1,720,961 research outputs found
Transcriptional control of adipocyte through nuclear hormone-sensitive lipase and ChREBPβ
No full textDans une première partie, mon projet de recherche s’intéresse au rôle du métabolisme adipocytaire, et en particulier, à l’implication de la lipase hormono-sensible (LHS) dans le contexte de la résistance à l’action de l’insuline associée à l’obésité. De précédents travaux du laboratoire ont montré que l’inhibition de la LHS améliore la sensibilité à l’insuline, par la modulation de l’interaction entre la LHS et le facteur de transcription ChREBP. La LHS bloque la translocation de ChREBP du cytosol vers le noyau et l’induction des gènes de la lipogenèse de novo (LDN), action démontrée dans l’adipocyte comme étant corrélée à une amélioration de la sensibilité à l’insuline. Cette découverte révèle un rôle non enzymatique de la LHS dans la régulation de la transcription. Suite à cette étude, nous avons observé qu’au-delà de la LDN, la déficience en LHS augmente l’expression de marqueurs du métabolisme oxydatif et diminue ceux de la voie TGFβ indépendamment de sa fonction enzymatique et de l’activité transcriptionnelle de ChREBP. A l’inverse, chez l’Homme et la souris, le développement d’une résistance à l’insuline adipocytaire diminue l’expression des gènes oxydatifs tout en augmentant ceux de la voie TGFβ. Ces observations suggèrent que la LHS est impliquée par divers mécanismes dans la régulation de la transcription de gènes liés à l’insulino-sensibilité. Nous démontrons que cette lipase est un nouvel acteur de la voie TGFβ en favorisant la régulation de la transcription médiée par le facteur SMAD3. Dans l’adipocyte, SMAD3 réprime l’expression de PGC1α, un cofacteur essentiel dans le contrôle transcriptionnel de la chaine respiratoire mitochondriale, de l’oxydation des acides gras et de la thermogénèse. Suite à une invalidation de la LHS, l’induction des gènes du métabolisme oxydatif est médiée par une augmentation de la transcription de PGC1α du fait d’un défaut d’activation de SMAD3. D’un point de vue mécanistique, nous avons observé que la LHS interagit physiquement avec SMAD3 sans se lier à SMAD4, le partenaire habituel des protéines SMAD. Cette interaction favorise la translocation de la LHS du cytosol vers le noyau. Dans l’espace nucléaire, l’intégrité du complexe LHS/SMAD3 est nécessaire pour réprimer la transcription de PGC1α via le recrutement du corépresseur SFPQ. Ces travaux révèlent une nouvelle localisation subcellulaire et une nouvelle fonction de la LHS dans le contrôle du métabolisme énergétique de l’adipocyte. Dans une second partie mon projet de recherche s’intéresse au facteur de transcription ChREBP présent sous deux isoformes nommés α et β. En réponse au glucose l’activité de ChREBPα induit l’expression de ChREBPβ, les deux facteurs vont ensuite coopérer pour contrôler la transcription de leurs gènes cibles. ChREBPβ est rapporté comme étant l’isoforme le plus actif et dont l’expression est positivement corrélée à la sensibilité à l’insuline. Son importance dans la régulation de la transcription n’a pas encore été directement démontré. Le laboratoire a créé le premier modèle invalidé spécifiquement pour ChREBPβ. Nous montrons qu’à la différence d’une délétion simultanée des deux isoformes, la simple invalidation de l’isoforme β ne joue pas un rôle causal dans le développement de perturbations métaboliques tel que la stéatose hépatique et l’insulino-résistance. L’induction des gènes cibles de ChREBP n’est pas altérée dans les différents tissus métaboliques, à l’exception du tissu adipeux brun. Dans ce tissu, la réduction des enzymes de la LDN est néanmoins moins importante que lors d’une délétion simultanée des deux isoformes et n’a pas de conséquence fonctionnelle. Cette étude met en avant l’importance de ChREBPα dans le métabolisme du glucose et remet en question le rôle de l’isoforme β dans la régulation de la transcription.The first part of my research topic focuses on adipocyte metabolism, and notably the involvement of the hormone sensitive lipase (HSL) in obesity-associated insulin resistance. Previous work of the lab has shown that HSL inhibition improves insulin sensitivity through modulation of physical interaction between HSL and ChREBP. HSL prevents ChREBP nuclear translocation and DNL genes expression correlated with insulin sensitivity. This finding highlights a new non enzymatic function of HSL in transcriptional regulation. Following this study, we observed that HSL invalidation increases expression of oxidative markers and decreases TGFβ target genes independently of its enzymatic function and ChREBP transcriptional activity. These observations suggest that HSL is involved in transcriptional control through various mechanisms. Here, we identify a pathway linking TGFβ signalling to mitochondrial oxidation and beige adipocyte features. The cytosolic lipolytic enzyme HSL, participates in the nucleus to SMAD3-mediated transcriptional repression of PGC1α, a master co-activator controlling OXPHOS and beige marker genes. In human and mouse adipocytes, there was a strong negative correlation between mitochondrial/beige marker and TGFβ target gene expression related to insulin sensitivity status. Depletion of HSL in human and mouse adipocytes resulted in induction of mitochondrial and beige markers and increased oxidative capacity whereas production of TGFβ-controlled extracellular matrix proteins was decreased. Increased expression of mitochondrial and beige markers was mediated by transcriptional induction of PGC1α. Pharmacological and genetic inhibition of the TGFβ pathway blunted PGC1α induction mediated by HSL depletion. Mechanistically, we observed that HSL physically interacts with SMAD3 but not with the usual partner of R-SMADs, SMAD4. HSL behaved as a canonical nuclear protein in the adipocyte and its nuclear localization was controlled by its phosphorylation status and TGFβ-mediated SMAD3 nuclear translocation. HSL/SMAD3-mediated repression of PGC1α transcription involved the RNA-binding and transcription factor SFPQ, another SMAD3 interacting protein. This study highlights a new HSL function in the transcriptional control of mitochondrial oxidative activity in adipocytes. The second part of my research topic focuses on the transcriptional factor ChREBP and the respective role of ChREBPα and ChREBPβ. Glucose stimulation increases ChREBPα activity which in turn induces ChREBPβ expression. Both isoforms cooperate for ChREBP target genes transcriptional control. ChREBPβ is a superactive isoform and its expression is positively correlated with insulin sensitivity. However, its importance in transcriptional regulation has not been directly demonstrated. The lab has created the first murine model specifically deficient for ChREBPβ. We show that unlike both isoforms deletion, ChREBPβ invalidation does not mediates metabolic dysfunction development such as liver steatosis and insulin resistance. Expression of ChREBP target genes is only modified in brown adipose tissue. In this tissue, decrease in DNL enzymes is less important upon ChREBPβ deletion compared to total knock-out and has no functional consequences. This study highlights ChREBPα importance in glucose metabolism and challenge the role of ChREBPβ in transcriptional control
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
Hormone-sensitive lipase: sixty years later
No full textInternational audienceHormone-sensitive lipase (HSL) was initially characterized as the hormonally regulated neutral lipase activity responsible for the breakdown of triacylglycerols into fatty acids in adipose tissue. This review aims at providing up-to-date information on structural properties, regulation of expression, activity and function as well as therapeutic potential. The lipase is expressed as different isoforms produced from tissue-specific alternative promoters. All isoforms are composed of an N-terminal domain and a C-terminal catalytic domain within which a regulatory domain containing the phosphorylation sites is embedded. Some isoforms possess additional N-terminal regions. The catalytic domain shares similarities with bacteria, fungus and vascular plant proteins but not with other mammalian lipases. HSL singularity is provided by regulatory and N-terminal domains sharing no homology with other proteins. HSL has a broad substrate specificity compared to other neutral lipases. It hydrolyzes acylglycerols, cholesteryl and retinyl esters among other substrates. A novel role of HSL, independent of its enzymatic function, has recently been described in adipocytes. Clinical studies revealed dysregulations of HSL expression and activity in disorders, such as lipodystrophy, obesity, type 2 diabetes and cancer-associated cachexia. Development of specific inhibitors positions HSL as a pharmacological target for the treatment of metabolic complications
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