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Estructuras cristalográficas de proteínas de virus animales implicadas en la interacción virus-hospedador
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Vaccinologie structurale anti-bunyavirus
No full textLes hantavirus, transmis par contact avec des rongeurs infectés, sont des virus émergents responsables de deux syndromes potentiellement mortels et pour lesquels il n'existe pas de traitement. Connaître l'organisation précise des glycoprotéines à la surface des virions ainsi que les bases moléculaires du mécanisme d'action des anticorps neutralisants est essentiel pour le développement de futurs vaccins et/ou traitements. A la surface des virions, les deux protéines d'enveloppe, Gn et Gc, s'associent en spikes tétramétriques, formant ainsi un maillage carré caractéristique. Ces glycoprotéines, qui sont les seules cibles des anticorps neutralisants, permettent l'entrée du virus dans les cellules cibles par endocytose après interaction avec un récepteur et contrôlent la fusion membranaire. Grâce à une approche combinant la cristallographie aux rayons X et des données issues de la microscopie électronique, nous avons pu obtenir la structure de l'hétérodimère Gn/Gc et construire un modèle de la surface antigénique des virions à une résolution atomique. En raison de l'important degré de conservation des glycoprotéines, nous supposons notre modèle applicable à l'ensemble des hantavirus. Nos résultats révèlent un mécanisme original par lequel Gn contrôle l'insertion de Gc dans la membrane-cible, empêchant ainsi toute fusion prématurée. Dans la deuxième partie du projet, nous avons étudié les structures cristallines de trois anticorps neutralisants humains en complexe avec les glycoprotéines virales. L'analyse de ces structures permet d'identifier des sites de vulnérabilité à la surface des virions et de comprendre le mécanisme de neutralisation de ces anticorps. De plus, nos résultats sont en faveur de l'existence d'un phénomène dynamique de « breathing » des spikes, similaire à celui décrit pour le virus de la dengue. Ces résultats pourront servir au développement de nouvelles stratégies vaccinales ainsi qu'à l'optimisation d'anticorps thérapeutiques.Present worldwide, hantaviruses are rodent-borne emerging viruses associated with two life-threatening syndromes for which no specific treatment is available. To develop them and be ready for future outbreaks, it is essential to have a detailed picture of the virus organization and to understand the molecular mechanism of antibody neutralization, paving the way to develop innovative vaccines. At the surface of the viral particle, the envelope glycoproteins, Gn and Gc, associate in tetrameric spikes forming a characteristic square lattice. The glycoproteins, which are the sole targets of neutralizing antibodies, drive virus entry via receptor-mediated endocytosis and endosomal membrane fusion. Using a hybrid approach combining high resolution X-ray structures of the viral glycoproteins and low-resolution cryo-electron tomography data, we have obtained the structure of the heterodimer Gn/Gc and fitted it into a 11 Å resolution cET map of Tula hantavirus, thus producing an atomic model of the complete surface lattice. Given the high amino acid sequence similarity between the envelope glycoproteins, we expect our model to be valid for all hantaviruses. Our results reveal an in-built mechanism controlling Gc membrane-insertion for fusion, that has not been previously described for other viral fusion proteins. In a second part of the project, we studied the crystal structures of three of neutralizing human antibodies in complex with the viral glycoproteins. Analysis of these structures allowed us to identify vulnerability sites on the spike and provided key information to elucidate the neutralization mechanism of these antibodies. Furthermore, our data support the hypothesis of a "breathing" phenomenon, such as described for dengue virus, and suggest the existence of an original neutralization mechanism where an antibody could capture the spike in an open conformation. These results can be useful for the optimization of therapeutic antibodies and the rational design a pan-hantaviral vaccine
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Production and Purification of Hantavirus Glycoproteins in Drosophila melanogaster S2 Cells
No full textInternational audienceHantaviruses, are rodent-borne viruses found worldwide that are transmitted to humans through inhalation of contaminated excreta. They can cause a renal or a pulmonary syndrome, depending on the virus, and no effective treatment is currently available for either of these diseases. Hantaviral particles are covered by a protein lattice composed of two glycoproteins (Gn and Gc) that mediate adsorption to target cells and fusion with endosomal membranes, making them prime targets for neutralizing antibodies. Here we present the methodology to produce soluble recombinant glycoproteins in different conformations, either alone or as a stabilized Gn/Gc complex, using stably transfected Drosophila S2 cells
The surface glycoproteins of hantaviruses
No full textInternational audienceHantaviruses are rodent-borne viruses distributed worldwide, transmitted through the air and with the ability to spread from person to person. They maintain a non-symptomatic persistent infection in their rodent hosts, but their spillover to humans produces a renal or pulmonary syndrome associated with high fatality rates. Hantavirus particles are lipid-enveloped and display a characteristic surface lattice built up of tetragonal spikes composed of two glycoproteins, Gn and Gc. The pleomorphism of these particles has hindered cryo-EM efforts to obtain detailed structural information and only by using a combination of X-ray crystallography and cryo-electron tomography it was possible to build an atomic model of the surface lattice. Here we review these structural efforts and the unanticipated evolutionary relations between hantaviruses and alphaviruses highlighted by these studies
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe 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
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