1,720,980 research outputs found
Virus-induced Glucocorticoid Insensitivity in the Airways
No full text© 2020 Asmaa Radwan Ahmed ElsayedChronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) pose a major public health burden. Hospitalization, mortality and increased health care costs owing to these diseases are amongst the consequences of exacerbations. Exacerbations are usually elicited by respiratory infections, allergens, environmental pollutants or occupational sensitizers. These factors may work in either an additive or synergistic manner. Regular management using inhaled glucocorticoids (GCs) has an unquestioned benefit in alleviating exacerbations unless the respiratory viruses were the trigger. Due to the few alternative anti-inflammatory therapies available, restoring glucocorticoid (GC) efficacy is indispensable. Among the respiratory viruses implicated in asthma/COPD exacerbations is respiratory syncytial virus (RSV); the prime respiratory virus associated with bronchiolitis and pneumonia in infants, young children, immunocompromised adults and the elderly worldwide. Despite the fact that RSV-induced pathogenesis is in part inflammatory, the beneficial effect of GCs in alleviating the symptoms or altering the course of illness is still debatable. Several reports suggested that RSV infection has a detrimental effect on GC signalling through mechanisms that are not yet defined.
Being the prime locus for viral infection and replication and the crucial target for glucocorticoid therapy as well, airway epithelium has been suggested as a key cell type in which virus-induced glucocorticoid resistance may occur. The airway epithelium releases a surplus of cytokines and chemokines leading to airway inflammation and airway structural changes seen in asthma. Among these inflammatory mediators is the transforming growth factor beta1 (TGF-b1). Our laboratory has identified TGF-b1 as the key mediator of glucocorticoid insensitivity in bronchial epithelial cells where it ablates glucocorticoid activity at pathophysiologically relevant picomolar concentrations. We, therefore, investigated the possible contribution of this key cytokine to RSV-induced GC resistance.
Data presented within this thesis has provided the first evidence that TGF-b1 drives RSV-induced GC-insensitivity in bronchial epithelium transformed with Ad12-SV40 2B (BEAS-2B) cell line. However, blanket inhibition of TGF-b1 using TGF-b receptor (activin-like kinase 5 (ALK5/ TGF-bR1 kinase) selective inhibitor, SB431542 compromises its beneficial pleiotropic effects leading to serious adverse effects. Our group has recently identified casein kinase 1delta /epsilon (CK1d/e) as a downstream effector of TGFb-induced remodelling and steroid resistance. Our data also implicated CK1d/e in RSV triggered impairment of GC responsiveness where pharmacological inhibition of CK1d/e by PF670462 has inhibited the expression and activity of TGF-b1 and subsequently prevented the GC impairment provoked by RSV infection in our in vitro model. Moreover, PF670462 has significantly subdued RSV-induced expression of pro-inflammatory gene suggesting the potential for additional beneficial anti-inflammatory activities mediated by PF670462. This potential was further confirmed in vivo, where we have provided evidence of an interaction between PF670462 and dexamethasone to achieve greater control of the pulmonary inflammation following RSV infection.
Moreover, we evaluated the contribution of different epithelial pattern recognition receptors (PRRs) involved in RSV sensing in the apparent resistance using a wide array of PRRs ligands. Among the ligands tested was polyinosinic:polycytidylic acid (poly I:C); a synthetic analogue of double-stranded RNA (dsRNA) that is frequently used as a viral mimic. Our results showed that that viral pathogen-associated molecular patterns (PAMPs), most importantly double-stranded RNA (dsRNA), activates toll-like receptor 3 (TLR3), activates toll-like receptor 3 (TLR3) that in turn signals through the extracellular signal-regulated kinase 1/2 (ERK1/2)-dependent pathway to promote TGF-b activity hence mediating GC resistance in airway epithelial cells. Genetic approaches established that targeting TLR3 may restore the responsiveness to glucocorticoids.
In conclusion, we demonstrated that RSV impairs glucocorticoid sensitivity in airways epithelium partly through TLR3 activation with subsequent release of TGF-b1, a potent mediator of glucocorticoid resistance. We also implicated CK1d/e in the apparent resistance. This thesis provided novel insights into mechanisms of glucocorticoid insensitivity in the airway epithelium. These findings offered two novel anchor points; CK1d/e and TLR3, for a potential treatment for the prevention/treatment of GC insensitivity occurring during RSV infection-induced bronchiolitis or asthma/ COPD exacerbations
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
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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