1,721,080 research outputs found
Integrated miRNA and mRNA expression profiling in inflamed colon of patients with ulcerative colitis.
No full textBACKGROUND: Ulcerative colitis (UC) is associated with differential colonic expression of genes involved in immune response (e.g. IL8) and barrier integrity (e.g. cadherins). MicroRNAs (miRNAs) are regulators of gene expression and are involved in various immune-related diseases. In this study, we investigated (1) if miRNA expression in UC mucosa is altered and (2) if any of these changes correlate with mucosal mRNA expression. Integration of mRNA and miRNA expression profiling may allow the identification of functional links between dysregulated miRNAs and their target mRNA. METHODOLOGY: Colonic mucosal biopsies were obtained from 17 UC (10 active and 7 inactive) patients and 10 normal controls. Total RNA was used to analyze miRNA and mRNA expression via Affymetrix miRNA 2.0 and Affymetrix Human Gene 1.0ST arrays, respectively. Both miRNA and gene expression profiles were integrated by correlation analysis to identify dysregulated miRNAs with their corresponding predicted target mRNA. Microarray data were validated with qRT-PCR. Regulation of IL8 and CDH11 expression by hsa-miR-200c-3p was determined by luciferase reporter assays. RESULTS: When comparing active UC patients vs. controls, 51 miRNAs and 1543 gene probe sets gave significantly different signals. In contrast, in inactive UC vs. controls, no significant miRNA expression differences were found while 155 gene probe sets had significantly different signals. We then identified potential target genes of the significantly dysregulated miRNAs and genes in active UC vs. controls and found a highly significant inverse correlation between hsa-miR-200c-3p and IL8, an inflammatory marker, and between hsa-miR-200c-3p and CDH11, a gene related to intestinal epithelial barrier function. We could demonstrate that hsa-miR-200c-3p directly regulates IL8 and CDH11 expression. CONCLUSION: Differential expression of immune- and barrier-related genes in inflamed UC mucosa may be influenced by altered expression of miRNAs. Integrated analysis of miRNA and mRNA expression profiles revealed hsa-miR-200c-3p for use of miRNA mimics as therapeutics
Interactions between intestinal microbiota and innate immunity receptor NOD2 in Crohn disease and colorectal cancer
No full textPathologie multifactorielle, la maladie de Crohn pourrait être la conséquence de facteurs environnementaux, génétiques et impliquerait également une dérégulation de la réponse immunitaire vis-à-vis du microbiote intestinal. En effet, des variations qualitatives et quantitatives du microbiote intestinal ont pu être mises en évidence chez les patients atteints de cette pathologie. Dysbiose également observée dans le cancer colorectal dont le risque de développement est doublé chez les patients atteints de maladie de Crohn.Dans cette étude, nous nous sommes intéressés au rôle du récepteur de l’immunité innée NOD2, dont les polymorphismes génétiques prédisposent à la maladie de Crohn ainsi qu’à l’influence du microbiote intestinal dans l’établissement de colites et du cancer colorectal.Un modèle murin de colite chimique et de cancer associé à la colite (CAC) a permis de mettre en évidence une aggravation des signes cliniques de ces pathologies chez les animaux Nod2-/- et Rip2-/- en comparaison aux animaux sauvages suggérant un rôle protecteur de NOD2 et de son adaptateur protéique RIP2 dans la colite et à plus long terme dans la tumorigenèse.En vue de déterminer l’origine de ce sur-risque observé chez les animaux Nod2 ou Rip2-déficients nous avons tout d’abord vérifié le caractère transmissible de la colite. Des expériences de co-hébergement et d’adoption ont montré une transmission de la susceptibilité associée aux animaux déficients à des animaux sauvages de manière horizontale (par les congénères) et verticale (par la mère). Une analyse systématique du microbiote dans le modèle de CAC a mis en évidence une réduction de la diversité microbienne ainsi qu’une dysbiose chez les animaux Nod2-/- suggérant une implication de la flore dans l’établissement du sur-risque observé chez les animaux déficients. L’administration d’une antibiothérapie à large spectre a conforté cette hypothèse en réduisant la susceptibilité des animaux Nod2-/-. Une analyse transcriptionnelle a été réalisée afin d’établir les mécanismes moléculaires associés à la colite en réponse au microbiote et a permis de mettre en cause l’IL-6 ainsi que ses gènes cibles déjà décrits pour leur caractère pro-tumoral. Implication confirmée par inhibition de la voie IL-6 à l’aide d’un anticorps bloquant son récepteur capable de réduire la tumorigenèse. Enfin, la génération de souris axéniques Nod2-/- et leur recolonisation par une flore issue de souris sauvages a montré la possibilité d’inverser le sur-risque observé chez les Nod2-/-.Pour conclure, dans un contexte déficient pour Nod2, une réponse inflammatoire à l’encontre du microbiote intestinal dépendante de l’IL-6 favoriserait la mise en place d’une flore délétère qui prédisposerait à la colite et au CAC. Le caractère transmissible de cette flore représente en soi un outil pour l’étude des interactions avec le système immunitaire inné et adaptatif. Enfin, la mise en évidence de la ou des bactéries colitogènes ainsi que des mécanismes inflammatoires impliqués, permettra la mise au point de thérapies ciblées en vue de réduire la tumorigenèse associée à une inflammation persistante chez les patients atteints de la maladie de Crohn.Crohn's disease is a multifactorial disease that could result from environmental factors, genetic factors and would also involved a dysregulation of the immune response against the intestinal microbiota. Indeed, qualitative and quantitative variations of the gut microbiota could be detected in Crohn’s patients or colorectal cancers patients. Moreover, risk of colorectal cancer development is two-fold increased in patients with Croh's disease.In this study, we focused on the role of innate immunity receptor Nod2, which polymorphisms predispose to Crohn's disease, and the influence of gut microbiota in the development of colitis and colorectal cancer.A chemical colitis model and chemical colitis associated cancer (CAC) in mouse highlighted an increased susceptibility of Nod2-/- and Rip2-/- animals compared to WT animals suggesting that NOD2 and its adaptor protein RIP2 can protect from colitis and tumorigenesis.To determine the origin of this increased risk observed in Nod2 or RIP2-deficient animals we first checked the transmissibility of colitis. Co-housing and cross-fostering experiments showed a transmission of susceptibility associated with deficient animals in WT animals horizontally (by congeners) and vertically (by mother). A systematic analysis of the microbiota in CAC model showed a reduction of microbial diversity and a dysbiosis in Nod2-/- animals suggesting an involvement of the flora in the establishment of the increased risk observed in deficient animals. Administration of a broad-spectrum antibiotherapy has confirmed this hypothesis by reducing the susceptibility of Nod2-/- animals. A transcriptional analysis was performed to determine the molecular mechanisms associated with colitis in response to microbiota and highlighted IL-6 and its target genes already described for theirs pro-tumoral effects. Involvement of IL-6 was confirmed by inhibition of IL-6 using an antibody blocking IL-6 receptor that can reduced tumorigenesis. Finally, the generation of germ free Nod2-deficient mice and recolonization by WT mice microbiota showed the ability to reverse the increased risk observed in Nod2-/- mice.Finally, in a context Nod2-deficient, an IL-6-dependent inflammatory response directed against intestinal microbiota, promote the establishment of pro-colitogenic microbiota and would predisposed to colitis and CAC. The transmissibility of this flora may be itself a tool to study interactions between innate and adaptive immune systems. Finally, identification of colitogenic bacteria and inflammatory mechanisms involved, will allow the development of therapies in order to reduce tumorigenesis associated with persistent inflammation in patients with Crohn disease
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
Influence of gut microbiota on the regulation of cancer immunosurveillance
No full textLa protéine 2 contenant un domaine d'oligomérisation de liaison aux nucléotides(NOD2) est apparue comme un acteur essentiel de l'équilibre entre les réponses immunitaires effectrices et tolérogènes. Il est bien connu que NOD2 active de multiples voies de signalisation pour produire des cytokines et des chimiokines qui agissent de concert pour contrôler l'étendue et la spécificité de la réponse immunitaire. Les mutations du gène codant pour NOD2 et la dérégulation de sa voie de signalisation en avalent été associées à une myriade de maladies inflammatoires chroniques, dont la maladie de Crohn. Bien qu'une réponse immunitaire disproportionnée soit observée chez les patients atteints de la maladie de Crohn, il reste contre-intuitif de lier une telle réponse inflammatoire chronique à ces mutations de perte de fonction de la protéine NOD2. Cette énigme renvoie inévitablement à la nécessité de mieux comprendre la régulation de la surveillance immunitaire au sein de la muqueuse intestinale, qui dépend du microbiome. Cela soulève notamment la possibilité qu'il existe des fonctions suppressives inexplorées pour NOD2. La réponse à cette question importante pourrait nous permettre d'ouvrir la voie à la conception de nouvelles thérapeutiques visant à limiter les fonctions tumorigènes de NOD2. Notamment, nous avons identifié NOD2comme un régulateur négatif du contrôle de la surveillance immunitaire médié par l'IL-10 par la souche biothérapeutique Clostridium butyricum MIYAIRI 588 qui potentialise l'entérotropisme de Rorgammat+Treg et le blocage de PD-1. En outre, cela m'a conduit à identifier que Nod1 et Nod2 ont des rôles distincts dans la surveillance immunitaire en tant que modificateurs génétiques de la progression des tumeurs intestinales. Plus précisément, ils ont respectivement des fonctions antitumorales et pro-tumorales, la perte de Nod2 ayant un impact dominant sur la croissance tumorale par rapport àNod1. Par conséquent, la croissance tumorale a été améliorée chez les souris déficientes en Ripk2 ou en Nod1:Nod2 par rapport à ce qui a été observé chez les souris WT lorsque des cellules MC38 syngéniques ont été transplantées. Des résultats similaires ont été observés lorsque des souris déficientes en Nod1 ont été traitées avec un inhibiteur spécifique de Ripk2 ou des souris de type sauvage avec de la vancomycine. L'ensemble de ces résultats ouvre des perspectives pour le développement de nouvelles stratégies de prévention et de traitement du cancer.The nucleotide-binding oligomerization domain-containing protein 2 (NOD2) has emerged as a key player in the balance between effector and tolerogenic immune responses. It is well known that NOD2 activates multiple signaling pathways to produce cytokines and chemokines that act in concert to control the extent and specificity of the immune response. Mutations in the gene encoding NOD2 and deregulation of its downstream signaling pathway have been associated with a myriad of chronic inflammatory diseases, including Crohn's disease. Although a disproportionate immune response is observed in Crohn's patients, it remains counterintuitive to link such a chronic inflammatory response to these loss-of-function mutations in theNOD2 protein. This conundrum inevitably points to the need to better understand the microbiome-dependent regulation of immune surveillance within the intestinal mucosa. In particular, it raises the possibility that there are unexplored suppressive functions for NOD2. Answering this important question could pave the way for the design of new therapeutics aimed at limiting the tumorigenic functions of NOD2. Notably, we identified NOD2 as a negative regulator of IL-10-mediated immune surveillance by the biotherapeutic strain Clostridium butyricum MIYAIRI 588, which potentiates Rorgammat+Treg enterotropism and PD-1 blockade. Furthermore, this led me to identify that Nod1 and Nod2 have distinct roles in immune surveillance as genetic modifiers of intestinal tumor progression. Specifically, they have antitumoral and pro-tumoral functions respectively, with loss of Nod2 having a dominant impact on tumor growth compared toNod1. Consequently, tumor growth was enhanced in Ripk2- or Nod1:Nod2-deficient mice compared with what was observed in WT mice when syngeneic MC38 cells were transplanted. Similar results were observed when Nod1-deficient mice were treated with a specific Ripk2 inhibitor or wild-type mice with vancomycin. Taken together, these results open up prospects for the development of new cancer prevention and treatment strategies
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