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    Contribution de la mécanique cellulaire au développement et au maintien de l'axe cryptes-villosités

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    Les tissus épithéliaux servent de barrières cruciales contre les contraintes externes tout en maintenant une stabilité structurelle essentielle pour la protection, la sécrétion et l'absorption. Les perturbations de l'intégrité épithéliale peuvent entraîner de graves conséquences, telles que l'altération fonctionnelle des organes ou la tumorigénèse. Dans cette thèse, nous utilisons l'épithélium de l'intestin grêle adulte comme modèle pour étudier la contribution de la mécanique cellulaire à la morphogenèse et à l'homéostasie du tissu. L'épithélium du petit intestin est un tissu monostratifié dynamique, organisé autour de l'axe cryptes-villosités. La villosité, qui fait saillie dans la lumière intestinale, est principalement composée de cellules différenciées spécialisées dans l'absorption des nutriments. La crypte, une invagination de l'épithélium dans le mésenchyme sous-jacent, sert de domaine prolifératif abritant les cellules souches intestinales. De récentes recherches ont révélé que la tension basale est une force motrice pour la morphogenèse tissulaire, en particulier dans le domaine différencié du petit intestin. Cependant, les mécanismes sous-jacents restent largement inexplorés. La première partie de cette thèse examine la mécanique cellulaire du domaine différencié de l'épithélium intestinal de la souris. Nous y avons découvert de nouvelles structures baptisées étoiles d'actine (AcSs), qui forment un réseau multicellulaire en étoile d'actomyosine dans le domaine basal de ces cellules, à la fois in vivo et in vitro. Ces structures sont essentielles pour maintenir la stabilité de l'épithélium en maximisant l'hexagonalité et le compactage des cellules et en minimisant les fluctuations de forme et l'activité protrusive des cellules, préservant ainsi l'état solide de l'épithélium. De plus, le réseau d'AcSs facilite la connectivité à longue portée et la coordination spatiale entre les cellules différenciées, soulignant son rôle dans le maintien de l'architecture du domaine différencié. Inspirés par l'hypothèse de De Ceccatty sur "l'histosquelette" chez les éponges, nous proposons que ce réseau représente un squelette à l'échelle tissulaire permettant de coordonner l'architecture et les fonctions du tissu épithélial intestinal des mammifères. La deuxième partie de cette thèse explore le rôle de la protéine EpCAM, un modulateur connu de la contractilité épithéliale, dans la cryptogenèse intestinale. La perte d'EpCAM est liée à plusieurs pathologies, y compris l'entéropathie congénitale en touffes (CTE), un trouble rare caractérisé par une diarrhée sévère et précoce et une insuffisance intestinale, nécessitant souvent une nutrition parentérale totale (TPN). Bien que l'impact de la déplétion d'EpCAM sur les villosités ait été largement étudié, ses effets sur les cryptes sont moins compris. En utilisant des biopsies de patients atteints de CTE et des organoïdes de souris knock-out pour EpCAM (EpCAM-KO), nous avons démontré qu'EpCAM est crucial pour la formation et l'homéostasie des cryptes. La perte d'EpCAM entraîne une morphologie anormale des cryptes et une homéostasie cellulaire perturbée. Nous avons observé une augmentation et une asymétrie des fissions des cryptes dans les biopsies de patients atteints de CTE et les organoïdes EpCAM-KO, indiquant le rôle d'EpCAM dans la régulation de la dynamique de fission des cryptes. Ainsi, EpCAM est nécessaire à la bonne formation, dynamique et homéostasie de la crypte intestinale. Dans l'ensemble, cette thèse fait progresser la compréhension de la morphogenèse et du maintien l'homéostasie de l'épithélium intestinal grâce à la découverte des étoiles d'actine et à la mise en évidence du rôle d'EpCAM dans la cryptogenèse, fournissant de nouvelles perspectives sur l'établissement, la compartimentation et le maintien de l'épithélium du petit intestin.Epithelial tissues serve as critical barriers against external constraints while maintaining structural stability essential for functions such as protection, secretion, and absorption. Disruptions in epithelial integrity can result in severe consequences, including impaired organ function and tumorigenesis. In this thesis, we use the adult small intestinal epithelium as a model to study the contribution of cell mechanics to the morphogenesis and homeostasis of the tissue. The small intestinal epithelium is a highly dynamic, monostratified tissue organized around the crypt-villus axis. The villus, protruding into the intestinal lumen, primarily consists of differentiated cells specialized for nutrient absorption. The crypt, an invagination of the epithelium into the underlying mesenchyme, serves as a proliferative domain housing intestinal stem cells. While epithelial morphogenesis has been broadly studied, recent research has revealed that basal tension is a driving force for tissue morphogenesis, particularly in the differentiated domain of the small intestine. However, the mechanisms underlying the production and regulation of these forces remain largely unexplored. The first part of this thesis examines the basal cell mechanics within the differentiated domain of the mouse small intestine epithelium. We uncovered novel structures termed actin stars (AcSs), which form a multicellular star-shaped actomyosin lattice network in the basal domain of these cells, both in-vivo and in-vitro. These structures are essential for maintaining epithelial tissue stability by maximizing cell hexagonality and packing, thereby preserving the solid-like order of the epithelium. The AcS network minimizes cell shape fluctuations and protrusive activity, enhancing structural integrity and reducing tissue fluidity. Moreover, the AcSs network facilitates long-range connectivity and spatial coordination among differentiated cells, further underscoring its role in maintaining the architecture of the differentiated domain. Drawing from De Ceccatty's hypothesis of the "histoskeleton" in sponges, we propose that actin stars represent a cytoskeletal network crucial for coordinating the architecture and functions of the mammalian intestinal epithelial tissue. The second part of this thesis investigates the role of EpCAM, a known modulator of epithelial contractility, in intestinal cryptogenesis. Loss of EpCAM has been linked to several pathological conditions, including congenital tufting enteropathy (CTE), a rare congenital disorder characterized by severe, early-onset diarrhea and intestinal failure, often necessitating total parenteral nutrition (TPN). While the impact of EpCAM depletion on the villus domain of the intestine has been extensively studied, its effects on the crypt remain less understood. Using biopsies from CTE patients and EpCAM knock-out (EpCAM-KO) mouse organoids, we demonstrated that EpCAM is crucial for proper crypt formation and homeostasis. Loss of EpCAM leads to abnormal crypt morphology and disrupted cell homeostasis. We observed increased and asymmetric crypt fissions in CTE patient biopsies and EpCAM-KO organoids, indicating EpCAM's role in regulating crypt fission dynamics. Our findings highlight EpCAM's significance in maintaining proper tension and geometry within the Paneth cell/stem cell cluster at the crypt base, essential for cellular remodeling during crypt fission. Silencing EpCAM disrupts niche cell cluster architecture and tension balance, leading to ectopic crypts and asymmetric fissions. Overall, this thesis advances our understanding of intestinal epithelial morphogenesis and homeostasis through the discovery of actin stars and the unveiling of EpCAM's role in cryptogenesis, providing new insights into the establishment, compartmentalization, and maintenance of the small intestinal epithelium

    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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