1,721,089 research outputs found
Pharmacological targeting of cathepsin C in novel therapeutic approach in granulomatosis with polyangiitis
No full textLes protéases à serine du neutrophile (PSN), maturées par une protéase à cystéine nommée la cathepsine C (CatC), sont des acteurs majeurs dans la dégradation tissulaire et la réponse immunitaire médiées par les polynucléaires neutrophiles (PNN). La protéinase 3 (PR3), l’une des PSN, est l’auto-antigène majeur de la granulomatose avec polyangéite (GPA) qui est une vascularite systémique auto-immune. Le ciblage pharmacologique des PSN par des inhibiteurs est une approche intéressante pour le traitement de la GPA mais également pour toutes les maladies inflammatoires chroniques impliquant les PSN mais reste sans résultat jusqu’à maintenant. L’inactivation génétique de la CatC chez les patients atteints du syndrome de Papillon-Lefèvre est associée à une élimination presque totale des PSN. Au cours de ce travail de thèse, nous avons ciblé la CatC à l’aide d’un inhibiteur de type nitrile dans un modèle de cellules souches différenciées en PNN et nous avons obtenu une élimination presque complète de la PR3 intracellulaire et membranaire. Dans un deuxième temps, nous avons identifié la cathepsine S (CatS) comme la protéase activatrice majeure de la CatC dans les précurseurs neutrophiliques. Nous avons donc ciblé la CatS avec un inhibiteur de type nitrile pendant la différentiation des PNN ce qui a diminué significativement les taux de PSN. L’inhibition pharmacologique de la CatC pourrait donc éliminer l’auto- antigène de la GPA et constituer une nouvelle stratégie thérapeutique innovante pour contrôler l’auto-immunité et l’inflammation associée dans cette pathologie. Une combinaison d’inhibiteurs de CatS et de CatC pourrait s’avérer plus efficace pour éliminer la PR3 ainsi que les PSN pro-inflammatoires dans la GPA et dans d’autres pathologies inflammatoires chroniques.Neutrophil serine proteases (NSP), maturated by cathepsin C (CatC), are the major players in neutrophil-mediated tissue degradation and immune response. Proteinase 3 (PR3) is the main target antigen of anti-neutrophil cytoplasmic auto-antibodies (ANCA) in granulomatosis with polyangiitis (GPA), a systemic small-vessel vasculitis. The pharmacological targeting of NSP by proteinase inhibitors is promising approach for GPA treatment but also for all chronic inflammatory diseases involving NSP but remains unsuccessful until now. The genetic inactivation of CatC in patients with Papillon-Lefèvre syndrome is associated with almost complete elimination of NSP in blood neutrophils. In this work, we targeted CatC using a nitrile inhibitor in neutrophil generated from umbilical cord stem cells and we observed strong reductions in intracellular and membrane- bound PR3. Among the five-proCatC activating proteases, we found CatS in neutrophilic precursor cells and in mature neutrophils. Pharmacological inhibition of CatS in neutrophils generated from stem cells resulted in significant reduction of cellular NSP. The pharmacological inhibition of CatC could help eliminate the auto- antigen of GPA and constitute a novel therapeutic strategy to reduce auto-immune inflammation in this pathology. Pharmacological targeting of both CatS and CatC might help to efficient inhibition and elimination of NSP in GPA and in chronic inflammatory diseases
Roles of cysteine cathepsins and their naturals inhibitors, cystatins in lung fibrosis
No full textLors de la fibrose pulmonaire idiopathique (FPI), la différenciation fibroblastique s’accompagne d’une accumulation excessive des composants de la matrice extracellulaire ainsi qu’à un dérèglement de la balance protéases / antiprotéases. Nous avons étudié le rôle des cathepsines à cystéine dans la myofibrogenèse et leur contribution potentielle à la physiopathologie de la fibrose pulmonaire chez l’Homme. Pour cela, le profil d’expression des cathepsines ainsi que de leurs inhibiteurs naturels a été évalué dans un modèle cellulaire expérimental, puis dans des myofibroblastes primaires et enfin dans des liquides de lavage broncho-Alvéolaires (LBA) de patients atteints de FPI. Nos résultats montrent que lors de la FPI la cystatine C (inhibiteur naturel des protéases à cystéine) régule les activités protéolytiques des cathepsines extracellulaires et pourrait ainsi contribuer à l’accumulation de collagènes. Elle serait un biomarqueur potentiel de la FPI. D’autre part la cathepsine B participe à la différentiation fibroblastique et son inhibition retarde la myofibrogenèse.During idiopathic pulmonary fibrosis (IPF), fibroblast differentiation is accompanied by an excessive accumulation of extracellular matrix components as well as an imbalance between proteases and theirs inhibitors. We evaluated the role of human cysteine cathepsins in myofibrogenesis and their potential contribution to the pathogenesis of IPF. Expression of cathepsins and their natural inhibitors have been studied in an experimental cell model, but also in primary myofibroblasts and in bronchoalveolar lavage fluids (BALF) of patients suffering from IPF. Our results show that cystatin C (a natural inhibitor of cysteine proteases) regulates the extracellular proteolytic activities of cathepsins and could contribute to the accumulation of collagens. Cystatin C could also be a potential biomarker of IPF. On the other hand, cathepsin B participates in fibroblast differentiation and its inhibition delays myofibrogenesis
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
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
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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