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Crohn's disease: an in vitro analysis of T lymphocyte function and response to commensal microbes
No full textInflammatory bowel disease is a chronic, relapsing inflammation of the intestine. Approximately 0.5% of the western world is estimated to suffer from the disease. Crohn’s disease, a type of inflammatory bowel disease, consists of a patchy inflammation, that can occur throughout the entire gastrointestinal tract. Due to the heterogeneous nature of Crohn’s disease, little is known about the mechanisms of disease pathogenesis. Compared to healthy individuals, patients with Crohn’s disease often have elevated levels of inflammatory T lymphocyte subsets, their associated effector cytokines, and higher intestinal permeability. Crohn’s disease has been associated with genetic risk factors, sedentary lifestyles, and a loss of tolerance to the commensal members of the microbiome.
In this research, T lymphocytes from non-IBD and Crohn’s disease patient peripheral blood mononuclear cells (PBMCs) were analysed for comparison. Flow cytometry was used to fluorescently label cells and analytes of interest. Visual analytic tools, such as CytoAnalytics’ EarlyBird and viSNE were used to visualise patient variation within, and between groups. It was hypothesised that Crohn’s disease T lymphocytes would have a bias for inflammation-inducing T lymphocyte subsets, and that these cells would have a higher capacity for inflammation, than non-IBD controls. Indeed, inflammatory T lymphocytes were present at higher frequencies in Crohn’s disease patient blood samples. Furthermore, Crohn’s disease patient PBMCs had a higher capacity for proliferation in response to T lymphocyte stimulation. In responses to the commensal bacterium, Faecalibacterium prausnitzii, Crohn’s disease patient PBMC Tregs increased in frequency, whereas CD4+ inflammatory T lymphocyte subsets maintained their frequency. In contrast, non-IBD PBMC Tregs were not influenced by co-culture with F. prausnitzii, and CD4+ inflammatory T lymphocyte subsets decreased in the presence of F. prausnitzii. Together, these data suggest that Crohn’s disease patient PBMCs respond abnormally to commensal bacteria, and this could play a role in disease pathogenesis.
Intestinal organoids are derived from patient colonic biopsy stem cells. Organoids provide a unique in vitro model for the observation of intestinal interactions. In this thesis, a 2D intestinal monolayer was developed from the culture of 3D intestinal organoids. 2D monolayers emulate epithelial intestinal barrier cellular organisation. A difficult question to answer in Crohn’s disease research is whether intestinal permeability and inflammation is a cause or consequence of disease. As such, patient organoids and bacteria were integrated into the model stepwise, to analyse the influence each component has on the system, in the absence, or presence, on an active immune presence. Using this model, it was found that monolayers derived from Crohn’s disease patients were more permeable than non-IBD controls. Furthermore, Crohn’s disease patient monolayers had deleterious interactions in co-culture with F. prausnitzii, resulting in reduced epithelial integrity; in contrast to non-IBD patient monolayers which were unaffected. The addition of matched PBMCs into Crohn’s disease patient monolayers exacerbated epithelial degradation in the presence of F. prausnitzii.
Taken together, it was found that Crohn’s disease patient PBMCs had greater inflammatory capacity than non-IBD control PBMCs. These data suggest that intestinal cells in patients with Crohn’s disease may have deleterious interactions with commensal bacteria, which could result in increased intestinal permeability. Furthermore, Crohn’s disease patient Treg responses to commensal bacteria suggest that intestinal areas of immune suppression may promote bacteria success, and potential dysbiosis. Translocation of the luminal microbiota into the lamina propria, combined with excessive T lymphocyte inflammatory capacity, could be an initial driving factor for Crohn’s disease pathogenesis.
Data in this thesis provide valuable insight into the initiation of epithelial degradation in patients with Crohn’s disease. These data suggest that epithelial degradation may occur in Crohn’s disease patients in response to commensal bacteria, even in the absence of an immune cell influence. With further development, the intestinal organoid monolayer model may provide insight into the mechanisms of epithelial degradation in individual patients. Further, the monolayer model may also provide a tool to optimise individual patient treatments, in vitro
Crohn's disease: an in vitro analysis of T lymphocyte function and response to commensal microbes
Get PDFInflammatory bowel disease is a chronic, relapsing inflammation of the intestine. Approximately 0.5% of the western world is estimated to suffer from the disease. Crohn’s disease, a type of inflammatory bowel disease, consists of a patchy inflammation, that can occur throughout the entire gastrointestinal tract. Due to the heterogeneous nature of Crohn’s disease, little is known about the mechanisms of disease pathogenesis. Compared to healthy individuals, patients with Crohn’s disease often have elevated levels of inflammatory T lymphocyte subsets, their associated effector cytokines, and higher intestinal permeability. Crohn’s disease has been associated with genetic risk factors, sedentary lifestyles, and a loss of tolerance to the commensal members of the microbiome.
In this research, T lymphocytes from non-IBD and Crohn’s disease patient peripheral blood mononuclear cells (PBMCs) were analysed for comparison. Flow cytometry was used to fluorescently label cells and analytes of interest. Visual analytic tools, such as CytoAnalytics’ EarlyBird and viSNE were used to visualise patient variation within, and between groups. It was hypothesised that Crohn’s disease T lymphocytes would have a bias for inflammation-inducing T lymphocyte subsets, and that these cells would have a higher capacity for inflammation, than non-IBD controls. Indeed, inflammatory T lymphocytes were present at higher frequencies in Crohn’s disease patient blood samples. Furthermore, Crohn’s disease patient PBMCs had a higher capacity for proliferation in response to T lymphocyte stimulation. In responses to the commensal bacterium, Faecalibacterium prausnitzii, Crohn’s disease patient PBMC Tregs increased in frequency, whereas CD4+ inflammatory T lymphocyte subsets maintained their frequency. In contrast, non-IBD PBMC Tregs were not influenced by co-culture with F. prausnitzii, and CD4+ inflammatory T lymphocyte subsets decreased in the presence of F. prausnitzii. Together, these data suggest that Crohn’s disease patient PBMCs respond abnormally to commensal bacteria, and this could play a role in disease pathogenesis.
Intestinal organoids are derived from patient colonic biopsy stem cells. Organoids provide a unique in vitro model for the observation of intestinal interactions. In this thesis, a 2D intestinal monolayer was developed from the culture of 3D intestinal organoids. 2D monolayers emulate epithelial intestinal barrier cellular organisation. A difficult question to answer in Crohn’s disease research is whether intestinal permeability and inflammation is a cause or consequence of disease. As such, patient organoids and bacteria were integrated into the model stepwise, to analyse the influence each component has on the system, in the absence, or presence, on an active immune presence. Using this model, it was found that monolayers derived from Crohn’s disease patients were more permeable than non-IBD controls. Furthermore, Crohn’s disease patient monolayers had deleterious interactions in co-culture with F. prausnitzii, resulting in reduced epithelial integrity; in contrast to non-IBD patient monolayers which were unaffected. The addition of matched PBMCs into Crohn’s disease patient monolayers exacerbated epithelial degradation in the presence of F. prausnitzii.
Taken together, it was found that Crohn’s disease patient PBMCs had greater inflammatory capacity than non-IBD control PBMCs. These data suggest that intestinal cells in patients with Crohn’s disease may have deleterious interactions with commensal bacteria, which could result in increased intestinal permeability. Furthermore, Crohn’s disease patient Treg responses to commensal bacteria suggest that intestinal areas of immune suppression may promote bacteria success, and potential dysbiosis. Translocation of the luminal microbiota into the lamina propria, combined with excessive T lymphocyte inflammatory capacity, could be an initial driving factor for Crohn’s disease pathogenesis.
Data in this thesis provide valuable insight into the initiation of epithelial degradation in patients with Crohn’s disease. These data suggest that epithelial degradation may occur in Crohn’s disease patients in response to commensal bacteria, even in the absence of an immune cell influence. With further development, the intestinal organoid monolayer model may provide insight into the mechanisms of epithelial degradation in individual patients. Further, the monolayer model may also provide a tool to optimise individual patient treatments, in vitro
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
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