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Implication du Fas ligand soluble dans les vascularites à ANCA
No full textCD95-ligand (CD95L) or FasL is mainly studied in its membrane form which induces an apoptotic death signal when it binds to its receptor CD95, ubiquitously expressed on the cell surface. This leads to the elimination of infected or tumor cells but also to the regulation of the immune system.The membrane form of CD95L is therefore widely described in the literature: following the binding of CD95L to its receptor, there is a conformational change in CD95 which then binds to the adaptor protein FADD which, in turn, recruits pro-caspase 8. This recruitment will allow the formation of the DISC complex (Death-Inducing Signaling Complex) allowing the pro-form of caspase 8 to give way to its active form, thus inducing apoptosis of the target cell.However, it has been shown that membrane CD95L can also be cleaved by metalloproteinases (MMPs) to generate a soluble factor, s-CD95L, circulating in trimeric form in the bloodstream. Upon binding the CD95 receptor, s-CD95L will induce non-apoptotic signaling. In this context, the FADD protein will not be recruited and a different complex will be formed: the MISC (Motility-Inducing Signaling Complex). Phospholipase C gamma 1 will also be recruited to the juxtamembrane portion of intracytoplasmic CD95, inducing an increase in intracellular calcium signaling. The formation of this new complex and signal plays an important role in the migration of Th17 lymphocytes in lupus patients.DB550 is a peptide that binds to CD95 and allows the specific blocking of the CD95-PLCgamma1 interaction without destabilizing DISC formation, which means that it inhibits non-apoptotic pathways without affecting the apoptotic pathways of the cell. Treatment of MRL/lpr mice (genetically predisposed to develop a lupus-like disease) with DB550 induces an overall improvement of the disease.ANCA-associated vasculitis (AAV) are a group of systemic autoimmune diseases that affect small vessels. Currently, patients with AAV are treated with non-specific immunosuppressive therapies and still have a very high relapse rate. It appears essential to identify a new and more specific therapeutic target.Therefore, we have obtained results and observations in patients with ANCA-associated vasculitis: the level of s-CD95L, at serum and tissue levels, is higher in patients compared to healthy subjects and this level is also correlated with disease activity.We were able to uncover the intracellular mechanism underlying the activation of neutrophils following their stimulation by s-CD95L. Indeed, neutrophils are able to migrate according to a s-CD95L gradient and, in a more inflammatory context, to produce a significant quantity of reactive oxygen species and pro-inflammatory cytokines as well as to potentially trigger mechanisms inducing the production of NETs (Neutrophil Extracellular Traps).Finally, in a mouse model of induced glomerulonephritis, thanks to DB550, we were able to considerably improve the symptoms of the disease (decrease in the number of glomerular crescents and in renal infiltration).These results demonstrate the involvement of s-CD95L in the pathophysiology of ANCA-associated vasculitis and place the soluble CD95L committed signaling pathway as a potential therapeutic target for these diseases.Le CD95-ligand (CD95L) ou FasL est essentiellement étudié sous sa forme membranaire qui induit un signal de mort apoptotique lorsqu’il se lie à son récepteur CD95, exprimé à la surface des cellules de manière ubiquitaire. Cela entraine donc une élimination des cellules infectées ou tumorales mais également une régulation du système immunitaire.La forme membranaire du CD95L est donc largement décrite dans la littérature : suite à la liaison du CD95L à son récepteur, on assiste à une modification conformationnelle de CD95 qui se lie alors à la protéine adaptatrice FADD qui, à son tour, recrute la pro-caspase 8. Ce recrutement permettra la formation du complexe DISC (Death-Inducing Signaling Complex) permettant à la pro-forme de la caspase 8 de laisser place à sa forme active, induisant alors l’apoptose de la cellule d’intérêt. Cependant, il a été montré que le CD95L membranaire peut également être clivé par des métalloprotéases (MMP) pour générer un facteur soluble, le s-CD95L, circulant sous forme trimérique dans la circulation sanguine. Lors de sa liaison au récepteur CD95, le s-CD95L induira alors une signalisation non apoptotique. Dans ce cadre, la protéine FADD ne sera pas recruté et un complexe différent sera formé : le MISC (Motility-Inducing Signaling Complex). La phospholipase C gamma 1 sera également recrutée au niveau de la portion juxtamembranaire du CD95 intracytoplasmique, induisant une augmentation du signal calcique intracellulaire. La formation de ce nouveau complexe et ce signal joue notamment un rôle important dans la migration des lymphocytes Th17 chez les patients lupiques. Le DB550 est un peptide se liant à CD95 et permettant le blocage spécifique de l’interaction CD95-PLCgamma1 sans déstabiliser la formation du DISC ce qui signifie qu’il inhibe les voies non apoptotiques sans affecter les voies apoptotiques de la cellule. Le traitement de souris MRL/lpr (génétiquement prédisposées à développer une maladie proche du lupus) par le DB550 induit une amélioration globale de la maladie. Les vascularites à ANCA (VAA) constituent un groupe de maladies auto-immunes systémiques qui touchent les vaisseaux de petits calibres. A l’heure actuelle, les patients atteints de VAA sont traités par des immunosuppresseurs non spécifiques et présentent un taux de rechute encore très important. Il apparaît essentiel d’identifier une nouvelle cible thérapeutique plus spécifique. De ce fait, nous avons obtenu des résultats et observations chez les patients atteints de vascularite à ANCA : le taux de s-CD95L, au niveau sérique et tissulaire, est plus élevé chez les patients comparés à des sujets sains et ce taux est également corrélé à l’activité de la maladie. Nous avons pu mettre en évidence le mécanisme intracellulaire sous-tendant l’activation des polynucléaires neutrophiles suite à leur stimulation par le s-CD95L. En effet, ces derniers sont capables de migrer en fonction d’un gradient de s-CD95L et, dans un contexte plus inflammatoire, de produire une quantité importante d’espèces réactives de l’oxygène et de cytokines pro-inflammatoires ainsi que de potentiellement mettre en place des mécanismes induisant la production de NETs (Neutrophil Extracellular Traps).Enfin, dans un modèle murin de glomérulonéphrite induite, grâce au DB550, nous avons pu améliorer considérablement les symptômes de la maladie (diminution du nombre de croissants glomérulaires, de l’infiltration rénale).Ces résultats permettent la mise en évidence de l’implication du s-CD95L dans la physiopathologie des vascularites à ANCA et placent la voie de signalisation engagée CD95L soluble comme une potentielle cible thérapeutique pour ces maladies
Involvement of soluble fas ligand in ANCA-associated vasculitis
No full textLe CD95-ligand (CD95L) ou FasL est essentiellement étudié sous sa forme membranaire qui induit un signal de mort apoptotique lorsqu’il se lie à son récepteur CD95, exprimé à la surface des cellules de manière ubiquitaire. Cela entraine donc une élimination des cellules infectées ou tumorales mais également une régulation du système immunitaire.La forme membranaire du CD95L est donc largement décrite dans la littérature : suite à la liaison du CD95L à son récepteur, on assiste à une modification conformationnelle de CD95 qui se lie alors à la protéine adaptatrice FADD qui, à son tour, recrute la pro-caspase 8. Ce recrutement permettra la formation du complexe DISC (Death-Inducing Signaling Complex) permettant à la pro-forme de la caspase 8 de laisser place à sa forme active, induisant alors l’apoptose de la cellule d’intérêt. Cependant, il a été montré que le CD95L membranaire peut également être clivé par des métalloprotéases (MMP) pour générer un facteur soluble, le s-CD95L, circulant sous forme trimérique dans la circulation sanguine. Lors de sa liaison au récepteur CD95, le s-CD95L induira alors une signalisation non apoptotique. Dans ce cadre, la protéine FADD ne sera pas recruté et un complexe différent sera formé : le MISC (Motility-Inducing Signaling Complex). La phospholipase C gamma 1 sera également recrutée au niveau de la portion juxtamembranaire du CD95 intracytoplasmique, induisant une augmentation du signal calcique intracellulaire. La formation de ce nouveau complexe et ce signal joue notamment un rôle important dans la migration des lymphocytes Th17 chez les patients lupiques. Le DB550 est un peptide se liant à CD95 et permettant le blocage spécifique de l’interaction CD95-PLCgamma1 sans déstabiliser la formation du DISC ce qui signifie qu’il inhibe les voies non apoptotiques sans affecter les voies apoptotiques de la cellule. Le traitement de souris MRL/lpr (génétiquement prédisposées à développer une maladie proche du lupus) par le DB550 induit une amélioration globale de la maladie. Les vascularites à ANCA (VAA) constituent un groupe de maladies auto-immunes systémiques qui touchent les vaisseaux de petits calibres. A l’heure actuelle, les patients atteints de VAA sont traités par des immunosuppresseurs non spécifiques et présentent un taux de rechute encore très important. Il apparaît essentiel d’identifier une nouvelle cible thérapeutique plus spécifique. De ce fait, nous avons obtenu des résultats et observations chez les patients atteints de vascularite à ANCA : le taux de s-CD95L, au niveau sérique et tissulaire, est plus élevé chez les patients comparés à des sujets sains et ce taux est également corrélé à l’activité de la maladie. Nous avons pu mettre en évidence le mécanisme intracellulaire sous-tendant l’activation des polynucléaires neutrophiles suite à leur stimulation par le s-CD95L. En effet, ces derniers sont capables de migrer en fonction d’un gradient de s-CD95L et, dans un contexte plus inflammatoire, de produire une quantité importante d’espèces réactives de l’oxygène et de cytokines pro-inflammatoires ainsi que de potentiellement mettre en place des mécanismes induisant la production de NETs (Neutrophil Extracellular Traps).Enfin, dans un modèle murin de glomérulonéphrite induite, grâce au DB550, nous avons pu améliorer considérablement les symptômes de la maladie (diminution du nombre de croissants glomérulaires, de l’infiltration rénale).Ces résultats permettent la mise en évidence de l’implication du s-CD95L dans la physiopathologie des vascularites à ANCA et placent la voie de signalisation engagée CD95L soluble comme une potentielle cible thérapeutique pour ces maladies.CD95-ligand (CD95L) or FasL is mainly studied in its membrane form which induces an apoptotic death signal when it binds to its receptor CD95, ubiquitously expressed on the cell surface. This leads to the elimination of infected or tumor cells but also to the regulation of the immune system.The membrane form of CD95L is therefore widely described in the literature: following the binding of CD95L to its receptor, there is a conformational change in CD95 which then binds to the adaptor protein FADD which, in turn, recruits pro-caspase 8. This recruitment will allow the formation of the DISC complex (Death-Inducing Signaling Complex) allowing the pro-form of caspase 8 to give way to its active form, thus inducing apoptosis of the target cell.However, it has been shown that membrane CD95L can also be cleaved by metalloproteinases (MMPs) to generate a soluble factor, s-CD95L, circulating in trimeric form in the bloodstream. Upon binding the CD95 receptor, s-CD95L will induce non-apoptotic signaling. In this context, the FADD protein will not be recruited and a different complex will be formed: the MISC (Motility-Inducing Signaling Complex). Phospholipase C gamma 1 will also be recruited to the juxtamembrane portion of intracytoplasmic CD95, inducing an increase in intracellular calcium signaling. The formation of this new complex and signal plays an important role in the migration of Th17 lymphocytes in lupus patients.DB550 is a peptide that binds to CD95 and allows the specific blocking of the CD95-PLCgamma1 interaction without destabilizing DISC formation, which means that it inhibits non-apoptotic pathways without affecting the apoptotic pathways of the cell. Treatment of MRL/lpr mice (genetically predisposed to develop a lupus-like disease) with DB550 induces an overall improvement of the disease.ANCA-associated vasculitis (AAV) are a group of systemic autoimmune diseases that affect small vessels. Currently, patients with AAV are treated with non-specific immunosuppressive therapies and still have a very high relapse rate. It appears essential to identify a new and more specific therapeutic target.Therefore, we have obtained results and observations in patients with ANCA-associated vasculitis: the level of s-CD95L, at serum and tissue levels, is higher in patients compared to healthy subjects and this level is also correlated with disease activity.We were able to uncover the intracellular mechanism underlying the activation of neutrophils following their stimulation by s-CD95L. Indeed, neutrophils are able to migrate according to a s-CD95L gradient and, in a more inflammatory context, to produce a significant quantity of reactive oxygen species and pro-inflammatory cytokines as well as to potentially trigger mechanisms inducing the production of NETs (Neutrophil Extracellular Traps).Finally, in a mouse model of induced glomerulonephritis, thanks to DB550, we were able to considerably improve the symptoms of the disease (decrease in the number of glomerular crescents and in renal infiltration).These results demonstrate the involvement of s-CD95L in the pathophysiology of ANCA-associated vasculitis and place the soluble CD95L committed signaling pathway as a potential therapeutic target for these diseases
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
Soluble CD95L in cancers and chronic inflammatory disorders, a new therapeutic target?
No full textAlthough CD95L (also known as FasL) is still predominantly considered as a death ligand that induces apoptosis in infected and transformed cells, substantial evidence indicate that it can also trigger non-apoptotic signaling pathways whose pathophysiological roles remain to be fully elucidated. The transmembrane ligand CD95L belongs to the tumor necrosis factor (TNF) superfamily. After cleavage by metalloprotease, its soluble form (s-CD95L) fails to trigger the apoptotic program but instead induces signaling pathways promoting the aggressiveness of certain inflammatory disorders such as autoimmune diseases and cancers. We propose to evaluate the various pathologies in which the metalloprotease-cleaved CD95L is accumulated and analyze whether this soluble ligand may play a significant role in the pathology progression. Based on the TNF?-targeting therapeutics, we envision that targeting the soluble form of CD95L may represent a very attractive therapeutic option in the pathologies depicted herein
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
Ageing and inflammation limit the induction of SARS-CoV-2-specific CD8+ T cell responses in severe COVID-19
Full text linkCD8+ T cells are critical for immune protection against severe COVID-19 during acute infection with SARS-CoV-2. However, the induction of antiviral CD8+ T cell responses varies substantially among infected people, and a better understanding of the mechanisms that underlie such immune heterogeneity is required for pandemic preparedness and risk stratification. In this study, we analyzed SARS-CoV-2-specific CD4+ and CD8+ T cell responses in relation to age, clinical status, and inflammation among patients infected primarily during the initial wave of the pandemic in France or Japan. We found that age-related contraction of the naive lymphocyte pool and systemic inflammation were associated with suboptimal SARS-CoV-2-specific CD4+ and, even more evidently, CD8+ T cell immunity in patients with acute COVID-19. No such differences were observed for humoral immune responses targeting the spike protein of SARS-CoV-2. We also found that the proinflammatory cytokine IL-18, concentrations of which were significantly elevated among patients with severe disease, suppressed the de novo induction and memory recall of antigen-specific CD8+ T cells, including those directed against SARS-CoV-2. These results potentially explain the vulnerability of older adults to infections that elicit a profound inflammatory response, exemplified by acute COVID-19
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
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