1,721,564 research outputs found
DISSECTING THE MECHANISMS OF NEUTROPHIL DYSREGULATION AND NEUROTOXICITY IN ALZHEIMER'S DISEASE
Get PDFAlzheimer’s disease (AD) constitutes the most common form of dementia worldwide and is characterized by the accumulation of extracellular senile plaques mediated by amyloid- (Aβ), intracellular neurofibrillary tangles, synaptic degeneration and neuronal injury. It is considered an urgent social and economic problem due to the lack of effective therapeutic therapies or curative approaches. Until recent times the central nervous system was considered an immune-privileged site, still, the contribution of peripheral immune cells to brain functions highlighted their role in CNS physiology and disease. Neutrophils constitute the most abundant leukocyte population in human circulation and our group has identified a crucial role for these cells in the pathogenesis of AD. Other reports have then further supported this role, emphasizing peripheral neutrophil hyperactivation in AD, although the cause is still unclear. The recent discovery of gastrointestinal dysbiosis in neurodegeneration, including AD, and the subsequent pro-inflammatory response associated with increased circulating microbial products points to a broad systemic dysregulation of the immune system in AD patients. Still, neutrophil dysregulation and its impact on peripheral and brain inflammation in AD are not well understood and were the focus of this doctoral thesis. In the first part, we studied peripheral neutrophil dysregulation and characterized intestinal microbiota changes of 3xTg-AD mice and healthy wild-type (WT) mice. Our results showed a profound dysbiosis characterized by an increase in pro-inflammatory bacteria in 3xTg-AD mice. In addition, we showed that dysbiosis was accompanied by inflammatory changes in the intestinal tract, including a decrease in the number of mucus-producing cells and an increase in permeability of the intestinal tract. Moreover, we identified enteric nervous system (ENS) degeneration and neutrophil infiltration as early events in AD pathogenesis, suggesting a link between neutrophils and intestinal changes in AD mice. To further connect dysbiosis and peripheral inflammation, we performed a phenotype characterization of circulating neutrophils. The analysis of peripheral blood identified a persistent state of neutrophilia and, most importantly, an increase of immature neutrophils in the 3xTg-AD mice, suggesting the activation of “emergency granulopoiesis”. Interestingly, we showed a positive correlation between intestinal permeability and the levels of circulating neutrophils, further showing an interplay between gut dysbiosis and granulopoiesis. To further understand the role of neutrophil pathological changes in AD, in the second part of this project, we studied neutrophil dysfunction from a “central” point of view. Importantly, scRNAseq of brain-infiltrating neutrophils revealed genes associated with neutrophil degranulation, which was later confirmed using flow cytometry. scRNA-seq also identified Ctse as one of the most upregulated genes in infiltrating neutrophils, suggesting its role in the pathogenesis of AD. Interestingly, in vitro stimulation of both human and mouse neutrophils with A led to an increase in the degranulation of neutrophils that was abolished when neutrophils were pretreated with a CTSE inhibitor. To address the potential of CTSE as a therapeutic target, we pre-treated neutrophils with a CTSE inhibitor and cocultured these cells with neurons observing a strong decrease in neuronal death when CTSE was blocked, pointing to CTSE as a key mediator of neutrophil neurotoxicity in AD. Overall, this thesis provides novel insights into neutrophil dysregulation in a mouse model of AD, suggesting that dysbiosis may contribute to peripheral neutrophil responses and neuroinflammation in AD. Furthermore, our data suggest that targeting neutrophil-dependent neurotoxic mechanisms may represent a novel and promising therapeutic strategy for AD
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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