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    Genvarianten der Immunregulation bei den Autoimmunopathien Hashimoto-Thyreoditis, Morbus Basedow und Morbus Addison

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    Ein charakteristisches Merkmal von Autoimmunerkrankungen ist der selektive Angriff des Immunsystems auf einen einzigen Zelltyp, ein Organ oder Gewebe durch bestimmte T- und B-Lymphozyten. Die genaue Ursache von Autoimmunerkrankungen bleibt bislang ungeklärt, jedoch scheint eine bestimmte genetische Konstellation bei Zusammentreffen mit im weitesten Sinne umweltbedingten Faktoren die Reaktionen zu erklären. Zu solchen umweltbedingten Faktoren gehören auch Infektionen. Häufig werden Assoziationen zwischen Infektion und autoimmuner Erkrankung beobachtet. Auch kann bei einer akuten Infektion ein vorhandener Autoimmunprozess exazerbieren. Eine schnelle Verteidigung gegen Infektionen gewährleistet das angeborene Immunsystem, bevor das adaptive Immunsystem zum Tragen kommt. Die Moleküle, die bei diesen Abwehrprozessen frei werden, können zur T-Zell-Vermehrung führen, die einerseits eine effektive Selbstverteidigung möglich macht; ander erseits können sie aber auch die Vermehrung autoreaktiver T-Zellen zur Folge haben. An frühen Vorgängen nach dem Kontakt mit einem Pathogen ist eine Vielzahl von Zyto- und Chemokinen beteiligt. Typ-1-Interferone (IFN1) sind ebensolche Zytokine, die vor allem in der Abwehr gegen Viren eine Rolle spielen und in mehrschrittigen Prozessen auch zur Aktivierung von T- und B-Zellen führen. IFIH1 ist ein intrazellulärer Rezeptor, der dsRNA im Zytosol detektiert und in der Folge die Transkription von IFN1 aktiviert. Veränderungen im Gen dieses Rezeptors zeigen Assoziationen zu Typ-1-Diabetes (T1D) und bieten einen funktionellen Berührungspunkt zwischen früher Infektabwehr durch das angeborene Immunsystem und der letztlich gewebszerstörerischen T- und B-Zell-Reaktion. In dieser Arbeit wurde daher die Assoziation dreier endokriner Autoimmunopathien mit dem IFH1-Polymorphismus rs1990760 durchgeführt, der in der Literatur als deutlich assoziiert mit T1D beschrieben wird. Mit Hashimoto-Thyreoditis, Morbus Basedow und Morbus Addison wurden Krankheiten gewählt, die im genetischen Hintergrund viele Gemeinsamkeiten untereinander und mit T1D aufweisen. Durch die in der Literatur beschriebenen Assoziationen mit T1D rückt nun der IFIH1-rs1990760 Polymorphismus potentiell auch in das genetische Anfälligkeitsprofil dieser endokrinen Autoimmunopathien. Für die Assoziationsanalyse wurde in dieser Arbeit DNA von betroffenen Individuen und gesunden Kontrollen mittels RT-PCR auf den IFIH1-Polymorphismus rs1990760 (Allele „A“/„G“) typisiert und die Genotyp- und Allelhäufigkeiten verglichen. Außerdem wurden Familienanalysen durchgeführt und die Transmission der Allele auf Unterschiede im Vererbungsverhalten hin untersucht. Es konnten keine statistisch relevanten Assoziationen zwischen dem IFIH1-Polymorphismus rs1990760 und Hashimoto-Thyreoditis, Morbus Basedow und Morbus Addison gefunden werden. Weiterhin wurden Subgruppen gebildet, um eventuell in der Gesamtgruppe nicht erkennbare Trends aufzudecken. Für Hashimoto-Thyreoditis und Morbus Basedow wurde der HLA-Typ DQ2 als Risikotyp angenommen, für Morbus Addison der Typ HLA-DQ2/DQ8. Der Antikörperstatus der untersuchten Individuen wurde ebenfalls in die Untersuchung einbezogen. In der Familienanalyse mit an Hashimoto-Thyreoditis erkranktem Kind wurden Subgruppen gebildet, die den TPO-Ak und Tg-Ak-Status der Eltern berücksichtigen. Bei Morbus Basedow wurde der TSH-R-Antikörper bei der Fall-Kontroll-Analyse zur Subgruppenbildung herangezogen. Wenn sich auch keine statistisch eindeutigen Assoziationen nachweisen ließen, so waren bei Hashimoto-Thyreoditis und Morbus Basedow in einigen Subgruppen doch Tendenzen zu erkennen, die eine Beteiligung des Polymorphismus an der genetischen Anfälligkeit vermuten lassen könnten. Die beobachteten Trends deuten darauf hin, dass in bestimmten Patientengruppen der untersuchte Polymorphismus eine Rolle in der Anfälligkeit spielen könnte.The selective targeting of a single cell type, organ or tissue by a certain population of autoreactive T- and B-cells is a characteristic feature of autoimmune diseases. This autoaggressive immune reaction leads to chronic inflammation, tissue destruction and subsequently to malfunction of the corresponding organ. The exact cause of autoimmune diseases still remains unclear, but there is strong evidence that most autoimmune diseases are linked to certain specific genes. Environmental triggers that encounter elegible genetic conditions are able to activate the autoimmune reactions. Infections rank among such environmental triggers. Associations between infections and autoimmune disease as well as exacerbation of ongoing autoimmune processes due to acute infection can be found frequently. The innate immune system enables the organism to rapid antimicrobial and antiviral defense, prior to the specific responses of adaptive immunity. Liberated molecules in early host defense of innate immunity can amplify protective T-cells. On the other hand proliferation of autoreactive T-cells might result. A variety of cyto– and chemokines is involved in the pathways of rapid innate immune reaction. Type-1-INFs are such cytokines, which primarily play a role in establishing an antiviral state. Downstream effects are also the activation of T-and-B-cell depending processes. IFIH1 is one intracellular receptor among others that leads to production of IFN. It detects dsRNA in the cytosol and subsequently activates the transcription of type-1-IFN. SNPs in the IFIH1-gene show associations with T1D and provide a functional link between early host defense by innate immunity and destructive autoaggressive tissue damage by T- or B-cellresponse. In this study, an association-analysis of three endocrine autoimmune diseases with the IFIH1-polymorphism rs1990760 has been carried out. Hashimoto-Thyroiditis, Graves' disease and Addison's disease were selected as their genetic profile shows many similarities among each other and with type 1 diabetes (T1D). The fact that associations with T1D and the IFIH1-rs1990760 polymorphism are described in literature points IFIH1 out as a canditate for associations with other autoimmune diseases. DNA of affected individuals has been genotyped for the IFIH1-rs199760 polymorphism „A/G“ by RT-PCR. Genotype- and allel-frequencies have been compared to those in healthy controls. Further family-studies of Hashimoto- and Basedow-families have been carried out. No significant differences were found between the allele and genotype frequencies for rs1990769 polymorphism in patients with Hashimoto's thyroiditis, Graves' disease, Addison's disease and healty controls. Furthermore, the interaction between rs1990760 polymorphism with human leukocyte antigen risk haplotype DQ2, the risk haplotypes DQ2/DQ8 and the status of thyroglobulin antibody, thyroid peroxidase antibody and TSH receptor antibody in patients and families were analysed. In some of the subgroups of Hashimoto's thyroiditis and Graves' disease trends were revealed, that suggest the IFIH1 polymorphism rs1990760 to play a role in the pathogenesis of those diseases. Thus, further investigations with larger study populations are needed to make definitive statements about associations between Hashimoto's-Thyroiditis, Graves' disease and Addison's disease and the IFIH1-polymorphism rs1990760

    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The 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

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    “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

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    We 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

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    We 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

    Author Index

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    koamabayili/VECTRON-author-checklist: VECTRON author checklist

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    We 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 Under Sail The Imagination of Jack London, 1893-1902

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    In 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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