1,720,968 research outputs found
Dynamics of mitohormesis and stem cell heterogeneity in therapy resistance of acute myeloid leukemia
No full textL'hétérogénéité dans les leucémies aiguës myéloïdes (LAM) constitue l'un des principaux défis de la prise en charge des patients, notamment après traitement. La persistance ou l'émergence de sous-populations nécessite une caractérisation fine afin d'éliminer ces cellules et prévenir les rechutes. Notre équipe a précédemment démontré que les cellules résistantes à la chimiothérapie cytarabine (AraC) étaient caractérisées par une forte activité mitochondriale. Cependant, les mécanismes responsables de ce statut énergétique n'étaient pas connus. Dans la première partie de mon travail, nous avons identifié un nouveau marqueur, le gène ENTPD1 codant pour l'éctonucléotidase CD39 comme étant enrichi dans les cellules résiduelles in vivo et chez les patients. Nous avons démontré un rôle non canonique de CD39 dans la régulation de la fonction mitochondriale des blastes leucémiques. Après chimiothérapie, les dommages causés aux cellules, incluant les mitochondries, déclenchent une réponse de stress mitochondrial, dépendante du facteur de transcription ATF4, qui induit la restauration mitochondriale en maintenant l'homéostasie mitochondriale, appelé mitohormésis. La forte production d'EROs mitochondriaux et totaux sont responsables de l'activation de cette voie et du stress oxydant généré. La production d'AMPc induite par la stimulation du récepteur purinergique P2RY13, un des co-récepteurs de CD39, active la voie de signalisation PKA, également un des acteurs de la régulation de l'activité mitochondriale. Ainsi, cibler CD39 ou les différentes voies de signalisations en aval de CD39 permet de sensibiliser à la chimiothérapie en bloquant l'activité mitochondriale in vitro et in vivo. De façon intéressante, l'idarubicine (IDA), une anthracycline utilisée en combinaison avec l'AraC, montre des effets opposés, en diminuant l'activité mitochondriale, un des mécanismes potentiels de sa synergie avec l'AraC. L'IDA induit un niveau élevé d'EROs, responsable de la mort des cellules mais également de l'augmentation de la protéine RE D1, induite lors de stress oxydant. REDD1 entraine l'inhibition de la voie mTORC1 ce qui conduit à l'inactivation d'ATF4, empêchant ainsi la mitohormésis. L'IDA réduit l'expression des gènes liés à l'oxydation des acides gras, processus biologique connu pour être associé à la résistance au venetoclax (VEN), un inhibiteur sélectif de la protéine anti-apoptotique BCL2. Par conséquent, l'association de l'IDA avec VEN est prometteuse et nous observons une plus forte activité anti-leucémique que les combinaisons thérapeutiques actuellement utilisées dans les LAM. Enfin, des analyses longitudinales à l'échelle de la cellule unique ont été réalisées afin d'étudier l'hétérogénéité transcriptionnelle et cellulaire à différents temps de traitements et de mieux comprendre le rôle de la population CD39high au sein des autres cellules résistantes. Nous avons identifié trois comportements cellulaires caractérisant des sous-populations de cellules souches leucémiques (CSL) distinctes : une population différenciée enrichie à la maladie résiduelle, avec un profil inflammatoire, CD39High et un taux élevé d'EROs, et deux autres populations cellulaires plus primitives, dont une population stable au cours du temps, avec une prédominance de CSL cyclantes et une population enrichie à la rechute avec la présence des CSL quiescentes. La caractérisation de ces différentes populations a tout d'abord été fait sur la base de l'expression de CD39, permettant de discriminer les populations CD39Low (CSL EROLow quiescentes + cyclantes) versus la population cellulaire CD39High (CSL EROhigh inflammatoire). Une étude fonctionnelle de ces trois populations, notamment au niveau métabolique et phénotypique, est en cours et permettra de développer une solution thérapeutique visant à éliminer toutes ces populations résistantes et prévenir la rechute.Heterogeneity in acute myeloid leukemia (AML) is one of the major challenges in patient management, particularly after treatment. An exhaustive examination of the persistence or emergence of cell populations is required to definitively eradicate relapse-initiating residual cells and prevent relapse. Our team previously demonstrated that relapse-initiating chemotherapy cytarabine (AraC)-resistant AML cells (RICs) were characterized by a high mitochondrial activity. However, the mechanisms underlying this elevated OxPHOS status have not been previously identified. In the first part of my PhD study, we observed the overexpression of the ENTPD1 gene, which encodes the ectonucleotidase CD39, in residual cells following chemotherapy in vivo and in patients. Until now, CD39 was known for its immunosuppressive role through the adenosine pathway. Here, we uncovered its novel role in regulating the mitochondrial oxidative phosphorylation status. After chemotherapy, cellular and mitochondrial damages triggered a mitochondrial stress response in an ATF4-dependent manner. This led to mitochondrial energetic and redox recovery, maintaining the mitochondrial homeostasis (called mitohormesis). The high mitochondrial and total ROS production was responsible for activating this pathway by generating oxidative stress in CD39-expressing cells. cAMP production upon the stimulation of the purinergic receptor P2RY13, a co-receptor of CD39, activated the PKA pathway, that is also involved in the regulation of mitochondrial activity. Thus, targeting CD39 or diverse components of its downstream signaling pathway enhanced anti-AML effect of AraC, by blocking the hyperactivation of mitochondrial activity in vivo. Idarubicin (an anthracycline used in combination with AraC in AML) showed the opposite effects, decreasing mitochondrial activity and ATF4 activation, potentially explaining its synergy with AraC. IDA induced high levels of ROS, responsible for cell death. This oxidative stress induced canonical stress protein REDD1 that, in turn, inhibited the mTORC1 pathway. This blocked the induction of ATF4 expression, thus preventing mitochondrial adaptation and mitohormesis. IDA also reduced the expression of fatty acid oxidation genes, known as one of the resistance pathway to anti-apoptotic BCL2 inhibitor venetoclax (VEN). Accordingly, the combination of IDA with VEN significantly increased anti-leukemic activity of IDA and was more potent than other combinatory therapies currently used in AML. Altogether, these two studies have shown that the redox balance is critical to control drug response through either cell resistance or cell death by the induction or blockage of a stress response and mitochondrial adaptation, respectively. Finally, longitudinal single-cell multi-omics analyses were performed to study transcriptional and cellular heterogeneity at different treatment time-points, and to better understand the role of the CD39high cell population within the community of drug resistant cell populations. We identified three cell behaviors characterizing distinct leukemic stem cell (LSC) populations: a differentiated population enriched at residual disease, with an inflammatory profile, CD39high and high levels of ROS, and two other more primitive cell populations, including a population stable over-time, with a predominance of cycling LSCs, and a population enriched at relapse with the presence of quiescent LSCs. These different LSC populations were further characterized after FACS-purification in the regard of CD39 expression, enabling the cell discrimination between CD39low cell populations (quiescent + cycling EROlow LSCs) and the CD39high cell population (inflammatory EROhigh LSCs). A functional study of these three cell populations, particularly at the metabolic and phenotypic levels, is currently underway and will support the development of a novel therapeutic solution killing all these resistant populations and preventing relapse
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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