1,720,958 research outputs found
Elucidating the Role of Cyclic GMP in Diarrhoea and Intestinal Inflammation
No full textCyclic guanosine 3’,5’-monophosphate (cGMP) performs a wide range of functions in various cell types and tissues. The cellular levels of cGMP are maintained by the enzymatic conversion of guanosine 5’-triphosphate (GTP) to cGMP by guanylyl cyclases, which can also be membrane-associated receptors. Receptor guanylyl cyclase C (GC-C; gene GUCY2C) is predominantly expressed on the apical surface of the intestinal epithelial cells. GC-C is activated by peptide hormones guanylin and uroguanylin and the heat-stable enterotoxin (ST) produced by enterotoxigenic E.coli that causes traveller’s diarrhoea.
Several disease-causing mutations in GUCY2C have been reported. Patients with gain-of-function mutations show diarrhoea and inflammatory bowel disease (IBD). Several cases of paediatric IBD have also been associated with mutations in GUCY2C. This study addresses the physiological implications of increased cGMP using a transgenic mouse model harbouring the first-identified hyperactive mutation in human patients leading to familial GUCY2C diarrhoea syndrome (FGDS). Mice with hyperactive GC-C showed increased levels of cGMP in intestinal epithelial cells, which led to activation of Cftr and inhibition of Nhe3, resulting in diarrhoea-like symptoms and increased luminal pH and faecal sodium levels. Global transcriptome analysis of the distal colon revealed activation of the interferon signalling pathway, and transgenic mice showed greater susceptibility to DSS-induced colitis.
Histological analysis of the terminal ileum revealed a reduction in functional Paneth cells, goblet cells, and mucus barrier. The barrier integrity of the small intestine was compromised in these mice. Global transcriptome analysis of the terminal ileum revealed a Th1-type gene signature. Immune cell profiling across the gut-associated lymphoid tissue (GALT) showed reduced regulatory dendritic cells and an increased abundance of CD4+ Th cells. Increased levels of Stat1 were observed in the ileal epithelial cells of these mice, along with elevated expression of interferon-stimulated genes.
Small intestinal organoids were prepared from wild type and transgenic mice. The organoids from transgenic mice showed greater swelling in the presence of ST and uroguanylin due to increased fluid secretion into the lumen. Administration of cGMP increased Stat1 phosphorylation in the intestinal organoids. Our observations suggest that high cGMP levels have epithelial cell-extrinsic and cell-intrinsic roles in inducing intestinal inflammation. Furthermore, the administration of zinc inhibited the activity of GC-C and reduced diarrhoea and intestinal inflammation in the transgenic mice. Thus, the similarities observed in these transgenic mice with that of chronic diarrhoea and IBD patients indicate that they can be used as a pre-clinical model to understand the effects of chronically elevated cGMP on intestinal pathophysiology and for identifying novel therapeutic strategies for patients with hyperactivating mutations in GUCY2C
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
The pseudokinase domain in receptor guanylyl cyclases
No full textCyclic GMP is produced by enzymes called guanylyl cyclases, of which the membrane-associated forms contain an intracellular pseudokinase domain that allosterically regulates the C-terminal guanylyl cyclase domain. Ligand binding to the extracellular domain of these single transmembrane-spanning domain receptors elicits an increase in cGMP levels in the cell. The pseudokinase domain (or kinase-homology domain) in these receptors appears to be critical for ligand-mediated activation. While the pseudokinase domain does not possess kinase activity, biochemical evidence indicates that the domain can bind ATP and thereby allosterically regulate the catalytic activity of these receptors. The pseudokinase domain also appears to be the site of interaction of regulatory proteins, as seen in the retinal guanylyl cyclases that are involved in visual signal transduction. In the absence of structural information on the pseudokinase-guanylyl cyclase domain organization of any member of this family of receptors, biochemical evidence has provided clues to the physical interaction of the pseudokinase and guanylyl cyclase domain. An α-helical linker region between the pseudokinase domain and the guanylyl cyclase domain regulates the basal activity of these receptors in the absence of a stimulatory ligand and is important for stabilizing the structure of the pseudokinase domain that can bind ATP. Here, we present an overview of salient features of ATP-mediated regulation of receptor guanylyl cyclases and describe biochemical approaches that allow a clearer understanding of the intricate interplay between the pseudokinase domain and catalytic domain in these proteins
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