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  • 1
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    In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-08-13
    Description: Influenza A viruses cause recurrent outbreaks at local or global scale with potentially severe consequences for human health and the global economy. Recently, a new strain of influenza A virus was detected that causes disease in and transmits among humans, probably owing to little or no pre-existing immunity to the new strain. On 11 June 2009 the World Health Organization declared that the infections caused by the new strain had reached pandemic proportion. Characterized as an influenza A virus of the H1N1 subtype, the genomic segments of the new strain were most closely related to swine viruses. Most human infections with swine-origin H1N1 influenza viruses (S-OIVs) seem to be mild; however, a substantial number of hospitalized individuals do not have underlying health issues, attesting to the pathogenic potential of S-OIVs. To achieve a better assessment of the risk posed by the new virus, we characterized one of the first US S-OIV isolates, A/California/04/09 (H1N1; hereafter referred to as CA04), as well as several other S-OIV isolates, in vitro and in vivo. In mice and ferrets, CA04 and other S-OIV isolates tested replicate more efficiently than a currently circulating human H1N1 virus. In addition, CA04 replicates efficiently in non-human primates, causes more severe pathological lesions in the lungs of infected mice, ferrets and non-human primates than a currently circulating human H1N1 virus, and transmits among ferrets. In specific-pathogen-free miniature pigs, CA04 replicates without clinical symptoms. The assessment of human sera from different age groups suggests that infection with human H1N1 viruses antigenically closely related to viruses circulating in 1918 confers neutralizing antibody activity to CA04. Finally, we show that CA04 is sensitive to approved and experimental antiviral drugs, suggesting that these compounds could function as a first line of defence against the recently declared S-OIV pandemic.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2748827/" 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/PMC2748827/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Itoh, Yasushi -- Shinya, Kyoko -- Kiso, Maki -- Watanabe, Tokiko -- Sakoda, Yoshihiro -- Hatta, Masato -- Muramoto, Yukiko -- Tamura, Daisuke -- Sakai-Tagawa, Yuko -- Noda, Takeshi -- Sakabe, Saori -- Imai, Masaki -- Hatta, Yasuko -- Watanabe, Shinji -- Li, Chengjun -- Yamada, Shinya -- Fujii, Ken -- Murakami, Shin -- Imai, Hirotaka -- Kakugawa, Satoshi -- Ito, Mutsumi -- Takano, Ryo -- Iwatsuki-Horimoto, Kiyoko -- Shimojima, Masayuki -- Horimoto, Taisuke -- Goto, Hideo -- Takahashi, Kei -- Makino, Akiko -- Ishigaki, Hirohito -- Nakayama, Misako -- Okamatsu, Masatoshi -- Takahashi, Kazuo -- Warshauer, David -- Shult, Peter A -- Saito, Reiko -- Suzuki, Hiroshi -- Furuta, Yousuke -- Yamashita, Makoto -- Mitamura, Keiko -- Nakano, Kunio -- Nakamura, Morio -- Brockman-Schneider, Rebecca -- Mitamura, Hiroshi -- Yamazaki, Masahiko -- Sugaya, Norio -- Suresh, M -- Ozawa, Makoto -- Neumann, Gabriele -- Gern, James -- Kida, Hiroshi -- Ogasawara, Kazumasa -- Kawaoka, Yoshihiro -- HHNSN266200700010C/NS/NINDS NIH HHS/ -- HHSN266200700010C/PHS HHS/ -- HHSN272200800060C/AI/NIAID NIH HHS/ -- R01 AI069274/AI/NIAID NIH HHS/ -- R01 AI069274-04/AI/NIAID NIH HHS/ -- U19 AI070503/AI/NIAID NIH HHS/ -- England -- Nature. 2009 Aug 20;460(7258):1021-5. doi: 10.1038/nature08260.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology, Shiga University of Medical Science, Ohtsu, Shiga 520-2192, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19672242" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antibodies, Viral/immunology ; Antiviral Agents/pharmacology ; Cell Line ; Dogs ; Female ; Ferrets/virology ; HN Protein/metabolism ; Humans ; Influenza A Virus, H1N1 Subtype/drug effects/enzymology/pathogenicity/*physiology ; Lung/immunology/pathology/virology ; Macaca fascicularis/immunology/virology ; Male ; Mice ; Mice, Inbred BALB C ; Neutralization Tests ; Orthomyxoviridae Infections/immunology/transmission/virology ; Primate Diseases/pathology/virology ; Swine/*virology ; Swine Diseases/pathology/virology ; Swine, Miniature/virology ; 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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  • 2
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    Cohesin mediates transcriptional insulation by CCCTC-binding factor (2008)
    Nature Publishing Group (NPG)
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    Publication Date: 2008-02-01
    Description: Cohesin complexes mediate sister-chromatid cohesion in dividing cells but may also contribute to gene regulation in postmitotic cells. How cohesin regulates gene expression is not known. Here we describe cohesin-binding sites in the human genome and show that most of these are associated with the CCCTC-binding factor (CTCF), a zinc-finger protein required for transcriptional insulation. CTCF is dispensable for cohesin loading onto DNA, but is needed to enrich cohesin at specific binding sites. Cohesin enables CTCF to insulate promoters from distant enhancers and controls transcription at the H19/IGF2 (insulin-like growth factor 2) locus. This role of cohesin seems to be independent of its role in cohesion. We propose that cohesin functions as a transcriptional insulator, and speculate that subtle deficiencies in this function contribute to 'cohesinopathies' such as Cornelia de Lange syndrome.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wendt, Kerstin S -- Yoshida, Keisuke -- Itoh, Takehiko -- Bando, Masashige -- Koch, Birgit -- Schirghuber, Erika -- Tsutsumi, Shuichi -- Nagae, Genta -- Ishihara, Ko -- Mishiro, Tsuyoshi -- Yahata, Kazuhide -- Imamoto, Fumio -- Aburatani, Hiroyuki -- Nakao, Mitsuyoshi -- Imamoto, Naoko -- Maeshima, Kazuhiro -- Shirahige, Katsuhiko -- Peters, Jan-Michael -- England -- Nature. 2008 Feb 14;451(7180):796-801. doi: 10.1038/nature06634. Epub 2008 Jan 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Research Institute of Molecular Pathology, Dr. Bohr Gasse 7, 1030 Vienna, Austria.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18235444" target="_blank"〉PubMed〈/a〉
    Keywords: Alleles ; Animals ; Brain/cytology/metabolism ; Cell Cycle Proteins/*metabolism ; Cell Differentiation ; Chromosomal Proteins, Non-Histone/*metabolism ; Consensus Sequence/genetics ; DNA/genetics/metabolism ; DNA-Binding Proteins/*metabolism ; Enhancer Elements, Genetic/genetics ; Female ; Gene Expression Regulation/*genetics ; Genome, Human/genetics ; HeLa Cells ; Humans ; Insulin-Like Growth Factor II/genetics ; Mice ; Mitosis ; Mothers ; Nuclear Proteins/*metabolism ; Promoter Regions, Genetic/genetics ; RNA, Long Noncoding ; RNA, Untranslated/genetics ; Repressor Proteins/*metabolism ; Transcription, Genetic/*genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
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    Response and resistance to MEK inhibition in leukaemias initiated by hyperactive Ras (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-09-04
    Description: The cascade comprising Raf, mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) is a therapeutic target in human cancers with deregulated Ras signalling, which includes tumours that have inactivated the Nf1 tumour suppressor. Nf1 encodes neurofibromin, a GTPase-activating protein that terminates Ras signalling by stimulating hydrolysis of Ras-GTP. We compared the effects of inhibitors of MEK in a myeloproliferative disorder (MPD) initiated by inactivating Nf1 in mouse bone marrow and in acute myeloid leukaemias (AMLs) in which cooperating mutations were induced by retroviral insertional mutagenesis. Here we show that MEK inhibitors are ineffective in MPD, but induce objective regression of many Nf1-deficient AMLs. Drug resistance developed because of outgrowth of AML clones that were present before treatment. We cloned clone-specific retroviral integrations to identify candidate resistance genes including Rasgrp1, Rasgrp4 and Mapk14, which encodes p38alpha. Functional analysis implicated increased RasGRP1 levels and reduced p38 kinase activity in resistance to MEK inhibitors. This approach represents a robust strategy for identifying genes and pathways that modulate how primary cancer cells respond to targeted therapeutics and for probing mechanisms of de novo and acquired resistance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119783/" 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/PMC4119783/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Lauchle, Jennifer O -- Kim, Doris -- Le, Doan T -- Akagi, Keiko -- Crone, Michael -- Krisman, Kimberly -- Warner, Kegan -- Bonifas, Jeannette M -- Li, Qing -- Coakley, Kristen M -- Diaz-Flores, Ernesto -- Gorman, Matthew -- Przybranowski, Sally -- Tran, Mary -- Kogan, Scott C -- Roose, Jeroen P -- Copeland, Neal G -- Jenkins, Nancy A -- Parada, Luis -- Wolff, Linda -- Sebolt-Leopold, Judith -- Shannon, Kevin -- K08 CA119105/CA/NCI NIH HHS/ -- K08 CA119105-01A1/CA/NCI NIH HHS/ -- K08 CA119105-02/CA/NCI NIH HHS/ -- K08 CA119105-03/CA/NCI NIH HHS/ -- K08 CA119105-04/CA/NCI NIH HHS/ -- R37 CA072614/CA/NCI NIH HHS/ -- R37 CA072614-11/CA/NCI NIH HHS/ -- R37 CA072614-12/CA/NCI NIH HHS/ -- R37 CA072614-13/CA/NCI NIH HHS/ -- R37 CA72614/CA/NCI NIH HHS/ -- T32 CA09043/CA/NCI NIH HHS/ -- T32HD044331/HD/NICHD NIH HHS/ -- U01 CA084221/CA/NCI NIH HHS/ -- U01 CA084221-06/CA/NCI NIH HHS/ -- U01 CA084221-07/CA/NCI NIH HHS/ -- U01 CA084221-08/CA/NCI NIH HHS/ -- U01 CA084221-09/CA/NCI NIH HHS/ -- U01 CA084221-10/CA/NCI NIH HHS/ -- U01 CA84221/CA/NCI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2009 Sep 17;461(7262):411-4. doi: 10.1038/nature08279. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pediatrics, 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/19727076" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Benzamides/pharmacology ; *Drug Resistance, Neoplasm/drug effects/genetics ; Genes, ras ; Guanine Nucleotide Exchange Factors/genetics/metabolism ; Leukemia, Myeloid, Acute/*drug therapy/enzymology/genetics/*metabolism ; Mice ; Mitogen-Activated Protein Kinase 14/genetics/metabolism ; Mitogen-Activated Protein Kinase Kinases/*antagonists & inhibitors/metabolism ; ras Proteins/genetics/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
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    Uptake through glycoprotein 2 of FimH(+) bacteria by M cells initiates mucosal immune response (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-11-13
    Description: The mucosal immune system forms the largest part of the entire immune system, containing about three-quarters of all lymphocytes and producing grams of secretory IgA daily to protect the mucosal surface from pathogens. To evoke the mucosal immune response, antigens on the mucosal surface must be transported across the epithelial barrier into organized lymphoid structures such as Peyer's patches. This function, called antigen transcytosis, is mediated by specialized epithelial M cells. The molecular mechanisms promoting this antigen uptake, however, are largely unknown. Here we report that glycoprotein 2 (GP2), specifically expressed on the apical plasma membrane of M cells among enterocytes, serves as a transcytotic receptor for mucosal antigens. Recombinant GP2 protein selectively bound a subset of commensal and pathogenic enterobacteria, including Escherichia coli and Salmonella enterica serovar Typhimurium (S. Typhimurium), by recognizing FimH, a component of type I pili on the bacterial outer membrane. Consistently, these bacteria were colocalized with endogenous GP2 on the apical plasma membrane as well as in cytoplasmic vesicles in M cells. Moreover, deficiency of bacterial FimH or host GP2 led to defects in transcytosis of type-I-piliated bacteria through M cells, resulting in an attenuation of antigen-specific immune responses in Peyer's patches. GP2 is therefore a previously unrecognized transcytotic receptor on M cells for type-I-piliated bacteria and is a prerequisite for the mucosal immune response to these bacteria. Given that M cells are considered a promising target for oral vaccination against various infectious diseases, the GP2-dependent transcytotic pathway could provide a new target for the development of M-cell-targeted mucosal vaccines.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Hase, Koji -- Kawano, Kazuya -- Nochi, Tomonori -- Pontes, Gemilson Soares -- Fukuda, Shinji -- Ebisawa, Masashi -- Kadokura, Kazunori -- Tobe, Toru -- Fujimura, Yumiko -- Kawano, Sayaka -- Yabashi, Atsuko -- Waguri, Satoshi -- Nakato, Gaku -- Kimura, Shunsuke -- Murakami, Takaya -- Iimura, Mitsutoshi -- Hamura, Kimiyo -- Fukuoka, Shin-Ichi -- Lowe, Anson W -- Itoh, Kikuji -- Kiyono, Hiroshi -- Ohno, Hiroshi -- DK43294/DK/NIDDK NIH HHS/ -- DK56339/DK/NIDDK NIH HHS/ -- England -- Nature. 2009 Nov 12;462(7270):226-30. doi: 10.1038/nature08529.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Epithelial Immunobiology, Research Center for Allergy and Immunology, RIKEN, Kanagawa 230-0045, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19907495" target="_blank"〉PubMed〈/a〉
    Keywords: Adhesins, Escherichia coli/genetics/immunology/*metabolism ; Animals ; Antigens, Bacterial/genetics/immunology/*metabolism ; Cell Line ; Epithelial Cells/*immunology/metabolism ; Escherichia coli/immunology/metabolism ; Fimbriae Proteins/genetics/immunology/*metabolism ; GPI-Linked Proteins ; Glycoproteins ; HeLa Cells ; Humans ; Immunity, Mucosal/*immunology ; Intestines/cytology ; Membrane Glycoproteins/*metabolism ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Peyer's Patches/*cytology/immunology ; Salmonella typhimurium/genetics/immunology/metabolism ; Substrate Specificity
    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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    Alpha-synuclein blocks ER-Golgi traffic and Rab1 rescues neuron loss in Parkinson's models (2006)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2006-06-24
    Description: Alpha-synuclein (alphaSyn) misfolding is associated with several devastating neurodegenerative disorders, including Parkinson's disease (PD). In yeast cells and in neurons alphaSyn accumulation is cytotoxic, but little is known about its normal function or pathobiology. The earliest defect following alphaSyn expression in yeast was a block in endoplasmic reticulum (ER)-to-Golgi vesicular trafficking. In a genomewide screen, the largest class of toxicity modifiers were proteins functioning at this same step, including the Rab guanosine triphosphatase Ypt1p, which associated with cytoplasmic alphaSyn inclusions. Elevated expression of Rab1, the mammalian YPT1 homolog, protected against alphaSyn-induced dopaminergic neuron loss in animal models of PD. Thus, synucleinopathies may result from disruptions in basic cellular functions that interface with the unique biology of particular neurons to make them especially vulnerable.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1983366/" 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/PMC1983366/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cooper, Antony A -- Gitler, Aaron D -- Cashikar, Anil -- Haynes, Cole M -- Hill, Kathryn J -- Bhullar, Bhupinder -- Liu, Kangning -- Xu, Kexiang -- Strathearn, Katherine E -- Liu, Fang -- Cao, Songsong -- Caldwell, Kim A -- Caldwell, Guy A -- Marsischky, Gerald -- Kolodner, Richard D -- Labaer, Joshua -- Rochet, Jean-Christophe -- Bonini, Nancy M -- Lindquist, Susan -- P50 NS038372/NS/NINDS NIH HHS/ -- R01-HG002923/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2006 Jul 21;313(5785):324-8. Epub 2006 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉School of Biological Sciences, University of Missouri-Kansas City, Kansas City, MO 64110, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16794039" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Genetically Modified ; Caenorhabditis elegans ; Cell Survival ; Cells, Cultured ; Disease Models, Animal ; Dopamine/physiology ; Drosophila ; Endoplasmic Reticulum/*metabolism ; Gene Expression ; Gene Library ; Golgi Apparatus/*metabolism ; Humans ; Mice ; Nerve Degeneration ; Neurons/cytology/*physiology ; Parkinsonian Disorders/metabolism/pathology/*physiopathology ; Proteasome Endopeptidase Complex/metabolism ; Protein Folding ; *Protein Transport ; Proteins/chemistry/metabolism ; Rats ; Recombinant Fusion Proteins/metabolism ; Saccharomyces cerevisiae/genetics/metabolism ; Saccharomyces cerevisiae Proteins/genetics/metabolism ; alpha-Synuclein/chemistry/genetics/*metabolism ; rab GTP-Binding Proteins/genetics/metabolism ; rab1 GTP-Binding Proteins/genetics/*metabolism
    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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  • 6
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    alpha-Klotho as a regulator of calcium homeostasis (2007)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2007-06-16
    Description: alpha-klotho was identified as a gene associated with premature aging-like phenotypes characterized by short lifespan. In mice, we found the molecular association of alpha-Klotho (alpha-Kl) and Na+,K+-adenosine triphosphatase (Na+,K+-ATPase) and provide evidence for an increase of abundance of Na+,K+-ATPase at the plasma membrane. Low concentrations of extracellular free calcium ([Ca2+]e) rapidly induce regulated parathyroid hormone (PTH) secretion in an alpha-Kl- and Na+,K+-ATPase-dependent manner. The increased Na+ gradient created by Na+,K+-ATPase activity might drive the transepithelial transport of Ca2+ in cooperation with ion channels and transporters in the choroid plexus and the kidney. Our findings reveal fundamental roles of alpha-Kl in the regulation of calcium metabolism.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Imura, Akihiro -- Tsuji, Yoshihito -- Murata, Miyahiko -- Maeda, Ryota -- Kubota, Koji -- Iwano, Akiko -- Obuse, Chikashi -- Togashi, Kazuya -- Tominaga, Makoto -- Kita, Naoko -- Tomiyama, Ken-ichi -- Iijima, Junko -- Nabeshima, Yoko -- Fujioka, Makio -- Asato, Ryo -- Tanaka, Shinzo -- Kojima, Ken -- Ito, Juichi -- Nozaki, Kazuhiko -- Hashimoto, Nobuo -- Ito, Tetsufumi -- Nishio, Takeshi -- Uchiyama, Takashi -- Fujimori, Toshihiko -- Nabeshima, Yo-ichi -- New York, N.Y. -- Science. 2007 Jun 15;316(5831):1615-8.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17569864" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Calcium/cerebrospinal fluid/*metabolism ; Cell Membrane/enzymology/metabolism ; Choroid Plexus/metabolism ; Cytoplasm/enzymology/metabolism ; Endoplasmic Reticulum/metabolism ; Endosomes/metabolism ; Enzyme Inhibitors/pharmacology ; Feedback, Physiological ; Glucuronidase/genetics/metabolism/*physiology ; Golgi Apparatus/metabolism ; HeLa Cells ; *Homeostasis ; Humans ; Ion Transport ; Kidney/enzymology/metabolism ; Mice ; Ouabain/pharmacology ; Parathyroid Glands/enzymology/metabolism ; Parathyroid Hormone/secretion ; Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
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  • 7
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    Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis (2008)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2008-02-02
    Description: Cathepsin K was originally identified as an osteoclast-specific lysosomal protease, the inhibitor of which has been considered might have therapeutic potential. We show that inhibition of cathepsin K could potently suppress autoimmune inflammation of the joints as well as osteoclastic bone resorption in autoimmune arthritis. Furthermore, cathepsin K-/- mice were resistant to experimental autoimmune encephalomyelitis. Pharmacological inhibition or targeted disruption of cathepsin K resulted in defective Toll-like receptor 9 signaling in dendritic cells in response to unmethylated CpG DNA, which in turn led to attenuated induction of T helper 17 cells, without affecting the antigen-presenting ability of dendritic cells. These results suggest that cathepsin K plays an important role in the immune system and may serve as a valid therapeutic target in autoimmune diseases.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Asagiri, Masataka -- Hirai, Toshitake -- Kunigami, Toshihiro -- Kamano, Shunya -- Gober, Hans-Jurgen -- Okamoto, Kazuo -- Nishikawa, Keizo -- Latz, Eicke -- Golenbock, Douglas T -- Aoki, Kazuhiro -- Ohya, Keiichi -- Imai, Yuuki -- Morishita, Yasuyuki -- Miyazono, Kohei -- Kato, Shigeaki -- Saftig, Paul -- Takayanagi, Hiroshi -- New York, N.Y. -- Science. 2008 Feb 1;319(5863):624-7. doi: 10.1126/science.1150110.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18239127" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD/metabolism ; Arthritis, Experimental/drug therapy/*immunology/*metabolism ; Autoimmune Diseases/drug therapy/immunology/*metabolism ; Bone Resorption ; Cathepsin K ; Cathepsins/antagonists & inhibitors/deficiency/*metabolism ; Cytokines/metabolism ; DNA/immunology/metabolism ; Dendritic Cells/drug effects/immunology ; Dinucleoside Phosphates/immunology/metabolism ; Encephalomyelitis, Autoimmune, Experimental/immunology/metabolism ; Endosomes/metabolism ; Freund's Adjuvant/immunology ; Lymphocyte Activation/drug effects ; Male ; Mice ; Osteoporosis/drug therapy ; Protease Inhibitors/pharmacology ; Rats ; *Signal Transduction ; T-Lymphocytes/drug effects/enzymology/immunology ; Toll-Like Receptor 9/*metabolism
    Print ISSN: 0036-8075
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    Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer (2009)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2009-05-23
    Description: Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2998180/" 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/PMC2998180/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Olive, Kenneth P -- Jacobetz, Michael A -- Davidson, Christian J -- Gopinathan, Aarthi -- McIntyre, Dominick -- Honess, Davina -- Madhu, Basetti -- Goldgraben, Mae A -- Caldwell, Meredith E -- Allard, David -- Frese, Kristopher K -- Denicola, Gina -- Feig, Christine -- Combs, Chelsea -- Winter, Stephen P -- Ireland-Zecchini, Heather -- Reichelt, Stefanie -- Howat, William J -- Chang, Alex -- Dhara, Mousumi -- Wang, Lifu -- Ruckert, Felix -- Grutzmann, Robert -- Pilarsky, Christian -- Izeradjene, Kamel -- Hingorani, Sunil R -- Huang, Pearl -- Davies, Susan E -- Plunkett, William -- Egorin, Merrill -- Hruban, Ralph H -- Whitebread, Nigel -- McGovern, Karen -- Adams, Julian -- Iacobuzio-Donahue, Christine -- Griffiths, John -- Tuveson, David A -- CA084291/CA/NCI NIH HHS/ -- CA101973/CA/NCI NIH HHS/ -- CA105490/CA/NCI NIH HHS/ -- CA111292/CA/NCI NIH HHS/ -- CA114028/CA/NCI NIH HHS/ -- CA15704/CA/NCI NIH HHS/ -- F32 CA123939/CA/NCI NIH HHS/ -- F32 CA123939-03X1/CA/NCI NIH HHS/ -- F32CA123887-01/CA/NCI NIH HHS/ -- F32CA123939-02/CA/NCI NIH HHS/ -- K08 CA106610/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2009 Jun 12;324(5933):1457-61. doi: 10.1126/science.1171362. Epub 2009 May 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK, Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 ORE, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19460966" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Agents/*administration & dosage/metabolism/therapeutic use ; *Antineoplastic Combined Chemotherapy Protocols ; Apoptosis/drug effects ; Carcinoma, Pancreatic Ductal/blood supply/*drug therapy/metabolism/pathology ; Cell Line, Tumor ; Cell Proliferation/drug effects ; Deoxycytidine/administration & dosage/*analogs & ; derivatives/metabolism/therapeutic use ; Disease Models, Animal ; Drug Resistance, Neoplasm ; Hedgehog Proteins/antagonists & inhibitors/*metabolism ; Humans ; Kruppel-Like Transcription Factors/metabolism ; Mice ; Neoplasm Transplantation ; Neovascularization, Pathologic ; Pancreatic Neoplasms/blood supply/*drug therapy/metabolism/pathology ; Receptors, G-Protein-Coupled/antagonists & inhibitors/metabolism ; Signal Transduction/drug effects ; Stromal Cells/drug effects/pathology ; Veratrum Alkaloids/*administration & dosage/pharmacokinetics/therapeutic use
    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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    Sequence- and target-independent angiogenesis suppression by siRNA via TLR3 (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-28
    Description: Clinical trials of small interfering RNA (siRNA) targeting vascular endothelial growth factor-A (VEGFA) or its receptor VEGFR1 (also called FLT1), in patients with blinding choroidal neovascularization (CNV) from age-related macular degeneration, are premised on gene silencing by means of intracellular RNA interference (RNAi). We show instead that CNV inhibition is a siRNA-class effect: 21-nucleotide or longer siRNAs targeting non-mammalian genes, non-expressed genes, non-genomic sequences, pro- and anti-angiogenic genes, and RNAi-incompetent siRNAs all suppressed CNV in mice comparably to siRNAs targeting Vegfa or Vegfr1 without off-target RNAi or interferon-alpha/beta activation. Non-targeted (against non-mammalian genes) and targeted (against Vegfa or Vegfr1) siRNA suppressed CNV via cell-surface toll-like receptor 3 (TLR3), its adaptor TRIF, and induction of interferon-gamma and interleukin-12. Non-targeted siRNA suppressed dermal neovascularization in mice as effectively as Vegfa siRNA. siRNA-induced inhibition of neovascularization required a minimum length of 21 nucleotides, a bridging necessity in a modelled 2:1 TLR3-RNA complex. Choroidal endothelial cells from people expressing the TLR3 coding variant 412FF were refractory to extracellular siRNA-induced cytotoxicity, facilitating individualized pharmacogenetic therapy. Multiple human endothelial cell types expressed surface TLR3, indicating that generic siRNAs might treat angiogenic disorders that affect 8% of the world's population, and that siRNAs might induce unanticipated vascular or immune effects.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642938/" 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/PMC2642938/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kleinman, Mark E -- Yamada, Kiyoshi -- Takeda, Atsunobu -- Chandrasekaran, Vasu -- Nozaki, Miho -- Baffi, Judit Z -- Albuquerque, Romulo J C -- Yamasaki, Satoshi -- Itaya, Masahiro -- Pan, Yuzhen -- Appukuttan, Binoy -- Gibbs, Daniel -- Yang, Zhenglin -- Kariko, Katalin -- Ambati, Balamurali K -- Wilgus, Traci A -- DiPietro, Luisa A -- Sakurai, Eiji -- Zhang, Kang -- Smith, Justine R -- Taylor, Ethan W -- Ambati, Jayakrishna -- 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 EY018836-01/EY/NEI NIH HHS/ -- England -- Nature. 2008 Apr 3;452(7187):591-7. doi: 10.1038/nature06765. Epub 2008 Mar 26.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Ophthalmology, University of Kentucky, Lexington, Kentucky 40506, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18368052" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Endothelial Cells/metabolism ; Genetic Therapy/*methods ; Humans ; Immunity, Innate/*immunology ; Interferon-gamma/immunology ; Interleukin-12/immunology ; Macular Degeneration/complications/genetics/therapy ; Mice ; Mice, Inbred C57BL ; Neovascularization, Pathologic/genetics/*immunology/*prevention & control/therapy ; RNA, Small Interfering/chemistry/genetics/*immunology/*metabolism ; Toll-Like Receptor 3/chemistry/genetics/*metabolism ; Vascular Endothelial Growth Factor A/genetics
    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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    Frequent inactivation of A20 in B-cell lymphomas (2009)
    Nature Publishing Group (NPG)
    Details
    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
    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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