1,720,954 research outputs found
Genetic and chemical validation of dihydrofolate reductase as a potential target for the treatment of NTM infections
No full textNontuberculous mycobacteria (NTM) are emerging opportunistic pathogens that can cause chronic, tuberculosis (TB)-like lung disease. One of the most clinically relevant and drug resistant NTM species is Mycobacterium abscessus (MAB). The success rate of treatment with antibiotics is low, due to the fact that NTM are intrinsically resistant to many of the standard anti-TB drugs. Patients undergo a prolonged multi-drug regimen, where treatment-associated toxicity is considerable. Despite the poor outcomes of therapy, there is limited NTM drug discovery work. Current efforts are limited by the lack of extensive knowledge on NTM drug targets and challenges in NTM drug susceptibility testing (DST) in the laboratory. This study aims to discover new drugs against MAB, where the guiding hypothesis is that anti-TB drug targets offer the most direct path to new antibiotics for NTM, but that we need new chemistry to act at these established targets. We used a combination of CRISPRi and chemistry to test whether dihydrofolate reductase (DHFR) would be a valid target for the treatment of MAB. We also set out to examine inter-assay variability when performing DST for known anti-TB drugs.In preliminary work, the CRISPRi methodology has been first validated in the model organism M. smegmatis and subsequently in MAB. With this technique, the DHFR gene, dfrA, was observed to be essential for in vitro growth of two subspecies of MAB. A series of candidate DHFR inhibitors has been tested for in vitro growth inhibition using broth microdilution and conventional agar dilution method. A number of these compounds showed potent antimicrobial activity against MAB (MIC90 at 10μM or lower). In the current study, inter-assay variability was assessed when measuring MIC of amikacin (AMK), rifampicin (RIF) and bedaquiline (BDQ) in MAB, using the following assays: agar dilution, OD600, BacTiter-Glo and AlamarBlue. Highest reproducibility was achieved by agar dilution and OD600 while AlamarBlue, and particularly BacTiter-Glo, gave inconsistent results. Together, these data suggest that DHFR can serve as a promising drug target for NTM infections, as shown via CRISPRi and chemical inhibition for MAB. We also found that different assays used for DST may yield discrepant results depending on the drug. Our data suggest that the OD600 assay is most suitable to guide compound selection for drug discovery against NTM. The lack of successful treatment continues to compromise health outcomes of patients. Novel therapeutic compounds are urgently needed for the treatment of NTM infections. This study aims to address this unmet need.Les mycobactéries non tuberculeuses (MNT) sont des agents pathogènes opportunistes émergents responsables de maladies pulmonaires graves et chroniques, semblable à la tuberculose (TB). Une des espèces de MNT la plus cliniquement pertinente est le Mycobacterium abscessus (MAB), démontrant une très haute résistance aux antibiotiques. Le taux de succès des traitements est faible dû à leur résistance intrinsèque à de nombreux médicaments antituberculeux. Les régimes thérapeutiques actuels sont longs et la toxicité associée au traitement est considérable. Malgré les résultats médiocres de la thérapie, la découverte de médicaments contre les MNT est limitée. Les efforts actuels sont limités par le manque de connaissances approfondies sur les cibles médicamenteuses des MNT et par les difficultés rencontrées lors de l’effectuation des tests de sensibilité en laboratoire. Cette étude vise à découvrir de nouveaux médicaments contre le MAB. Notre hypothèse est que de nouveaux composés contre les cibles des médicaments antituberculeux actuels offrent la voie la plus directe pour la découverte de nouvelles thérapies antimicrobiennes contre les MNT. Nous avons utilisé une combinaison de CRISPRi et de chimie pour vérifier si la dihydrofolate réductase (DHFR) constituerait une cible valable pour le traitement du MAB. Nous avons également examiné la variabilité entre différents essais de sensibilité pour des médicaments antituberculeux connus. La méthodologie de CRISPRi a d'abord été validée dans l'organisme modèle M. smegmatis, puis dans le MAB. Avec cette technique, le gène DHFR, dfrA, s'est révélé essentiel pour la croissance in vitro de deux sous-espèces de MAB. Une série d'inhibiteurs de DHFR candidats a été testée pour l'inhibition de croissance in vitro en utilisant la microdilution en milieu liquide et la méthode de dilution en gélose conventionnelle. Quelques composés ont montré une activité antimicrobienne significante contre le MAB (CMI 90 à 10 μM ou moins). Dans la présente étude, la variabilité inter-essais a été évaluée lors de la mesure de la CMI de l'amikacine (AMK), de la rifampicine (RIF) et de la bédaquiline (BDQ) dans le MAB, en utilisant les tests suivants: dilution en gélose, OD600, BacTiter-Glo et AlamarBlue. La reproductibilité été la plus élevée pour la dilution en gélose et l'OD600, tandis qu'AlamarBlue, et en particulier BacTiter-Glo, donnait des résultats incohérents. Ensemble, ces données suggèrent que la DHFR peut constituer une cible médicamenteuse prometteuse pour les infections à MNT, comme indiqué par CRISPRi et l'inhibition chimique du MAB. Nous avons également constaté que différents essais de sensibilité pouvaient donner des résultats discordants dépendamment du médicament. Nos données suggèrent que le test OD600 est le plus approprié pour guider la sélection de composés en vue de la découverte de médicaments contre MNT. L'absence de traitement efficace continue de compromettre la santé des patients. De nouveaux composés thérapeutiques sont nécessaires contre les infections à MNT. Cette étude cible à combler ce besoin critique afin d'améliorer la qualité de vie des patients affectés
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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