1,720,953 research outputs found
Characterization of novel NEDDylation inhibitors in in vitro models of atherogenesis
No full textIntracellular protein degradation is controlled by the ubiquitin-proteasome system (UPS) through post-translational modification of target proteins with ubiquitin. The central components of the UPS are cullin-RING ligases (CRLs). The CRLs’ ubiquitin ligase activity is regulated by post-translational modification with NEDD8 (neural precursor cells expressed developmentally downregulated-8), a protein structurally similar to ubiquitin. NEDDylation impacts cell homeostasis, cell death, and physiological cell functions by mediating the degradation of critical regulatory proteins. Especially the CSN (constitutive photomorphogenesis 9 (COP9) signalosome), which catalyzes the removal of NEDD8, is considered a promising therapeutical target in cancer research. Still, various studies indicate that the CSN also has a central role in inflammation and atherosclerosis. Recent efforts have identified multiple compounds that negatively impact NEDDylation. These compounds, at least partially, mimic, and consequently allow to study the CSN. MLN4924, which affects the E1 enzyme and therefore fully blocks NEDDylation, is atheroprotective in vivo and in vitro. To target cullin-NEDDylation more specifically, novel defective in cullin NEDDylation protein 1 (DCN1) inhibitors, which impair a later timepoint in the NEDDylation cascade, have been developed.
This thesis evaluated the effects of the novel DCN1 inhibitors NAcM-OPT and -COV, which had only been applied in cancer cell models so far, in murine and human monocyte and macrophage models in the context of atherosclerosis in vitro. The results suggested a less pronounced impact on CUL1- and CUL3-NEDDylation levels compared to MLN4924 in vitro. Still, the covalently binding NAcM-COV resulted in a more potent reduction of cullin-NEDDylation than the non-covalently binding NAcM-OPT. The atheroprotective effect of MLN4924 on macrophage protein secretion in vitro could not be observed when using the novel DCN1 inhibitors. Interestingly, treatment with NAcM-COV and MLN4924 significantly impaired monocyte mobility and viability in vitro.
This study provided first insights into the effectiveness of the novel DCN1 inhibitors on murine and human monocyte and macrophage models in the context of atherogenesis in vitro. This thesis pinpointed novel DCN1 inhibitors as a promising addition to the research of the CSN as they allow insight into specifically targeting CUL1- and CUL3-NEDDylation. These more specific inhibitors of NEDDylation could be future therapeutic alternatives to MLN4924 as they might result in fewer side effects.Das Ubiquitin-Proteasom-System (UPS) steuert den intrazellulären Proteinabbau durch posttranslationale Modifikation der Zielproteine mit Ubiquitin. Die zentralen Schaltstellen des UPS sind Cullin-RING-Ligasen (CRLs), deren Ubiquitin-Ligase-Aktivität durch NEDD8 (neural precursor cells expressed developmentally downregulated-8) reguliert wird. Die NEDDylierung beeinflusst die Zellhomöostase und physiologische Zellfunktionen, indem sie den Abbau regulatorischer Proteine vermittelt. Das CSN (constitutive photomorphogenesis 9 (COP9) signalosome), welches die Entfernung von NEDD8 katalysiert, gilt daher als vielversprechendes therapeutisches Ziel in der Krebsforschung. Des Weiteren deuten verschiedene Studien darauf hin, dass das CSN auch bei Entzündungen und Atherosklerose eine wichtige Rolle spielt. In den letzten Jahren wurden mehrere Verbindungen identifiziert, die die NEDDylierung inhibieren und somit zumindest teilweise die Aktivität des CSN widerspiegeln. MLN4924, ein Inhibitor welcher die gesamte NEDDylierung blockiert, wirkt in vivo und in vitro atheroprotektiv. DCN1 (defective in cullin NEDDylation protein 1) Inhibitoren, die einen späteren Zeitpunkt in der NEDDylierungskaskade beeinträchtigen und nicht die NEDDylierung aller Culline beeinflussen, ermöglichen es, den Einfluss der Cullin-NEDDylierung gezielter zu erforschen.
In dieser Arbeit wurden die Wirkungen der neuartigen DCN1 Inhibitoren NAcM-OPT und -COV, welche bis dato nur an Krebszellmodellen getestet wurden, in murinen und humanen Monozyten- und Makrophagenmodellen in vitro im Kontext atherosklerotischer Entzündungsprozesse evaluiert. Die Ergebnisse deuteten auf einen weniger ausgeprägten Einfluss auf die CUL1- und CUL3-NEDDylierung im Vergleich zu MLN4924 hin. Dennoch führte das kovalent bindende NAcM-COV zu einer stärkeren Reduktion der Cullin-NEDDylierung als das nicht kovalent bindende NAcM-OPT. Die starke atheroprotektive Wirkung von MLN4924 auf die Sekretion inflammatorischer Mediatoren aus Makrophagen in vitro wurde mit den neuen DCN1 Inhibitoren nicht beobachtet. Interessanterweise beeinträchtigte die Behandlung mit NAcM-COV und MLN4924 die Mobilität und Vitalität der Monozyten in vitro.
Zusammenfassend lieferte diese Dissertation erste Einblicke in die Wirksamkeit der neuartigen DCN1 Inhibitoren an murinen und menschlichen Monozyten- und Makrophagenmodellen im Kontext der Atherogenese in vitro. Hierbei wurden die neuartigen DCN1 Inhibitoren als vielversprechende Ergänzung der Erforschung des CSN identifiziert, da sie Einblicke in die gezielte Regulation der CUL1- und CUL3-NEDDylierung ermöglichen. Perspektivisch könnten sich spezifischere NEDDylierungsinhibitoren auch als nebenwirkungsärmere therapeutische Alternativen zu MLN4924 etablieren
Going Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
No full text“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
No full textWe 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
No full textWe 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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