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  • 1
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    Pin1 promotes GR transactivation by enhancing recruitment to target genes (2013)
    Oxford University Press
    Details
    Publication Date: 2013-10-08
    Description: The glucocorticoid receptor (GR) is a ligand activated transcription factor, serving to regulate both energy metabolism and immune functions. Factors that influence cellular sensitivity to glucocorticoids (GC) are therefore of great interest. The N-terminal of the GR contains numerous potential proline-directed phosphorylation sites, some of which can regulate GR transactivation. Unrestricted proline isomerisation can be inhibited by adjacent serine phosphorylation and requires a prolyl isomerise, Pin1. Pin1 therefore determines the functional outcome of proline-directed kinases acting on the GR, as cis / trans isomers are distinct pools with different interacting proteins. We show that Pin1 mediates GR transactivation, but not GR trans-repression. Two N-terminal GR serines, S203 and S211, are targets for Pin1 potentiation of GR transactivation, establishing a direct link between Pin1 and the GR. We also demonstrate GC-activated co-recruitment of GR and Pin1 to the GILZ gene promoter. The Pin1 effect required both its WW and catalytic domains, and GR recruitment to its GRE was Pin1-dependent. Therefore, Pin1 is a selective regulator of GR transactivation, acting through N-terminal phospho-serine residues to regulate GR recruitment to its target sites in the genome. As Pin1 is dysregulated in disease states, this interaction may contribute to altered GC action in inflammatory conditions.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Viral replication. Structural basis for RNA replication by the hepatitis C virus polymerase (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-02-14
    Description: Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding of NS5B, the viral RNA-dependent RNA polymerase. Here we study the details of HCV RNA replication by determining crystal structures of stalled polymerase ternary complexes with enzymes, RNA templates, RNA primers, incoming nucleotides, and catalytic metal ions during both primed initiation and elongation of RNA synthesis. Our analysis revealed that highly conserved active-site residues in NS5B position the primer for in-line attack on the incoming nucleotide. A beta loop and a C-terminal membrane-anchoring linker occlude the active-site cavity in the apo state, retract in the primed initiation assembly to enforce replication of the HCV genome from the 3' terminus, and vacate the active-site cavity during elongation. We investigated the incorporation of nucleotide analog inhibitors, including the clinically active metabolite formed by sofosbuvir, to elucidate key molecular interactions in the active site.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Appleby, Todd C -- Perry, Jason K -- Murakami, Eisuke -- Barauskas, Ona -- Feng, Joy -- Cho, Aesop -- Fox, David 3rd -- Wetmore, Diana R -- McGrath, Mary E -- Ray, Adrian S -- Sofia, Michael J -- Swaminathan, S -- Edwards, Thomas E -- New York, N.Y. -- Science. 2015 Feb 13;347(6223):771-5. doi: 10.1126/science.1259210.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. todd.appleby@gilead.com tedwards@be4.com. ; Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. ; Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA. todd.appleby@gilead.com tedwards@be4.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25678663" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Catalytic Domain ; Conserved Sequence ; Crystallography, X-Ray ; Hepacivirus/enzymology/genetics/*physiology ; Molecular Sequence Data ; Protein Structure, Secondary ; RNA Replicase/*chemistry ; RNA, Viral/*biosynthesis ; Ribonucleotides/*chemistry ; Sofosbuvir ; Uridine Monophosphate/analogs & derivatives/chemistry ; Viral Nonstructural Proteins/*chemistry ; *Virus Replication
    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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    Therapeutic efficacy of the small molecule GS-5734 against Ebola virus in rhesus monkeys (2016)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2016-03-05
    Description: The most recent Ebola virus outbreak in West Africa, which was unprecedented in the number of cases and fatalities, geographic distribution, and number of nations affected, highlights the need for safe, effective, and readily available antiviral agents for treatment and prevention of acute Ebola virus (EBOV) disease (EVD) or sequelae. No antiviral therapeutics have yet received regulatory approval or demonstrated clinical efficacy. Here we report the discovery of a novel small molecule GS-5734, a monophosphoramidate prodrug of an adenosine analogue, with antiviral activity against EBOV. GS-5734 exhibits antiviral activity against multiple variants of EBOV and other filoviruses in cell-based assays. The pharmacologically active nucleoside triphosphate (NTP) is efficiently formed in multiple human cell types incubated with GS-5734 in vitro, and the NTP acts as an alternative substrate and RNA-chain terminator in primer-extension assays using a surrogate respiratory syncytial virus RNA polymerase. Intravenous administration of GS-5734 to nonhuman primates resulted in persistent NTP levels in peripheral blood mononuclear cells (half-life, 14 h) and distribution to sanctuary sites for viral replication including testes, eyes, and brain. In a rhesus monkey model of EVD, once-daily intravenous administration of 10 mg kg(-1) GS-5734 for 12 days resulted in profound suppression of EBOV replication and protected 100% of EBOV-infected animals against lethal disease, ameliorating clinical disease signs and pathophysiological markers, even when treatments were initiated three days after virus exposure when systemic viral RNA was detected in two out of six treated animals. These results show the first substantive post-exposure protection by a small-molecule antiviral compound against EBOV in nonhuman primates. The broad-spectrum antiviral activity of GS-5734 in vitro against other pathogenic RNA viruses, including filoviruses, arenaviruses, and coronaviruses, suggests the potential for wider medical use. GS-5734 is amenable to large-scale manufacturing, and clinical studies investigating the drug safety and pharmacokinetics are ongoing.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Warren, Travis K -- Jordan, Robert -- Lo, Michael K -- Ray, Adrian S -- Mackman, Richard L -- Soloveva, Veronica -- Siegel, Dustin -- Perron, Michel -- Bannister, Roy -- Hui, Hon C -- Larson, Nate -- Strickley, Robert -- Wells, Jay -- Stuthman, Kelly S -- Van Tongeren, Sean A -- Garza, Nicole L -- Donnelly, Ginger -- Shurtleff, Amy C -- Retterer, Cary J -- Gharaibeh, Dima -- Zamani, Rouzbeh -- Kenny, Tara -- Eaton, Brett P -- Grimes, Elizabeth -- Welch, Lisa S -- Gomba, Laura -- Wilhelmsen, Catherine L -- Nichols, Donald K -- Nuss, Jonathan E -- Nagle, Elyse R -- Kugelman, Jeffrey R -- Palacios, Gustavo -- Doerffler, Edward -- Neville, Sean -- Carra, Ernest -- Clarke, Michael O -- Zhang, Lijun -- Lew, Willard -- Ross, Bruce -- Wang, Queenie -- Chun, Kwon -- Wolfe, Lydia -- Babusis, Darius -- Park, Yeojin -- Stray, Kirsten M -- Trancheva, Iva -- Feng, Joy Y -- Barauskas, Ona -- Xu, Yili -- Wong, Pamela -- Braun, Molly R -- Flint, Mike -- McMullan, Laura K -- Chen, Shan-Shan -- Fearns, Rachel -- Swaminathan, Swami -- Mayers, Douglas L -- Spiropoulou, Christina F -- Lee, William A -- Nichol, Stuart T -- Cihlar, Tomas -- Bavari, Sina -- R01 AI113321/AI/NIAID NIH HHS/ -- R01AI113321/AI/NIAID NIH HHS/ -- England -- Nature. 2016 Mar 17;531(7594):381-5. doi: 10.1038/nature17180. Epub 2016 Mar 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland 21702, USA. ; United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, Maryland 21702, USA. ; Gilead Sciences, Foster City, California 94404, USA. ; Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA. ; Boston University School of Medicine, Boston, Massachusetts 02118, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26934220" target="_blank"〉PubMed〈/a〉
    Keywords: Alanine/*analogs & derivatives/pharmacokinetics/pharmacology/therapeutic use ; Amino Acid Sequence ; Animals ; Antiviral Agents/pharmacokinetics/pharmacology/*therapeutic use ; Cell Line, Tumor ; Ebolavirus/drug effects ; Female ; HeLa Cells ; Hemorrhagic Fever, Ebola/*drug therapy/prevention & control ; Humans ; Macaca mulatta/*virology ; Male ; Molecular Sequence Data ; Organ Specificity ; Prodrugs/pharmacokinetics/pharmacology/therapeutic use ; Ribonucleotides/pharmacokinetics/pharmacology/*therapeutic use
    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
    Electronic Resource
    Electronic Resource
    α-β Phase Re-Transformation Kinetics in Nickel Sulphide (1999)
    Springer
    Journal of thermal analysis and calorimetry 56 (1999), S. 429-435 
    Details
    ISSN: 1572-8943
    Keywords: DSC ; nickel sulphide ; TG ; toughened glass ; X-ray diffraction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Nickel sulphide (NiS) was characterised using X-ray diffraction, thermal gravimetric analysis (TG) and differential scanning calorimetry (DSC). The 'as received' Millerite, stoichiometric NiS, observed to be slightly nickel deficient, was found to readily decompose in a nitrogen atmosphere at elevated temperatures (450°C max.) to the sulphur deficient Godlevskite, Ni7S6. DSC and X-ray measurements demonstrated that the high temperature form of the Godlevskite was readily stabilised at room temperature. The kinetics of the α-β re-transformation in Godlevskite were then investigated using DSC and were observed to be first order.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1010179424043
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  • 5
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    A medium-scale traveling ionospheric disturbance observed from the ground and from space (2011)
    Wiley
    Details
    Publication Date: 2011-09-30
    Description: We report ultraviolet optical observations from space of a Medium-Scale Traveling Ionospheric Disturbance (MSTID) made during the Combined Radio Interferometry and COSMIC Experiment in Tomography Campaign (CRICKET) held on September 15, 2007 at ∼8:30 UT. The experiment used a Constellation Observing System for Meteorology, Ionosphere, and Climate (COSMIC also known as FORMOSAT-3) satellite in conjunction with the Very Large Array (VLA) radio telescope, located near Socorro, NM, to study the ionosphere from the global scale down to the regional scale while the TIDs propagated through it. The COSMIC/FORMOSAT-3 satellite measured the F region electron density both horizontally and with altitude while the VLA measured the directions and speeds of the TIDs. These observations provide new information on this poorly understood class of TID and demonstrate the possibility of studying MSTIDs using space-based optical instruments.
    Print ISSN: 0048-6604
    Electronic ISSN: 1944-799X
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 6
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    Characteristics of intense space weather events as observed from a low latitude station during solar minimum (2011)
    Wiley
    Details
    Publication Date: 2011-10-13
    Description: Using a dual-frequency high-resolution software-based GPS receiver, TEC and phase have been monitored from Calcutta, India situated near the northern crest of the Equatorial Ionization Anomaly for studying some Space Weather events during 2008–2010. Data from a dual-frequency Ionospheric TEC and Scintillation Monitor operational at this station under the international SCINDA program of the U.S. Air Force have also been used. This paper presents two cases of intense Space Weather events occurring in the equatorial latitudes under magnetically quiet conditions during the abnormally prolonged minimum of solar cycle 24. High values of S4 with maximum ∼0.8 were noted on GPS links located almost due south of Calcutta (22.58°N, 88.38°E geographic; magnetic dip: 32°N) when the look angles of the satellites are more-or-less aligned with the axis of the anisotropic field-aligned irregularities over the magnetic equator. Associated bite-outs in TEC of amplitude 40 units were recorded in the local post-sunset hours. Well-defined patches of phase scintillations and associated cycle slips were identified. On these days, higher values of ambient ionization were noted and the diurnal maximum of the electrojet strength was found to be delayed followed by a significant rise of the F region with a high upward drift velocity over the magnetic equator around sunset indicated by ionosonde. Measurements of in situ ion density using LEO DMSP corroborate the F region height rise. Presence of irregularities in ionization density distributions around 450km was found from C/NOFS measurements.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 7
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    Role of Neutral Wind in the Performance of Artificial Neural Network based TEC models at Diverse Longitudes in the Low Latitudes (2015)
    Wiley
    Details
    Publication Date: 2015-02-21
    Description: The equatorial ionosphere is characterized by (i) large values of Total Electron Content (TEC) and sharp latitudinal gradients of TEC, (ii) steep temporal variation of TEC, (iii) large diurnal variation of TEC and (iv) post-sunset secondary enhancement of TEC. These features cause major limitations in accuracy of standard ionospheric TEC models in this region. Three artificial neural network (ANN) based models have been developed based on real time low latitude TEC data along 77°E, 88°E and 121°E longitudes in the region between the magnetic equator and locations beyond the northern crest of Equatorial Ionization Anomaly (EIA) to predict the vertical TEC values. ANN models have shown more accurate predictions than other standard ionospheric TEC models like International Reference Ionosphere (IRI), Parameterized Ionospheric Model (PIM) and NeQuick. Effects of the neutral wind in the variation of TEC are significant and have been incorporated as inputs to these ANN models. The outputs with neutral wind incorporated shows better correspondence with measured TEC than the models without neutral wind inputs. The longitudinally separated models have been used to find any longitudinal differences in TEC along equatorial regions. The causes behind the longitudinal differences in TEC and its diurnal variations in these regions have been explained in terms of the geomagnetic declination and inclination angle along with the role of zonal wind.
    Print ISSN: 0148-0227
    Topics: Geosciences , Physics
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 8
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    The long noncoding RNA SPRIGHTLY acts as an intranuclear organizing hub for pre-mRNA molecules (2017)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2017-05-04
    Description: Molecular mechanisms by which long noncoding RNA (lncRNA) molecules may influence cancerous condition are poorly understood. The aberrant expression of SPRIGHTLY lncRNA, encoded within the drosophila gene homolog Sprouty-4 intron, is correlated with a variety of cancers, including human melanomas. We demonstrate by SHAPE-seq and dChIRP that SPRIGHTLY RNA secondary structure has a core pseudoknotted domain. This lncRNA interacts with the intronic regions of six pre-mRNAs: SOX5 , SMYD3 , SND1 , MEOX2 , DCTN6 , and RASAL2 , all of which have cancer-related functions. Hemizygous knockout of SPRIGHTLY by CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 in melanoma cells significantly decreases SPRIGHTLY lncRNA levels, simultaneously decreases the levels of its interacting pre-mRNA molecules, and decreases anchorage-independent growth rate of cells and the rate of in vivo tumor growth in mouse xenografts. These results provide the first demonstration of an lncRNA’s three-dimensional coordinating role in facilitating cancer-related gene expression in human melanomas.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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  • 9
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    Muon-spin rotation measurements of the vortex state in Sr2RuO4: Type-1.5 superconductivity, vortex clustering, and a crossover from a triangular to a square vortex lattice (2014)
    American Physical Society (APS)
    Details
    Publication Date: 2014-03-07
    Description: Author(s): S. J. Ray, A. S. Gibbs, S. J. Bending, P. J. Curran, E. Babaev, C. Baines, A. P. Mackenzie, and S. L. Lee Muon-spin rotation has been used to probe the vortex state in Sr2RuO4. At moderate fields and temperatures a lattice of triangular symmetry is observed, crossing over to a lattice of square symmetry with increasing field and temperature. At lower fields it is found that there are large regions of th... [Phys. Rev. B 89, 094504] Published Thu Mar 06, 2014
    Keywords: Superfluidity and superconductivity
    Print ISSN: 1098-0121
    Electronic ISSN: 1095-3795
    Topics: Physics
    Published by American Physical Society (APS)
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  • 10
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    Drive-induced delocalization in the Aubry-André model (2018)
    American Physical Society (APS)
    Details
    Publication Date: 2018-01-04
    Description: Author(s): S. Ray, A. Ghosh, and S. Sinha Motivated by the recent experiment by Bordia et al. [ Nat. Phys. 13 , 460 (2017) ], we study the single particle delocalization phenomena of the Aubry-André (AA) model subjected to periodic drives. In two distinct cases we construct an equivalent classical description to illustrate that the drive-induc... [Phys. Rev. E 97, 010101(R)] Published Wed Jan 03, 2018
    Keywords: Statistical Physics
    Print ISSN: 1539-3755
    Electronic ISSN: 1550-2376
    Topics: Physics
    Published by American Physical Society (APS)
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