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  • 1
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    Patient-specific induced pluripotent stem-cell-derived models of LEOPARD syndrome (2010)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2010-06-11
    Description: The generation of reprogrammed induced pluripotent stem cells (iPSCs) from patients with defined genetic disorders holds the promise of increased understanding of the aetiologies of complex diseases and may also facilitate the development of novel therapeutic interventions. We have generated iPSCs from patients with LEOPARD syndrome (an acronym formed from its main features; that is, lentigines, electrocardiographic abnormalities, ocular hypertelorism, pulmonary valve stenosis, abnormal genitalia, retardation of growth and deafness), an autosomal-dominant developmental disorder belonging to a relatively prevalent class of inherited RAS-mitogen-activated protein kinase signalling diseases, which also includes Noonan syndrome, with pleomorphic effects on several tissues and organ systems. The patient-derived cells have a mutation in the PTPN11 gene, which encodes the SHP2 phosphatase. The iPSCs have been extensively characterized and produce multiple differentiated cell lineages. A major disease phenotype in patients with LEOPARD syndrome is hypertrophic cardiomyopathy. We show that in vitro-derived cardiomyocytes from LEOPARD syndrome iPSCs are larger, have a higher degree of sarcomeric organization and preferential localization of NFATC4 in the nucleus when compared with cardiomyocytes derived from human embryonic stem cells or wild-type iPSCs derived from a healthy brother of one of the LEOPARD syndrome patients. These features correlate with a potential hypertrophic state. We also provide molecular insights into signalling pathways that may promote the disease phenotype.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885001/" 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/PMC2885001/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carvajal-Vergara, Xonia -- Sevilla, Ana -- D'Souza, Sunita L -- Ang, Yen-Sin -- Schaniel, Christoph -- Lee, Dung-Fang -- Yang, Lei -- Kaplan, Aaron D -- Adler, Eric D -- Rozov, Roye -- Ge, Yongchao -- Cohen, Ninette -- Edelmann, Lisa J -- Chang, Betty -- Waghray, Avinash -- Su, Jie -- Pardo, Sherly -- Lichtenbelt, Klaske D -- Tartaglia, Marco -- Gelb, Bruce D -- Lemischka, Ihor R -- 5R01GM078465/GM/NIGMS NIH HHS/ -- R01 GM078465/GM/NIGMS NIH HHS/ -- R01 GM078465-03/GM/NIGMS NIH HHS/ -- England -- Nature. 2010 Jun 10;465(7299):808-12. doi: 10.1038/nature09005.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Gene and Cell Medicine, Black Family Stem Cell Institute, Mount Sinai School of Medicine, New York, New York 10029, USA. xcarvajal@gmail.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20535210" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Cell Differentiation ; Cell Line ; Cell Lineage ; Cells, Cultured ; Embryonic Stem Cells/metabolism ; Enzyme Activation ; Female ; Fibroblasts/metabolism/pathology ; Gene Expression Profiling ; Homeodomain Proteins/genetics ; Humans ; Induced Pluripotent Stem Cells/enzymology/metabolism/*pathology ; LEOPARD Syndrome/drug therapy/metabolism/*pathology ; Male ; Mitogen-Activated Protein Kinases/metabolism ; *Models, Biological ; Myocytes, Cardiac/metabolism/pathology ; NFATC Transcription Factors/genetics/metabolism ; Octamer Transcription Factor-3/genetics ; Phosphoproteins/analysis ; Polymerase Chain Reaction ; *Precision Medicine ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics/metabolism ; SOXB1 Transcription Factors/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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  • 2
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    The growth factor progranulin binds to TNF receptors and is therapeutic against inflammatory arthritis in mice (2011)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2011-03-12
    Description: The growth factor progranulin (PGRN) has been implicated in embryonic development, tissue repair, tumorigenesis, and inflammation, but its receptors remain unidentified. We report that PGRN bound directly to tumor necrosis factor receptors (TNFRs) and disturbed the TNFalpha-TNFR interaction. PGRN-deficient mice were susceptible to collagen-induced arthritis, and administration of PGRN reversed inflammatory arthritis. Atsttrin, an engineered protein composed of three PGRN fragments, exhibited selective TNFR binding. PGRN and Atsttrin prevented inflammation in multiple arthritis mouse models and inhibited TNFalpha-activated intracellular signaling. Collectively, these findings demonstrate that PGRN is a ligand of TNFR, an antagonist of TNFalpha signaling, and plays a critical role in the pathogenesis of inflammatory arthritis in mice. They also suggest new potential therapeutic interventions for various TNFalpha-mediated pathologies and conditions, including rheumatoid arthritis.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3104397/" 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/PMC3104397/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tang, Wei -- Lu, Yi -- Tian, Qing-Yun -- Zhang, Yan -- Guo, Feng-Jin -- Liu, Guang-Yi -- Syed, Nabeel Muzaffar -- Lai, Yongjie -- Lin, Edward Alan -- Kong, Li -- Su, Jeffrey -- Yin, Fangfang -- Ding, Ai-Hao -- Zanin-Zhorov, Alexandra -- Dustin, Michael L -- Tao, Jian -- Craft, Joseph -- Yin, Zhinan -- Feng, Jian Q -- Abramson, Steven B -- Yu, Xiu-Ping -- Liu, Chuan-ju -- AI43542/AI/NIAID NIH HHS/ -- AR040072/AR/NIAMS NIH HHS/ -- AR050620/AR/NIAMS NIH HHS/ -- AR053210/AR/NIAMS NIH HHS/ -- GM061710/GM/NIGMS NIH HHS/ -- R01 AI030165/AI/NIAID NIH HHS/ -- R01 AI030165-20/AI/NIAID NIH HHS/ -- R01 GM061710/GM/NIGMS NIH HHS/ -- R01 GM061710-08/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2011 Apr 22;332(6028):478-84. doi: 10.1126/science.1199214. Epub 2011 Mar 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Orthopaedic Surgery, New York University School of Medicine and NYU Hospital for Joint Diseases, New York, NY 10003, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21393509" target="_blank"〉PubMed〈/a〉
    Keywords: Adolescent ; Adult ; Aged ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/metabolism/pharmacology/therapeutic use ; Arthritis, Experimental/*drug therapy/*immunology/pathology/physiopathology ; Cartilage, Articular/metabolism/pathology ; Female ; Humans ; Intercellular Signaling Peptides and ; Proteins/chemistry/genetics/*metabolism/therapeutic use ; Ligands ; Male ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; Mice, Transgenic ; Middle Aged ; Protein Interaction Domains and Motifs ; Receptors, Tumor Necrosis Factor, Type I/genetics/*metabolism ; Receptors, Tumor Necrosis Factor, Type II/genetics/*metabolism ; Recombinant Fusion Proteins/metabolism/pharmacology/therapeutic use ; Recombinant Proteins/therapeutic use ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology/physiology ; Tumor Necrosis Factor-alpha/*metabolism ; Young Adult
    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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  • 3
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    Acceleration of electrons and ions by strong lower-hybrid turbulence in solar flares (1994)
    In:  CASI
    Details
    Publication Date: 2019-06-28
    Description: One of the outstanding problems in solar flare theory is how to explain the 10-20 keV and greater hard x-ray emissions by a thick target bremsstrahlung model. The model requires the acceleration mechanism to accelerate approximately 10(exp 35) electrons sec(exp -l) with comparable energies, without producing a large return current which persists for long time scales after the beam ceases to exist due to Lenz's law, thereby, producing a self-magnetic field of order a few mega-Gauss. In this paper, we investigate particle acceleration resulting from the relaxation of unstable ion ring distributions, producing strong wave activity at the lower hybrid frequency. It is shown that strong lower hybrid wave turbulence collapses in configuration space producing density cavities containing intense electrostatic lower hybrid wave activity. The collapse of these intense nonlinear wave packets saturate by particle acceleration producing energetic electron and ion tails. There are several mechanisms whereby unstable ion distributions could be formed in the solar atmosphere, including reflection at perpendicular shocks, tearing modes, and loss cone depletion. Numerical simulations of ion ring relaxation processes, obtained using a 2 1/2-D fully electromagnetic, relativistic particle in cell code are discussed. We apply the results to the problem of explaining energetic particle production in solar flares. The results show the simultaneous acceleration of both electrons and ions to very high energies: electrons are accelerated to energies in the range 10-500 keV, while ions are accelerated to energies of the order of MeVs, giving rise to x-ray emission and gamma-ray emission respectively. Our simulations also show wave generation at the electron cyclotron frequency. We suggest that these waves are the solar millisecond radio spikes. The strong turbulence collapse process leads to a highly filamented plasma producing many localized regions for particle acceleration and resulting in approximately 10(exp 17) electron 'beamlets' of width approximately equal to 10 lambda sub De which eliminates the production of large magnetic fields. In this paper, we demonstrate that the model produces an energetic electron spectrum with the right flux to account for the hard x-ray observations.
    Keywords: SOLAR PHYSICS
    Type: NASA-TM-109723 , NAS 1.15:109723 , RAL-94-022
    Format: application/pdf
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  • 4
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    Lower hybrid resonance acceleration of electrons and ions in solar flares and the associated microwave emission (1993)
    In:  Other Sources
    Details
    Publication Date: 2019-07-13
    Description: The particle acceleration processes here studied are driven by the relaxation of unstable ion ring distributions; these produce strong wave activity at the lower hybrid resonance frequency which collapses, and forms energetic electron and ion tails. The results obtained are applied to the problem posed by the production of energetic particles by solar flares. The numerical simulation results thus obtained by a 2 1/2-dimensional particle-in-cell code show a simultaneous acceleration of electrons to 10-500 keV energies, and of ions to as much as the 1 MeV range; the energy of the latter is still insufficient to account for gamma-ray emission in the 4-6 MeV range, but furnish a seed population for further acceleration.
    Keywords: SOLAR PHYSICS
    Type: Astrophysical Journal, Part 1 (ISSN 0004-637X); 409; 1; p. 465-475.
    Format: text
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  • 5
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    Simulation studies of electron acceleration by ion ring distributions in solar flares (1990)
    In:  Other Sources
    Details
    Publication Date: 2019-07-12
    Description: A 2.5-dimensional fully relativistic EM, particle-in-cell code (PIC) is used to investigate a potential electron acceleration mechanism in solar flares. The free energy is provided by ions which have a ring velocity distribution about the magnetic-field direction. Ion rings may be produced by perpendicular shocks, which could in turn be generated by the super-Alfvenic motion of magnetic flux tubes emerging from the photosphere or by coronal mass ejections. Such ion distributions are known to be unstable to the generation of lower hybrid waves, which have phase velocities in excess of the electron thermal speed parallel to the field and can, therefore, resonantly accelerate electrons in that direction. The simulations show the transfer of perpendicular ion energy to energetic electrons via lower hybrid wave turbulence. With plausible ion ring velocities, the process can account for the observationally inferred fluxes and energies of non-thermal electrons during the impulsive phase of flares.
    Keywords: SOLAR PHYSICS
    Type: Solar Physics (ISSN 0038-0938); 130; 229-241
    Format: text
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