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Effects of Small Molecules Mimicking cTnI Phosphorylation on the Hypertrophic Cardiomyopathy-Causing R92L-cTnT Mutation
No full textThe cardiac sarcomere is the contractile unit of the heart. It is composed of regulatory filaments: thick filament, thin filament and titin. Titin acts as a molecular spring, keeping the thick filament centered in the sarcomere. The thick filament is primarily composed of myosin, which acts as the motor protein for sarcomere contraction. The thin filament (TF) is composed of the proteins actin, tropomyosin (TPM), and the troponin (Tn) complex (consisting of troponin C, T, and I). The thin filament is responsible for the regulation of calcium-sensitive contraction. Ca2+ binding to cTnC results in conformational changes in the TF that allow for actomyosin cross-bridges, generating force during contraction. Mutations in sarcomeric proteins have been linked to genetic cardiomyopathy forms such as hypertrophic cardiomyopathy (HCM). Impaired left ventricular relaxation and dysregulated Ca2+ homeostasis are common in HCM, often contributing to diastolic dysfunction. The Arg92Leu (R92L) mutation is a missense substitution in the gene TNNT2, that encodes for cTnT. This mutation is an HCM-causing mutation resulting in left ventricular hypertrophy and impaired diastolic function due to allosterically mediated changes to protein flexibility and cTnT binding properties to tropomyosin. Protein kinase A (PKA) mediated phosphorylation of cTnI-S23S24 has been shown to be important to early sarcomeric relaxation, and the phosphorylation potential of cTnI is reduced in the R92L-cTnT mutation. The R92L-cTnT mutation also has decreased rates of calcium dissociation from cTnI compared to wildtype. Mimicking cTnI phosphorylation increases the rate of calcium dissociation in both wildtype and R92L-cTnT reconstituted protein and mouse models. A sequence of screens was designed to identify small molecules that result in time-resolved fluorescence structural changes, as well as changes in the stopped-flow calcium dissociation kinetics. The stopped-flow calcium dissociation kinetics screen was conducted on a fully reconstituted cardiac thin filament, using bacterially-expressed protein based on the human sequences. The Selleck and ACDD Diversity drug libraries underwent structural and stopped-flow Ca2+ dissociation kinetics screening, and compounds that increased the percent change of stopped-flow Ca2+ dissociation kinetics were selected as candidates to undergo further screening. We hypothesize that the effect on the percent change in Ca2+ dissociation rates due to individual small molecules will translate from in vitro to ex vivo studies. NADH-coupled myofibril ATPase was used to assess the effects of the small molecules on the R92L-cTnT myofibrils, which have increased actomyosin interactions at baseline. The two small molecule candidates with the most significant decreases in ATPase rate were then tested on isolated R92L-cTnT cardiomyocytes for analysis on a more complex ex vivo system level. Data collected on isolated myofibrils and cardiomyocytes will provide information regarding how the small molecules affect the impaired function caused by the R92L-cTnT mutation, with the possibility of identifying candidates to proceed to in vivo studies on mouse models. Results of these studies will provide information about the validity of the primary structural and the secondary calcium dissociation kinetics screens as a method identify small molecules that bind to the thin filament and modulate ATPase activity
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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