1,720,956 research outputs found
Shedding a new light on protein conformational dynamics: development and application of FlAsH-BRET conformation sensors
No full textAs key effector units of the cell, understanding structure and function relationships of proteins are integral to explaining physiology and, in turn, pathophysiology. With the cost of drug development soaring and success dwindling, new ways to probe protein function will be at the forefront of innovation. A protein's function is the product of its conformational dynamics, where distinct 3-dimensional conformations of a protein dictate its various effects on the cell. Though highly valuable technologies capable of reporting on protein conformation currently exist, X-ray crystallography and nuclear magnetic resonance among others, their capacity to report on dynamic events and/or in physiologically relevant assay conditions are limited.This thesis describes the development and application of biosensors capable of reporting on protein conformation in live human cells. Biosensors were developed for two classes of protein targets, ion channels – Kir3, and G protein-coupled receptors (GPCR) - FP and AT1R, together representing the targets of a majority of current prescription drugs. The biosensor design was based on bioluminescence resonance energy transfer (BRET) and required the insertion of a bioluminescent protein and a short peptide sequences within the protein of interest. Due to the specific affinity for the peptide sequence of an organic fluorophore, fluorescein biarsenical hairpin binder (FlAsH), the latter could be used as a resonance energy transfer acceptor to probe the different conformations of the protein of interest without disrupting its function.Both panels of biosensors successfully reported on ligand-induced conformational rearrangements in the target proteins and correlated with functional effects. The GPCR biosensors were further applied to enrich our understanding of receptor dimerization and allosteric communication between proteins, in this case, the FP/AT1R heterodimer.Comprendre la relation entre la structure et la fonction des protéines est essentiel pour expliquer la physiologie, et par conséquent, la pathophysiologie. Par ailleurs, devant le constat que le coût lié au développement du médicament ne cesse d'augmenter alors que le taux de succès diminue, de nouveaux moyens de sonder la fonction des protéines devraient être à l'avant-garde de l'innovation. Les effets sur la cellule d'une protéine s'expliquent en partie par ses propriétés dynamiques, c'est-à-dire qu'une même protéine induit des effets différents selon la conformation tridimensionnelle qu'elle adopte. Bien qu'il existe des technologies permettant d'étudier la conformation des protéines, telles que la cristallographie par rayons X et la résonance magnétique nucléaire, leur capacité à déceler des événements dynamiques et/ou à les évaluer dans des conditions physiologiques est limitée.Cette thèse décrit le développement et l'application de biosenseurs capables de détecter les changements conformationnels des protéines dans les cellules humaines vivantes. Deux classes de biosenseurs ont été développées pour étudier les protéines ciblées par la majorité des médicaments prescrits, soit les canaux ioniques – Kir3 et les récepteurs couplés aux protéines G (RCPG) – FP et AT1R. La conception des biosenseurs, basée sur le transfert d'énergie par résonance de bioluminescence (BRET), a nécessité l'insertion d'une protéine bioluminescente et d'une séquence peptidique à l'intérieur de la protéine d'intérêt. Grâce à l'affinité spécifique pour la séquence peptidique d'un fluorophore organique, une fluorescéine arsénique (FlAsH), ce dernier a pu être utilisé comme accepteur de transfert d'énergie par résonance pour sonder les différentes conformations de la protéine d'intérêt sans en perturber sa fonction. Les deux classes de biosenseurs ont détecté avec succès les changements conformationnels des protéines induits par un ligand et ces changements ont été corrélés aux effets fonctionnels de ces mêmes protéines. L'utilisation des biosenseurs de RCPG a permis d'enrichir notre compréhension de la dimérisation des récepteurs et de la communication allostérique entre les protéines, en ce cas, l'heterodimère de FP/AT1R
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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