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  • 1
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    Role for piRNAs and noncoding RNA in de novo DNA methylation of the imprinted mouse Rasgrf1 locus (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-05-14
    Description: Genomic imprinting causes parental origin-specific monoallelic gene expression through differential DNA methylation established in the parental germ line. However, the mechanisms underlying how specific sequences are selectively methylated are not fully understood. We have found that the components of the PIWI-interacting RNA (piRNA) pathway are required for de novo methylation of the differentially methylated region (DMR) of the imprinted mouse Rasgrf1 locus, but not other paternally imprinted loci. A retrotransposon sequence within a noncoding RNA spanning the DMR was targeted by piRNAs generated from a different locus. A direct repeat in the DMR, which is required for the methylation and imprinting of Rasgrf1, served as a promoter for this RNA. We propose a model in which piRNAs and a target RNA direct the sequence-specific methylation of Rasgrf1.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368507/" 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/PMC3368507/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Watanabe, Toshiaki -- Tomizawa, Shin-ichi -- Mitsuya, Kohzoh -- Totoki, Yasushi -- Yamamoto, Yasuhiro -- Kuramochi-Miyagawa, Satomi -- Iida, Naoko -- Hoki, Yuko -- Murphy, Patrick J -- Toyoda, Atsushi -- Gotoh, Kengo -- Hiura, Hitoshi -- Arima, Takahiro -- Fujiyama, Asao -- Sado, Takashi -- Shibata, Tatsuhiro -- Nakano, Toru -- Lin, Haifan -- Ichiyanagi, Kenji -- Soloway, Paul D -- Sasaki, Hiroyuki -- R01 CA098597/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2011 May 13;332(6031):848-52. doi: 10.1126/science.1203919.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Human Genetics and Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Shizuoka, 411-8540, Japan. toshwatatoshiakiwatanabe@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21566194" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Argonaute Proteins ; *DNA Methylation ; *Genomic Imprinting ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondrial Proteins/genetics/metabolism ; Models, Genetic ; Mutation ; Phospholipase D/genetics/metabolism ; Proteins/genetics/metabolism ; RNA, Small Interfering/*genetics/metabolism ; RNA, Untranslated/*genetics/metabolism ; Repetitive Sequences, Nucleic Acid ; Retroelements ; Spermatogonia/metabolism ; Testis/embryology/metabolism ; Transcription, Genetic ; ras-GRF1/*genetics
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Neuromuscular disease. DOK7 gene therapy benefits mouse models of diseases characterized by defects in the neuromuscular junction (2014)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2014-09-23
    Description: The neuromuscular junction (NMJ) is the synapse between a motor neuron and skeletal muscle. Defects in NMJ transmission cause muscle weakness, termed myasthenia. The muscle protein Dok-7 is essential for activation of the receptor kinase MuSK, which governs NMJ formation, and DOK7 mutations underlie familial limb-girdle myasthenia (DOK7 myasthenia), a neuromuscular disease characterized by small NMJs. Here, we show in a mouse model of DOK7 myasthenia that therapeutic administration of an adeno-associated virus (AAV) vector encoding the human DOK7 gene resulted in an enlargement of NMJs and substantial increases in muscle strength and life span. When applied to model mice of another neuromuscular disorder, autosomal dominant Emery-Dreifuss muscular dystrophy, DOK7 gene therapy likewise resulted in enlargement of NMJs as well as positive effects on motor activity and life span. These results suggest that therapies aimed at enlarging the NMJ may be useful for a range of neuromuscular disorders.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Arimura, Sumimasa -- Okada, Takashi -- Tezuka, Tohru -- Chiyo, Tomoko -- Kasahara, Yuko -- Yoshimura, Toshiro -- Motomura, Masakatsu -- Yoshida, Nobuaki -- Beeson, David -- Takeda, Shin'ichi -- Yamanashi, Yuji -- G0701521/Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Sep 19;345(6203):1505-8. doi: 10.1126/science.1250744.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan. ; Department of Occupational Therapy, Nagasaki University School of Health Sciences, Nagasaki, Japan. ; Department of Electrical and Electronics Engineering, Faculty of Engineering, Nagasaki Institute of Applied Science, Nagasaki, Japan. ; Laboratory of Developmental Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. ; Neurosciences Group, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. ; Division of Genetics, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. yyamanas@ims.u-tokyo.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25237101" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Dependovirus ; Disease Models, Animal ; Female ; Genetic Therapy/*methods ; Genetic Vectors/administration & dosage ; Humans ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Muscle Proteins/*genetics ; Muscle, Skeletal/*innervation/physiopathology ; Muscular Dystrophies, Limb-Girdle/genetics/*pathology/*therapy ; Neuromuscular Junction/*pathology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
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    In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-06-10
    Description: Stem cells reside in a specialized regulatory microenvironment or niche, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity. The niche may also protect stem cells from environmental insults including cytotoxic chemotherapy and perhaps pathogenic immunity. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche in the bone marrow, a site where immune reactivity exists. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (T(reg)) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with T(reg) cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. T(reg) cells seem to participate in creating a localized zone where HSPCs reside and where T(reg) cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725645/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725645/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fujisaki, Joji -- Wu, Juwell -- Carlson, Alicia L -- Silberstein, Lev -- Putheti, Prabhakar -- Larocca, Rafael -- Gao, Wenda -- Saito, Toshiki I -- Lo Celso, Cristina -- Tsuyuzaki, Hitoshi -- Sato, Tatsuyuki -- Cote, Daniel -- Sykes, Megan -- Strom, Terry B -- Scadden, David T -- Lin, Charles P -- AI041521/AI/NIAID NIH HHS/ -- CA111519/CA/NCI NIH HHS/ -- HL097748/HL/NHLBI NIH HHS/ -- HL97794/HL/NHLBI NIH HHS/ -- P01 AI041521/AI/NIAID NIH HHS/ -- P01 AI073748/AI/NIAID NIH HHS/ -- P01 CA111519/CA/NCI NIH HHS/ -- P01 CA111519-05/CA/NCI NIH HHS/ -- R01 HL097748/HL/NHLBI NIH HHS/ -- R01 HL097748-02/HL/NHLBI NIH HHS/ -- R01 HL097794/HL/NHLBI NIH HHS/ -- R01 HL097794-02/HL/NHLBI NIH HHS/ -- England -- Nature. 2011 Jun 8;474(7350):216-9. doi: 10.1038/nature10160.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. jfujisaki@partners.org〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21654805" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Survival/immunology ; Cells, Cultured ; Forkhead Transcription Factors/metabolism ; Graft Survival/*immunology ; Hematopoietic Stem Cells/cytology/*immunology ; Humans ; *Imaging, Three-Dimensional ; Interleukin-10/deficiency/genetics/immunology/metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Stem Cell Niche/cytology/*immunology ; T-Lymphocytes, Regulatory/*immunology/metabolism ; Time Factors ; Transplantation, Homologous/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 4
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    Completion of the entire hepatitis C virus life cycle in genetically humanized mice (2013)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2013-08-02
    Description: More than 130 million people worldwide chronically infected with hepatitis C virus (HCV) are at risk of developing severe liver disease. Antiviral treatments are only partially effective against HCV infection, and a vaccine is not available. Development of more efficient therapies has been hampered by the lack of a small animal model. Building on the observation that CD81 and occludin (OCLN) comprise the minimal set of human factors required to render mouse cells permissive to HCV entry, we previously showed that transient expression of these two human genes is sufficient to allow viral uptake into fully immunocompetent inbred mice. Here we demonstrate that transgenic mice stably expressing human CD81 and OCLN also support HCV entry, but innate and adaptive immune responses restrict HCV infection in vivo. Blunting antiviral immunity in genetically humanized mice infected with HCV results in measurable viraemia over several weeks. In mice lacking the essential cellular co-factor cyclophilin A (CypA), HCV RNA replication is markedly diminished, providing genetic evidence that this process is faithfully recapitulated. Using a cell-based fluorescent reporter activated by the NS3-4A protease we visualize HCV infection in single hepatocytes in vivo. Persistently infected mice produce de novo infectious particles, which can be inhibited with directly acting antiviral drug treatment, thereby providing evidence for the completion of the entire HCV life cycle in inbred mice. This genetically humanized mouse model opens new opportunities to dissect genetically HCV infection in vivo and provides an important preclinical platform for testing and prioritizing drug candidates and may also have utility for evaluating vaccine efficacy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858853/" 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/PMC3858853/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Dorner, Marcus -- Horwitz, Joshua A -- Donovan, Bridget M -- Labitt, Rachael N -- Budell, William C -- Friling, Tamar -- Vogt, Alexander -- Catanese, Maria Teresa -- Satoh, Takashi -- Kawai, Taro -- Akira, Shizuo -- Law, Mansun -- Rice, Charles M -- Ploss, Alexander -- R01 AI072613/AI/NIAID NIH HHS/ -- R01 AI079031/AI/NIAID NIH HHS/ -- R01 AI099284/AI/NIAID NIH HHS/ -- R01 AI107301/AI/NIAID NIH HHS/ -- R01 CA057973/CA/NCI NIH HHS/ -- R01AI072613/AI/NIAID NIH HHS/ -- R01AI079031/AI/NIAID NIH HHS/ -- R01AI099284/AI/NIAID NIH HHS/ -- R01CA057973/CA/NCI NIH HHS/ -- RC1 DK087193/DK/NIDDK NIH HHS/ -- RC1DK087193/DK/NIDDK NIH HHS/ -- England -- Nature. 2013 Sep 12;501(7466):237-41. doi: 10.1038/nature12427. Epub 2013 Jul 31.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23903655" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD81/genetics/metabolism ; Cell Line ; Cyclophilin A/genetics/metabolism ; *Disease Models, Animal ; *Genetic Engineering ; Hepacivirus/immunology/*physiology ; Hepatitis C/*genetics/immunology/*virology ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Occludin/genetics/metabolism ; STAT1 Transcription Factor/deficiency ; Viremia/virology ; Virion/growth & development/physiology ; *Virus Replication
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 5
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    Rapid modelling of cooperating genetic events in cancer through somatic genome editing (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-10-23
    Description: Cancer is a multistep process that involves mutations and other alterations in oncogenes and tumour suppressor genes. Genome sequencing studies have identified a large collection of genetic alterations that occur in human cancers. However, the determination of which mutations are causally related to tumorigenesis remains a major challenge. Here we describe a novel CRISPR/Cas9-based approach for rapid functional investigation of candidate genes in well-established autochthonous mouse models of cancer. Using a Kras(G12D)-driven lung cancer model, we performed functional characterization of a panel of tumour suppressor genes with known loss-of-function alterations in human lung cancer. Cre-dependent somatic activation of oncogenic Kras(G12D) combined with CRISPR/Cas9-mediated genome editing of tumour suppressor genes resulted in lung adenocarcinomas with distinct histopathological and molecular features. This rapid somatic genome engineering approach enables functional characterization of putative cancer genes in the lung and other tissues using autochthonous mouse models. We anticipate that this approach can be used to systematically dissect the complex catalogue of mutations identified in cancer genome sequencing studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292871/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4292871/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanchez-Rivera, Francisco J -- Papagiannakopoulos, Thales -- Romero, Rodrigo -- Tammela, Tuomas -- Bauer, Matthew R -- Bhutkar, Arjun -- Joshi, Nikhil S -- Subbaraj, Lakshmipriya -- Bronson, Roderick T -- Xue, Wen -- Jacks, Tyler -- K99 CA169512/CA/NCI NIH HHS/ -- P30 CA014051/CA/NCI NIH HHS/ -- P30-CA14051/CA/NCI NIH HHS/ -- R00 CA169512/CA/NCI NIH HHS/ -- T32 GM007287/GM/NIGMS NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2014 Dec 18;516(7531):428-31. doi: 10.1038/nature13906. Epub 2014 Oct 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA. ; 1] Tufts University, Boston, Massachusetts 02115, USA [2] Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [2] Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA [3] Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25337879" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/*genetics/pathology ; Animals ; *Caspase 9 ; *Clustered Regularly Interspaced Short Palindromic Repeats ; Disease Models, Animal ; Genes, Tumor Suppressor ; *Genetic Engineering ; Genome/*genetics ; Humans ; Lentivirus/genetics ; Lung Neoplasms/*genetics/pathology ; Mice ; Mice, Inbred C57BL ; Models, Genetic ; Mutation/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 6
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    Regulation of circadian behaviour and metabolism by synthetic REV-ERB agonists (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-03-31
    Description: Synchronizing rhythms of behaviour and metabolic processes is important for cardiovascular health and preventing metabolic diseases. The nuclear receptors REV-ERB-alpha and REV-ERB-beta have an integral role in regulating the expression of core clock proteins driving rhythms in activity and metabolism. Here we describe the identification of potent synthetic REV-ERB agonists with in vivo activity. Administration of synthetic REV-ERB ligands alters circadian behaviour and the circadian pattern of core clock gene expression in the hypothalami of mice. The circadian pattern of expression of an array of metabolic genes in the liver, skeletal muscle and adipose tissue was also altered, resulting in increased energy expenditure. Treatment of diet-induced obese mice with a REV-ERB agonist decreased obesity by reducing fat mass and markedly improving dyslipidaemia and hyperglycaemia. These results indicate that synthetic REV-ERB ligands that pharmacologically target the circadian rhythm may be beneficial in the treatment of sleep disorders as well as metabolic diseases.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3343186/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Solt, Laura A -- Wang, Yongjun -- Banerjee, Subhashis -- Hughes, Travis -- Kojetin, Douglas J -- Lundasen, Thomas -- Shin, Youseung -- Liu, Jin -- Cameron, Michael D -- Noel, Romain -- Yoo, Seung-Hee -- Takahashi, Joseph S -- Butler, Andrew A -- Kamenecka, Theodore M -- Burris, Thomas P -- DK080201/DK/NIDDK NIH HHS/ -- DK088499/DK/NIDDK NIH HHS/ -- DK089984/DK/NIDDK NIH HHS/ -- MH092769/MH/NIMH NIH HHS/ -- R01 DK073189/DK/NIDDK NIH HHS/ -- R01 DK080201/DK/NIDDK NIH HHS/ -- R01 DK080201-05/DK/NIDDK NIH HHS/ -- R01 MH092769/MH/NIMH NIH HHS/ -- R01 MH092769-02/MH/NIMH NIH HHS/ -- R01 MH093429/MH/NIMH NIH HHS/ -- R01 MH093429-01A1/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Mar 29;485(7396):62-8. doi: 10.1038/nature11030.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, Florida 33458, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22460951" target="_blank"〉PubMed〈/a〉
    Keywords: Adipose Tissue/drug effects/metabolism ; Animals ; Biological Clocks/drug effects/genetics/physiology ; Circadian Rhythm/*drug effects/genetics/*physiology ; Disease Models, Animal ; Energy Metabolism/*drug effects ; HEK293 Cells ; Humans ; Hypothalamus/drug effects/metabolism ; Liver/drug effects/metabolism ; Metabolome/drug effects ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Muscle, Skeletal/drug effects/metabolism ; Nuclear Receptor Subfamily 1, Group D, Member 1/*antagonists & ; inhibitors/metabolism ; Obesity/chemically induced/drug therapy/metabolism ; Pyrrolidines/*pharmacology ; Receptors, Cytoplasmic and Nuclear/*antagonists & inhibitors/metabolism ; Repressor Proteins/*antagonists & inhibitors/metabolism ; Thiophenes/*pharmacology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 7
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    Compensatory dendritic cell development mediated by BATF-IRF interactions (2012)
    Nature Publishing Group (NPG)
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    Publication Date: 2012-09-21
    Description: The AP1 transcription factor Batf3 is required for homeostatic development of CD8alpha(+) classical dendritic cells that prime CD8 T-cell responses against intracellular pathogens. Here we identify an alternative, Batf3-independent pathway in mice for CD8alpha(+) dendritic cell development operating during infection with intracellular pathogens and mediated by the cytokines interleukin (IL)-12 and interferon-gamma. This alternative pathway results from molecular compensation for Batf3 provided by the related AP1 factors Batf, which also functions in T and B cells, and Batf2 induced by cytokines in response to infection. Reciprocally, physiological compensation between Batf and Batf3 also occurs in T cells for expression of IL-10 and CTLA4. Compensation among BATF factors is based on the shared capacity of their leucine zipper domains to interact with non-AP1 factors such as IRF4 and IRF8 to mediate cooperative gene activation. Conceivably, manipulating this alternative pathway of dendritic cell development could be of value in augmenting immune responses to vaccines.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3482832/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tussiwand, Roxane -- Lee, Wan-Ling -- Murphy, Theresa L -- Mashayekhi, Mona -- KC, Wumesh -- Albring, Jorn C -- Satpathy, Ansuman T -- Rotondo, Jeffrey A -- Edelson, Brian T -- Kretzer, Nicole M -- Wu, Xiaodi -- Weiss, Leslie A -- Glasmacher, Elke -- Li, Peng -- Liao, Wei -- Behnke, Michael -- Lam, Samuel S K -- Aurthur, Cora T -- Leonard, Warren J -- Singh, Harinder -- Stallings, Christina L -- Sibley, L David -- Schreiber, Robert D -- Murphy, Kenneth M -- AI076427-02/AI/NIAID NIH HHS/ -- P30 CA91842/CA/NCI NIH HHS/ -- R01 AI036629/AI/NIAID NIH HHS/ -- R01 AI076427/AI/NIAID NIH HHS/ -- R01 CA043059/CA/NCI NIH HHS/ -- T32 AI007163/AI/NIAID NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Oct 25;490(7421):502-7. doi: 10.1038/nature11531. Epub 2012 Sep 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22992524" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigen Presentation ; Antigens, CD/metabolism ; Antigens, CD8/immunology/metabolism ; Basic-Leucine Zipper Transcription ; Factors/chemistry/deficiency/genetics/*metabolism ; CD4-Positive T-Lymphocytes/cytology/immunology ; CTLA-4 Antigen/metabolism ; Cell Differentiation ; Cell Line, Tumor ; Cell Lineage ; Dendritic Cells/*cytology/immunology/*metabolism ; Female ; Fibrosarcoma/immunology/metabolism/pathology ; Gene Expression Regulation ; Integrin alpha Chains/metabolism ; Interferon Regulatory Factors/deficiency/genetics/*metabolism ; Interleukin-10/metabolism ; Interleukin-12/immunology/metabolism ; Leucine Zippers ; Male ; Mice ; Mice, Inbred C57BL ; Neoplasm Transplantation ; Oncogene Protein p65(gag-jun)/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Repressor Proteins/deficiency/genetics ; T-Lymphocytes, Helper-Inducer/cytology/immunology/metabolism ; Toxoplasma/immunology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    Pretreatment mitochondrial priming correlates with clinical response to cytotoxic chemotherapy (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-10-29
    Description: Cytotoxic chemotherapy targets elements common to all nucleated human cells, such as DNA and microtubules, yet it selectively kills tumor cells. Here we show that clinical response to these drugs correlates with, and may be partially governed by, the pretreatment proximity of tumor cell mitochondria to the apoptotic threshold, a property called mitochondrial priming. We used BH3 profiling to measure priming in tumor cells from patients with multiple myeloma, acute myelogenous and lymphoblastic leukemia, and ovarian cancer. This assay measures mitochondrial response to peptides derived from proapoptotic BH3 domains of proteins critical for death signaling to mitochondria. Patients with highly primed cancers exhibited superior clinical response to chemotherapy. In contrast, chemoresistant cancers and normal tissues were poorly primed. Manipulation of mitochondrial priming might enhance the efficacy of cytotoxic agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280949/" 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/PMC3280949/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ni Chonghaile, Triona -- Sarosiek, Kristopher A -- Vo, Thanh-Trang -- Ryan, Jeremy A -- Tammareddi, Anupama -- Moore, Victoria Del Gaizo -- Deng, Jing -- Anderson, Kenneth C -- Richardson, Paul -- Tai, Yu-Tzu -- Mitsiades, Constantine S -- Matulonis, Ursula A -- Drapkin, Ronny -- Stone, Richard -- Deangelo, Daniel J -- McConkey, David J -- Sallan, Stephen E -- Silverman, Lewis -- Hirsch, Michelle S -- Carrasco, Daniel Ruben -- Letai, Anthony -- P01CA068484/CA/NCI NIH HHS/ -- P01CA139980/CA/NCI NIH HHS/ -- R01 CA129974/CA/NCI NIH HHS/ -- R01 CA129974-05/CA/NCI NIH HHS/ -- R01CA129974/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2011 Nov 25;334(6059):1129-33. doi: 10.1126/science.1206727. Epub 2011 Oct 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22033517" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Animals ; Antineoplastic Agents/*therapeutic use ; *Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Child ; Disease-Free Survival ; Drug Resistance, Neoplasm ; Female ; Humans ; Leukemia, Myeloid, Acute/drug therapy/physiopathology ; Male ; Membrane Potential, Mitochondrial ; Mice ; Mice, Inbred C57BL ; Middle Aged ; Mitochondria/*physiology ; Multiple Myeloma/drug therapy/physiopathology ; Neoplasms/*drug therapy/*physiopathology ; Ovarian Neoplasms/drug therapy/physiopathology ; Peptide Fragments/metabolism ; Permeability ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/physiopathology ; Proto-Oncogene Proteins c-bcl-2/chemistry/metabolism ; Remission Induction ; Signal Transduction
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
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    Regulation of myeloid leukaemia by the cell-fate determinant Musashi (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-07-20
    Description: Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918284/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ito, Takahiro -- Kwon, Hyog Young -- Zimdahl, Bryan -- Congdon, Kendra L -- Blum, Jordan -- Lento, William E -- Zhao, Chen -- Lagoo, Anand -- Gerrard, Gareth -- Foroni, Letizia -- Goldman, John -- Goh, Harriet -- Kim, Soo-Hyun -- Kim, Dong-Wook -- Chuah, Charles -- Oehler, Vivian G -- Radich, Jerald P -- Jordan, Craig T -- Reya, Tannishtha -- AI067798/AI/NIAID NIH HHS/ -- CA122206/CA/NCI NIH HHS/ -- CA140371/CA/NCI NIH HHS/ -- CA18029/CA/NCI NIH HHS/ -- DK072234/DK/NIDDK NIH HHS/ -- DK63031/DK/NIDDK NIH HHS/ -- DP1 CA174422/CA/NCI NIH HHS/ -- DP1 OD006430/OD/NIH HHS/ -- DP1 OD006430-01/OD/NIH HHS/ -- DP1 OD006430-02/OD/NIH HHS/ -- DP1OD006430/OD/NIH HHS/ -- HL097767/HL/NHLBI NIH HHS/ -- P01 CA018029/CA/NCI NIH HHS/ -- R01 CA140371/CA/NCI NIH HHS/ -- R01 DK063031/DK/NIDDK NIH HHS/ -- R01 DK063031-01/DK/NIDDK NIH HHS/ -- R01 DK063031-01S1/DK/NIDDK NIH HHS/ -- R01 DK063031-02/DK/NIDDK NIH HHS/ -- R01 DK063031-03/DK/NIDDK NIH HHS/ -- R01 DK063031-04/DK/NIDDK NIH HHS/ -- R01 DK063031-05/DK/NIDDK NIH HHS/ -- R01 DK063031-06/DK/NIDDK NIH HHS/ -- R01 DK063031-07/DK/NIDDK NIH HHS/ -- R01 DK063031-07S1/DK/NIDDK NIH HHS/ -- R01 DK063031-08/DK/NIDDK NIH HHS/ -- R01 DK072234/DK/NIDDK NIH HHS/ -- R01 DK072234-01A1/DK/NIDDK NIH HHS/ -- R01 DK072234-02/DK/NIDDK NIH HHS/ -- R01 DK072234-03/DK/NIDDK NIH HHS/ -- R01 DK072234-04/DK/NIDDK NIH HHS/ -- R01 HL097767/HL/NHLBI NIH HHS/ -- R01 HL097767-01/HL/NHLBI NIH HHS/ -- R01 HL097767-02/HL/NHLBI NIH HHS/ -- T32 GM007184-33/GM/NIGMS NIH HHS/ -- U19 AI067798/AI/NIAID NIH HHS/ -- U19 AI067798-010006/AI/NIAID NIH HHS/ -- U19 AI067798-020006/AI/NIAID NIH HHS/ -- U19 AI067798-030006/AI/NIAID NIH HHS/ -- U19 AI067798-040006/AI/NIAID NIH HHS/ -- U19 AI067798-050006/AI/NIAID NIH HHS/ -- England -- Nature. 2010 Aug 5;466(7307):765-8. doi: 10.1038/nature09171. Epub 2010 Jul 18.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20639863" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Blast Crisis/genetics/metabolism/pathology ; *Cell Differentiation/genetics ; Disease Progression ; Fusion Proteins, bcr-abl/genetics/metabolism ; Gene Expression Regulation, Neoplastic ; Homeodomain Proteins/genetics/metabolism ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics/*metabolism/*pathology ; Membrane Proteins/biosynthesis/genetics/metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/biosynthesis/genetics/metabolism ; Nuclear Pore Complex Proteins/genetics/metabolism ; Oncogene Proteins, Fusion/genetics/metabolism ; Prognosis ; RNA-Binding Proteins/biosynthesis/genetics/*metabolism ; Receptor, Notch1/metabolism ; Signal Transduction ; Tumor Suppressor Protein p53/metabolism ; Up-Regulation
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 10
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    Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-01-19
    Description: Influenza A virus, being responsible for seasonal epidemics and reoccurring pandemics, represents a worldwide threat to public health. High mutation rates facilitate the generation of viral escape mutants, rendering vaccines and drugs directed against virus-encoded targets potentially ineffective. In contrast, targeting host cell determinants temporarily dispensable for the host but crucial for virus replication could prevent viral escape. Here we report the discovery of 287 human host cell genes influencing influenza A virus replication in a genome-wide RNA interference (RNAi) screen. Using an independent assay we confirmed 168 hits (59%) inhibiting either the endemic H1N1 (119 hits) or the current pandemic swine-origin (121 hits) influenza A virus strains, with an overlap of 60%. Notably, a subset of these common hits was also essential for replication of a highly pathogenic avian H5N1 strain. In-depth analyses of several factors provided insights into their infection stage relevance. Notably, SON DNA binding protein (SON) was found to be important for normal trafficking of influenza virions to late endosomes early in infection. We also show that a small molecule inhibitor of CDC-like kinase 1 (CLK1) reduces influenza virus replication by more than two orders of magnitude, an effect connected with impaired splicing of the viral M2 messenger RNA. Furthermore, influenza-virus-infected p27(-/-) (cyclin-dependent kinase inhibitor 1B; Cdkn1b) mice accumulated significantly lower viral titres in the lung, providing in vivo evidence for the importance of this gene. Thus, our results highlight the potency of genome-wide RNAi screening for the dissection of virus-host interactions and the identification of drug targets for a broad range of influenza viruses.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Karlas, Alexander -- Machuy, Nikolaus -- Shin, Yujin -- Pleissner, Klaus-Peter -- Artarini, Anita -- Heuer, Dagmar -- Becker, Daniel -- Khalil, Hany -- Ogilvie, Lesley A -- Hess, Simone -- Maurer, Andre P -- Muller, Elke -- Wolff, Thorsten -- Rudel, Thomas -- Meyer, Thomas F -- England -- Nature. 2010 Feb 11;463(7282):818-22. doi: 10.1038/nature08760. Epub 2010 Jan 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Molecular Biology Department, Max Planck Institute for Infection Biology, Chariteplatz 1, 10117 Berlin, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20081832" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; *Biological Factors/genetics/metabolism ; Cell Line ; Cells, Cultured ; Chick Embryo ; Cyclin-Dependent Kinase Inhibitor p27/deficiency/genetics/metabolism ; Epithelial Cells/virology ; Genome, Human/genetics ; *Host-Pathogen Interactions/genetics/physiology ; Humans ; Influenza A Virus, H1N1 Subtype/classification/*growth & development ; Influenza, Human/*genetics/*virology ; Lung/cytology ; Mice ; Mice, Inbred C57BL ; Protein-Serine-Threonine Kinases/genetics ; Protein-Tyrosine Kinases/genetics ; *RNA Interference ; Virus Replication/*physiology
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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