1,720,953 research outputs found
Understanding the molecular and intracellular function of vitamin D in the immune system: Implications for translation.
No full textVitamin D is a hormone that can be obtained from food (e.g. fatty fish and dairy products), but is mainly made in the skin where sunlight exposure converts it into its biologically active metabolite, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). The widespread expression of the vitamin D receptor (VDR) and vitamin D3-metabolizing enzymes in almost all cells of the immune system indicates a role for 1,25(OH)2D3 as a modulator of immune responses. In dendritic cells (DCs), 1,25(OH)2D3 interferes with the differentiation and maturation process resulting in the induction of a tolerogenic state. Tolerogenic DCs (tolDCs) are characterized by downregulated antigen-presentation, reduced costimulation and low pro-inflammatory cytokine production. As a result, tolDCs are poor T cell stimulators and induce T cell hyporesponsiveness. In addition, tolDC mediate a shift in T cell polarization from Th1/17 responses to more tolerogenic responses, with the induction of regulatory T cells (Tregs). On the other hand, 1,25(OH)2D3 are also able to directly modulate activated T cells. In these cells, 1,25(OH)2D3 decreases the production of pro-inflammatory cytokines and induces Tregs.
An important role for 1,25(OH)2D3 and its nuclear receptor in the development of type 1 diabetes (T1D) has been suggested by the discrepancy observed between absence of ligand and absence of receptor. Vitamin D3 deficiency in early life is associated with elevated risk for T1D, while the VDR null mouse model, lacking a functional VDR, do not present with aggravated disease. This difference indicates an important role for the unliganded VDR in the immune response. In the first part of this project, we investigated whether an unliganded VDR could affect the phenotype and function of murine bone marrow-derived DCs (BMDCs). Therefore, we studied myeloid BMDCs generated ex vivo from bone marrow precursors of VDR null, with a truncated, non-functional VDR, and VDR ∆AF-2 mice, with a mutated C‑terminal activation factor AF-2 domain thus rendering ligand-induced gene transcription impossible. To our surprise, the unliganded VDR did not affect BMDC phenotype or their T cell stimulatory capacity compared to VDR null BMDCs. These data indicate that an unliganded VDR does not elicit a more inflammatory phenotype in BMDCs.
Currently, no therapies for T1D are established which tackle the underlying immune attack. In general, immunotherapies focus on the inhibition of pathogenic immune cell activation and the (re-)establishment of self-tolerance against autoantigens. Given the interesting characteristics of Tregs and tolDCs to induce antigen-specific protection, cellular immunotherapies like adoptive T cell transfer and tolDC-based vaccines provide promising strategies for autoimmune diseases. In this regard, 1,25(OH)2D3 or its low‑calcemic analog TX527 are ideal for ex vivo modulation of autologous T cells and DCs.
Previously, our group showed successful ex vivo modulation of T cells isolated from healthy donors by 1,25(OH)2D3 as well as its analog TX527. However, for the clinical applicability of autologous adoptive T cell therapy, validation in samples from patients with T1D is required, especially as a defect in Treg function has been shown in T1D. Therefore, we further explored whether autologous T cells obtained from patients with T1D could be ex vivo modulated by 1,25(OH)2D3 and its analog TX527. Indeed, treatment with 1,25(OH)2D3 and TX527 increased the frequency of CD4+CD25highCD127low Tregs, with elevated CTLA-4 expression in this population. Moreover, exposure to 1,25(OH)2D3 and TX527 imprinted a unique homing signature and reduced the production of effector cytokines in the T cells isolated from T1D patients. In addition, both 1,25(OH)2D3 and TX527 promoted the formation of a stable Treg phenotype, which is essential for their possible clinical application as they will be reintroduced in an inflammatory microenvironment.
For the third part of this PhD project, we build further on a previous finding in our lab that demonstrated that the induction of the tolDC profile by 1,25(OH)2D3 is accompanied by an early and transcriptionally mediated metabolic reprogramming. We previously showed that glucose availability and glycolytic metabolism are crucial to induce and maintain tolDCs. This observation strokes with the emerging concept of immunometabolism which states that intracellular metabolism determines the phenotype and function of immune cells. In this regard, we aimed to find a primary target of vitamin D3 that could act as a metabolic switch in tolDCs. We identified the glycolytic enzyme PFKFB4 as strongly and directly upregulated by 1,25(OH)2D3 in differentiating monocytes. Pharmacological inhibition of PFKFB4 activity by the small molecule inhibitor 5-MPN could interfere with the increase in glucose metabolism, and more specifically glucose oxidation, which are hallmark features of tolDC. Moreover, PFKFB4 inhibition altered tolDC phenotype and their ability to induce functional Tregs. A better understanding of the metabolic pathways influenced by 1,25(OH)2D3 in human tolDCs will aid the development and improve the efficacy of tolDC-based immunotherapies.status: Publishe
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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