1,720,954 research outputs found
Assessment of protein kinases as therapeutic targets. Application to the rational design of allosteric covalent inhibitors.
No full textLes protéines kinases sont l’une des familles de cibles thérapeutiques les plus étudiées par l’industrie pharmaceutique. Elles représentent pourtant un défi majeur car beaucoup d’inhibiteurs de kinases sont rejetés des phases cliniques, pour des problèmes de sélectivité ou par manque d’efficacité. Le succès récent d’inhibiteurs covalents de la kinase EGFR laisse à penser que cette nouvelle génération d’inhibiteurs peut résoudre les problèmes précités, en réagissant avec une cystéine peu conservée du site de liaison de l’ATP, ce qui leur confère une très bonne affinité. Afin d’évaluer l’étendue des opportunités pour la conception d’inhibiteurs covalents adressant d’autres membres de la famille, nous avons voulu identifier en automatique les kinases humaines disposant d’une cystéine accessible dans leur site de liaison. Puisque la forme de ce site dépend de la conformation adoptée, nous avons procédé à une étude préliminaire consistant à distinguer les diverses conformations adoptées parmi l’ensemble des structures 3D de kinases disponibles. Une fois ces résultats obtenus, nous avons conçu un inhibiteur susceptible d’inactiver la kinase KIT de manière covalente en réagissant avec une cystéine faiblement conservée et qui n’est accessible que lorsque KIT adopte la conformation inactive « DFG out ». La liaison covalente entre notre inhibiteur et KIT a été validée par spectrométrie de masse. Des tests d’activité sur l’ensemble des kinases ont confirmé l’affinité de cet inhibiteur pour KIT et son très bon profil de sélectivité. De fait, ce travail constitue un référentiel pour la conception d’une nouvelle génération d’inhibiteurs de kinases hautement efficaces et sélectifs.The protein kinase family is one of the most pursued classes of therapeutic targets in the pharmaceutical industry. It is also one of the most challenging families since many kinase inhibitors are rejected from clinical trials, because of either selectivity problems or a lack of efficacy. The recent success of a few covalent inhibitors of EGFR kinase indicates that this new generation of inhibitors could solve both of these problems at the same time, by reacting with an unconserved cysteine residue of the ATP binding site using an electrophilic group attached to the ligand, and providing high affinity. In order to investigate the opportunities for the design of covalent inhibitors addressing other members of the kinase family, our main focus consisted in automatically identifying all human kinases bearing a reactive cysteine in their binding site. Since the shape of the binding site depends on the kinase conformation, we performed a preliminary study to distinguish the different adopted conformations among all the available kinase 3D structures. With our results in hand, we designed a inhibitor liable to covalently bind and inactivate KIT kinase by reacting with a cysteine residue specific to a small kinase subset and accessible only in the inactive “DFG out” kinase conformation that KIT can adopt. The covalent bond between our inhibitor and KIT was confirmed by mass spectrometry. Activity assays on a large panel of kinases confirmed the affinity of this inhibitor for KIT and its very good selectivity profile. Finally, this work gives insights on how to design a new generation of highly selective and efficient kinase inhibitors
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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