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Étude des mécanismes de résistance naturelle de la protéase de VIH-2 (PR2) contre les inhibiteurs de protéase par des approches de bioinformatique structurale pour la recherche d'inhibiteurs ciblés de PR2
No full textHuman Immunodeficiency Virus (HIV) of type 2 (HIV-2) is predominant in West Africa compared to HIV of type 1 (HIV-1), which is prevalent worldwide. The therapeutic arsenal against HIV-2 corresponds to antiretroviral drugs developed against HIV-1, and HIV-2 is naturally resistant to some of these drugs. One possible strategy is to target one of the proteins involved in the viral replication of HIV-2. In our study, we chose the target proteases of HIV-2 (PR2), an enzyme involved in the production of infectious viral particles. It is therefore important to research and design new molecules inhibiting PR2.The aim of this thesis is to improve understanding of the factors contributing to the selectivity and efficacy of HIV-1 protease inhibitors (PR1), which are modified or absent from PR2 using structural bioinformatics and statistical protocols developed within the research team. To do so, we sought (i) to better understand the flexibility of PR2 upon ligand binding, (ii) to explore the impact of sequence variations between PR1 and PR2 on their three-dimensional structure (3D) and (iii) on their binding site.Our results identified the variable regions of PR2 that deform upon the ligand binding, particularly the elbows and flaps regions. Although both PR2 dimer chains have the same amino acid sequence, some binding site residues have different conformations between the two chains, defined as asymmetry, allowing PR2 to recognize and bind various ligands. The comparison of PR1 and PR2 structures showed that some regions have different structural variability between PR1 and PR2 and that some of these differences are due to substitutions between the two proteases as for the elbows region. These structural differences could alter the flexibility of the PR2 flaps regions relative to PR1, and thus play a role in the transition from the semi-open form to the closed form, and have an impact on ligand binding. In addition, we have shown that some substitutions in the binding site (T31S, V32I, M46I, I47V, L76M, and V82I) result in structural changes in the main and side chains of residues involved in the interaction with ligands that can alter interaction with them ; these structural changes seem to explain the interaction differences observed in the literature for amprenavir and darunavir in PR2 compared to PR1. The set of observed structural changes provides a better understanding of the PR2 resistance mechanisms against IPs, which provides information for developing PR2-specific IPs.Le Virus de l'immunodéficience humaine (VIH) de type 2 (VIH-2) est prédominant essentiellement en Afrique de l’Ouest comparé au VIH de type 1 (VIH-1) qui est répandu dans le monde entier. L'arsenal thérapeutique contre VIH-2 correspond aux anti-rétroviraux développés pour lutter contre le VIH-1, or le VIH-2 est naturellement résistant à certains de ces médicaments. Une stratégie possible est de cibler une des protéines impliquées dans le cycle viral du VIH-2. Dans notre cas, nous avons choisi d'étudier la cible des protéases du VIH-2 (PR2), enzyme impliquée dans la maturation des protéines du virus. Il est donc important de rechercher et de développer de nouvelles molécules inhibitrices de la PR2.Le projet de cette thèse est d’améliorer la compréhension des facteurs contribuant à la sélectivité et l’efficacité des inhibiteurs pour la protéase du VIH-1 (PR1), qui sont modifiés ou absents de la PR2 à l’aide d’outils de bioinformatique structurale et de protocoles statistiques développés au sein de l’équipe. Pour cela, nous avons cherché (i) à mieux comprendre la flexibilité de la PR2 lors de la fixation des ligands, (ii) à explorer l’impact des variations de séquence entre PR1 et PR2 sur leur structure tridimensionnelle (3D) et (iii) sur leur site de liaison.Nos résultats ont mis en évidence les régions variables de la PR2 qui se déforment lors de la fixation des ligands, particulièrement les régions elbows et flaps. Bien que les deux chaînes du dimère de la PR2 présentent la même séquence en acides aminés, certains résidus du site de liaison ont des conformations différentes entre les deux chaînes, traduites par une asymétrie, ce qui permet à la PR2 de reconnaître et fixer des ligands divers et variés.La comparaison des structures de PR1 et PR2 a montré que certaines régions présentent des variabilités structurales différentes entre PR1 et PR2 et que certaines de ces différences sont dues aux substitutions entre les deux protéases comme pour la région des elbows. Ces différences structurales pourraient modifier la flexibilité des régions flaps de la PR2 par rapport à PR1, et ainsi jouer un rôle dans la transition de l’état semi-ouvert à l'état fermé, et avoir un impact sur la fixation des ligands. De plus, nous avons montré que certaines substitutions dans le site de liaison (T31S, V32I, M46I, I47V, L76M et V82I) entraînent des changements structuraux des chaînes principales et latérales de résidus impliqués dans l’interaction avec les ligands pouvant ainsi modifier l’interaction avec ceux-ci ; ces changements structuraux semblent expliquer les différences d’interaction observées dans la littérature pour l’amprenavir et le darunavir chez PR2 par rapport à PR1. L’ensemble des changements structuraux observés permettent de mieux comprendre les mécanismes de résistance de PR2 contre les IPs, ce qui permet de fournir des informations pour développer des IPs spécifiques à PR2
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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