1,721,015 research outputs found
Unravelling the phenotype of pancreatic islet-resident macrophages : potential gatekeepers of β cell redox balance
No full textLes cellules β sont les principales composantes de l’îlot pancréatique, où elles jouent un rôle majeur par la sécrétion d’insuline afin de réguler la glycémie. Les îlots pancréatiques contiennent d’autres types cellulaires, parmi lesquels des cellules immunitaires résidentes, composées majoritairement de macrophages. Ces macrophages ont un phénotype activé, plutôt inflammatoire à l’homéostasie. Les mécanismes moléculaires d’une telle activation n’étant pas connus, mon projet de thèse a pour but de définir le phénotype et le rôle des macrophages des îlots à l’homéostasie et lors d’un régime obésogène. Dans un modèle murin, en combinant des techniques de cytométrie et de séquençage, nous avons confirmé le phénotype pro-inflammatoire des macrophages de l’îlot pancréatique avec une forte expression génique de cytokines et chimiokines telles qu’Il1b ou Ccl4, ainsi qu’une expression membranaire de CD11c et CMH-II à l’homéostasie. De plus, nous avons identifié 3 sous-populations de macrophages résidents de l‘îlot pancréatique, parmi lesquelles deux sous-populations liées et associées d’une part à un profil de sécrétion de facteurs inflammatoires, et d’autre part, à un profil métabolique antioxydant. Ces macrophages antioxydants sont caractérisés par l’expression de nombreux gènes de la voie du glutathion impliquée dans la dégradation des espèces réactives de l’oxygène (ROS). Ainsi, nous proposons que le niveau élevé de glutathion dans les macrophages de l’îlot conditionne leur activité inflammatoire. Afin de tester notre hypothèse, nous avons modulé la production et l’utilisation du glutathion dans les macrophages par des composés pharmacologiques, et nous avons observé que l’inhibition de la voie glutathion induit une diminution significative de l’expression génique des facteurs inflammatoires. Ainsi, la voie du glutathion semble importante pour maintenir le phénotype pro-inflammatoire des macrophages de l’îlot pancréatique. Le glutathion étant produit à partir de cystine, nous avons développé un modèle d’inhibition de la production du glutathion en ciblant le transporteur de cystine xCT, qui semble spécifique aux macrophages dans l’îlot. Ainsi, nous mettons en évidence dans des modèles de reconstitution xCT KO spécifique des cellules immunitaires, une augmentation du stress oxydatif des macrophages, associé à une augmentation des ROS qui s’accompagne d’une augmentation du stress oxydatif aussi chez les cellules β et d’une altération de leur fonction. L’état oxydant des cellules β semble être associé à une modulation du métabolisme du fer, ion essentiel à leur fonction. Nous mettons ainsi en évidence une forte interaction entre les macrophages et les cellules β et proposons que les macrophages de l’îlot participent au maintien des capacités antioxydants des cellules β. Lors de l’obésité, induite par un régime riche en graisses, nous avons mis en évidence que la densité des macrophages et leur phénotype inflammatoire ne semble pas être modulés. En revanche, ils pourraient participer à garantir une bonne fonction endocrine par l’apport de glutamine. Ainsi, mes travaux ont permis de mettre en évidence l’implication des voies antioxydants dans le phénotype des macrophages de l’îlot ainsi qu’une implication potentielle des macrophages de l’îlot pancréatique dans la régulation de l’équilibre oxydant et de la fonction des cellules β.Β cells are the main compounds of the pancreatic islet, to maintain normoglycemia through insulin secretion. Inside islets, there are immune cells, mainly macrophages who display an activated and inflammatory phenotype at steady state. The molecular mechanisms underlying this activation are not well described. My PhD project aims at studying the phenotype and function of these islet macrophages at steady state and during diet-induced obesity. By combining single cell RNA sequencing and flow cytometry in mouse models, we confirmed the inflammatory phenotype at steady state of islet macrophages. Islet macrophages express at homeostasis, pro-inflammatory cytokines such as Il1b, Tnf or Ccl4, and have a membranous expression of MHC-II and CD11c, surface markers associated with activated macrophage phenotype. Using clustering method, we defined a continuum of 3 associated subpopulations of islet resident macrophages including profiles differentially characterized by i) inflammatory secretory and ii) an antioxidant profile. The antioxidant macrophage subpopulation was marked by genes encoding for the glutathione pathway, involved in the detoxification of reactive oxygen species (ROS). Based on this pioneer observation, we propose that the glutathione pathway in macrophages may modulate its inflammatory status. To confirm our hypothesis, using pharmacological agents, we antagonized glutathione pathway, and observed a significant decrease of proinflammatory factors. Our analyses show that the glutathione pathway contributes to the activated phenotype of islet macrophages. The glutathione production is limited by cystine availability. We developed an inhibitory model of glutathione production by blocking the cystine transporter xCT, highly expressed in islet macrophages. Using this mouse model, we performed bone marrow transplantation experiments to limit cystine importation restricted to immune cells. We showed an increase of oxidative stress associated with an increase of ROS production by macrophages in reconstituted xCT KO mice. Analysis of β cells showed an increase of ROS and an increase of insulin secretion. The β cells redox status seems to be associated to alteration of iron metabolism, an ion essential for endocrine function. Our data propose for the first time that interaction between macrophages and β cells may be key in the maintenance of islet homeostasis by modulating the cellular stress in β cells. In a diet-induced obesity model, we observed an increase of islet macrophage counts closely related with the increased of islet size. Our analyses also revealed a minor regulation of macrophages inflammatory state but it highlighted the rewiring of cellular metabolism, suggesting the contribution of islet macrophages in the maintenance of endocrine function through glutamine exchange. My PhD work highlighted the implication of redox pathways on islet macrophage phenotype, and potential new functions of islet macrophages in the modulation of β cell oxidative state
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
Decoding the role of GPS2 in transcriptional control of inflammation of adipose tissue during obesity
No full textL'obésité est aujourd’hui considérée comme une maladie inflammatoire chronique dite de « bas grade » principalement caractérisée par une augmentation de l’inflammation du tissu adipeux. Les adipocytes et les macrophages sont connus pour jouer un rôle clé dans l’établissement, la progression et le maintien de l'inflammation. Dans mon projet de thèse, nous nous sommes particulièrement intéressés aux mécanismes transcriptionnels impliqués dans l'inflammation chronique en décodant l'action du corégulateur transcriptionnel GPS2 (G protein pathway suppressor 2) dans les adipocytes et les macrophages du tissu adipeux. Dans un premiers temps, nous avons étudié la régulation et les actions de GPS2 (et ses partenaires SMRT et NCOR) dans le tissu adipeux humains de sujets obèses par rapport à des sujets minces. Dans cette première étude, nous avons identifié un mécanisme épigénomique qui participe à la régulation de la transcription des gènes inflammatoires dans les adipocytes lors de l’obésité. Nous avons démontré que la dérégulation de GPS2 contribuait à l'inflammation du tissu adipeux en permettant à la dérépression de certains gènes inflammatoires dont l’interleukine 6. Dans la deuxième étude, nous avons caractérisé les conséquences de l’invalidation de GPS2 dans le phénotype inflammatoire des macrophages ainsi que les conséquences in vivo sur la progression de l’insulino-résistance. Pour ceci, nous avons généré un modèle de souris où GPS2 a été spécifiquement invalidé dans les macrophages (GPS2-MacKO). De manière intéressante, les souris GPS2-MacKO, présentent une expression accrue des gènes impliqués dans la voie de signalisation des TLR et des chimiokines dans les macrophages isolés. Par conséquent, une augmentation significative de l'infiltration des macrophages dans le tissu adipeux est observée dans un contexte d’obésité induisant une altération de l’homéostasie glucidique. Par nos approches génomiques, transcriptomiques et épigénomiques, nous avons pu révéler les voies de signalisations spécifiquement contrôlées par GPS2. Ces travaux démontrent également l’importance des régulations épigénomiques dans l'inflammation métabolique du tissu adipeux durant l'obésité.Obesity is now considered a chronic low-grade inflammatory disease with increased levels of inflammatory mediators both in circulation and adipose tissue. Among adipose tissue cell types, adipocytes and macrophages are known to play key roles in the progression of inflammation by establishing and maintaining it. In this PhD project, we particularly focus on the transcriptional mechanisms behind the chronic low-grade inflammation by deciphering the action of GPS2 in adipocytes and adipose tissue macrophages. We initially studied the gene regulation and the actions of GPS2 and its partners in adipose tissue and adipocytes of human obese subjects compared to lean subjects. In this first study we identified a novel regulatory pathway that participates in the transcriptional control of inflammation associated with obesity, both in adipose tissue and adipocytes. We have shown that GPS2 and SMRT were differentially expressed and regulated in obese adipocytes. In addition, this dysregulation contributes to inflammation of the adipose tissue by allowing the derepression of specific inflammatory genes. In a second study, in order to go further in the characterisation of the in vivo function of GPS2, we generated a mouse model were GPS2 was specifically invalidated in macrophages. Models of diet-induced obesity were applied in these experiments. Interestingly, GPS2-MacKO mice showed an increased expression of inflammatory genes both in adipose tissue and isolated ATMs (F4/80+ cells) associated with a significant increase of macrophages infiltration in the adipose tissue. Finally, we observed that GPS2-MacKO mice had impaired glucose metabolism as they presented high glucose intolerance as well as an important insulin resistance
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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