1,720,964 research outputs found
Elaboration of 4′-Phosphopantetheine Adenylyltransferase inhibitors and Benzoxaboroles as antimalarial agents
Get PDFMalaria continues to be one of the leading causes of morbidity and mortality in the impoverished parts of the world with majority of the disease burden in Sub-Saharan Africa. The World Health Organization (WHO) 2021 report estimates at least 241 million cases and 627 000 deaths due to malaria in 2020. This is an increase compared to 2019 (227 million cases and 558 000 deaths), and it is also attributed to plateaued declines in malaria cases since 2015 and the 2020 COVID-19 pandemic. The WHO African region accounts for about 95% of the cases, and the mortality in children under 5 years of age is still alarmingly high. Further complicating the situation is the rise in drug-resistant species of the causative agent of the most lethal malaria, Plasmodium falciparum (P. falciparum). P. falciparum has developed resistance against almost all clinically used antimalarials, and there are mounting reports of resistance to artemisinins which are currently the most commonly used antimalarials. Artemisinins are fast-acting and are coupled with longer-acting partner drugs in artemisinin combination therapy (ACT). In South-East Asia, slow parasite clearances and high recrudescence rates following ACT have been reported and resistance to artemisinin partner drugs have been established. Resistance markers to artemisinins have also been identified even in Africa. Therefore, novel antimalarials with better activity against resistant parasites not quickly prone to rapid resistance development are urgently needed. These drugs must have novel modes of actions and act against novel targets in the parasite. To that end, this PhD project explored novel scaffolds on which to base future antimalarial drug discovery projects. A 500-member compound library of the bacterial 4′-Phosphopantetheine adenylyltransferase (PPAT) inhibitors obtained from AstraZeneca (AZ) containing two chemical series, viz. Ugi and cyclohexyl pyrimidine series, was subjected to the medium-throughput screening at the University of Cape Town (UCT)'s Holistic Drug Discovery and Development Centre (H3D). PPAT is a previously unexplored target in P. falciparum, and the current study aimed to reposition both the target and the bacterial PPAT inhibitors for malaria. As such, four hits (two from each series) with moderate antiplasmodium activity against the drugsensitive PfNF54 strain with IC50's between 1.04 µM and 2.9 µM were identified. These compounds were resynthesized but were found not to validate with the exception of one compound 2/MM1-19 from the Ugi series, albeit at 2-fold less activity than the hit (IC50 = 5.2 µM). The structure-activity relationship (SAR) based on this compound summarized in Figure 1 yielded compounds with abrogated antiplasmodium activity (IC50's >6 µM, which is the highest concentration tested in this assay). In addition to the aforementioned series, bacterial PPAT inhibitors reported by Novartis were explored, and a similar triazolopyrimidine series resulted in a hit compound 28/MM2-145 with PfNF54 IC50 = 2.2 µM. Formal hit assessment study of this compound with the SAR strategy proposed in Figure 2 resulted in compounds with low antiplasmodium activity. The Ugi series compound 2/MM1-19 and the triazolopyrimidine series compound 28/MM2-145 were found not to possess gametocytocidal activity when tested against the early and late-stage gametocytes. The compounds were also not found to be acting on the coenzyme A (CoA) biosynthesis pathway and thus unlikely inhibiting the PfPPAT when subjected to chemical rescue experiments in the presence of high concentration of metabolites of the pathway or the end-product CoA. The metabolomics data showed that compound 2/MM1-19 caused an increase in pyrimidine biosynthesis precursors N-carbamoyl-L-aspartate (N-Carb-Asp) and dihydroorotate (DHO) and a marked decrease in a number of peptides. 28/MM2-145 was found to cause an increase in pyrimidine biosynthesis precursors. The increase in pyrimidine biosynthesis precursors implicates pathways similar to those targeted by known antimalarials like atovaquone whose action is along the mitochondrial electron transport chain. Compound 2/MM1-19 did not inhibit -hematin formation (IC50 =1541 µM) as seen by decreased peptides in the parasite culture. In summary, the proposed PPAT inhibitors studied in this thesis were found to exhibit weak antiplasmodium activity and to be acting on different pathways beyond those involving Co-A biosynthesis. Penicillin binding protein (PBP) inhibitors from an antibacterial programme at H3D were screened for antiplasmodium activity. This identified a hit compound H3D006145 (43/MM2-92) with activity against PfNF54 (IC50 = 1.06 µM) and no cytotoxicity against Chinese Hamster Ovarian (CHO) and HepG2 cell lines at the highest concentration tested (IC50's >50 µM). A formal hit assessment was undertaken for this compound with the proposed SAR plan summarized in Figure 3. The SAR explorations showed that the methyl esters (PfNF54 IC50's between 0.4 and >6 µM) had better activity than the ethyl esters (PfNF54 IC50's between 1.21 and >6 µM) and the carboxylic acids were more active than the former two series (PfNF54 IC50's = 0.12–2.6 µM). These three series were all found to have no gametocytocidal activity against the early and late stages of gametocyte development and were noncytotoxic against mammalian CHO and HepG2 cell-lines at the maximum concentration tested (IC50's >50 µM). The investigation of the possible pathways targeted by this class of benzoxaboroles through metabolomics resulted in ambiguous metabolomic profiles which could not identify the exact metabolites resulting from the parasite treatment. Furthermore, the assessment of a selected representative analogue 45/MM2-91 for cross-resistance in a pool of barcoded resistant mutants with parasites resistant to known antimalarials and those in clinical development showed that the compound was not cross-resistant. This benzoxaboroles class was also found to have high in vitro microsomal stability when incubated with human, rat, and mouse liver microsomes with 91–99%, 90–99% and 87–97% of the compound remaining at 30 min, respectively. Retrospective rationalization of the binding mode in the editing domain of the P. falciparum LeucyltRNA (LeuRS) showed that these compounds have favourable interactions similar to previously reported related compounds. Lastly, the investigation of physicochemical properties determined both computationally and experimentally showed that the benzoxaborole series reported in this thesis possess drug-like characteristics. In conclusion, this study identified a new class of benzoxaboroles with sub-micromolar antiplasmodium activity and properties that supports its progression to a proof-ofconcept in vivo efficacy study in a mouse infection model
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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