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Erhöhte Differenzierung von humanen regulatorischen T-Zellen durch Blockade des Melastatin-ähnlichen Transienten Rezeptor Potential Kationen Kanal 7 (TRPM7)
Get PDFMagnesium ist für den menschlichen Köper nicht nur als essentielles Element an mehreren hundert enzymatischen Reaktionen beteiligt, sondern beeinflusst auch die Immunantwort des Körpers. So führt ein Mangel an Mg2+ zu verstärkten Entzündungsprozessen. Ein weiterer Hinweis für die Rolle von Mg2+ in der Immunzellaktivierung ist ein humaner X-chromosomaler Immundefekt, welcher mit dem vermuteten Mg2+-Transporter 1 (MagT1) in Verbindung gebracht wird. Das weist auf eine wesentliche Rolle von Mg2+ bei der Aktivierung von Immunzellen hin. Kürzlich wurde diese Ansicht jedoch durch einen Bericht von Gilmore et al. in Frage gestellt. Die Rolle von MagT1 als Transporter und seine Expression in der Plasmamembran wurden angezweifelt. Daher muss die Bedeutung des Mg2+ leitenden Transient Receptor Potential Kanals (TRPM7) als Schlüsselakteur in diesen Prozessen weiter untersucht werden. TRPM7 wird nicht nur in Immunzellen stark exprimiert, sondern kontrolliert auch die zelluläre Mg2+-Homostase. Seine Kanalaktivität wird durch Mg2+ und Mg.ATP negativ reguliert
Ziel dieser Arbeit war es, die Analyse der Expression von TRPM7 in verschiedenen T-Zellsubtypen sowie dessen Rolle bei der Differenzierung von CD4+ T-Lymphozyten zu untersuchen. Es wurden naïve CD4+ T-Zellen isoliert und gezielt stimuliert, um unterschiedliche T Zell-Subtypen zu erzeugen, welche unter Verwendung molekularer und biochemischer Analysen, Ganzzell-Elektrophysiologie sowie bildgebender Verfahren auf Expressionsniveaus, Funktion und Regulation von TRPM7 untersucht wurden. In der elektrophysiologischen Charakterisierung lies sich TRPM7 in allen untersuchten T-Lymphozyten-Subtypen nachweisen. Wobei nTregs eine signifikant geringere funktionelle TRPM7-Expression als die naïven CD4+ T-Lymphozyten aufwiesen. Verschiedene extrazelluläre Mg2+-Konzentrationen führten in den untersuchten T Lymphozyten-Subtypen zu unterschiedlicher Aktivierung des TRPM7-Kanals. Die untersuchten nTregs zeigten eine stärkere Aktivierung von TRPM7 bei fehlendem Mg2+ als naïve CD4+ T-Lymphozyten. Um den Einfluss von TRPM7 auf T-Lymphozyten näher zu untersuchen, erfolgten in vitro Differenzierungsexperimente mit naïven T-Zellen mit oder ohne TRPM7-Blocker und mit variierenden Mg2+-Spiegeln. Während ein erhöhter Mg2+-Spiegel einen negativen Einfluss auf die Differenzierungsrate von iTregs hatte, führten sowohl die Wegnahme von Mg2+ aus dem Medium als auch die TRPM7-Inhibition durch die bekannten Kanalblocker, Waixenicin A und NS8593, zu einer erhöhten Differenzierungsrate von iTregs. Dieses könnte eine Erklärung dafür sein, weshalb ein Mg2+-Defizit in vivo zu einer Schwächung des Immunsystems führt. Die in vorliegender Arbeit dargelegten Befunde legen einen Einfluss von TRPM7 auf immunologische Prozesse nahe.Not only is magnesium (Mg2+) involved in the human body as an essential element in several hundred enzymatic reactions, it also affects the body's immune response. Studies show a lack of Mg2+ leads to increased inflammatory reaction. An indication of the role of Mg2+ in immune cell activation is a human X-linked immunodeficiency associated with the putative Mg2+ transporter 1 (MagT1). This indicates an essential role of Mg2+ in the activation of immune cells. Recently, the role of MagT1 as a transporter and its expression in the plasma membrane were questioned by Gilmore et al. Therefore, the importance of the Mg2+-conducting transient receptor potential channel (TRPM7) as a key player in these processes, needs further investigation. TRPM7 is not only highly expressed in immune cells but also controls cellular Mg2+- homeostasis. Its channel activity is negatively regulated by Mg2+ and Mg.ATP. The aim of this work was to analyze the expression of TRPM7 in different T cell subtypes as well as its role in the differentiation of CD4+ T lymphocytes. Naïve CD4+ T lymphocytes were isolated and selectively stimulated to generate different T cell subtypes, which were analyzed for expression levels, function and regulation of TRPM7 using molecular and biochemical analyzes, whole cell electrophysiology and imaging techniques.
In the electrophysiological characterization TRPM7 could be detected in all examined T lymphocyte subtypes. The functional TRPM7 expression was significantly lower in nTregs than in naïve CD4+ T-lymphocytes. In the examined T lymphocyte subtypes different extracellular Mg2+ concentrations led to different activation of the TRPM7 channel. The investigated nTregs showed a stronger activation of TRPM7 in the absence of Mg2+ than naïve CD4+ T-lymphocytes.
In order to further investigate the influence of TRPM7 on the differentiation of CD4+ T lymphocyte subsets, naïve T cells were differentiated in vitro with or without TRPM7 blockers and varying Mg2+ concentrations . While increased Mg2+ levels had a negative impact on the rate of differentiation of iTregs, both the removal of Mg2+ from the medium and the inhibition of TRPM7 by the known channel blockers, waixenicin A and NS8593, led to an increased differentiation rate of iTregs. This might explain why systemic Mg2+ deficiency is often accompanied by a diminished immune system. The experiments presented herein suggest an influence of TRPM7 in immunological processes
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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