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  • 1
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    Maximum-Likelihood Recurrence Parameters and Conditional Probability of a Ground-Rupturing Earthquake on the Southern Alpine Fault, South Island, New Zealand (2015)
    Seismological Society of America (SSA)
    Details
    Publication Date: 2015-01-30
    Description: The Alpine fault in south Westland, New Zealand, releases strains of Pacific–Australian relative plate motion in large earthquakes with an average interevent spacing of ~330 years. A new record of earthquake recurrence has been developed at Hokuri Creek, with evidence for 22 events. The youngest Hokuri Creek earthquake overlaps in time and is believed to be the same as the oldest of another site about 100 km to the northwest near Haast. The combined record spans the last 7900 years and includes 24 events. We study the recurrence rate and conditional probability of ground ruptures from this record using a new likelihood-based approach for estimation of recurrence model parameters. Paleoseismic parameter estimation includes both dating and natural recurrence uncertainties. Lognormal and Brownian passage time (BPT) models are considered. The likelihood surface has distribution location and width parameters as axes, the mean and standard deviation of the log recurrence for the lognormal, and the mean and coefficient of variation for the BPT. The maximum-likelihood (ML) point gives the parameters most likely to have given rise to the data. The ML point, 50-year conditional probabilities of a ground-rupturing earthquake are 26.8% and 26.1% for the lognormal and BPT models, respectively. Contours of equal likelihood track the parameter pairs that are equally probable to have given rise to the observed data. Conditional probabilities on the lognormal 95% boundary around the ML point range from 18.2% to 35.8%. An empirical distribution model completely based on past recurrence times gives a similar conditional probability of 27.1% (9.6%–50.2%). In contrast, the time-independent conditional probability estimate of 13.6% (8.8%–19.1%) is about half that of the time-dependent models. A nonparametric test of earthquake recurrence at Hokuri Creek indicates that time-dependent recurrence models best represent the southern Alpine fault of the South Island, New Zealand.
    Print ISSN: 0037-1106
    Electronic ISSN: 1943-3573
    Topics: Geosciences , Physics
    Published by Seismological Society of America (SSA)
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  • 2
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    Generation of an LFA-1 antagonist by the transfer of the ICAM-1 immunoregulatory epitope to a small molecule (2002)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2002-02-09
    Description: The protein-protein interaction between leukocyte functional antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) is critical to lymphocyte and immune system function. Here, we report on the transfer of the contiguous, nonlinear epitope of ICAM-1, responsible for its association with LFA-1, to a small-molecule framework. These LFA-1 antagonists bound LFA-1, blocked binding of ICAM-1, and inhibited a mixed lymphocyte reaction (MLR) with potency significantly greater than that of cyclosporine A. Furthermore, in comparison to an antibody to LFA-1, they exhibited significant anti-inflammatory effects in vivo. These results demonstrate the utility of small-molecule mimics of nonlinear protein epitopes and the protein epitopes themselves as leads in the identification of novel pharmaceutical agents.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Gadek, T R -- Burdick, D J -- McDowell, R S -- Stanley, M S -- Marsters, J C Jr -- Paris, K J -- Oare, D A -- Reynolds, M E -- Ladner, C -- Zioncheck, K A -- Lee, W P -- Gribling, P -- Dennis, M S -- Skelton, N J -- Tumas, D B -- Clark, K R -- Keating, S M -- Beresini, M H -- Tilley, J W -- Presta, L G -- Bodary, S C -- New York, N.Y. -- Science. 2002 Feb 8;295(5557):1086-9.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Bioorganic Chemistry, Genentech, One DNA Way, South San Francisco, CA 94080, USA. trg@gene.com〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/11834839" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/chemical ; synthesis/chemistry/metabolism/pharmacology ; Cyclosporine/pharmacology ; Dermatitis, Irritant/drug therapy ; Dinitrofluorobenzene ; Drug Design ; Enzyme-Linked Immunosorbent Assay ; Epitopes ; Female ; Humans ; Immunoglobulin Fab Fragments/immunology/pharmacology ; Immunosuppressive Agents/chemical synthesis/chemistry/metabolism/*pharmacology ; Intercellular Adhesion Molecule-1/chemistry/*immunology/*metabolism ; Lymphocyte Culture Test, Mixed ; Lymphocyte Function-Associated Antigen-1/immunology/*metabolism ; Mice ; Mice, Inbred BALB C ; Molecular Mimicry ; Mutagenesis ; Protein Structure, Secondary ; Structure-Activity Relationship ; Thiophenes/*chemical synthesis/chemistry/metabolism/*pharmacology ; beta-Alanine/analogs & derivatives/*chemical ; synthesis/chemistry/metabolism/*pharmacology
    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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    Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist (2015)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2015-12-19
    Description: Voltage-gated sodium (Nav) channels propagate action potentials in excitable cells. Accordingly, Nav channels are therapeutic targets for many cardiovascular and neurological disorders. Selective inhibitors have been challenging to design because the nine mammalian Nav channel isoforms share high sequence identity and remain recalcitrant to high-resolution structural studies. Targeting the human Nav1.7 channel involved in pain perception, we present a protein-engineering strategy that has allowed us to determine crystal structures of a novel receptor site in complex with isoform-selective antagonists. GX-936 and related inhibitors bind to the activated state of voltage-sensor domain IV (VSD4), where their anionic aryl sulfonamide warhead engages the fourth arginine gating charge on the S4 helix. By opposing VSD4 deactivation, these compounds inhibit Nav1.7 through a voltage-sensor trapping mechanism, likely by stabilizing inactivated states of the channel. Residues from the S2 and S3 helices are key determinants of isoform selectivity, and bound phospholipids implicate the membrane as a modulator of channel function and pharmacology. Our results help to elucidate the molecular basis of voltage sensing and establish structural blueprints to design selective Nav channel antagonists.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Ahuja, Shivani -- Mukund, Susmith -- Deng, Lunbin -- Khakh, Kuldip -- Chang, Elaine -- Ho, Hoangdung -- Shriver, Stephanie -- Young, Clint -- Lin, Sophia -- Johnson, J P Jr -- Wu, Ping -- Li, Jun -- Coons, Mary -- Tam, Christine -- Brillantes, Bobby -- Sampang, Honorio -- Mortara, Kyle -- Bowman, Krista K -- Clark, Kevin R -- Estevez, Alberto -- Xie, Zhiwei -- Verschoof, Henry -- Grimwood, Michael -- Dehnhardt, Christoph -- Andrez, Jean-Christophe -- Focken, Thilo -- Sutherlin, Daniel P -- Safina, Brian S -- Starovasnik, Melissa A -- Ortwine, Daniel F -- Franke, Yvonne -- Cohen, Charles J -- Hackos, David H -- Koth, Christopher M -- Payandeh, Jian -- New York, N.Y. -- Science. 2015 Dec 18;350(6267):aac5464. doi: 10.1126/science.aac5464.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biology, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Discovery Chemistry, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA 94080, USA. ; Department of Chemistry, Xenon Pharmaceuticals Inc., Burnaby, British Columbia, V5G 4W8, Canada. ; Department of Neuroscience, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com. ; Department of Structural Biology, Genentech Inc., South San Francisco, CA 94080, USA. hackos.david@gene.com koth.christopher@gene.com payandeh.jian@gene.com.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26680203" target="_blank"〉PubMed〈/a〉
    Keywords: Amino Acid Sequence ; Cell Membrane/chemistry ; Crystallization/methods ; Crystallography, X-Ray ; DNA Mutational Analysis ; Humans ; Models, Molecular ; Molecular Sequence Data ; NAV1.7 Voltage-Gated Sodium Channel/*chemistry/genetics ; Pain Perception/drug effects ; Protein Engineering ; Protein Isoforms/antagonists & inhibitors/chemistry ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sodium Channel Blockers/*chemistry/*pharmacology ; Sulfonamides/*chemistry/*pharmacology ; Thiadiazoles/*chemistry/*pharmacology
    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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  • 4
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    High-resolution comparative analysis of great ape genomes (2018)
    American Association for the Advancement of Science (AAAS)
    In: Science
    Details
    Publication Date: 2018-06-08
    Description: Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly and full-length complementary DNA sequencing with a multiplatform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. By comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single– to mega–base pair–sized variants. We identified ~17,000 fixed human-specific structural variants identifying genic and putative regulatory changes that have emerged in humans since divergence from nonhuman apes. Interestingly, these variants are enriched near genes that are down-regulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.
    Keywords: Genetics, Online Only
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Geosciences , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 5
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    Micro-dystrophin and follistatin co-delivery restores muscle function in aged DMD model (2013)
    Oxford University Press
    Details
    Publication Date: 2013-11-22
    Description: Pharmacologic strategies have provided modest improvement in the devastating muscle-wasting disease, Duchenne muscular dystrophy (DMD). Pre-clinical gene therapy studies have shown promise in the mdx mouse model; however, studies conducted after disease onset fall short of fully correcting muscle strength or protecting against contraction-induced injury. Here we examine the treatment effect on muscle physiology in aged dystrophic mice with significant disease pathology by combining two promising therapies: micro-dystrophin gene replacement and muscle enhancement with follistatin, a potent myostatin inhibitor. Individual treatments with micro-dystrophin and follistatin demonstrated marked improvement in mdx mice but were insufficient to fully restore muscle strength and response to injury to wild-type levels. Strikingly, when combined, micro-dystrophin/follistatin treatment restored force generation and conferred resistance to contraction-induced injury in aged mdx mice. Pre-clinical studies with miniature dystrophins have failed to demonstrate full correction of the physiological defects seen in mdx mice. Importantly, the addition of a muscle enhancement strategy with delivery of follistatin in combination with micro-dystrophin gene therapy completely restored resistance to eccentric contraction-induced injury and improved force. Eccentric contraction-induced injury is a pre-clinical parameter relevant to the exercise induced injury that occurs in DMD patients, and herein, we demonstrate compelling evidence for the therapeutic potential of micro-dystrophin/follistatin combinatorial therapy.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Liquefaction Induced during the 2010-2011 Canterbury, New Zealand, Earthquake Sequence and Lessons Learned for the Study of Paleoliquefaction Features (2017)
    Seismological Society of America (SSA)
    Details
    Publication Date: 2017-08-26
    Description: Very large to moderate earthquakes in the 2010–2011 Canterbury sequence induced liquefaction in parts of Christchurch city and the surrounding region on the South Island of New Zealand. Detailed information gathered about this case of recurrent liquefaction offers important lessons for the study of paleoliquefaction features and the paleoearthquakes that caused them. The Canterbury case demonstrates that liquefaction features are important indicators of strong ground shaking in regions where fault ruptures do not necessarily propagate to the surface, may be masked by later sedimentation, or are otherwise difficult to recognize. Comparison of the liquefaction fields produced by the 2010 M  7.1 Darfield and 2011 M  6.2 Christchurch earthquakes in the Canterbury sequence highlights the influence of site conditions on the geographical distribution of liquefaction features and underscores the need to consider liquefaction susceptibility of sediment and depth of the water table when using paleoliquefaction features to interpret the source area and magnitude of paleoearthquakes. The epicentral distance and size of liquefaction features that formed during the Darfield and Christchurch earthquakes corroborate and further constrain empirical relations used to estimate source areas and magnitudes of paleoearthquakes. Formation of compound sand blows, composed of multiple sand–silt couplets resulting from repeated liquefaction during the Canterbury earthquakes, supports previous interpretations of compound sand blows in the central and western United States. In addition, paleoliquefaction features found in excavations of sand blows that formed during the 2010–2011 Canterbury earthquakes indicate that sites of modern liquefaction are prime targets for paleoliquefaction studies. The depositional environments where liquefaction features form and are preserved help to guide searches for paleoliquefaction features. Information from many sites across a region is needed to develop a chronology of past liquefaction events, to define their liquefaction fields, and to estimate the source areas and magnitudes of paleoearthquakes.
    Print ISSN: 0895-0695
    Electronic ISSN: 1938-2057
    Topics: Geosciences
    Published by Seismological Society of America (SSA)
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  • 7
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    Recombinant AAV serotype 1 transduction efficiency and tropism in the murine brain (2003)
    Springer Nature
    Details
    Publication Date: 2003-08-01
    Print ISSN: 0969-7128
    Electronic ISSN: 1476-5462
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 8
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    Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia (2003)
    Springer Nature
    Details
    Publication Date: 2003-01-01
    Print ISSN: 0969-7128
    Electronic ISSN: 1476-5462
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 9
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    Production of recombinant adeno-associated virus vectors using a packaging cell line and a hybrid recombinant adenovirus (1999)
    Springer Nature
    Details
    Publication Date: 1999-02-01
    Print ISSN: 0969-7128
    Electronic ISSN: 1476-5462
    Topics: Biology , Medicine
    Published by Springer Nature
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  • 10
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    Unusual kinematics of the Papatea fault (2016 Kaikoura earthquake) suggest anelastic rupture (2019)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2019
    Description: 〈p〉A key paradigm in seismology is that earthquakes release elastic strain energy accumulated during an interseismic period on approximately planar faults. Earthquake slip models may be further informed by empirical relations such as slip to length. Here, we use differential lidar to demonstrate that the Papatea fault—a key element within the 2016 M〈sub〉w〈/sub〉 7.8 Kaikōura earthquake rupture—has a distinctly nonplanar geometry, far exceeded typical coseismic slip-to-length ratios, and defied Andersonian mechanics by slipping vertically at steep angles. Additionally, its surface deformation is poorly reproduced by elastic dislocation models, suggesting the Papatea fault did not release stored strain energy as typically assumed, perhaps explaining its seismic quiescence in back-projections. Instead, it slipped in response to neighboring fault movements, creating a localized space problem, accounting for its anelastic deformation field. Thus, modeling complex, multiple-fault earthquakes as slip on planar faults embedded in an elastic medium may not always be appropriate.〈/p〉
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
    Published by American Association for the Advancement of Science (AAAS)
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