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Understanding the crucial roles of lipid synthesis in Leishmania proliferation and stress response
No full textLeishmaniasis are a group of neglected tropical diseases transmitted through the bite of female phlebotomine sandflies. The causative agents are protozoan parasites of the genus Leishmania which alternate between flagellated promastigotes colonizing the midgut of sandflies and non-flagellated amastigotes residing in the macrophages of mammals. The 3 forms of Leishmaniasis are cutaneous, mucocutaneous and visceral caused by L. major, L. mexicana and L. donovani. Without a safe vaccine, disease management primarily depends on vector control and drugs like pentavalent antimonials, itraconazole, myriocin administered in high doses, having adverse side effects and increased drug resistance Discoveries that reveal fundamental insights into Leishmania biology can lead to new drug targets, better treatments, and improved vector control strategies. Therefore, research involving the identification and characterization of metabolic pathways that could provide new drug targets is of considerable value. Understanding biology behind lipid synthesis and acquisition in Leishmania is important because lipids play a crucial role in cell homeostasis. Plasma membrane and other organelle membrane contain lipids as important constituents, so understanding how important lipids like PC, sterol and sphingolipid are synthesized de novo and utilized for both life stages of Leishmania in sandfly and mammalian hosts, respectively is crucial. The long-term goal can be utilizing this new biological knowledge about lipid synthesis and acquisition by applying them to identify possible novel drug targets against the parasite. Potentially, we can generate novel inhibitors or use this knowledge to create combinatorial treatment with existing chemotherapeutics helping to cure Leishmaniasis (second-deadliest parasitic disease after malaria).
Phosphatidylcholine (PC) is the most abundant group of phospholipids in eukaryotes constituting 30–35% of total lipids in Leishmania. PC synthesis mainly occurs via the choline branch of the Kennedy pathway (choline choline-phosphate CDP-choline PC) and the N-methylation of phosphatidylethanolamine (PE). In addition, Leishmania parasites can also acquire lipids from the host or culture medium. Our previous study on the choline-phosphate cytidylyltransferase (CPCT) demonstrates that the formation of CDP-choline from choline-phosphate and CTP is dispensable for the promastigotes and amastigotes of Leishmania major. Thus, these parasites may bypass CPCT through an alternative route of CDP-choline production, PE N-methylation or lipid salvage. In this study, we assessed the function and essentiality of choline ethanolamine phosphotransferase (CEPT) which is directly responsible for the de novo synthesis of both PC and PE. This is important because in addition to being principle membrane components, PC and PE are precursors for a number of vital intermediates including diacylglycerol, lysophospholipid and phosphatidic acid. Understanding how Leishmania generate PC and PE may reveal new ways to block their growth. Our data indicate that L. major CEPT is localized in the ER and possesses the activity to synthesize PC from CDP-choline and diacylglycerol. Targeted deletion of CEPT is only possible in the presence of an episomal CEPT in the promastigote stage of L. major. These chromosomal null parasites require the episomal expression of CEPT for survival in culture, confirming its essentiality during the promastigote stage. In contrast, during in vivo infection of BALB/c mice, these chromosomal null parasites appeared to lose the episomal copy of CEPT while maintaining a normal level of virulence, replication and cellular PC. Therefore, while the de novo synthesis of PC/PE is indispensable for proliferation of promastigotes, intracellular amastigotes could acquire the majority of their lipids from the host.
Within the mid gut of sand fly, Leishmania promastigotes need to colonize, proliferate and differentiate while facing a number of challenges including sand fly immunity, nutrient competition, potential microbial toxins and osmolality changes associated with sugar and blood meal digestion. Sterols and sphingolipids are key components of the plasma membrane and regulate diverse processes including membrane stability, ligand-receptor interaction, and vesicular trafficking. Previous findings show, sphingolipids and sterol biosynthetic pathway enzymes are crucial for stress response and virulence. To decipher the protective role of these lipids in Leishmania, we examined the sensitivity of ergosterol and sphingolipid mutants to membrane perturbation agents, bacterial toxins and osmotic stress. My results show sterol and sphingolipid inhibition result in mitochondrial abnormalities, making Leishmania hypersensitive to temperature, osmostress and Pentamidine (mitochondrion targeting drug), thereby indicating sterols and sphingolipids crucially maintain Leishmania homeostasis during temperature and osmotic stress encountered in its lifecycle. Alteration of lipid synthesis can make Leishmania extremely vulnerable to membrane stress and nutrient deprivation. My work also tries to improve current drug efficacy by combined usage of lower doses of existing drugs like Pentamidine and Antimony tartrate respectively with sterol inhibitor Itraconazole and sphingolipid inhibitor Myriocin respectively against Leishmania spp ( L.major, L. mexicana and L. donovani) in vitro with least to no side effects. My results show various Leishmania spp. (L. major, L. mexicana, L. donovani) on sterol inhibition with sublytic Itraconazole doses, and sphingolipid inhibition with sublytic Myriocin doses will show hypersensitivity to sublytic doses of Pentamidine and Antimony tartrate when used in combination. The significance of this proposed work is to find better combinatorial treatment strategies against Leishmaniasis with existing drugs and inhibitors with least possible doses, having least to no side effects.
Future work will elucidate: 1) how sterol/sphingolipid synthesis affects the composition and physiology of plasma membrane, and 2) how lipids in plasma membrane affect the transmission of Leishmania parasites in the sand fly.Embargo status: Restricted until 01/2027. To request the author grant access, click on the PDF link to the left
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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