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No full textSystemic autoinflammatory diseases (SAIDs) are rare disorders characterized by recurrent febrile attacks and systemic sterile inflammation. Mutations in genes that cause dysregulation of the innate immune system underlie the etiology of several SAIDs. The study ofmfinogenic SAIDsled to the discovery of inflammasomes, which are intracellular multiprotein signaling complexes that regulate pro-inflammatory ILID and IL18 cytokine secretion. Despite the identification of the genetic defects in several SAIDs, the pathogenicity of the identified mutations is difficult to assess as the majority are missense variations. The report of patients with a clinical presentation of monogenic SAIDs, but in the absence of germline mutations in disease-causing genes, and the poor understanding of the cellular and molecular bases of complex multifactorial polygenic disorders like adult onset still's disease (AOSD) make diagnosis and effective treatment challenging.The work presented in this thesis aimed at (i) Studying the functional consequences of an identified NLRP3 variant in two apparently unrelated ARPU-AID families; (ii) identifying the molecular bases of chronic inflammatory urticaria, and (iii) Studying the molecular and cellular bases of AOSD.We identified a heterozygous missense NLRP3 variant (c.1322C>T, p.A441V) in a multigenerational French family and in a sporadic case presented with two different NLRP3- AID phenotypes. Although microsatellite analyses flanking NLRP3 showed that the two unrelated families share the same disease haplotype, whole-genome SNP genotyping revealed that the mutation occurred independently in the two families, in keeping with a recurrent mutational event. In vitro functional assays showed that the mutated NLRP3 protein -as compared to the wild-type- is associated with significantly higher ASC speck formation and ILl b secretion, two major readouts of inflammasome activation. Gene expression profile in patients' monocytes showed that is highly correlated with the disease activity explaining therefore the heterogeneous clinical phenotype associated with this mutation.In order to identify the molecular bases of histamine-resistant chronic urticarial skin rash associated with systemic inflammation in two sporadic cases, next generation sequencing (NGS) was performed targeting the main genes implicated in SAIDs. A somatic mosaic NLRP3 variant was identified in both patients. Despite the late-disease onset, the mutations were widely distributed in different patients' cells. In vifro functional studies of the identified variants clearly demonstrated a gain-of-function effect on NLRP3-inflammasome activation. Accordingly, the patients showed a clinical response to anti-IU therapy highlighting the importance of molecular diagnostic tools for targeted treatment.Plasma cytokine profile in AOSD patients revealed significantly elevated plasma IL18 levels as compared to healthy controls. Whether or not IL18 is a disease biomarker remains to eb established. Primary results from cytokine expression analysis in AOSD patients' monocytes and macrophages suggested that monocytes may play an important role in disease pathogenesis.In conclusion, this work showed the importance of functional studies and patients' cells in order to validate the pathogenicity of sequence variants and the use of NGS as a diagnostic tool for the molecular bases of SAIDs. The results obtained on AOSD pave the way for further studies which could open up to targeted therapies.
Bases moléculaires et cellulaires des maladies autoinflammatoires systémiques, y compris la maladie de Still
No full textLes maladies auto-inflammatoires systémiques (SAIDs) sont des maladies rares caractérisées par des attaques fébriles récurrentes et une inflammation systémique stérile. Leur étiologie est expliquée par des mutations dans des gènes induisant une dérégulation du système immunitaire. Les travaux présentés dans cette thèse visaient à (i) étudier les conséquences fonctionnelles d’un variant NLRP3 identifié dans deux familles distinctes, (ii) identifier les bases moléculaires de l’urticaire inflammatoire chronique et (iii) étudier les bases moléculaires et cellulaires de la maladie de Still de l’adulte (MSA). Nous avons identifié un variant NLRP3 (c.1322C>T, p.A441V) présent à l’état hétérozygote dans une famille française multi-générationnelle et chez un cas sporadique, présentant deux phénotypes NLRP3-AID différents. Des tests fonctionnels in vitro ont montré que la protéine NLRP3 mutée induit une augmentation significative de la formation de specks ASC et de la sécrétion d’IL1β, deux résultantes de l’activation de l’inflammation. Afin d’identifier chez deux cas sporadiques, les bases moléculaires de l’urticaire inflammatoire chronique associé à une inflammation systémique, des analyses de séquençage NGS ont été effectuées. Un variant NLRP3 présent à l’état de mosaïque somatique a été identifié chez les deux patients. Les études fonctionnelles in vitro du variant ont démontré un effet gain de fonction sur l’activation de l’inflammasome NLRP3. Le profil de cytokines plasmatiques chez les patients avec une MSA a révélé des taux d’IL18 très élevés. Des premiers résultats suggèrent que les monocytes peuvent jouer un rôle important dans la pathogenèse de la maladie.Systemic autoinflammatory diseases (SAIDs) are rare disorders characterized by recurrent febrile attacks and systemic sterile inflammation. Mutations in genes that cause dysregulation of the innate immune system underlie the etiology of several SAIDs. The work presented in this thesis aimed at (i) Studying the functional consequences of an identified NLRP3 variant in two apparently unrelated NLRP3-AID families (ii) identifying the molecular bases of chronic inflammatory urticaria and (iii) studying the molecular and cellular bases of AOSD We identified a heterozygous missense NLRP3 variant (c.1322C>T, p.A441V) in a multigenerational French family and in a sporadic case presenting with two different NLRP3-AID phenotypes. In vitro functional assays showed that the mutated NLRP3 protein is associated with significantly higher ASC speck formation and IL1β secretion, two major readouts of inflammasome activation. In order to identify the molecular bases of histamine-resistant chronic urticarial skin rash associated with systemic inflammation in two sporadic cases, next generation sequencing was performed. A somatic mosaic NLRP3 variant was identified in both patients. Despite the late-disease onset, the mutations were widely distributed in different patients’ cells. In vitro functional studies of the identified variants clearly demonstrated a gain-of-function effect on NLRP3-inflammasome activation. Plasma cytokine profile in AOSD patients revealed significantly elevated plasma IL18 levels as compared to healthy controls. Primary results from cytokine profile in AOSD patients’ monocytes and macrophages suggested that monocytes may play an important role in disease pathogenesi
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
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