1,721,173 research outputs found
ANTIBIOTICS TARGETING TUBERCULOSIS: BIOSYNTHESIS OF A-102395 AND DISCOVERY OF NOVEL ACTINOMYCINS
Full text linkThe increase in antibiotic resistance of many bacterial strains including multidrug-resistant tuberculosis (MDR-TB) due to over- and misuse of antibiotics is a serious medical and economical problem. Therefore discovery and development of new antibiotics are urgently needed. Two projects were undertaken to address the need for new anti-tuberculosis antibiotics.
1. Discovery of new chemical entities. A-102395, a new nucleoside inhibitor of bacterial MraY (translocase I, EC 2.7.8.13) that is essential for bacterial survival, was isolated from the culture broth of Amycolatopsis sp. SANK 60206 in 2007. Although A-102395 is a potent inhibitor of translocase I with IC50 of 11 nM, it contradictingly does not have any antibiotic activity. A-102395 is a derivative of capuramycin with a unique aromatic side chain. A semisynthetic derivative of capuramycin is currently in clinical trials as an anti-tuberculosis antibiotic, suggesting potential for using A-102395 as a starting point for antibiotic discovery. The biosynthetic gene cluster of A-102395 was identified, including 35 putative open reading frames responsible for biosynthesis and resistance. A series of gene inactivation abolished the A-102395 production, indicating those genes within the cluster are essential for A-102395 biosynthesis. Functional characterization of Cpr17, which has sequence similarity to aminoglycoside phosphotransferases, revealed that it functions as a phosphotransferase conferring self-resistance by using GTP as phosphate donor. Furthermore the enzyme is characterized by low substrate specificity, as Cpr17 was capable of modifying a large series of natural or semi-synthesized analogues of capuramycins. A series of organism-specific high-throughput screening models for potential antibacterial agents targeting on bacterial cell wall synthesis have been established, including Escherichia coli and Mycobacterium tuberculosis. For this screen ten enzymes were successfully used to reconstitute cell wall biosynthesis in vitro. This screening is expected to allow us to identify the targets of novel antibiotics rapidly and in a cost-efficient manner.
2. Rediscovering old antibiotics. As part of our long term goal of discovering and developing novel anti-tuberculosis antibiotics, four novel actinomycins were isolated from the scale-up fermentation of Streptomyces sp. Gö-GS12, and their structures were characterized using mass spectrometry and 1D and 2D NMR. Their antibacterial activity against Gram-positive and Gram-negative strains were determined, as well as their cytotoxicity
The Biosynthesis of Capuramycin-type Antibiotics: Identification of the A-102395 Biosynthetic Gene Cluster, Mechanism of Self-Resistence, and Formation of Uridine-5\u27-Carboxamide
Full text linkA-500359s, A-503083s, and A-102395 are capuramycin-type nucleoside antibiotics that were discovered using a screen to identify inhibitors of bacterial translocase I, an essential enzyme in peptidoglycan cell wall biosynthesis. Like the parent capuramycin, A-500359s and A-503083s consist of three structural components: a uridine-5\u27-carboxamide (CarU), a rare unsaturated hexuronic acid, and an aminocaprolactam, the last of which is substituted by an unusual arylamine-containing polyamide in A-102395. The biosynthetic gene clusters for A-500359s and A-503083s have been reported, and two genes encoding a putative non-heme Fe(II)-dependent α-ketoglutarate:UMP dioxygenase and an l-Thr:uridine-5\u27-aldehyde transaldolase were uncovered, suggesting that C-C bond formation during assembly of the high carbon (C6) sugar backbone of CarU proceeds from the precursors UMP and l-Thr to form 5\u27-C-glycyluridine (C7) as a biosynthetic intermediate. Here, isotopic enrichment studies with the producer of A-503083s were used to indeed establish l-Thr as the direct source of the carboxamide of CarU. With this knowledge, the A-102395 gene cluster was subsequently cloned and characterized. A genetic system in the A-102395-producing strain was developed, permitting the inactivation of several genes, including those encoding the dioxygenase (cpr19) and transaldolase (cpr25), which abolished the production of A-102395, thus confirming their role in biosynthesis. Heterologous production of recombinant Cpr19 and CapK, the transaldolase homolog involved in A-503083 biosynthesis, confirmed their expected function. Finally, a phosphotransferase (Cpr17) conferring self-resistance was functionally characterized. The results provide the opportunity to use comparative genomics along with in vivo and in vitro approaches to probe the biosynthetic mechanism of these intriguing structures
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe 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
Full text link“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
Full text linkWe 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
Full text linkWe 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
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