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Regulation of IL-4 mediated signalling in primary human bronchial fibroblasts by IL-13Rα2
No full textFibroblasts are key effector cells involved in airway inflammation and remodelling in asthma. Interleukin (IL)-4 and IL-13 are important cytokines in the asthma phenotype which act on fibroblasts and other cell types. These cytokines exhibit overlapping functions through use of a common receptor, IL-4Rα:IL-13Rα1. Another receptor, IL 13 Receptor α2 (IL-13Rα2), originally thought to be a decoy receptor for IL-13, has recently been shown to attenuate responses to IL-4 as well as IL-13, by an unknown mechanism. In this thesis, I tested the hypothesis that IL-13Rα2 is responsible for the regulation of IL-4 mediated signalling in bronchial fibroblasts and that regulation by IL-13Rα2 is altered in asthma. The expression of IL-4 and IL-13 receptors on human bronchial fibroblasts (HBFs) was highly dynamic. IL-13Rα2 expression was significantly increased in response to both IL-4 and IL-13 over 24 hours, requiring de novo protein synthesis. A significant rapid reduction in IL-4Rα expression was also observed in response to either ligand, although levels rapidly returned to normal after removal of the stimulus. Use of a neutralizing antibody showed that induction of IL 13Rα2 suppressed STAT-6 activation and the pro-inflammatory effects of IL-4 and IL-13. No difference was observed in receptor expression levels or the regulatory effects of IL-13Rα2 between healthy and asthmatic subjects. IL-13Rα2 was also up-regulated by a range of Th1 stimuli including IFNγ and IFNβ, as well as double stranded RNA (dsRNA), with no disease-related differences. The up-regulation of IL 13Rα2 in response to dsRNA hampered attempts to knock down surface expression of IL-13Rα2 using siRNA, but revealed a potential role for IL-13Rα2 in the anti-viral response due to its ability to down-regulate responses to IL-4 and IL-13. An over expression model of IL-13Rα2 identified the potential for IL-4 to cause activation of STAT3 mediated by IL-13Rα2. In HBFs naturally expressing high levels of IL-13Rα2, addition of IL-4, but not IL-13, significantly increased activation of STAT3, a transcription factor associated with cell survival. Whilst IL-13Rα2 may have beneficial anti-inflammatory effects by suppressing STAT-6 mediated responses, further work is required to determine potential pro-fibrotic consequences of IL-4/IL-13Rα2 mediated STAT3 activation in HBFs. Since no difference was observed in IL-13Rα2 expression or in its anti-inflammatory efficacy in HBFs from normal or asthmatic donors, these data suggest that the atopic environment is more important than intrinsic differences in the ability of asthma-derived fibroblasts to respond to IL-4 and IL-13
The innate antiviral response upregulates IL-13 receptor ?2 in bronchial fibroblasts
No full textIFN-? induces IL-13R?2 expression, leading to a consequential suppression of responsiveness to IL-13. These data suggest cross-talk between TH1 and TH2 pathways and point to an immunomodulatory role for IL-13R?2 in human bronchial fibroblasts during viral infectio
The association of the cytoplasmic domains of interleukin 4 receptor alpha and interleukin 13 receptor alpha 2 regulates interleukin 4 signaling
Get PDFInterleukin-4 (IL-4) and Interleukin-13 (IL-13), key cytokines in the pathogenesis of allergic inflammatory disease, mediate their effects via a receptor composed of IL-13R?1 and IL-4R?. A third (decoy) receptor called IL-13R?2 regulates interleukin signaling through this receptor complex. We employed a variety of biophysical and cell-based techniques to decipher the role of this decoy receptor in mediating IL-4 signaling though the IL-4R?–IL-13R?1 receptor complex. Surface plasmon resonance (SPR) analysis showed that IL-13R?2 does not bind IL-4, and does not affect binding of IL-4 to IL-4R?. These results indicate that the extracellular domains of IL-4R? and IL-13R?2 are not involved in the regulation of IL-4 signaling by IL-13R?2. We next used a two-hybrid system to show that the cytoplasmic domains of IL-4R? and IL-13R?2 interact, and that the secondary structure of the IL-13R?2 intracellular domain is critical for this interaction. The cellular relevance of this interaction was next investigated. BEAS-2B bronchial epithelial cells that stably express full length IL-13R?2, or IL-13R?2 lacking its cytoplasmic domain, were established. Over expression of IL-13R?2 attenuated IL-4 and IL-13 mediated STAT6 phosphorylation. IL-13R?2 lacking its cytoplasmic domain continued to attenuate IL-13-mediated signaling, but had no effect on IL-4-mediated STAT6 signaling. Our results suggest that the physical interaction between the cytoplasmic domains of IL-13R?2 and IL-4R? regulates IL-4 signaling through the IL-4R?–IL-13R?1 receptor complex.<br/
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
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