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Effets du donneur de peroxynitrite, la 3-morpholinosydnonimine, sur les cellules endothéliales. Rôle du facteur de transcription Nrf2 et de la voie UPR.
No full textIn physiological conditions, endothelial cells produce superoxide anions (O2•-) and nitric oxide (NO). O2•- are precursors, among others, of hydrogen peroxide, involved in signaling processes leading to the regulation of gene expression. At higher concentrations, hydrogen peroxide promotes the formation of the cytotoxic hydroxyl radicals. NO, in turn, exerts well-recognized beneficial effects on the cardiovascular system by inducing in particular the relaxation of smooth muscle cells. But when the NO concentration becomes too high, it competes with superoxide dismutases and reacts with O2•- to form peroxynitrite. The latter is a highly reactive molecule, attacking fatty acids, nucleic acids and proteins (with the formation of, for instance, 3-nitrotyrosine) and involved in endothelial dysfunction, a phenomenon at the basis of cardiovascular diseases. Reactive oxygen or nitrogen species can therefore, depending on the conditions, act as second messengers at low concentrations or as toxic molecules inducing oxidative stress at higher concentrations. Under normal conditions, the production of peroxynitrite is low and the damage that it could cause is limited by various defense systems, such as the Nrf2 (nuclear transcription factor erythroid 2p45 - related factor) and the UPR pathways (Unfolded Protein Response). Nrf2 is a transcription factor that responds to oxidative stress and regulates the expression of genes encoding detoxifying or antioxidant proteins such as heme oxygenase-1 (HO-1) or NAD(P)H quinone oxidoreductase 1 (NQO1). The UPR is an intracellular signaling pathway activated by the accumulation of misfolded proteins in the endoplasmic reticulum leading to the activation of various proteins such as the PERK kinase and the ATF6 transcription factor. The UPR aims to increase the synthesis of chaperonnes including BiP and GRP94, and thus increase the cellular capacity to fold or eliminate misfolded proteins. However, if the stress is too intense or too long, the UPR can induce cell death by apoptosis in particular via the activation of the transcription factor CHOP (CAAT/ enhancer binding protein (C/EBP) homologous protein). The objective of this thesis was to better understand the effects of peroxynitrite on endothelial cells, by discriminating, on one hand, its role as second messenger triggering defense responses to stress and, on the other hand, its toxicity leading to apoptosis. To achieve this goal, we chose an experimental system for peroxynitrite formation, SIN-1 (3-morpholinosydnonimine). We also tried to develop "more physiological" systems of peroxynitrite generation in vitro. Among the systems described to generate peroxynitrite, we chose homocysteine, hypoxia/reoxygenation, oxidized LDL and angiotensin-II. In this study, we developped an experimental model of endothelial cell exposure to peroxynitrite by incubating human endothelial cells in culture (the EAhy926 cell line and the primary culture, HUVEC) in the presence of SIN-1. Firstly, we tested the cytotoxicity of SIN-1 and we characterized the peroxynitrite formation induced by SIN-1 in these cellular models by following the oxidation of the hydroxyphenyl fluorescein probe and the formation of 3-nitrotyrosine by Western blot with anti-3-NT antibodies. Secondly, we demonstrated the activation of the Nrf2 and UPR pathways by SIN-1. We also showed that SIN-1 was able to exert a protective effect in serum-starved EAhy926 cells. By investigating some of the molecular mechanisms involved in the cytoprotective effect of SIN-1, we found that, via Nrf2 and HO-1 proteins, SIN-1 induced a decrease in DNA fragmentation and increased LC3-II formation in serum-starved endothelial cells. We also evaluated the effects of more physiological conditions (homocysteine, hypoxia/reoxygenation, oxidized LDL and angiotensin-II) on the peroxynitrite formation. It seems that the latter is generated in the presence of oxidized LDL and angiotensin-II combined with a NO donor. However, more investigations are necessary to further optimize some of these "more physiological" conditions on the peroxynitrite formation and to confirm the cytoprotective effect of peroxynitrite observed in serum-starved endothelial cells exposed to SIN-1. Altogether, our results indicate that in a narrow range of concentration, peroxynitrite formed after SIN-1 stimulation, activates the Nrf2 and UPR pathways, leading to a cytoprotective effect in serum-starved endothelial cells. This protective effect is achieved by stimulating the endothelial cells either after or before a period of serum starvation. The latter is in agreement with so called conditioning experiments in vivo. This work provides some new insights in the balance between survival signals or cell death triggered by peroxynitrite and highlights under which conditions this balance leads to endothelial cell death, in the context of endothelial dysfunction, involved in the early stages of atherosclerosis. It also suggests that a drastic anti-oxidant therapy targetting cardiovascular diseases could have drawbacks, as it abolishes the positive effects of reactive oxygen and nitrogen species.En conditions physiologiques, les cellules endothéliales produisent des anions superoxyde (O2•-) et du monoxyde d’azote (NO). Les O2•- sont des précurseurs, entre autres, du peroxyde d’hydrogène, impliqué dans des processus de signalisation aboutissant à des régulations d’expression génique. A plus forte concentration, le peroxyde d’hydrogène favorise la formation de radicaux hydroxyl, cytotoxiques. Le NO, quant à lui, a une action bénéfique reconnue sur le système cardiovasculaire en induisant notamment la relaxation des cellules musculaires lisses. Mais lorsque la concentration en NO est trop importante, il entre en compétition avec les superoxyde dismutases et réagit avec les O2•- pour former le peroxynitrite. Ce dernier est une molécule hautement réactionnelle, réagissant avec les acides gras, les acides nucléiques et les protéines (avec par exemple, la formation de 3-nitrotyrosines) et impliquée dans le dysfonctionnement endothélial, phénomène à la base des maladies cardiovasculaires. Les espèces réactives de l’oxygène ou de l’azote peuvent donc, selon les conditions, jouer un rôle de messagers secondaires à faible concentration ou de molécules toxiques induisant un stress oxydatif à plus forte concentration. En conditions normales, la production de peroxynitrite est faible et les dommages qu’il pourrait induire sont limités par divers systèmes de défense. Parmi ces moyens de défense, il y a la voie du facteur de transcription Nrf2 (« nuclear transcription factor erythroid 2p45 – related factor ») et la voie UPR (« Unfolded Protein Response »). Nrf2 est un facteur de transcription qui répond aux stress oxydatifs et régule l’expression des gènes codant pour des protéines anti-oxydantes ou détoxifiantes telles que l’hème oxygénase-1 (HO-1) ou la NAD(P)H quinone oxydoréductase 1 (NQO1). La voie UPR est une voie de signalisation intracellulaire cytoprotectrice activée par l’accumulation de protéines mal repliées dans le réticulum endoplasmique aboutissant à l’activation de divers acteurs moléculaires dont la kinase PERK et le facteur de transcription ATF6. La voie UPR a pour but d’augmenter la synthèse des chaperonnes dont BiP et Grp94, et ainsi d’augmenter la capacité de bien replier et d’éliminer les protéines mal repliées. Cependant, si le stress est trop intense ou de trop longue durée, la voie UPR peut induire la mort cellulaire par apoptose notamment via le facteur de transcription CHOP (« CAAT/Enhancer binding protein (C/EBP) homologous protein »). L’objectif de ce travail de thèse était de mieux comprendre les effets du peroxynitrite dans les cellules endothéliales, en discriminant d’une part sa fonction de messager secondaire déclenchant des réponses de défense au stress, et d’autre part, sa toxicité pouvant mener à l’apoptose. Pour ce faire, nous avons choisi un système expérimental de formation de peroxynitrite, le SIN-1 (3-morpholinosydnonimine). Nous avons aussi essayé de mettre au point différents systèmes dits « plus physiologiques » de génération de peroxynitrite in vitro. Parmi les systèmes décrits pour générer du peroxynitrite, nous avons choisi l’homocystéine, l’hypoxie/réoxygénation, les LDL oxydées et l’angiotensine-II. Au cours de ce travail, nous avons développé un modèle expérimental d’exposition des cellules endothéliales au peroxynitrite en incubant des cellules endothéliales humaines en culture (lignée EAhy926 et cellules en primo-culture HUVEC) en présence de SIN-1. Dans un premier temps, nous avons testé la cytotoxicité du SIN-1 et nous avons caractérisé la formation de peroxynitrite à partir de SIN-1 dans ces modèles cellulaires en suivant l’oxydation de la sonde hydroxyphényl fluorescéine et la formation de 3-nitrotyrosines par une analyse en Western blot avec des anticorps dirigés contre les 3-nitrotyrosines. Dans un second temps, nous avons mis en évidence l’activation de la voie Nrf2 et de la voie UPR par le SIN-1 et nous avons démontré que le SIN-1 exerce un effet protecteur dans les cellules EAhy926 soumises à une privation de sérum. En décortiquant les mécanismes moléculaires impliqués dans l’effet cytoprotecteur du SIN-1, nous avons constaté que, via les protéines Nrf2 et HO-1, le SIN-1 induit une diminution de la fragmentation de l’ADN et une augmentation de la formation de LC3-II dans les cellules endothéliales soumises à une privation de sérum. Au cours de ce travail, nous avons également évalué l’effet de conditions particulières (homocystéine, hypoxie/réoxygénation, LDL oxydées et angiotensine-II) sur la formation de peroxynitrite. Il semblerait que ce dernier soit généré en présence de LDL oxydées et d’angiotensine-II combinée à un donneur de NO. Toutefois, de plus amples investigations sont encore nécessaires afin de pouvoir optimaliser ces conditions dites « plus physiologiques » sur la formation de peroxynitrite et confirmer l’effet cytoprotecteur du peroxynitrite observé dans des cellules endothéliales soumises à une privation de sérum et exposées au SIN-1. Les résultats obtenus au cours de ce travail montrent donc que, dans une gamme de concentration étroite, le peroxynitrite formé suite à la stimulation des cellules endothéliales avec le SIN-1, permet de les protéger contre la toxicité induite par une privation de sérum, que la stimulation avec le SIN-1 soit réalisée après ou avant la privation de sérum, cette dernière condition se rapprochant des expériences dites de conditionnement in vivo. Ce travail nous a donc permis de mieux comprendre l’équilibre entre les signaux de survie ou de mort cellulaires déclenchés par le peroxynitrite et de préciser dans quelles conditions cet équilibre bascule vers la mort des cellules endothéliales, dans le contexte du dysfonctionnement endothélial, impliqué dans les étapes précoces de l'athérosclérose. Il suggère également qu’une thérapie anti-oxydante trop drastique des maladies cardiovasculaires risque de supprimer les actions positives des espèces réactives de l’oxygène et des espèces réactives de l’azote présents en faible concentration.(DOCSC03) -- FUNDP, 201
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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