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Assessing the role of gut barrier integrity in the pathogenesis of autoimmune diabetes.
Get PDFAn increase in gut barrier (GB) permeability and abnormal crosstalk between commensal gut microbiota and immune cells underlies the pathogenesis of Type 1 Diabetes (T1D). The gut microbiota plays a pivotal role in triggering this “leaky gut” condition, as suggested by the presence of dysbiosis in T1D patients and at-risk-individuals. Particularly, the presence of LPScarrying bacteria in children is associated with higher risk to develop T1D but the mechanism through which LPS modulates T1D are unknown. Epithelial Toll-like receptors (TLRs) signaling are important in the cross-talk between the host and the gut microbiota. Under homeostatic conditions, commensal LPS triggers the activation of a tolerogenic TLR4-mediated pathway on intestinal epithelial cells (IEC) through activation of the TRAF3 signaling pathway and promotes Treg cell differentiation thus maintaining immune tolerance and GB integrity; on the other hand, a dysregulated overactivation of epithelial TLR4 signaling induces the activation of a proinflammatory pathway through MYD88-TRAF6 signaling contributing to intestinal inflammation, damage of the GB and breakage of intestinal immune homeostasis. Here, we tested the hypothesis that loss of GB integrity and intestinal inflammation present in patients and preclinical models of T1D is due to a dysregulated epithelial TLR4 signaling. Our in-vivo and in-vitro data show that NOD mice, the spontaneous preclinical model of T1D, carry an inherent overstimulation of the epithelial TLR4-induced TRAF6 signaling pathway under basal homeostatic conditions at the expenses of the tolerogenic TRAF3-mediated signaling pathway. Furthermore, IEC of NOD have an impaired response to the commensal LPS in-vivo leading to defective FoxP3+Treg cell differentiation, impaired mucus barrier structure and intestinal inflammation compared to non- autoimmune strains of mice (i.e., C57BL/6 mice) as well as diabetes-resistant NOD mice, thus suggesting that the abnormal response to commensal LPS is directly linked to T1D pathogenesis. The abnormal activation of the MYD88-TRAF6 signaling was confirmed in NOD-derived intestinal organoids and is related to altered posttranscriptional regulation mechanisms as demonstrated by decreased expression of miR-146a, a key regulator of the TLR4 signaling, in IEC of both newborn and adult NOD mice compared to the non-autoimmune counterpart. Importantly, our findings in the preclinical model were validated in human T1D patients in which we found that an overactivation of the TLR4-induced TRAF6-mediated inflammatory pathway in the small intestinal mucosa. Here we demonstrate that preclinical models and humans affected by autoimmune T1D have a dysregulated response to commensal LPS that triggers a pro-inflammatory TLR4-signaling pathways possibly leading to damage of GB integrity and reduced intestinal immune tolerance. Further studies are necessary to link the defective response to commensal LPS to activation of islet-reactive T cells and autoimmune pathogenesis of T1D in preclinical models and humans.Studi in letteratura evidenziano che l’aumento della permeabilità della barriera intestinale (BI), insieme a un’alterata interazione tra il microbiota intestinale commensale e le cellule del sistema immunitario mucosale, sono correlati alla patogenesi del diabete di tipo 1 (T1D). La presenza di disbiosi microbica sia nei pazienti affetti da T1D ma anche in individui a rischio di sviluppare T1D suggerisce che il microbiota ha un un ruolo chiave nello sviluppo di T1D. Studi più approfonditi hanno evidenziato che la presenza di batteri portatori di lipopolisaccaride (LPS) è associata a un rischio maggiore di sviluppare il T1D nei bambini. Nonostante ciò, il meccanismo attraverso il quale l’LPS batterico modula la patogenesi del T1D è ancora poco noto. Le interazioni tra microbiota commensale e l’ospite avvengono tramite una classe di recettori chiamati “Toll-like receptors” (TLRs). L’LPS batterico viene riconosciuto nello specifico dal TLR4 il quale, in condizioni omeostatiche, innesca l'attivazione di una via tollerogenica mediata dal secondo messaggero intracellulare TRAF3, il quale promuove il differenziamento delle cellule T regolatorie (Treg) mantenendo così la tolleranza immunitaria e l'integrità della BI. Al contrario, in presenza di un’alterata iperattivazione del TLR4 si attiva la via infiammatoria mediata dai messaggeri intracellulari MYD88 e TRAF6 con conseguente danno della BI e rottura dell'omeostasi immunitaria intestinale. Nel presente studio, abbiamo testato l'ipotesi secondo la quale la perdita dell’integrità della BI nei pazienti e nei modelli preclinici di T1D sia dovuta a un’alterazione della segnalazione del recettore TLR4 nell’epitelio intestinale in risposta all’LPS batterico. Dai nostri esperimenti in-vivo e in-vitro è emerso che i topi NOD, il modello preclinico spontaneo di T1D, presentano nella BI un’iperattivazione intrinseca della via di segnalazione infiammatoria mediata dai messaggeri intracellulari MYD88 e TRAF6 in condizioni omeostatiche. Inoltre, a seguito del trattamento in-vivo la BI del topo NOD ha dimostrato una risposta compromessa all'LPS commensale con conseguente differenziazione difettosa delle cellule Treg, al contrario del modello murino non-autoimmune di controllo, i topi C57BL/6, e di un gruppo di topi NOD resistenti al T1D. La risposta compromessa all'LPS nel topo NOD è stata confermata anche da esperimenti svolti con organoidi intestinali. Inoltre, da ulteriori esperimenti è emerso che il topo NOD presenta alterazioni nei meccanismi post-trascrizionali che controllano la segnalazione intracellulare mediata dal TLR4, nello specifico riguardo il miR-146a, un RNA non codificante che controlla la segnalazione intracellulare mediata dal TLR4. In aggiunta, grazie alla collaborazione con l’unità di gastroenterologia dell’ospedale San Raffaele, abbiamo analizzato la segnalazione intracellulare del TLR4 anche nell’epitelio intestinale isolato da biopsie duodenali di pazienti affetti da T1D ed è emerso che, rispetto a soggetti di controllo, anche la mucosa intestinale dei pazienti è caratterizzata da un amento dell’espressione genica del recettore TLR4 e del messaggero intracellulare infiammatorio TRAF6. In conclusione, i nostri dati suggeriscono che sia i modelli preclinici sia soggetti affetti da T1D rispondono all’LPS commensale innescando una via di segnalazione mediata dal TLR4 di tipo infiammatorio, che potrebbe portare a danni all'integrità della BI e ad una ridotta tolleranza immunitaria intestinale. Sono tuttavia necessari ulteriori studi per collegare la risposta difettosa all'LPS commensale con l’attivazione delle cellule T auto-reattive specifiche per le isole pancreatiche che caratterizzano la patogenesi autoimmune del T1D
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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