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Links between inadequate immune responses to viral infections and disease outcome in humans
Get PDFDeux pandémies virales touchent aujourd’hui des millions d’individus : la pandémie du Coronavirus Disease 2019 (COVID-19), causée par le Syndrome respiratoire aigu sévère coronavirus 2 (SRAS-CoV-2) et celle du Syndrome d’Immunodéficience Acquise (SIDA) causée par le Virus de l’Immunodéficience Humaine (VIH). Ces deux maladies diffèrent par leur physiopathologie, dont une meilleure compréhension a permis le développement de traitements efficaces. Pourtant, ces deux pandémies persistent. Une infection par SARS-CoV-2 peut être mortelle en raison d’une réponse immunitaire exacerbée et potentiellement retardée. Le VIH à l’inverse échappe continuellement à la réponse immunitaire, l’affaiblissant au cours des années jusqu’au développement du SIDA, ouvrant la porte à des maladies opportunistes mortelles. L’intérêt global de cette thèse était d’étudier comment la réponse immunitaire échoue pour ces deux infections.
L’objectif de la première étude était de trouver un biomarqueur sanguin robuste et fiable pour prédire le risque de mortalité des patients hospitalisés pour la COVID-19. Nous avons mesuré la quantité d’ARN viral, de cytokines et de marqueurs de dommages tissulaires, ainsi que la réponse humorale contre le virus dans des échantillons de plasma de 279 patients à travers trois cohortes. Nous avons trouvé que l’ARN viral mesuré environ 11 jours après le début des symptômes, et ajusté pour l’âge et le sexe, peut prédire la mortalité dans les 60 jours suivant le début des symptômes. Nous avons également trouvé que des fortes concentrations de cytokines inflammatoires et de marqueurs de dommages tissulaires, ainsi qu’un faible niveau d’anticorps liant le Region Binding Domain (RBD) de la protéine Spike de SARS-CoV-2, sont aussi associées à la mortalité. Dans un deuxième projet, nous nous sommes servis d’outils de réduction de dimensionnalités combinant les facteurs associés à la mortalité, permettant une stratification des patients en quatre groupes basés uniquement sur leur profil immuno-virologique plasmatique. Un seul de ces groupes est lié à une plus grande mortalité. Mis ensemble, nos travaux permettent une meilleure compréhension de l’hétérogénéité des patients hospitalisés pour la COVID-19, incluant l’identification des patients à haut risque de mortalité. Ces données pourraient servir à cibler les traitements thérapeutiques selon la réponse immunologique du patient.
Notre troisième étude portait sur l’étude de la dysfonction des lymphocytes T CD4+ spécifiques du VIH. Ceux-ci sont affaiblis par l’infection au VIH et perdent leur capacité à combattre l’infection. Notre objectif était de caractériser la réponse au blocage du point de contrôle immunitaire (BPCI - immunothérapie qui renverse partiellement la dysfonction des lymphocytes T) PD-1 parmi les divers types des lymphocytes T CD4+. Nous avons d’abord comparé l’état de dysfonction des lymphocytes chez deux cohortes de personnes vivant avec le VIH (PVVIH) non-traitées. Pour l’une des deux cohortes, la virémie est contrôlée par le système immunitaire (cohorte dite de « Contrôleurs Élites »), à l’inverse de la seconde cohorte (dite « Virémique »). Les lymphocytes T CD4+ des personnes virémiques perdent leur activité antivirale et ont une forte expression de points de contrôles immunitaires. Au contraire, les contrôleurs élites ont une charge virale indétectable en l’absence de thérapie antirétrovirale (TAR), et des lymphocytes T CD4+ relativement fonctionnels. En réponse au BPCI, les lymphocytes T CD4+ spécifiques du VIH démontrent une plus grande réponse chez les PVVIH virémiques, via l’augmentation du nombre de cellules produisant des cytokines. Chez ces individus, toutes les fonctions mesurées augmentent, à l’exception des cytokines associées aux cellules T CD4+ folliculaires auxiliaires qui sont impliquées dans l’amorçage des réponses immunologiques des lymphocytes B. Ces données montrent qu’il existe une réponse spécifique des sous-types de lymphocytes T CD4+ aux BPCI. Ce projet démontre l’avantage du blocage du ligand de PD-1 (PD-L1) sur les effets hétérogènes au niveau unicellulaire, soulignant l’importance de considérer les T CD4+ dans les analyses futures des essais cliniques évaluant le bénéfice des BPCI.
Mis ensemble, cette thèse permet une meilleure caractérisation de la réponse immunologique contre un virus à infection aiguë et, dans un second temps, un autre à infection chronique. Ces études permettent une meilleure compréhension de l’hétérogénéité dans la réponse immunologique des personnes infectées qui, si prise en compte dans des essais cliniques, pourrait aider à expliquer la variété de l’efficacité des traitements.Viral infections are a major cause of disease in humans. Pandemics refer to virulent viruses that spread across more than one continent. In the last century, two major such pandemics have occurred with still-current repercussions: the acquired immunodeficiency syndrome (AIDS) pandemic caused by the Human Immunodeficiency Virus (HIV), and the Coronavirus Disease 2019 (COVID-19) pandemic by the severe acute respiratory coronavirus 2 (SARS-CoV-2). The diseases caused by both of these viruses are very different in their pathophysiology. A better elucidation of these diseases has already allowed researchers to develop therapeutic treatments against these infections; however, both pandemics caused by these viruses are ongoing. While SARS-CoV-2 proves to ultimately be fatal by an exacerbated and perhaps delayed immune response against the virus, HIV rather evades the host’s immune response, weakening it over time until inducing a severe immunocompromised state, opening the door for fatal opportunistic diseases. The overarching goal of this thesis was to study the failings of the immune response against each virus, and extract information useful to guide therapeutic practices.
The objective of the first study was to find a robust and reproducible predictor of fatal outcome among patients hospitalized for their COVID-19. We profiled the plasma of a total of 279 patients across three independent cohorts to measure SARS-CoV-2 viral RNA, antibody responses against the virus and the quantities of inflammatory cytokines and markers of tissue damage. We found that plasma viral RNA could reproducibly predict fatal outcome on samples collected at 11 days after symptom onset, when adjusted for age and sex. Plasma vRNA’s predictive accuracy was maintained at earlier timepoints. We also found that low SARS-CoV-2-region-binding-domain (RBD)-specific IgG, low SARS-CoV-2-specific antibody-dependent cellular cytotoxicity, and elevated cytokines and injury markers were also strongly associated with mortality. In a second study using dimensionality reduction tools, we were able to separate our cohort in four distinct « patient clusters », based on their immunovirological plasma profile, with one cluster enriched in fatal outcomes. Our findings better characterize the heterogeneity of hospitalized COVID-19 cases, and may be useful in directing targeted therapeutic treatments.
In our third study, our objective was to characterize the response of dysfunctional HIV-specific CD4+ T cells to immune checkpoint blockade (ICB) across multiple subsets. We first sought to compare the functional state of HIV-specific CD4+ T cells among two cohorts of HIV-infected untreated indivduals, based on their ability to spontaneously control viral replication. Elite controllers, who have no detectable viral load in the absence of anti-retroviral therapy (ART), had more functional HIV-specific CD4+ T cells than their viremic counterparts, as well as lower levels of dysfunction-related transcription factors and immune checkpoint expression. We then compared the response of HIV-specific CD4+ T cells to ICB and saw greater increase in functionality in the dysfunctional cells of viremic individuals. All functions assessed were increased except for B-cell helping T follicular-helper-associated functions, underlying subset-specific responses to ICB. This effect was largely lost once ART was initiated, suggesting that the use of ICB would be optimal right before the initiation of ART.
Together, our results contribute to a better understanding of two pandemic-causing viral infections, and reveal key considerations for therapy
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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