1,720,965 research outputs found
Modulation of HIV-1 replication and regulation by SARS-CoV-2 : GCN2 kinase as a key restriction factor of viral infections
No full textGCN2 est une kinase cellulaire humaine impliquée dans la réponse au stress intégrée (ISR). Une fois activée, elle phosphoryle le facteur d’initiation de la traduction eIF2α, induisant une inhibition globale de la traduction et favorisant l’expression du facteur de transcription ATF4. Ce dernier active l’expression de gènes impliqués dans l’adaptation au stress ou l’apoptose. GCN2 est un senseur des carences en acides aminés, mais de plus en plus d’études révèlent son implication dans la réponse antivirale de la cellule. En effet GCN2 est activée lors de l’infection par certains virus et sa délétion favorise la réplication virale. Les hypothèses concernant le mode d’activation de la kinase pendant l’infection impliquent des interactions directes avec des facteurs viraux, et des mécanismes liés à la machinerie de traduction. Dans le cas du VIH-1, GCN2 interagit avec l’intégrase (IN) du virus et phosphoryle la sérine 255. L’IN catalyse l’intégration de l’ADN viral dans le génome de l’hôte infecté. Sa phosphorylation par GCN2 diminue l’intégration et par conséquent la réplication. Pour contrecarrer cet effet restrictif de GCN2, les virus ont développé des mécanismes d’échappement. C’est notamment le cas avec le VIH-1 ou encore le SRAS-CoV qui diminuent le niveau de protéines GCN2 pendant l’infection (protéolyse). Dans ce contexte, les objectifs de cette thèse étaient (1) de développer des modulateurs de l’interaction entre GCN2 et l’IN du VIH-1 et d’évaluer le potentiel impact de ces molécules sur la réplication du virus, et (2) d’étudier le rôle de GCN2 lors de l’infection par un autre virus, le SRAS-CoV-2. Après avoir mis en place un test de suivi de l’interaction IN-GCN2 basé sur la technologie AlphaLISA, nous avons criblé 2 chimiothèques différentes et identifié 18 molécules actives. L’étude de la relation structure-activité de ces composés ainsi que la mesure de leur activité en cellules nous a permis d’identifier des structures chimiques qui pourraient servir de base pour le développement d’inhibiteurs de l’interaction. En parallèle, nous avons généré une lignée cellulaire permissive à l’infection par le SRAS-CoV-2 et détecté une régulation négative de la kinase lors de l’infection. Nous avons identifié les partenaires de GCN2 dans ce contexte infectieux, incluant des facteurs viraux et une protéine cellulaire de la voie de dégradation protéique. Nous avons montré que cette voie n’est pas directement responsable de la régulation de GCN2, mais que la kinase pourrait être dégradée par la protéase du SRAS-CoV-2. De nouveaux travaux seront nécessaires afin d’élucider le rôle de GCN2 dans la réplication du SRAS-CoV-2.GCN2 is a human cellular kinase involved in the integrated stress response (ISR). Once activated, it phosphorylates the translation initiation factor eIF2α, inducing a global inhibition of translation and promoting the expression of the transcription factor ATF4. The latter activates the expression of genes involved in adaptation to stress or apoptosis. GCN2 is a sensor of amino acid starvation, but an increasing number of studies reveal its involvement in the cell's antiviral response. Indeed, GCN2 is activated during infection by different viruses and its deletion enhances viral replication. Hypotheses regarding the mode of kinase activation during infection involve direct interactions with viral factors, and mechanisms linked to the translation machinery. In the case of HIV-1, GCN2 interacts with the viral integrase (IN) which is phosphorylated on its serine 255. IN catalyzes the integration of viral DNA into the genome of the infected host. Its phosphorylation by GCN2 reduces integration and therefore replication. To counteract this restrictive effect of GCN2, viruses have developed escape mechanisms. For example, GCN2 protein level reduces upon infection by HIV-1 or SARS-CoV. In this context, the aims of this thesis were (1) to develop modulators of the interaction between GCN2 and HIV-1 IN and to assess the potential impact of these molecules on viral replication, and (2) to study the role of GCN2 during SARS-CoV-2 infection. After setting up an assay to monitor the GCN2-IN interaction using AlphaLISA technology, we screened 2 different chemical libraries and identified 18 active molecules. The study of their structure-activity relationship as well as the measurement of their activity in cells allowed us to identify chemical structures that could serve as a basis for the development of inhibitors of the interaction. In parallel, we generated a cell line permissive to SARS-CoV-2 infection and detected a downregulation of the kinase upon infection. We then identified GCN2 partners in this context, including viral factors and a cellular protein of the protein degradation pathway. We showed that this pathway is not directly responsible for the regulation of GCN2, but rather that the kinase may be degraded by the SARS-CoV-2 protease. Further work will be necessary to elucidate the role of GCN2 in SARS-CoV-2 replication
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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