1,720,961 research outputs found
The actin-nucleator promoting factor WASp regulates endo-lysosomal maturation and Toll-like receptor 9 signaling in Dendritic Cells.
No full textToll-like receptors (TLRs) are innate immune receptors, which play a key role in both innate and adaptive immune responses, are important to recognize pathogenic components and to trigger inflammatory responses. However, TLRs could be inappropriately activated by self and endogenous nucleic acids leading to unwarranted inflammation with dangerous outcomes, including autoimmune diseases. Intracellular TLRs compartmentalization is essential to regulate initiation and termination of signalling, thereby avoiding excessive inflammation. Therefore, studies of mechanisms and adaptors that limit unrestrained activation of innate immune cells upon TLRs triggering are of increasing interest as their potential in understanding autoimmunity.
Wiskott-Aldrich Syndrome (WAS) is a X-linked primary immune deficiency, caused by mutations on WAS-protein (WASp), a hematopoietic specific actin nucleator promoting factor (NPFs). WAS is characterized by recurrent infections, and a marked predisposition to develop autoimmune phenomena.
This thesis aimed to dissect the molecular mechanism that leads to excessive production of type-I interferon in the context of WAS, using a model of WASp null dendritic cells (WKO DCs).
First, we developed and validated new cellular models to study WASp. We demonstrated that, after TLR9 stimulation, WKO cells produce higher amount of type-I IFN and proinflammatory cytokines, both in BM-DCs and Hoxb8-DCs models. Moreover, our dose-response assay of endogenous ligands showed that WKO display a lower TLR9 activation threshold compared to wild-type (WT) DCs.
Intriguingly, our morphological analysis revealed structural alterations in endo-lysosomes of WKO DCs. Using flow cytometry and endocytic probes we observed that the lack of WASp leads to aberration in cargo recycling and degradation.
We then investigated whether WKO structural and functional remodeling could influence TLR9-ligand intracellular trafficking. By blocking protein synthesis, we demonstrated that WASp expression is important to control TLR9 degradation rate. In addition, biochemical and immunofluorescence analysis revealed that exogenous and endogenous TLR9 ligands are engulfed in WKO cells. In particular, ligands traffic slowly across the first endocytic organelles and are degraded less efficiently than in WT DCs. Finally, using actin inhibitors, we observed that treated cells display impaired endo-lysosome maturation and reduced TLR9 degradation. Most importantly, TLR9 signalling is enhanced leading to higher production of type-I IFN. Taken together, these results prove that the perturbation of actin dynamics closely resembles WASp deficiency phenotype.
In conclusion, our findings shed light on the mechanism underlying excessive TLR9 activation: actin nucleation mediated by WASp is required to maintain a correct endo-lysosomal organization and to control TLR9 threshold, activation and signalling in DCs
Study on mupirocin treatment in cutaneous lupus erythematosus: comment on the article by Abernathy-Close et al
No full textAbernathy-Close et al1 provide a valuable contribution to theunderstanding of therapy for cutaneous lupus erythematosus(CLE) through their proof-of-concept study examining the effectsof mupirocin, a topical antibiotic, on inflammatory pathways withinCLE lesions. Their data indicate a correlation between reducedStaphylococcus aureus bacterial load and a subsequent declinein local inflammation, as well as decreased expression of inflam-matory genes, .particularly those related to type I interferon (IFN)signaling. These findings highlight the pivotal role of the skinmicrobiome in influencing immune responses and advancingtreatment options for lupus-associated skin lesion
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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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