1,720,996 research outputs found
Effetto della tetraciclina a dosi auxiniche sulla flora microbica intestinale del vitello
No full textROLE OF INTESTINAL CX3CR1+ MACROPHAGES IN THE DEVELOPMENT OF COLITIS-ASSOCIATED CANCER: FOCUS ON THE RELEVANCE OF THE MICROBIOME AND HEME-OXYGENASE-1
Full text linkGut represents a complex landscape in which commensal bacteria, harmless antigens and food proteins are strictly in contact with the immune system that has to be able to maintain a balance between the immune response and tolerance. In this context, mononuclear phagocytes are the most abundant population and macrophages represent a key player in this process of discrimination by allowing a peaceful coexistence. If this crucial checkpoint is lost, immune system is activated and falls in a dangerous and prolonged inflammation. Recent studies have described CX3CR1+ cells as a population of resident macrophages able to sample the gut lumen and to produce the anti-inflammatory cytokine IL-10 in order to maintain homeostasis. These macrophages are characterized by the expression of the chemokine receptor CX3CR1; however, how this receptor is involved in the molecular mechanisms that regulate the inflammatory response is largely unknown.
The global aim of this thesis is to define the role of mucosal CX3CR1+ macrophages during acute and chronic inflammation and in the process of intestinal carcinogenesis, and to investigate the molecular mechanisms by which these immune cells maintain gut homeostasis.
We analyzed the behavior of these macrophages in mice lacking the CX3CR1 receptor (CX3CR1GFP/GFP) and in wild type heterozygous mice (CX3CR1GFP/+). Firstly, we characterized them as a macrophagic population expressing CX3CR1, F4/80, CD11b and CD64 confirming the data present in literature.
As the behavior of these cells is less defined during the resolution of inflammation, we performed a model of recovery from colitis and we found that KO mice displayed higher signs of inflammation compared to WT mice, and they were not able to recover as WT mice did. From the molecular point of view, we found that the inflammatory mediators were up-regulated in KO mice as well as members of the IL-10 family cytokines. The only mediator resulting down-regulated in KO mice was heme-oxygenase-1 (hemox-1).
Hemox-1 is an anti-inflammatory enzyme over-expressed during tissue injury that is able to promote bacteria clearance. This regulation of this molecule is very complex and involves also IL-10. However, despite KO mice produced more IL-10, in an attempt to switch off inflammation, they were not able to produce an adequate amount of hemox-1.
We reproduced, in vitro, the model of colitis and we showed that macrophages from KO mice responded to the inflammatory stimulus (LPS) with an aberrant response, up-regulating both pro and anti-inflammatory mediators, but not hemox-1. Moreover, we observed a synergism between LPS and the chemokine Fracktalkine/CX3CL1 (FKN) in the production of hemox-1 in WT mice and also found that stimulation with FKN alone was sufficient to produce hemox-1 in WT mice, unveiling a previously unidentified role of the chemokine receptor CX3CR1 in the regulation of hemox-1.
Using the AOM/DSS model of colitis-induced carcinogenesis (CAC), a study that has never been performed in these genetically modified mice, we found significantly higher signs of inflammation in KO mice in terms of both cytokine production and immune cell infiltration, as well as higher score of tissue damage and number of polyps. Also in the CAC model, KO mice attempt to switch off inflammation by over-producing IL-10 levels; furthermore, hemox-1 was under-expressed. We therefore decided to enhance hemox-1 production using cobalt protoporphyrin IX (coPP), a compound able to stimulate hemox-1 in the intestine. The experiments revealed that treatment with coPP was able to revert the phenotype in KO mice, resulting in marked lower inflammation and reduced tumor load. To corroborate these findings, we investigated a genetic model of intestinal tumorigenesis (APCmin mice) and generated APCmin CX3CR1GFP/+ WT mice and APCmin CX3CR1GFP/GFP KO mice. Also in this tumor model, mice deficient for the CX3CR1 receptor demonstrated higher inflammation, lower Hemox-1 and more extensive tumorigenesis, thus overall confirming the results obtained with the sporadic CAC model.
Hemox-1 acts on macrophages by stimulating the processes of phagocytosis; accordingly, we found that bacteria phagocytosis was significantly impaired in KO mice. The sequencing of the microbiota in the stools of mice treated with the AOM-DSS model, revealed a different microbiota composition, in particular, Akkermansia were down represented in KO mice. Akkermansia is reported to be impaired during inflammatory bowel diseases, leading to the rise of other bacteria and to an overall dysregulation of the total microbiome composition. This dysbiosis might be involved in disease relapse and rise of chronic inflammation that can lead to cancer development.
Overall, we unveiled a new pathway by which intestinal CX3CR1+ macrophages operate to maintain gut homeostasis. If the CX3CL1-CX3CR1 checkpoint is lost, the FKN-induced production of hemox-1 is missing and an aberrant inflammatory response could persist and be corroborated by a state of dysbiosis. In this landscape, chronic inflammation and the impaired resolution could, over time, promote tumor development. Finally, we confirmed that treatment with the chemical compound coPP up-regulates hemox-1 also in the absence of functional CX3CR1 receptor, and drastically ameliorates the intestinal disease. These findings open a new scenario in the use of hemox-1-inducing drugs to restore the correct intestinal homeostasis in a therapeutic context
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
Sturttura e propretà meccaniche di materiali polimerici a base di polibutilentereftalato (PBT) ottenuti da miscelazione reattiva
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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
Assessing the Mvar generation values to price the reactive support to a hierarchical voltage control
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