1,720,960 research outputs found
IMMUNOLOGICALLY DISCERNIBLE CELL SURFACE VARIANTS FOR USE IN CELL THERAPY
No full textThe invention relates to a mammalian cell, particularly a human cell, expressing a first isoform of a surface protein, wherein the first isoform is functionally indistinguishable, but immunologically distinguishable from a second isoform, for use in a medical treatment of a patient having cells expressing the second isoform form of the surface protein. The invention further relates to an agent selected from 1) a compound comprising, or consisting of, an antibody or antibody-like molecule and 2) an immune effector cell bearing an antibody-like molecule or an immune effector cell bearing a chimeric antigen receptor, for use in a method of treatment of a medical condition, wherein the agent is specifically reactive to either a first or a second isoform of a surface protein, wherein the first isoform is functionally indistinguishable, but immunologically distinguishable from the second isoform, and wherein the agent is administered to ablate a cell bearing the isoform that the agent is reactive to
ICOS dependent homeostasis and functions of Foxp3+ regulatory T cells in the pancreatic islets of non-obese diabetic mice
No full textType 1 Diabetes (T1D) development in non-obese diabetic (NOD) mice is accompanied by an age-associated waning of CD4+Foxp3+ regulatory T (Treg) cell function. Previous results from our laboratory have shown that T1D progression is associated with a temporal loss in the capacity of CD4+Foxp3+ Treg cells to expand and survive in the β-islets. This in turn perturbs the Treg and effector T (Teff) cell balance and results in anti-islet immune responses. It has also been shown that ICOS blockade in neonatal NOD.BDC2.5 transgenic mice, whose T cells recognize a β-islet-specific auto-antigen, disrupts the Teff/Treg cell balance, and exacerbates T1D. This suggests that ICOS may be important in controlling Treg cell function. We hypothesized that ICOS expression by Foxp3+ Treg cells and ICOS-mediated signals, are critical for the stabilization of Treg cell function in the pre-diabetic islets of NOD mice. First, we show that ICOS is preferentially expressed by intra-islet Treg cells, which cycle vigorously in situ and express the IL-2 receptor α chain (CD25) at higher levels than ICOS- Treg cells. We also found that ICOS+ Treg cells preferentially up-regulate CXCR3 homing receptor in response to inflammation in the pancreatic environment in which CXCR3’s ligands, CXCL9, 10 and 11 are expressed by islet-residing Foxp3+ Treg cells, innate cells and by insulin producing β-islets. By examining the functional relevance of ICOS+ Treg cells we found that ICOS+ Treg cells, compared to ICOS- Treg cells, are endowed with a greater suppressive capacity in vitro and in vivo, and produce the immunomodulatory cytokine IL-10. Furthermore, the importance of ICOS signaling is demonstrated by Ab-mediated blockade or genetic deficiency in ICOS, which selectively abrogates Treg-mediated T1D protection, and exacerbates disease in BDC2.5 mice. Our results also show that ICOS+ Treg cells, in contrast to ICOS- Treg cells, are more responsive to IL-2, a cytokine essential for the survival, fitness and functional stability of Treg cells. Additionally, in vivo ICOS expression on Treg cells can be restored by il2 allelic variants or IL-2 therapy demonstrating an essential role for IL-2 in sustaining ICOS+ Treg cells. Finally, we found that expression of the KLRG1 marker tracks a homeostatically impaired and fatigued ICOS+ Treg cell population. These ICOS+KLRG1+ Treg cells display increased susceptibility to cell death, loss of Foxp3 expression and poor suppressive potential that further contributes to T1D progression in our model. Altogether, we demonstrate that ICOS is critical for the homeostasis and functional stability of Treg cells and maintenance of T1D protection. Elucidation of the mechanisms involved in maintaining self-tolerance will build on our current understanding of autoimmune disorders, and provide possible therapeutic tools to combat diseases like T1D.Le développement du diabète de type 1 (T1D) dans les souris diabétiques non-obèses (NOD) s’accompagne d’un déclin fonctionnel des cellules T CD4+Foxp3+ régulatrices (Treg). Nous avons précédemment démontré que la progression du T1D est associée à la perte progressive par les cellules Treg de la capacité de proliférer et de survivre dans les îlots de Langerhans du pancréas, ce qui perturbe l’équilibre entre Treg et cellules T effectrices (Teff), et déclenche la réponse immunitaire contre les cellules bêta du pancréas. Il a également été démontré que le blocage de ICOS chez les souriceaux nouveau-nés de la lignée transgénique NOD.BDC2.5, dont les cellules T reconnaissent spécifiquement un antigène du soi exprimé par les cellules bêta, engendre un débalancement des cellules Teff vis-à-vis des Treg, et aggrave le T1D, ce qui suggère un rôle important de ICOS dans la régulation des cellules Treg. Nous proposons ici que l’expression de ICOS par les cellules Treg Foxp3+, et les signaux induits par ICOS, sont indispensables à une fonction stable des cellules Treg au sein des îlots des souris NOD pré-diabétiques.Nous montrons que les cellules Treg situées dans les îlots expriment préférentiellement ICOS, prolifèrent vigoureusement et expriment de plus hauts niveaux de la chaine alpha du récepteur de l’IL2 (CD25) que les cellules Treg ICOS-. De plus, nous avons trouvé que les cellules Treg ICOS+ sont plus susceptibles d’exprimer le récepteur d’adressage CXCR3 dans le contexte inflammatoire du pancréas, où les chimiokines CXCL9, 10 et 11 sont exprimées par les cellules Treg Foxp3+, les cellules immunitaires innées et les cellules bêta productrices d’insuline. Un examen approfondi de la pertinence fonctionnelle des cellules Treg ICOS+ nous a également permis d’établir que ces cellules présentent une meilleure capacité de suppression in vitro et in vivo, et produisent l’interleukine immuno-régulatrice IL-10. De plus, l’importance des signaux transmis par ICOS est démontrée par la perte d’ICOS, par blocage par anticorps ou par déficience génétique, qui conduit à l’abrogation de la protection contre le T1D par les cellules Treg, et accélère la maladie chez les souris BDC2.5. Nos résultats démontrent également que les cellules Treg qui expriment ICOS sont plus sensibles à l’IL-2, une cytokine essentielle à la survie, la santé et la stabilité fonctionnelle des cellules Treg. De plus, l’expression d’ICOS par les cellules Treg peut être restaurée par des variants alléliques du gène de l’il2 ou par l’injection directe d’IL-2, ce qui démontre le rôle indispensable de l’IL-2 dans le support des cellules Treg ICOS+. Enfin, nous observons que l’expression du récepteur KLRG1 permet l’identification d’une population de cellules Treg ICOS+ compromises et épuisées, qui présentent une susceptibilité accrue à la mort cellulaire, la perte de l’expression de Foxp3, et une fonction suppressive diminuée qui contribue à la progression du T1D dans notre model.En conclusion, nous démontrons que ICOS est indispensable à l’homéostasie et la stabilité fonctionnelle des cellules Treg dans les îlots de Langerhans pré-diabétiques, et au maintien de la protection contre le T1D. Elucider les mécanismes impliqués dans le maintien de la tolérance au soi permettra d’améliorer notre compréhension des désordres auto-immuns, et pourra apporter des outils thérapeutiques dans le combat contre des maladies telles que le T1D
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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