single mispatterned ventricular chamber lacking septation. Thus ventricular septation is established by a steep and correctly positioned Tbx5 gradient. Our findings provide a molecular mechanism for the evolution of the amniote ventricle, and support the concept that altered expression of developmental regulators is a key mechanism of vertebrate evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753965/" 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/PMC2753965/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Koshiba-Takeuchi, Kazuko -- Mori, Alessandro D -- Kaynak, Bogac L -- Cebra-Thomas, Judith -- Sukonnik, Tatyana -- Georges, Romain O -- Latham, Stephany -- Beck, Laurel -- Henkelman, R Mark -- Black, Brian L -- Olson, Eric N -- Wade, Juli -- Takeuchi, Jun K -- Nemer, Mona -- Gilbert, Scott F -- Bruneau, Benoit G -- C06 RR018928/RR/NCRR NIH HHS/ -- P01 HL089707/HL/NHLBI NIH HHS/ -- P01 HL089707-01A1/HL/NHLBI NIH HHS/ -- P01HL089707/HL/NHLBI NIH HHS/ -- R01 HL064658/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 Sep 3;461(7260):95-8. doi: 10.1038/nature08324.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gladstone Institute of Cardiovascular Disease, San Francisco, California 94158, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727199" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chick Embryo ; *Evolution, Molecular ; Gene Expression Regulation, Developmental ; Heart/anatomy & histology/*embryology ; Lizards/anatomy & histology/*embryology/genetics ; Mice ; Organogenesis ; T-Box Domain Proteins/deficiency/genetics/metabolism ; Turtles/anatomy & histology/*embryology/genetics
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  • 66
    Publication Date: 2009-07-22
    Description: Acquired uniparental disomy (aUPD) is a common feature of cancer genomes, leading to loss of heterozygosity. aUPD is associated not only with loss-of-function mutations of tumour suppressor genes, but also with gain-of-function mutations of proto-oncogenes. Here we show unique gain-of-function mutations of the C-CBL (also known as CBL) tumour suppressor that are tightly associated with aUPD of the 11q arm in myeloid neoplasms showing myeloproliferative features. The C-CBL proto-oncogene, a cellular homologue of v-Cbl, encodes an E3 ubiquitin ligase and negatively regulates signal transduction of tyrosine kinases. Homozygous C-CBL mutations were found in most 11q-aUPD-positive myeloid malignancies. Although the C-CBL mutations were oncogenic in NIH3T3 cells, c-Cbl was shown to functionally and genetically act as a tumour suppressor. C-CBL mutants did not have E3 ubiquitin ligase activity, but inhibited that of wild-type C-CBL and CBL-B (also known as CBLB), leading to prolonged activation of tyrosine kinases after cytokine stimulation. c-Cbl(-/-) haematopoietic stem/progenitor cells (HSPCs) showed enhanced sensitivity to a variety of cytokines compared to c-Cbl(+/+) HSPCs, and transduction of C-CBL mutants into c-Cbl(-/-) HSPCs further augmented their sensitivities to a broader spectrum of cytokines, including stem-cell factor (SCF, also known as KITLG), thrombopoietin (TPO, also known as THPO), IL3 and FLT3 ligand (FLT3LG), indicating the presence of a gain-of-function that could not be attributed to a simple loss-of-function. The gain-of-function effects of C-CBL mutants on cytokine sensitivity of HSPCs largely disappeared in a c-Cbl(+/+) background or by co-transduction of wild-type C-CBL, which suggests the pathogenic importance of loss of wild-type C-CBL alleles found in most cases of C-CBL-mutated myeloid neoplasms. Our findings provide a new insight into a role of gain-of-function mutations of a tumour suppressor associated with aUPD in the pathogenesis of some myeloid cancer subsets.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanada, Masashi -- Suzuki, Takahiro -- Shih, Lee-Yung -- Otsu, Makoto -- Kato, Motohiro -- Yamazaki, Satoshi -- Tamura, Azusa -- Honda, Hiroaki -- Sakata-Yanagimoto, Mamiko -- Kumano, Keiki -- Oda, Hideaki -- Yamagata, Tetsuya -- Takita, Junko -- Gotoh, Noriko -- Nakazaki, Kumi -- Kawamata, Norihiko -- Onodera, Masafumi -- Nobuyoshi, Masaharu -- Hayashi, Yasuhide -- Harada, Hiroshi -- Kurokawa, Mineo -- Chiba, Shigeru -- Mori, Hiraku -- Ozawa, Keiya -- Omine, Mitsuhiro -- Hirai, Hisamaru -- Nakauchi, Hiromitsu -- Koeffler, H Phillip -- Ogawa, Seishi -- 2R01CA026038-30/CA/NCI NIH HHS/ -- England -- Nature. 2009 Aug 13;460(7257):904-8. doi: 10.1038/nature08240. Epub 2009 Jul 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Genomics Project, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19620960" target="_blank"〉PubMed〈/a〉
    Keywords: Allelic Imbalance ; Amino Acid Sequence ; Animals ; Base Sequence ; Chromosomes, Human, Pair 11/genetics ; Female ; *Genes, Tumor Suppressor ; Humans ; Leukemia, Myeloid/*genetics/metabolism/pathology ; Male ; Mice ; Mice, Knockout ; Mice, Nude ; Models, Molecular ; Molecular Sequence Data ; Mutant Proteins/chemistry/genetics/*metabolism ; Mutation ; NIH 3T3 Cells ; Neoplasm Transplantation ; Oncogenes/genetics ; Phosphorylation ; Protein Conformation ; Proto-Oncogene Proteins c-cbl/antagonists & ; inhibitors/chemistry/deficiency/*genetics/*metabolism ; Ubiquitination ; Uniparental Disomy/genetics ; ras Proteins/genetics/metabolism
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  • 67
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    Nature Publishing Group (NPG)
    Publication Date: 2009-10-16
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mucke, Lennart -- England -- Nature. 2009 Oct 15;461(7266):895-7. doi: 10.1038/461895a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19829367" target="_blank"〉PubMed〈/a〉
    Keywords: Age of Onset ; Aging ; *Alzheimer Disease/diagnosis/epidemiology/etiology/physiopathology/therapy ; Amyloid beta-Peptides/metabolism ; Animals ; Controlled Clinical Trials as Topic ; Genetic Testing ; Humans ; Mice ; Stem Cell Transplantation ; Treatment Failure ; United States/epidemiology
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  • 68
    Publication Date: 2009-11-27
    Description: Receptor-activator of NF-kappaB ligand (TNFSF11, also known as RANKL, OPGL, TRANCE and ODF) and its tumour necrosis factor (TNF)-family receptor RANK are essential regulators of bone remodelling, lymph node organogenesis and formation of a lactating mammary gland. RANKL and RANK are also expressed in the central nervous system. However, the functional relevance of RANKL/RANK in the brain was entirely unknown. Here we report that RANKL and RANK have an essential role in the brain. In both mice and rats, central RANKL injections trigger severe fever. Using tissue-specific Nestin-Cre and GFAP-Cre rank(floxed) deleter mice, the function of RANK in the fever response was genetically mapped to astrocytes. Importantly, Nestin-Cre and GFAP-Cre rank(floxed) deleter mice are resistant to lipopolysaccharide-induced fever as well as fever in response to the key inflammatory cytokines IL-1beta and TNFalpha. Mechanistically, RANKL activates brain regions involved in thermoregulation and induces fever via the COX2-PGE(2)/EP3R pathway. Moreover, female Nestin-Cre and GFAP-Cre rank(floxed) mice exhibit increased basal body temperatures, suggesting that RANKL and RANK control thermoregulation during normal female physiology. We also show that two children with RANK mutations exhibit impaired fever during pneumonia. These data identify an entirely novel and unexpected function for the key osteoclast differentiation factors RANKL/RANK in female thermoregulation and the central fever response in inflammation.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanada, Reiko -- Leibbrandt, Andreas -- Hanada, Toshikatsu -- Kitaoka, Shiho -- Furuyashiki, Tomoyuki -- Fujihara, Hiroaki -- Trichereau, Jean -- Paolino, Magdalena -- Qadri, Fatimunnisa -- Plehm, Ralph -- Klaere, Steffen -- Komnenovic, Vukoslav -- Mimata, Hiromitsu -- Yoshimatsu, Hironobu -- Takahashi, Naoyuki -- von Haeseler, Arndt -- Bader, Michael -- Kilic, Sara Sebnem -- Ueta, Yoichi -- Pifl, Christian -- Narumiya, Shuh -- Penninger, Josef M -- England -- Nature. 2009 Nov 26;462(7272):505-9. doi: 10.1038/nature08596.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19940926" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Astrocytes/drug effects/metabolism ; Body Temperature Regulation/*drug effects/*physiology ; Child ; Dinoprostone/metabolism ; Female ; Fever/*chemically induced/complications/*metabolism ; Gene Expression Profiling ; Humans ; Injections, Intraventricular ; Male ; Mice ; Mice, Inbred C57BL ; Pneumonia/complications/metabolism ; RANK Ligand/administration & dosage/antagonists & ; inhibitors/metabolism/*pharmacology ; Rats ; Rats, Wistar ; Receptor Activator of Nuclear Factor-kappa B/genetics/*metabolism ; Receptors, Prostaglandin E/metabolism ; Receptors, Prostaglandin E, EP3 Subtype ; *Sex Characteristics
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  • 69
    Publication Date: 2009-02-17
    Description: Injury or impaired clearance of apoptotic cells leads to the pathological accumulation of necrotic corpses, which induce an inflammatory response that initiates tissue repair. In addition, antigens present in necrotic cells can sometimes provoke a specific immune response and it has been argued that necrosis could explain adaptive immunity in seemingly infection-free situations, such as after allograft transplantation or in spontaneous and therapy-induced tumour rejection. In the mouse, the CD8alpha+ subset of dendritic cells phagocytoses dead cell remnants and cross-primes CD8+ T cells against cell-associated antigens. Here we show that CD8alpha+ dendritic cells use CLEC9A (also known as DNGR-1), a recently-characterized C-type lectin, to recognize a preformed signal that is exposed on necrotic cells. Loss or blockade of CLEC9A does not impair the uptake of necrotic cell material by CD8+ dendritic cells, but specifically reduces cross-presentation of dead-cell-associated antigens in vitro and decreases the immunogenicity of necrotic cells in vivo. The function of CLEC9A requires a key tyrosine residue in its intracellular tail that allows the recruitment and activation of the tyrosine kinase SYK, which is also essential for cross-presentation of dead-cell-associated antigens. Thus, CLEC9A functions as a SYK-coupled C-type lectin receptor to mediate sensing of necrosis by the principal dendritic-cell subset involved in regulating cross-priming to cell-associated antigens.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671489/" 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/PMC2671489/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sancho, David -- Joffre, Olivier P -- Keller, Anna M -- Rogers, Neil C -- Martinez, Dolores -- Hernanz-Falcon, Patricia -- Rosewell, Ian -- Reis e Sousa, Caetano -- A3598/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Apr 16;458(7240):899-903. doi: 10.1038/nature07750.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Immunobiology Laboratory, London Research Institute, Lincoln's Inn Fields Laboratories, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19219027" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD8/metabolism ; CD8-Positive T-Lymphocytes/immunology ; Cells, Cultured ; Cross-Priming/immunology ; Dendritic Cells/*immunology/*metabolism ; Humans ; Lectins, C-Type/deficiency/genetics/*metabolism ; Ligands ; Mice ; Necrosis/*immunology/*metabolism ; Phagocytosis ; Receptors, Immunologic/deficiency/genetics/*metabolism ; Receptors, Mitogen/genetics/*metabolism ; Signal Transduction
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  • 70
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    Nature Publishing Group (NPG)
    Publication Date: 2009-09-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2009 Sep 10;461(7261):158. doi: 10.1038/461158a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741676" target="_blank"〉PubMed〈/a〉
    Keywords: Animal Use Alternatives/economics/*methods/trends ; Animals ; Chemical Industry/economics/*methods ; Cosmetics/adverse effects/toxicity ; Europe ; Humans ; Mice ; Rats ; Toxicity Tests/economics/*methods/trends ; Toxicology/economics/*methods/trends ; United States
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  • 71
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    Nature Publishing Group (NPG)
    Publication Date: 2009-08-21
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2009 Aug 20;460(7258):947-8. doi: 10.1038/460947a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19693060" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Laboratory ; Collagen Type I/genetics/metabolism ; Diagnostic Tests, Routine/*methods ; *Disease Models, Animal ; Forkhead Transcription Factors/genetics/metabolism ; Germany ; Humans ; Mice ; Mice, Mutant Strains ; Mice, Transgenic ; *Phenotype
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  • 72
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    Nature Publishing Group (NPG)
    Publication Date: 2009-08-14
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2009 Aug 13;460(7257):788. doi: 10.1038/460788a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19675616" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Laboratory ; Biomedical Research/methods/trends ; Databases, Factual ; European Union ; Gene Knockout Techniques/trends ; Genomics/*trends ; Humans ; International Cooperation ; Mice ; *Models, Animal ; National Institutes of Health (U.S.) ; *Rats/genetics/physiology ; Systems Biology/methods/*trends ; United States
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  • 73
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    Nature Publishing Group (NPG)
    Publication Date: 2009-11-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Downward, Julian -- England -- Nature. 2009 Nov 5;462(7269):44-5. doi: 10.1038/462044a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19890318" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Apoptosis ; Humans ; Lung Neoplasms/genetics/*metabolism/*pathology ; Mice ; NF-kappa B/antagonists & inhibitors/*metabolism ; Oncogene Protein p21(ras)/genetics/*metabolism ; Protein-Serine-Threonine Kinases/antagonists & inhibitors/*metabolism ; *Signal Transduction
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  • 74
    Publication Date: 2009-06-19
    Description: Pluripotency of embryonic stem (ES) cells is controlled by defined transcription factors. During differentiation, mouse ES cells undergo global epigenetic reprogramming, as exemplified by X-chromosome inactivation (XCI) in which one female X chromosome is silenced to achieve gene dosage parity between the sexes. Somatic XCI is regulated by homologous X-chromosome pairing and counting, and by the random choice of future active and inactive X chromosomes. XCI and cell differentiation are tightly coupled, as blocking one process compromises the other and dedifferentiation of somatic cells to induced pluripotent stem cells is accompanied by X chromosome reactivation. Recent evidence suggests coupling of Xist expression to pluripotency factors occurs, but how the two are interconnected remains unknown. Here we show that Oct4 (also known as Pou5f1) lies at the top of the XCI hierarchy, and regulates XCI by triggering X-chromosome pairing and counting. Oct4 directly binds Tsix and Xite, two regulatory noncoding RNA genes of the X-inactivation centre, and also complexes with XCI trans-factors, Ctcf and Yy1 (ref. 17), through protein-protein interactions. Depletion of Oct4 blocks homologous X-chromosome pairing and results in the inactivation of both X chromosomes in female cells. Thus, we have identified the first trans-factor that regulates counting, and ascribed new functions to Oct4 during X-chromosome reprogramming.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3057664/" 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/PMC3057664/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Donohoe, Mary E -- Silva, Susana S -- Pinter, Stefan F -- Xu, Na -- Lee, Jeannie T -- GM58839/GM/NIGMS NIH HHS/ -- R01 GM058839/GM/NIGMS NIH HHS/ -- R01 GM058839-10/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 2;460(7251):128-32. doi: 10.1038/nature08098. Epub 2009 Jun 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19536159" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; *Chromosome Pairing ; Female ; Humans ; Male ; Mice ; Octamer Transcription Factor-3/deficiency/genetics/*metabolism ; Protein Binding ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/*metabolism ; SOXB1 Transcription Factors ; Transcriptional Activation ; X Chromosome/*genetics/*metabolism ; X Chromosome Inactivation/*genetics ; YY1 Transcription Factor/metabolism
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  • 75
    Publication Date: 2009-08-29
    Description: 〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2974062/" 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/PMC2974062/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Krizhanovsky, Valery -- Lowe, Scott W -- P01 CA087497/CA/NCI NIH HHS/ -- P01 CA087497-090003/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- England -- Nature. 2009 Aug 27;460(7259):1085-6. doi: 10.1038/4601085a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19713919" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Aging ; Cell Division ; *Cellular Reprogramming ; Cyclin-Dependent Kinase Inhibitor p16/deficiency/genetics/metabolism ; Fibroblasts/cytology/metabolism ; Humans ; Mice ; Neoplasms/metabolism/pathology/therapy ; Pluripotent Stem Cells/*cytology/*metabolism ; Tumor Suppressor Protein p53/deficiency/genetics/*metabolism
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  • 76
    Publication Date: 2009-12-04
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Drew, Liam J -- MacDermott, Amy B -- England -- Nature. 2009 Dec 3;462(7273):580-1. doi: 10.1038/462580a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19956249" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Humans ; Mice ; Neuronal Plasticity/physiology ; Neurosciences ; Pain/*physiopathology ; Sensory Receptor Cells/*physiology ; Touch/*physiology ; Vesicular Glutamate Transport Proteins/physiology
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  • 77
    Publication Date: 2009-04-24
    Description: Ca(2+) mobilization from intracellular stores represents an important cell signalling process that is regulated, in mammalian cells, by inositol-1,4,5-trisphosphate (InsP(3)), cyclic ADP ribose and nicotinic acid adenine dinucleotide phosphate (NAADP). InsP(3) and cyclic ADP ribose cause the release of Ca(2+) from sarcoplasmic/endoplasmic reticulum stores by the activation of InsP(3) and ryanodine receptors (InsP(3)Rs and RyRs). In contrast, the nature of the intracellular stores targeted by NAADP and the molecular identity of the NAADP receptors remain controversial, although evidence indicates that NAADP mobilizes Ca(2+) from lysosome-related acidic compartments. Here we show that two-pore channels (TPCs) comprise a family of NAADP receptors, with human TPC1 (also known as TPCN1) and chicken TPC3 (TPCN3) being expressed on endosomal membranes, and human TPC2 (TPCN2) on lysosomal membranes when expressed in HEK293 cells. Membranes enriched with TPC2 show high affinity NAADP binding, and TPC2 underpins NAADP-induced Ca(2+) release from lysosome-related stores that is subsequently amplified by Ca(2+)-induced Ca(2+) release by InsP(3)Rs. Responses to NAADP were abolished by disrupting the lysosomal proton gradient and by ablating TPC2 expression, but were only attenuated by depleting endoplasmic reticulum Ca(2+) stores or by blocking InsP(3)Rs. Thus, TPCs form NAADP receptors that release Ca(2+) from acidic organelles, which can trigger further Ca(2+) signals via sarcoplasmic/endoplasmic reticulum. TPCs therefore provide new insights into the regulation and organization of Ca(2+) signals in animal cells, and will advance our understanding of the physiological role of NAADP.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761823/" 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/PMC2761823/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Calcraft, Peter J -- Ruas, Margarida -- Pan, Zui -- Cheng, Xiaotong -- Arredouani, Abdelilah -- Hao, Xuemei -- Tang, Jisen -- Rietdorf, Katja -- Teboul, Lydia -- Chuang, Kai-Ting -- Lin, Peihui -- Xiao, Rui -- Wang, Chunbo -- Zhu, Yingmin -- Lin, Yakang -- Wyatt, Christopher N -- Parrington, John -- Ma, Jianjie -- Evans, A Mark -- Galione, Antony -- Zhu, Michael X -- 070772/Wellcome Trust/United Kingdom -- FS/05/050/British Heart Foundation/United Kingdom -- P30 NS045758/NS/NINDS NIH HHS/ -- P30 NS045758-05/NS/NINDS NIH HHS/ -- P30 NS045758-059003/NS/NINDS NIH HHS/ -- P30-NS045758/NS/NINDS NIH HHS/ -- R01 DK081654/DK/NIDDK NIH HHS/ -- R01 DK081654-01A1/DK/NIDDK NIH HHS/ -- R01 NS042183/NS/NINDS NIH HHS/ -- R01 NS042183-04/NS/NINDS NIH HHS/ -- R21 NS056942/NS/NINDS NIH HHS/ -- R21 NS056942-01/NS/NINDS NIH HHS/ -- England -- Nature. 2009 May 28;459(7246):596-600. doi: 10.1038/nature08030. Epub 2009 Apr 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Integrative Physiology, College of Medicine and Veterinary Medicine, University of Edinburgh, Hugh Robson Building, Edinburgh EH8 9XD, Scotland, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19387438" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/*metabolism ; Calcium Channels/genetics/*metabolism ; *Calcium Signaling/drug effects ; Cell Line ; Chickens ; Humans ; Hydrogen-Ion Concentration ; Insulin-Secreting Cells/drug effects/metabolism ; Mice ; Mice, Knockout ; Molecular Sequence Data ; NADP/*analogs & derivatives/metabolism/pharmacology ; Organelles/drug effects/*metabolism ; Protein Binding
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  • 78
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    Nature Publishing Group (NPG)
    Publication Date: 2009-05-30
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanderson, Katharine -- England -- Nature. 2009 May 28;459(7246):500-2. doi: 10.1038/459500a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19478761" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cystathionine gamma-Lyase/deficiency/genetics/metabolism ; Humans ; Hydrogen Sulfide/*metabolism/therapeutic use ; Hypertension/metabolism ; Inflammation/metabolism ; Mice ; Nitric Oxide/metabolism/therapeutic use ; Protein Processing, Post-Translational ; Vasodilation/physiology
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  • 79
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    Nature Publishing Group (NPG)
    Publication Date: 2009-06-06
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Abbott, Alison -- England -- Nature. 2009 Jun 4;459(7247):620-1. doi: 10.1038/459620a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19494875" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Japan ; Maine ; Mice ; *Mice, Mutant Strains ; Organizations, Nonprofit/legislation & jurisprudence ; Patents as Topic/*legislation & jurisprudence
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  • 80
    Publication Date: 2009-03-06
    Description: AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3616311/" 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/PMC3616311/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Canto, Carles -- Gerhart-Hines, Zachary -- Feige, Jerome N -- Lagouge, Marie -- Noriega, Lilia -- Milne, Jill C -- Elliott, Peter J -- Puigserver, Pere -- Auwerx, Johan -- 231138/European Research Council/International -- DK069966/DK/NIDDK NIH HHS/ -- DK59820/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Apr 23;458(7241):1056-60. doi: 10.1038/nature07813.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institut de Genetique et de Biologie Moleculaire et Cellulaire, CNRS/INSERM/ULP, 67404 Illkirch, France.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19262508" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases/*metabolism ; Acetylation ; Aminoimidazole Carboxamide/analogs & derivatives ; Animals ; Cell Line ; *Energy Metabolism/genetics ; Enzyme Activation ; Forkhead Transcription Factors/genetics ; Gene Expression Regulation ; Genes, Mitochondrial/genetics ; Male ; Mice ; Muscle, Skeletal/cytology/enzymology/metabolism ; Mutation ; NAD/*metabolism ; Oxygen Consumption ; Phosphorylation ; Ribonucleotides ; Sirtuin 1 ; Sirtuins/*metabolism ; Trans-Activators/genetics/metabolism ; Transcription Factors ; Transcription, Genetic
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  • 81
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    Nature Publishing Group (NPG)
    Publication Date: 2009-04-03
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naeem, Shahid -- England -- Nature. 2009 Apr 2;458(7238):579-80. doi: 10.1038/458579a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19340066" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bacteria/drug effects/isolation & purification/*metabolism ; *Biodiversity ; Mice ; *Models, Biological ; Nitrates/metabolism ; Nitrites/metabolism ; *Selection, Genetic ; Stress, Physiological
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  • 82
    Publication Date: 2009-03-06
    Description: Adaptive immune responses rely on differentiation of CD4 T helper cells into subsets with distinct effector functions best suited for host defence against the invading pathogen. Interleukin (IL)-17-producing T helper cells (T(H)17) are a recently identified subset, separate from the T helper type 1 (T(H)1) and T helper type 2 (T(H)2) subsets. Synergy between the cytokines transforming growth factor-beta and IL-6 in vitro induces development of T(H)17 cells in mouse and human systems, whereas IL-23 supports expansion of these cells. However, it is not known which conditions in vivo would induce this combination of cytokines. Furthermore, it is enigmatic that a combination of pro-inflammatory and anti-inflammatory cytokines would be required to generate an effector T(H)17 response. Here we show that the relevant physiological stimulus triggering this combination of cytokines is the recognition and phagocytosis of infected apoptotic cells by dendritic cells. Phagocytosis of infected apoptotic cells uniquely triggers the combination of IL-6 and transforming growth factor-beta through recognition of pathogen-associated molecular patterns and phosphatidylserine exposed on apoptotic cells, respectively. Conversely, phagocytosis of apoptotic cells in the absence of microbial signals induces differentiation of the closely related regulatory T cells, which are important for controlling autoimmunity. Blocking apoptosis during infection of the mouse intestinal epithelium with the rodent pathogen Citrobacter rodentium, which models human infections with the attaching and effacing enteropathogenic and enterohaemorrhagic Escherichia coli, impairs the characteristic T(H)17 response in the lamina propria. Our results demonstrate that infected apoptotic cells are a critical component of the innate immune signals instructing T(H)17 differentiation, and point to pathogens particularly adept at triggering apoptosis that might preferentially induce T(H)17-mediated immunity. Because T(H)17 cells have been correlated with autoimmune diseases, investigation of the pathways of innate recognition of infected apoptotic cells might lead to improved understanding of the causative defects in autoimmunity.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Torchinsky, Miriam Beer -- Garaude, Johan -- Martin, Andrea P -- Blander, J Magarian -- AI073899/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Mar 5;458(7234):78-82. doi: 10.1038/nature07781.〈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/19262671" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Apoptosis ; *Cell Differentiation ; Citrobacter rodentium/*immunology/physiology ; Dendritic Cells/immunology/metabolism ; Immunity, Innate/*immunology ; Interleukin-10/biosynthesis/immunology ; Interleukin-17/*immunology/metabolism ; Interleukin-23/immunology ; Interleukin-6/biosynthesis ; Ligands ; Mice ; Mice, Inbred C57BL ; Phagocytosis ; T-Lymphocytes, Helper-Inducer/*cytology/*immunology/metabolism ; Toll-Like Receptors/immunology/metabolism ; Transforming Growth Factor beta/immunology
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  • 83
    Publication Date: 2009-04-28
    Description: Cortical gamma oscillations (20-80 Hz) predict increases in focused attention, and failure in gamma regulation is a hallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons at varied frequencies (8-200 Hz) selectively amplifies gamma oscillations. In contrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655711/" 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/PMC3655711/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cardin, Jessica A -- Carlen, Marie -- Meletis, Konstantinos -- Knoblich, Ulf -- Zhang, Feng -- Deisseroth, Karl -- Tsai, Li-Huei -- Moore, Christopher I -- R01 NS045130/NS/NINDS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 4;459(7247):663-7. doi: 10.1038/nature08002. Epub 2009 Apr 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉McGovern Institute for Brain Research and Department of Brain and Cognitive Sciences, MIT, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19396156" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Chlamydomonas reinhardtii ; Electrophysiology ; Gene Expression Regulation ; Gene Knock-In Techniques ; Interneurons/*physiology ; Mice ; Photic Stimulation ; Pyramidal Cells/physiology ; Rhodopsin/genetics/metabolism ; Somatosensory Cortex/*cytology/*metabolism
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  • 84
    Publication Date: 2009-09-18
    Description: The cerebral cortex is a laminated sheet of neurons composed of the arrays of intersecting radial columns. During development, excitatory projection neurons originating from the proliferative units at the ventricular surface of the embryonic cerebral vesicles migrate along elongated radial glial fibres to form a cellular infrastructure of radial (vertical) ontogenetic columns in the overlaying cortical plate. However, a subpopulation of these clonally related neurons also undergoes a short lateral shift and transfers from their parental to the neighbouring radial glial fibres, and intermixes with neurons originating from neighbouring proliferative units. This columnar organization acts as the primary information processing unit in the cortex. The molecular mechanisms, role and significance of this lateral dispersion for cortical development are not understood. Here we show that an Eph receptor A (EphA) and ephrin A (Efna) signalling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns. In contrast to the relatively uniform labelling of the developing cortical plate by various molecular markers and retrograde tracers in wild-type mice, we found alternating labelling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and ephrin-As during neuronal migration. This so far unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874978/" 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/PMC2874978/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Torii, Masaaki -- Hashimoto-Torii, Kazue -- Levitt, Pat -- Rakic, Pasko -- R01 DA022785/DA/NIDA NIH HHS/ -- R01 DA022785-03/DA/NIDA NIH HHS/ -- R01 DA023999/DA/NIDA NIH HHS/ -- R01 DA023999-01A1/DA/NIDA NIH HHS/ -- R01 DA023999-02/DA/NIDA NIH HHS/ -- R01 NS014841/NS/NINDS NIH HHS/ -- R01 NS014841-30/NS/NINDS NIH HHS/ -- R01 NS014841-31/NS/NINDS NIH HHS/ -- R01 NS038296/NS/NINDS NIH HHS/ -- R01 NS038296-09/NS/NINDS NIH HHS/ -- R01 NS038296-10/NS/NINDS NIH HHS/ -- England -- Nature. 2009 Sep 24;461(7263):524-8. doi: 10.1038/nature08362. Epub 2009 Sep 16.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Neurobiology and Kavli Institute for Neuroscience, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06510, USA. masaaki.torii@yale.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19759535" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Movement ; Cerebral Cortex/anatomy & histology/cytology/*embryology/metabolism ; Ephrins/deficiency/genetics/*metabolism ; Mice ; Mice, Knockout ; Neocortex/cytology/metabolism ; Neurons/*cytology/*metabolism ; Organogenesis ; Rats ; Receptors, Eph Family/deficiency/genetics/*metabolism ; *Signal Transduction
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  • 85
    Publication Date: 2009-08-07
    Description: The contribution of changes in cis-regulatory elements or trans-acting factors to interspecies differences in gene expression is not well understood. The mammalian beta-globin loci have served as a model for gene regulation during development. Transgenic mice containing the human beta-globin locus, consisting of the linked embryonic (epsilon), fetal (gamma) and adult (beta) genes, have been used as a system to investigate the temporal switch from fetal to adult haemoglobin, as occurs in humans. Here we show that the human gamma-globin (HBG) genes in these mice behave as murine embryonic globin genes, revealing a limitation of the model and demonstrating that critical differences in the trans-acting milieu have arisen during mammalian evolution. We show that the expression of BCL11A, a repressor of human gamma-globin expression identified by genome-wide association studies, differs between mouse and human. Developmental silencing of the mouse embryonic globin and human gamma-globin genes fails to occur in mice in the absence of BCL11A. Thus, BCL11A is a critical mediator of species-divergent globin switching. By comparing the ontogeny of beta-globin gene regulation in mice and humans, we have shown that alterations in the expression of a trans-acting factor constitute a critical driver of gene expression changes during evolution.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749913/" 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/PMC3749913/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sankaran, Vijay G -- Xu, Jian -- Ragoczy, Tobias -- Ippolito, Gregory C -- Walkley, Carl R -- Maika, Shanna D -- Fujiwara, Yuko -- Ito, Masafumi -- Groudine, Mark -- Bender, M A -- Tucker, Philip W -- Orkin, Stuart H -- P01 HL032262/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Aug 27;460(7259):1093-7. doi: 10.1038/nature08243. Epub 2009 Aug 5.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology/Oncology, Children's Hospital Boston and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Stem Cell 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/19657335" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carrier Proteins/genetics/*metabolism ; Embryo, Mammalian/metabolism ; Evolution, Molecular ; Fetus/metabolism ; *Gene Expression Regulation, Developmental ; Gene Silencing ; Globins/*genetics ; Hematopoiesis ; Humans ; Mice ; Nuclear Proteins/genetics/*metabolism ; Species Specificity ; beta-Globins/genetics ; gamma-Globins/genetics
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  • 86
    Publication Date: 2009-11-10
    Description: CD4(+) T helper cells are well known for their role in providing critical signals during priming of cytotoxic CD8(+) T lymphocyte (CTL) responses in vivo. T-cell help is required for the generation of primary CTL responses as well as in promoting protective CD8(+) memory T-cell development. However, the role of CD4 help in the control of CTL responses at the effector stage is unknown. Here we show that fully helped effector CTLs are themselves not self-sufficient for entry into the infected tissue, but rely on the CD4(+) T cells to provide the necessary cue. CD4(+) T helper cells control the migration of CTL indirectly through the secretion of IFN-gamma and induction of local chemokine secretion in the infected tissue. Our results reveal a previously unappreciated role of CD4 help in mobilizing effector CTL to the peripheral sites of infection where they help to eliminate infected cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789415/" 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/PMC2789415/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakanishi, Yusuke -- Lu, Bao -- Gerard, Craig -- Iwasaki, Akiko -- AI054359/AI/NIAID NIH HHS/ -- AI062428/AI/NIAID NIH HHS/ -- AI39759/AI/NIAID NIH HHS/ -- HL51366/HL/NHLBI NIH HHS/ -- R01 AI054359/AI/NIAID NIH HHS/ -- R01 AI054359-06A2/AI/NIAID NIH HHS/ -- R01 AI062428/AI/NIAID NIH HHS/ -- R01 AI062428-05/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Nov 26;462(7272):510-3. doi: 10.1038/nature08511. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898495" target="_blank"〉PubMed〈/a〉
    Keywords: Adoptive Transfer ; Animals ; Chemokines/immunology/secretion ; *Chemotaxis ; Female ; Herpes Simplex/immunology/virology ; Herpesvirus 2, Human/*immunology ; Immunity, Mucosal/immunology ; Interferon-gamma/antagonists & inhibitors/immunology/secretion ; Mice ; Mice, Inbred C57BL ; Models, Immunological ; Mucous Membrane/immunology/virology ; Receptors, CXCR3/metabolism ; T-Lymphocytes, Cytotoxic/*cytology/*immunology ; T-Lymphocytes, Helper-Inducer/*immunology/secretion ; Vagina/*immunology/*virology
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  • 87
    Publication Date: 2009-10-02
    Description: Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL(Deltas/Deltas)) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL(Deltam/Deltam)) could not kill cells through Fas activation. FasL(Deltam/Deltam) mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL(gld/gld) mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL(Deltam/Deltam) mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL(gld/gld) mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2785124/" 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/PMC2785124/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉O' Reilly, Lorraine A -- Tai, Lin -- Lee, Lily -- Kruse, Elizabeth A -- Grabow, Stephanie -- Fairlie, W Douglas -- Haynes, Nicole M -- Tarlinton, David M -- Zhang, Jian-Guo -- Belz, Gabrielle T -- Smyth, Mark J -- Bouillet, Philippe -- Robb, Lorraine -- Strasser, Andreas -- CA043540-18/CA/NCI NIH HHS/ -- CA80188-6/CA/NCI NIH HHS/ -- R01 CA043540/CA/NCI NIH HHS/ -- R01 CA043540-18/CA/NCI NIH HHS/ -- R01 CA080188-06/CA/NCI NIH HHS/ -- England -- Nature. 2009 Oct 1;461(7264):659-63. doi: 10.1038/nature08402.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19794494" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Antinuclear/immunology ; Antigens, CD95/*metabolism ; *Apoptosis ; Cell Membrane/*metabolism ; Cytidine Deaminase/metabolism ; Cytotoxicity, Immunologic ; Fas Ligand Protein/deficiency/genetics/*metabolism/secretion ; Glomerulonephritis/metabolism ; Histiocytic Sarcoma/metabolism ; Hypergammaglobulinemia/metabolism ; Lupus Erythematosus, Systemic/metabolism ; Lymphatic Diseases/metabolism ; Mice ; Mice, Inbred C57BL ; Mutation ; Splenomegaly/metabolism ; T-Lymphocytes/immunology/metabolism
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  • 88
    Publication Date: 2009-05-22
    Description: Consistent with the role of microRNAs (miRNAs) in down-regulating gene expression by reducing the translation and/or stability of target messenger RNAs, the levels of specific miRNAs are important for correct embryonic development and have been linked to several forms of cancer. However, the regulatory mechanisms by which primary miRNAs (pri-miRNAs) are processed first to precursor miRNAs (pre-miRNAs) and then to mature miRNAs by the multiprotein Drosha and Dicer complexes, respectively, remain largely unknown. The KH-type splicing regulatory protein (KSRP, also known as KHSRP) interacts with single-strand AU-rich-element-containing mRNAs and is a key mediator of mRNA decay. Here we show in mammalian cells that KSRP also serves as a component of both Drosha and Dicer complexes and regulates the biogenesis of a subset of miRNAs. KSRP binds with high affinity to the terminal loop of the target miRNA precursors and promotes their maturation. This mechanism is required for specific changes in target mRNA expression that affect specific biological programs, including proliferation, apoptosis and differentiation. These findings reveal an unexpected mechanism that links KSRP to the machinery regulating maturation of a cohort of miRNAs that, in addition to its role in promoting mRNA decay, independently serves to integrate specific regulatory programs of protein expression.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768332/" 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/PMC2768332/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trabucchi, Michele -- Briata, Paola -- Garcia-Mayoral, Mariaflor -- Haase, Astrid D -- Filipowicz, Witold -- Ramos, Andres -- Gherzi, Roberto -- Rosenfeld, Michael G -- 082088/Wellcome Trust/United Kingdom -- DK018477/DK/NIDDK NIH HHS/ -- DK39949/DK/NIDDK NIH HHS/ -- GFP04003/Telethon/Italy -- HL065445/HL/NHLBI NIH HHS/ -- MC_U117533887/Medical Research Council/United Kingdom -- MC_U117574558/Medical Research Council/United Kingdom -- R37 DK039949/DK/NIDDK NIH HHS/ -- R37 DK039949-26/DK/NIDDK NIH HHS/ -- R37 DK039949-27/DK/NIDDK NIH HHS/ -- WT022088MA/Wellcome Trust/United Kingdom -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 18;459(7249):1010-4. doi: 10.1038/nature08025. Epub 2009 May 20.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Howard Hughes Medical Institute, Department and School of Medicine, University of California, San Diego, 9500 Gilman Drive, Room 345, La Jolla, California 92093-0648, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19458619" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Mice ; MicroRNAs/*biosynthesis/genetics/metabolism ; RNA Processing, Post-Transcriptional ; RNA-Binding Proteins/*metabolism ; Ribonuclease III/chemistry/metabolism ; Trans-Activators/*metabolism
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  • 89
    Publication Date: 2009-12-17
    Description: The majority of excitatory synapses in the mammalian CNS (central nervous system) are formed on dendritic spines, and spine morphology and distribution are critical for synaptic transmission, synaptic integration and plasticity. Here, we show that a secreted semaphorin, Sema3F, is a negative regulator of spine development and synaptic structure. Mice with null mutations in genes encoding Sema3F, and its holoreceptor components neuropilin-2 (Npn-2, also known as Nrp2) and plexin A3 (PlexA3, also known as Plxna3), exhibit increased dentate gyrus (DG) granule cell (GC) and cortical layer V pyramidal neuron spine number and size, and also aberrant spine distribution. Moreover, Sema3F promotes loss of spines and excitatory synapses in dissociated neurons in vitro, and in Npn-2(-/-) brain slices cortical layer V and DG GCs exhibit increased mEPSC (miniature excitatory postsynaptic current) frequency. In contrast, a distinct Sema3A-Npn-1/PlexA4 signalling cascade controls basal dendritic arborization in layer V cortical neurons, but does not influence spine morphogenesis or distribution. These disparate effects of secreted semaphorins are reflected in the restricted dendritic localization of Npn-2 to apical dendrites and of Npn-1 (also known as Nrp1) to all dendrites of cortical pyramidal neurons. Therefore, Sema3F signalling controls spine distribution along select dendritic processes, and distinct secreted semaphorin signalling events orchestrate CNS connectivity through the differential control of spine morphogenesis, synapse formation, and the elaboration of dendritic morphology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2842559/" 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/PMC2842559/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tran, Tracy S -- Rubio, Maria E -- Clem, Roger L -- Johnson, Dontais -- Case, Lauren -- Tessier-Lavigne, Marc -- Huganir, Richard L -- Ginty, David D -- Kolodkin, Alex L -- F32 NS051003/NS/NINDS NIH HHS/ -- P50 MH06883/MH/NIMH NIH HHS/ -- R01 DC-006881/DC/NIDCD NIH HHS/ -- R01 MH059199/MH/NIMH NIH HHS/ -- R01 MH059199-07/MH/NIMH NIH HHS/ -- R01 MH059199-08/MH/NIMH NIH HHS/ -- R01 MH059199-09/MH/NIMH NIH HHS/ -- R01 MH059199-10/MH/NIMH NIH HHS/ -- R01 MH59199/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Dec 24;462(7276):1065-9. doi: 10.1038/nature08628. Epub 2009 Dec 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20010807" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Central Nervous System/cytology/drug effects/*growth & ; development/*metabolism/ultrastructure ; Female ; Gene Expression Regulation, Developmental ; Male ; Mice ; Mice, Knockout ; Neuropilin-1/metabolism ; Neuropilin-2/metabolism ; Pyramidal Cells/*cytology/drug effects/*growth & development/ultrastructure ; Recombinant Proteins/pharmacology ; Semaphorins/genetics/*metabolism/pharmacology ; Signal Transduction ; Synapses/drug effects/*physiology/ultrastructure
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  • 90
    Publication Date: 2009-06-12
    Description: Osteoblasts and endothelium constitute functional niches that support haematopoietic stem cells in mammalian bone marrow. Adult bone marrow also contains adipocytes, the number of which correlates inversely with the haematopoietic activity of the marrow. Fatty infiltration of haematopoietic red marrow follows irradiation or chemotherapy and is a diagnostic feature in biopsies from patients with marrow aplasia. To explore whether adipocytes influence haematopoiesis or simply fill marrow space, we compared the haematopoietic activity of distinct regions of the mouse skeleton that differ in adiposity. Here we show, by flow cytometry, colony-forming activity and competitive repopulation assay, that haematopoietic stem cells and short-term progenitors are reduced in frequency in the adipocyte-rich vertebrae of the mouse tail relative to the adipocyte-free vertebrae of the thorax. In lipoatrophic A-ZIP/F1 'fatless' mice, which are genetically incapable of forming adipocytes, and in mice treated with the peroxisome proliferator-activated receptor-gamma inhibitor bisphenol A diglycidyl ether, which inhibits adipogenesis, marrow engraftment after irradiation is accelerated relative to wild-type or untreated mice. These data implicate adipocytes as predominantly negative regulators of the bone-marrow microenvironment, and indicate that antagonizing marrow adipogenesis may enhance haematopoietic recovery in clinical bone-marrow transplantation.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2831539/" 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/PMC2831539/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Naveiras, Olaia -- Nardi, Valentina -- Wenzel, Pamela L -- Hauschka, Peter V -- Fahey, Frederic -- Daley, George Q -- DP1 OD000256/OD/NIH HHS/ -- DP1 OD000256-01/OD/NIH HHS/ -- R01 DK059279/DK/NIDDK NIH HHS/ -- R01 DK059279-06/DK/NIDDK NIH HHS/ -- R01 DK070055/DK/NIDDK NIH HHS/ -- R01 DK070055-01/DK/NIDDK NIH HHS/ -- T32- HL -7623/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jul 9;460(7252):259-63. doi: 10.1038/nature08099. Epub 2009 Jun 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Pediatric Hematology/Oncology, Children's Hospital Boston and Dana Farber Cancer Institute, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19516257" target="_blank"〉PubMed〈/a〉
    Keywords: Adipocytes/cytology/drug effects/*physiology ; Adipogenesis/drug effects ; Adiposity/physiology ; Animals ; Benzhydryl Compounds ; Bone Marrow Cells/*cytology/*metabolism ; Bone Marrow Transplantation ; Cell Line ; Epoxy Compounds/pharmacology ; Femur ; *Hematopoiesis/drug effects ; Hematopoietic Stem Cells/cytology/metabolism ; Homeostasis ; Mice ; Mice, Inbred C57BL ; Osteogenesis ; Spine/cytology/metabolism ; Stromal Cells ; Tail ; Thorax ; Tibia
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  • 91
    Publication Date: 2009-10-23
    Description: The tumour stroma is believed to contribute to some of the most malignant characteristics of epithelial tumours. However, signalling between stromal and tumour cells is complex and remains poorly understood. Here we show that the genetic inactivation of Pten in stromal fibroblasts of mouse mammary glands accelerated the initiation, progression and malignant transformation of mammary epithelial tumours. This was associated with the massive remodelling of the extracellular matrix (ECM), innate immune cell infiltration and increased angiogenesis. Loss of Pten in stromal fibroblasts led to increased expression, phosphorylation (T72) and recruitment of Ets2 to target promoters known to be involved in these processes. Remarkably, Ets2 inactivation in Pten stroma-deleted tumours ameliorated disruption of the tumour microenvironment and was sufficient to decrease tumour growth and progression. Global gene expression profiling of mammary stromal cells identified a Pten-specific signature that was highly represented in the tumour stroma of patients with breast cancer. These findings identify the Pten-Ets2 axis as a critical stroma-specific signalling pathway that suppresses mammary epithelial tumours.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2767301/" 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/PMC2767301/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Trimboli, Anthony J -- Cantemir-Stone, Carmen Z -- Li, Fu -- Wallace, Julie A -- Merchant, Anand -- Creasap, Nicholas -- Thompson, John C -- Caserta, Enrico -- Wang, Hui -- Chong, Jean-Leon -- Naidu, Shan -- Wei, Guo -- Sharma, Sudarshana M -- Stephens, Julie A -- Fernandez, Soledad A -- Gurcan, Metin N -- Weinstein, Michael B -- Barsky, Sanford H -- Yee, Lisa -- Rosol, Thomas J -- Stromberg, Paul C -- Robinson, Michael L -- Pepin, Francois -- Hallett, Michael -- Park, Morag -- Ostrowski, Michael C -- Leone, Gustavo -- P01 CA097189/CA/NCI NIH HHS/ -- P01 CA097189-050002/CA/NCI NIH HHS/ -- P01CA097189/CA/NCI NIH HHS/ -- R01 CA053271/CA/NCI NIH HHS/ -- R01 CA085619/CA/NCI NIH HHS/ -- R01 CA085619-05/CA/NCI NIH HHS/ -- R01 CA121275/CA/NCI NIH HHS/ -- R01 CA121275-02/CA/NCI NIH HHS/ -- R01 HD047470/HD/NICHD NIH HHS/ -- R01 HD047470-05/HD/NICHD NIH HHS/ -- R01CA053271/CA/NCI NIH HHS/ -- R01CA85619/CA/NCI NIH HHS/ -- R01HD47470/HD/NICHD NIH HHS/ -- England -- Nature. 2009 Oct 22;461(7267):1084-91. doi: 10.1038/nature08486.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Genetics, College of Biological Sciences, The Ohio State University, Columbus, Ohio 43210, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847259" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Breast Neoplasms/*metabolism/*pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic ; Extracellular Matrix/metabolism ; Fibroblasts/*metabolism ; Gene Deletion ; Gene Expression Regulation, Neoplastic ; Humans ; Immunity, Innate ; Mammary Neoplasms, Experimental/metabolism/pathology ; Mice ; Mice, Transgenic ; Neoplasms, Glandular and Epithelial/*metabolism/*pathology ; PTEN Phosphohydrolase/deficiency/genetics/*metabolism ; Proto-Oncogene Protein c-ets-2/deficiency/metabolism ; Stromal Cells/*metabolism
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  • 92
    Publication Date: 2009-02-13
    Description: The first recurrent translocation event in prostate cancer has been recently described; it results in the translocation of an ETS (E26 transformation specific) transcription factor (ERG or ETV1) to the TMPRSS2 promoter region, which contains androgen responsive elements. The TMPRSS2:ERG genetic rearrangement has been reported to occur in approximately 40% of primary prostate tumours (ETV1 genetic rearrangements occur at a much lower frequency), and it results in the aberrant androgen-regulated expression of ERG. Tomlins et al. concluded that ETS genetic rearrangements are sufficient to initiate prostate neoplasia. However, here we show that ETS genetic rearrangements may in fact represent progression events rather than initiation events in prostate tumorigenesis. To this end, we demonstrate that the prostate-specific overexpression of ERG does not initiate prostate tumorigenesis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2967456/" 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/PMC2967456/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carver, Brett S -- Tran, Jennifer -- Chen, Zhenbang -- Carracedo-Perez, Arkaitz -- Alimonti, Andrea -- Nardella, Caterina -- Gopalan, Anuradha -- Scardino, Peter T -- Cordon-Cardo, Carlos -- Gerald, William -- Pandolfi, Pier Paolo -- P50 CA092629/CA/NCI NIH HHS/ -- P50 CA092629-10/CA/NCI NIH HHS/ -- R01 CA082328/CA/NCI NIH HHS/ -- R01 CA082328-12/CA/NCI NIH HHS/ -- R01 MD004038/MD/NIMHD NIH HHS/ -- U01 CA084292/CA/NCI NIH HHS/ -- U01 CA084292-10/CA/NCI NIH HHS/ -- England -- Nature. 2009 Feb 12;457(7231):E1; discussion E2-3. doi: 10.1038/nature07738.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212347" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Transformation, Neoplastic/*genetics/metabolism/pathology ; DNA-Binding Proteins/genetics ; Disease Progression ; Gene Expression ; Male ; Mice ; Mice, Transgenic ; Oncogene Proteins/genetics/metabolism ; Prostatic Neoplasms/*genetics/metabolism ; Transcription Factors/genetics ; *Translocation, Genetic
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  • 93
    Publication Date: 2009-03-31
    Description: The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sato, Toshiro -- Vries, Robert G -- Snippert, Hugo J -- van de Wetering, Marc -- Barker, Nick -- Stange, Daniel E -- van Es, Johan H -- Abo, Arie -- Kujala, Pekka -- Peters, Peter J -- Clevers, Hans -- England -- Nature. 2009 May 14;459(7244):262-5. doi: 10.1038/nature07935. Epub 2009 Mar 29.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute and University Medical Center Utrecht, Uppsalalaan 8, 3584CT Utrecht, The Netherlands.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19329995" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Culture Techniques/*methods ; Cell Lineage ; Cell Separation ; Gene Expression Regulation, Developmental ; Intestines/*anatomy & histology/*cytology/metabolism ; Mesoderm/cytology/metabolism ; Mice ; Multipotent Stem Cells/cytology/metabolism ; Organoids/*cytology/growth & development/metabolism ; Paneth Cells/metabolism ; Receptors, G-Protein-Coupled/*metabolism ; Receptors, Notch/metabolism ; Regeneration ; Stem Cell Niche ; Stem Cells/*cytology/*metabolism
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  • 94
    Publication Date: 2009-02-13
    Description: Despite decades of research, the identity of the cells generating the first haematopoietic cells in mammalian embryos is unknown. Indeed, whether blood cells arise from mesodermal cells, mesenchymal progenitors, bipotent endothelial-haematopoietic precursors or haemogenic endothelial cells remains controversial. Proximity of endothelial and blood cells at sites of embryonic haematopoiesis, as well as their similar gene expression, led to the hypothesis of the endothelium generating blood. However, owing to lacking technology it has been impossible to observe blood cell emergence continuously at the single-cell level, and the postulated existence of haemogenic endothelial cells remains disputed. Here, using new imaging and cell-tracking methods, we show that embryonic endothelial cells can be haemogenic. By continuous long-term single-cell observation of mouse mesodermal cells generating endothelial cell and blood colonies, it was possible to detect haemogenic endothelial cells giving rise to blood cells. Living endothelial and haematopoietic cells were identified by simultaneous detection of morphology and multiple molecular and functional markers. Detachment of nascent blood cells from endothelium is not directly linked to asymmetric cell division, and haemogenic endothelial cells are specified from cells already expressing endothelial markers. These results improve our understanding of the developmental origin of mammalian blood and the potential generation of haematopoietic stem cells from embryonic stem cells.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eilken, Hanna M -- Nishikawa, Shin-Ichi -- Schroeder, Timm -- England -- Nature. 2009 Feb 12;457(7231):896-900. doi: 10.1038/nature07760.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Institute of Stem Cell Research, Helmholtz Center Munich-German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19212410" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blood Cells/*cytology ; *Cell Differentiation ; Cell Line ; Embryo, Mammalian/cytology/embryology ; Embryonic Stem Cells/cytology ; Hemangioblasts/*cytology ; *Image Processing, Computer-Assisted ; Mesoderm/cytology ; Mice ; Microscopy, Fluorescence ; *Video Recording
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  • 95
    Publication Date: 2009-10-23
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eisenstein, Michael -- England -- Nature. 2009 Oct 22;461(7267):1149-52. doi: 10.1038/4611149a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19847270" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Mice ; Mice, Transgenic ; Neural Pathways/anatomy & histology/*cytology ; Neuroanatomical Tract-Tracing Techniques/*methods ; Neuroanatomy/*methods ; Neurons/*metabolism
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  • 96
    Publication Date: 2009-11-10
    Description: Direct reprogramming of somatic cells into induced pluripotent stem (iPS) cells can be achieved by overexpression of Oct4, Sox2, Klf4 and c-Myc transcription factors, but only a minority of donor somatic cells can be reprogrammed to pluripotency. Here we demonstrate that reprogramming by these transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to iPS cells on continued growth and transcription factor expression. Additional inhibition of the p53/p21 pathway or overexpression of Lin28 increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog overexpression accelerated reprogramming in a predominantly cell-division-rate-independent manner. Quantitative analyses define distinct cell-division-rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggest that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789972/" 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/PMC2789972/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hanna, Jacob -- Saha, Krishanu -- Pando, Bernardo -- van Zon, Jeroen -- Lengner, Christopher J -- Creyghton, Menno P -- van Oudenaarden, Alexander -- Jaenisch, Rudolf -- R01 CA087869/CA/NCI NIH HHS/ -- R01 CA087869-09/CA/NCI NIH HHS/ -- R01 HD045022/HD/NICHD NIH HHS/ -- R01 HD045022-06/HD/NICHD NIH HHS/ -- R01-CA087869/CA/NCI NIH HHS/ -- R01-HDO45022/PHS HHS/ -- R37 CA084198/CA/NCI NIH HHS/ -- R37 CA084198-09/CA/NCI NIH HHS/ -- R37-CA084198/CA/NCI NIH HHS/ -- U54CA143874/CA/NCI NIH HHS/ -- England -- Nature. 2009 Dec 3;462(7273):595-601. doi: 10.1038/nature08592. Epub 2009 Nov 8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA. Hanna@wi.mit.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19898493" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Cell Differentiation ; Cell Division ; Cell Line ; *Cellular Reprogramming ; Gene Expression Regulation, Developmental ; Mice ; Mice, SCID ; Models, Biological ; Pluripotent Stem Cells/*cytology/*metabolism ; Time Factors ; Transcription Factors/genetics/metabolism
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  • 97
    Publication Date: 2009-05-15
    Description: Biomechanical forces are emerging as critical regulators of embryogenesis, particularly in the developing cardiovascular system. After initiation of the heartbeat in vertebrates, cells lining the ventral aspect of the dorsal aorta, the placental vessels, and the umbilical and vitelline arteries initiate expression of the transcription factor Runx1 (refs 3-5), a master regulator of haematopoiesis, and give rise to haematopoietic cells. It remains unknown whether the biomechanical forces imposed on the vascular wall at this developmental stage act as a determinant of haematopoietic potential. Here, using mouse embryonic stem cells differentiated in vitro, we show that fluid shear stress increases the expression of Runx1 in CD41(+)c-Kit(+) haematopoietic progenitor cells, concomitantly augmenting their haematopoietic colony-forming potential. Moreover, we find that shear stress increases haematopoietic colony-forming potential and expression of haematopoietic markers in the para-aortic splanchnopleura/aorta-gonads-mesonephros of mouse embryos and that abrogation of nitric oxide, a mediator of shear-stress-induced signalling, compromises haematopoietic potential in vitro and in vivo. Collectively, these data reveal a critical role for biomechanical forces in haematopoietic development.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2782763/" 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/PMC2782763/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adamo, Luigi -- Naveiras, Olaia -- Wenzel, Pamela L -- McKinney-Freeman, Shannon -- Mack, Peter J -- Gracia-Sancho, Jorge -- Suchy-Dicey, Astrid -- Yoshimoto, Momoko -- Lensch, M William -- Yoder, Mervin C -- Garcia-Cardena, Guillermo -- Daley, George Q -- R01 AI080759/AI/NIAID NIH HHS/ -- R01 AI080759-01/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2009 Jun 25;459(7250):1131-5. doi: 10.1038/nature08073. Epub 2009 May 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19440194" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Aorta/cytology/embryology ; *Cell Differentiation ; Cell Line ; Cells, Cultured ; Core Binding Factor Alpha 2 Subunit/genetics ; Embryonic Stem Cells ; Endothelium-Dependent Relaxing Factors/pharmacology ; Female ; Gene Expression Regulation, Developmental ; Hematopoiesis/*physiology ; Hematopoietic Stem Cells/*cytology/drug effects ; Mice ; Nitric Oxide/pharmacology ; Pregnancy ; *Stress, Mechanical
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  • 98
    Publication Date: 2009-02-03
    Description: It has been proposed that during embryonic development haematopoietic cells arise from a mesodermal progenitor with both endothelial and haematopoietic potential called the haemangioblast. A conflicting theory instead associates the first haematopoietic cells with a phenotypically differentiated endothelial cell that has haematopoietic potential (that is, a haemogenic endothelium). Support for the haemangioblast concept was initially provided by the identification during mouse embryonic stem cell differentiation of a clonal precursor, the blast colony-forming cell (BL-CFC), which gives rise to blast colonies with both endothelial and haematopoietic components. Although recent studies have now provided evidence for the presence of this bipotential precursor in vivo, the precise mechanism for generation of haematopoietic cells from the haemangioblast still remains completely unknown. Here we demonstrate that the haemangioblast generates haematopoietic cells through the formation of a haemogenic endothelium intermediate, providing the first direct link between these two precursor populations. The cell population containing the haemogenic endothelium is transiently generated during BL-CFC development. This cell population is also present in gastrulating mouse embryos and generates haematopoietic cells on further culture. At the molecular level, we demonstrate that the transcription factor Tal1 (also known as Scl; ref. 10) is indispensable for the establishment of this haemogenic endothelium population whereas the core binding factor Runx1 (also known as AML1; ref. 11) is critical for generation of definitive haematopoietic cells from haemogenic endothelium. Together our results merge the two a priori conflicting theories on the origin of haematopoietic development into a single linear developmental process.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2661201/" 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/PMC2661201/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lancrin, Christophe -- Sroczynska, Patrycja -- Stephenson, Catherine -- Allen, Terry -- Kouskoff, Valerie -- Lacaud, Georges -- A5297/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- England -- Nature. 2009 Feb 12;457(7231):892-5. doi: 10.1038/nature07679. Epub 2009 Jan 28.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Stem Cell Biology Group.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19182774" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Core Binding Factor Alpha 2 Subunit/metabolism ; Embryo, Mammalian/cytology/embryology ; Gene Expression Regulation, Developmental ; Hemangioblasts/*cytology ; Hematopoietic Stem Cells/*cytology ; Mice ; Mice, Inbred ICR ; Oncogene Proteins, Fusion/metabolism
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  • 99
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    Unknown
    Nature Publishing Group (NPG)
    Publication Date: 2009-09-11
    Description: 〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nelson, Bryn -- England -- Nature. 2009 Sep 10;461(7261):160-3. doi: 10.1038/461160a.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19741679" target="_blank"〉PubMed〈/a〉
    Keywords: *Access to Information/legislation & jurisprudence ; Animals ; Archives ; Confidentiality/standards ; Databases, Factual/standards/trends/*utilization ; Human Genome Project ; Humans ; Information Storage and Retrieval/*methods/standards/trends/*utilization ; *Internet/utilization ; Mice ; Periodicals as Topic/standards ; Publishing/standards ; Research/standards ; Research Design ; *Research Personnel/psychology ; Time Factors
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  • 100
    Publication Date: 2009-03-27
    Description: Haematopoietic stem and progenitor cells (HSPCs) change location during development and circulate in mammals throughout life, moving into and out of the bloodstream to engage bone marrow niches in sequential steps of homing, engraftment and retention. Here we show that HSPC engraftment of bone marrow in fetal development is dependent on the guanine-nucleotide-binding protein stimulatory alpha subunit (Galpha(s)). HSPCs from adult mice deficient in Galpha(s) (Galpha(s)(-/-)) differentiate and undergo chemotaxis, but also do not home to or engraft in the bone marrow in adult mice and demonstrate a marked inability to engage the marrow microvasculature. If deleted after engraftment, Galpha(s) deficiency did not lead to lack of retention in the marrow, rather cytokine-induced mobilization into the blood was impaired. Testing whether activation of Galpha(s) affects HSPCs, pharmacological activators enhanced homing and engraftment in vivo. Galpha(s) governs specific aspects of HSPC localization under physiological conditions in vivo and may be pharmacologically targeted to improve transplantation efficiency.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2761017/" 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/PMC2761017/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Adams, Gregor B -- Alley, Ian R -- Chung, Ung-Il -- Chabner, Karissa T -- Jeanson, Nathaniel T -- Lo Celso, Cristina -- Marsters, Emily S -- Chen, Min -- Weinstein, Lee S -- Lin, Charles P -- Kronenberg, Henry M -- Scadden, David T -- U54 HL081030/HL/NHLBI NIH HHS/ -- U54 HL081030-01/HL/NHLBI NIH HHS/ -- England -- Nature. 2009 May 7;459(7243):103-7. doi: 10.1038/nature07859. Epub 2009 Mar 25.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19322176" target="_blank"〉PubMed〈/a〉
    Keywords: Adjuvants, Immunologic/pharmacology ; Animals ; Bone Marrow/drug effects/embryology/*physiology ; Bone Marrow Transplantation/physiology ; Cell Movement/drug effects/physiology ; Cholera Toxin/pharmacology ; GTP-Binding Protein alpha Subunits, Gs/genetics/*metabolism ; Granulocyte Colony-Stimulating Factor/metabolism ; Hematopoietic Stem Cells/*physiology ; Mice ; Mice, Inbred C57BL ; Signal Transduction/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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