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  • 1
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    Inter-individual differences in CpG methylation at D4Z4 correlate with clinical variability in FSHD1 and FSHD2 (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-13
    Description: Facioscapulohumeral muscular dystrophy (FSHD: MIM#158900) is a common myopathy with marked but largely unexplained clinical inter- and intra-familial variability. It is caused by contractions of the D4Z4 repeat array on chromosome 4 to 1–10 units (FSHD1), or by mutations in the D4Z4-binding chromatin modifier SMCHD1 (FSHD2). Both situations lead to a partial opening of the D4Z4 chromatin structure and transcription of D4Z4-encoded polyadenylated DUX4 mRNA in muscle. We measured D4Z4 CpG methylation in control, FSHD1 and FSHD2 individuals and found a significant correlation with the D4Z4 repeat array size. After correction for repeat array size, we show that the variability in clinical severity in FSHD1 and FSHD2 individuals is dependent on individual differences in susceptibility to D4Z4 hypomethylation. In FSHD1, for individuals with D4Z4 repeat arrays of 1–6 units, the clinical severity mainly depends on the size of the D4Z4 repeat. However, in individuals with arrays of 7–10 units, the clinical severity also depends on other factors that regulate D4Z4 methylation because affected individuals, but not non-penetrant mutation carriers, have a greater reduction of D4Z4 CpG methylation than can be expected based on the size of the pathogenic D4Z4 repeat array. In FSHD2, this epigenetic susceptibility depends on the nature of the SMCHD1 mutation in combination with D4Z4 repeat array size with dominant negative mutations being more deleterious than haploinsufficiency mutations. Our study thus identifies an epigenetic basis for the striking variability in onset and disease progression that is considered a clinical hallmark of FSHD.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Structural basis of RNA recognition and activation by innate immune receptor RIG-I (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-09-29
    Description: Retinoic-acid-inducible gene-I (RIG-I; also known as DDX58) is a cytoplasmic pathogen recognition receptor that recognizes pathogen-associated molecular pattern (PAMP) motifs to differentiate between viral and cellular RNAs. RIG-I is activated by blunt-ended double-stranded (ds)RNA with or without a 5'-triphosphate (ppp), by single-stranded RNA marked by a 5'-ppp and by polyuridine sequences. Upon binding to such PAMP motifs, RIG-I initiates a signalling cascade that induces innate immune defences and inflammatory cytokines to establish an antiviral state. The RIG-I pathway is highly regulated and aberrant signalling leads to apoptosis, altered cell differentiation, inflammation, autoimmune diseases and cancer. The helicase and repressor domains (RD) of RIG-I recognize dsRNA and 5'-ppp RNA to activate the two amino-terminal caspase recruitment domains (CARDs) for signalling. Here, to understand the synergy between the helicase and the RD for RNA binding, and the contribution of ATP hydrolysis to RIG-I activation, we determined the structure of human RIG-I helicase-RD in complex with dsRNA and an ATP analogue. The helicase-RD organizes into a ring around dsRNA, capping one end, while contacting both strands using previously uncharacterized motifs to recognize dsRNA. Small-angle X-ray scattering, limited proteolysis and differential scanning fluorimetry indicate that RIG-I is in an extended and flexible conformation that compacts upon binding RNA. These results provide a detailed view of the role of helicase in dsRNA recognition, the synergy between the RD and the helicase for RNA binding and the organization of full-length RIG-I bound to dsRNA, and provide evidence of a conformational change upon RNA binding. The RIG-I helicase-RD structure is consistent with dsRNA translocation without unwinding and cooperative binding to RNA. The structure yields unprecedented insight into innate immunity and has a broader impact on other areas of biology, including RNA interference and DNA repair, which utilize homologous helicase domains within DICER and FANCM.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430514/" 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/PMC3430514/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Jiang, Fuguo -- Ramanathan, Anand -- Miller, Matthew T -- Tang, Guo-Qing -- Gale, Michael Jr -- Patel, Smita S -- Marcotrigiano, Joseph -- AI080659/AI/NIAID NIH HHS/ -- GM55310/GM/NIGMS NIH HHS/ -- P30 EB009998/EB/NIBIB NIH HHS/ -- R01 AI060389/AI/NIAID NIH HHS/ -- R01 AI060389-11/AI/NIAID NIH HHS/ -- R01 AI080659/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Sep 25;479(7373):423-7. doi: 10.1038/nature10537.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21947008" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphatases/metabolism ; Adenosine Triphosphate/analogs & derivatives/chemistry/metabolism ; DEAD-box RNA Helicases/*chemistry/immunology/*metabolism ; Enzyme Activation ; Fluorometry ; Humans ; Immunity, Innate/*immunology ; Models, Molecular ; Nucleic Acid Conformation ; Pliability ; Protein Binding ; Protein Structure, Tertiary ; Proteolysis ; RNA, Double-Stranded/chemistry/*metabolism ; RNA-Binding Proteins/chemistry/immunology/metabolism ; Scattering, Small Angle ; Structure-Activity Relationship ; Substrate Specificity ; Trypsin/metabolism ; X-Ray Diffraction
    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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  • 3
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    Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2 (2014)
    Nature Publishing Group (NPG)
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    Publication Date: 2014-02-21
    Description: Hepatitis C virus (HCV) is a significant public health concern with approximately 160 million people infected worldwide. HCV infection often results in chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. No vaccine is available and current therapies are effective against some, but not all, genotypes. HCV is an enveloped virus with two surface glycoproteins (E1 and E2). E2 binds to the host cell through interactions with scavenger receptor class B type I (SR-BI) and CD81, and serves as a target for neutralizing antibodies. Little is known about the molecular mechanism that mediates cell entry and membrane fusion, although E2 is predicted to be a class II viral fusion protein. Here we describe the structure of the E2 core domain in complex with an antigen-binding fragment (Fab) at 2.4 A resolution. The E2 core has a compact, globular domain structure, consisting mostly of beta-strands and random coil with two small alpha-helices. The strands are arranged in two, perpendicular sheets (A and B), which are held together by an extensive hydrophobic core and disulphide bonds. Sheet A has an IgG-like fold that is commonly found in viral and cellular proteins, whereas sheet B represents a novel fold. Solution-based studies demonstrate that the full-length E2 ectodomain has a similar globular architecture and does not undergo significant conformational or oligomeric rearrangements on exposure to low pH. Thus, the IgG-like fold is the only feature that E2 shares with class II membrane fusion proteins. These results provide unprecedented insights into HCV entry and will assist in developing an HCV vaccine and new inhibitors.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4126800/" 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/PMC4126800/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Khan, Abdul Ghafoor -- Whidby, Jillian -- Miller, Matthew T -- Scarborough, Hannah -- Zatorski, Alexandra V -- Cygan, Alicja -- Price, Aryn A -- Yost, Samantha A -- Bohannon, Caitlin D -- Jacob, Joshy -- Grakoui, Arash -- Marcotrigiano, Joseph -- AI070101/AI/NIAID NIH HHS/ -- DK083356/DK/NIDDK NIH HHS/ -- P50 GM103368/GM/NIGMS NIH HHS/ -- P51 OD011132/OD/NIH HHS/ -- P51 RR000165/RR/NCRR NIH HHS/ -- R01 AI070101/AI/NIAID NIH HHS/ -- R01 AI080659/AI/NIAID NIH HHS/ -- R01 DK083356/DK/NIDDK NIH HHS/ -- RR-00165/RR/NCRR NIH HHS/ -- T32 AI007403/AI/NIAID NIH HHS/ -- T32 AI007610/AI/NIAID NIH HHS/ -- England -- Nature. 2014 May 15;509(7500):381-4. doi: 10.1038/nature13117. Epub 2014 Feb 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Center for Advanced Biotechnology and Medicine, Department of Chemistry and Chemical Biology, Rutgers University, 679 Hoes Lane West, Piscataway, New Jersey 08854, USA. ; Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA. ; 1] Division of Microbiology and Immunology, Emory Vaccine Center, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA [2] Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, Georgia 30322, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24553139" target="_blank"〉PubMed〈/a〉
    Keywords: Crystallography, X-Ray ; Disulfides/chemistry ; Hepacivirus/*chemistry/physiology ; Hydrogen-Ion Concentration ; Hydrophobic and Hydrophilic Interactions ; Immunoglobulin Fab Fragments/chemistry/metabolism ; Immunoglobulin G/chemistry ; Models, Molecular ; Protein Folding ; Protein Structure, Tertiary ; Scattering, Small Angle ; Surface Properties ; Viral Envelope Proteins/*chemistry/metabolism ; Viral Fusion Proteins ; Viral Hepatitis Vaccines ; Virus Internalization
    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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    Patterned vasculature enhances tissue function [Engineering] (2013)
    National Academy of Sciences
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    Publication Date: 2013-05-08
    Description: Tissue vascularization and integration with host circulation remains a key barrier to the translation of engineered tissues into clinically relevant therapies. Here, we used a microtissue molding approach to demonstrate that constructs containing highly aligned “cords” of endothelial cells triggered the formation of new capillaries along the length of the...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 5
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    Structural and functional insights into alphavirus polyprotein processing and pathogenesis (2012)
    National Academy of Sciences
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    Publication Date: 2012-09-25
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    The catalytic cycle of  -lactam synthetase observed by x-ray crystallographic snapshots (2002)
    National Academy of Sciences
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    Publication Date: 2002-10-30
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    Spectroscopic studies of CdTe(111) bulk and surface electronic structure (2015)
    American Physical Society (APS)
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    Publication Date: 2015-06-02
    Description: Author(s): Jie Ren, Li Fu, Guang Bian, Manhong Wong, Tao Wang, Gangqiang Zha, Wanqi Jie, T. Miller, M. Z. Hasan, and T.-C. Chiang Cadmium telluride (CdTe) is a direct band-gap semiconducting material with broad applications in optoelectronic devices. Here we report on a high-resolution angle-resolved photoemission (ARPES) study of CdTe ( 111 ) surfaces prepared by sputtering and annealing that show a ( 2 × 2 ) reconstruction as obser... [Phys. Rev. B 91, 235303] Published Mon Jun 01, 2015
    Keywords: Semiconductors II: surfaces, interfaces, microstructures, and related topics
    Print ISSN: 1098-0121
    Electronic ISSN: 1095-3795
    Topics: Physics
    Published by American Physical Society (APS)
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  • 8
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    Structure of the Alphavirus polyprotein P23 [Biochemistry] (2012)
    National Academy of Sciences
    Details
    Publication Date: 2012-10-10
    Description: Alphaviruses, a group of positive-sense RNA viruses, are globally distributed arboviruses capable of causing rash, arthritis, encephalitis, and death in humans. The viral replication machinery consists of four nonstructural proteins (nsP1–4) produced as a single polyprotein. Processing of the polyprotein occurs in a highly regulated manner, with cleavage at the...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 9
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    Capped RNA recognition by RIG-I [Biochemistry] (2016)
    National Academy of Sciences
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    Publication Date: 2016-01-21
    Description: RNAs with 5′-triphosphate (ppp) are detected in the cytoplasm principally by the innate immune receptor Retinoic Acid Inducible Gene-I (RIG-I), whose activation triggers a Type I IFN response. It is thought that self RNAs like mRNAs are not recognized by RIG-I because 5′ppp is capped by the addition of a...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 10
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    The autoinhibitory CARD2-Hel2i Interface of RIG-I governs RNA selection (2016)
    Oxford University Press
    Details
    Publication Date: 2016-01-30
    Description: RIG-I (Retinoic Acid Inducible Gene-I) is a cytosolic innate immune receptor that detects atypical features in viral RNAs as foreign to initiate a Type I interferon signaling response. RIG-I is present in an autoinhibited state in the cytoplasm and activated by blunt-ended double-stranded (ds)RNAs carrying a 5' triphosphate (ppp) moiety. These features found in many pathogenic RNAs are absent in cellular RNAs due to post-transcriptional modifications of RNA ends. Although RIG-I is structurally well characterized, the mechanistic basis for RIG-I's remarkable ability to discriminate between cellular and pathogenic RNAs is not completely understood. We show that RIG-I's selectivity for blunt-ended 5'-ppp dsRNAs is 3000 times higher than non-blunt ended dsRNAs commonly found in cellular RNAs. Discrimination occurs at multiple stages and signaling RNAs have high affinity and ATPase turnover rate and thus a high k atpase / K d . We show that RIG-I uses its autoinhibitory CARD2-Hel2i (second CARD-helicase insertion domain) interface as a barrier to select against non-blunt ended dsRNAs. Accordingly, deletion of CARDs or point mutations in the CARD2-Hel2i interface decreases the selectivity from 3000 to 150 and 750, respectively. We propose that the CARD2-Hel2i interface is a ‘gate’ that prevents cellular RNAs from generating productive complexes that can signal.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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