Kinetics and Ligand-Binding Preferences of Mycobacterium tuberculosis Thymidylate Synthases, ThyA and ThyX

Mycobacterium tuberculosis kills approximately 2 million people each year and presents an urgent need to identify new targets and new antitubercular drugs. Thymidylate synthase (TS) enzymes from other species offer good targets for drug development and the M. tuberculosis genome contains two putative TS enzymes, a conventional ThyA and a flavin-based ThyX. In M. tuberculosis, both TS enzymes have been implicated as essential for growth, either based on drug-resistance studies or genome-wide mutagenesis screens. To facilitate future small molecule inhibitors against these proteins, a detailed enzymatic characterization was necessary.After cloning, overexpression, and purification, the thymidylate-synthesizing ability of ThyA and ThyX gene products were directly confirmed by HPLC analysis of reaction products and substrate saturation kinetics were established. 5-Fluoro-2'-deoxyuridine 5'-monophosphate (FdUMP) was a potent inhibitor of both ThyA and ThyX, offering important clues to double-targeting strategies. In contrast, the folate-based 1843U89 was a potent inhibitor of ThyA but not ThyX suggesting that it should be possible to find ThyX-specific antifolates. A turnover-dependent kinetic assay, combined with the active-site titration approach of Ackermann and Potter, revealed that both M. tuberculosis enzymes had very low k(cat) values. One possible explanation for the low catalytic activity of M. tuberculosis ThyX is that its true biological substrates remain to be identified. Alternatively, this slow-growing pathogen, with low demands for TMP, may have evolved to down-regulate TS activities by altering the turnover rate of individual enzyme molecules, perhaps to preserve total protein quantities for other purposes. In many organisms, TS is often used as a part of larger complexes of macromolecules that control replication and DNA repair.Thus, the present enzymatic characterization of ThyA and ThyX from M. tuberculosis provides a framework for future development of cell-active inhibitors and the biological roles of these TS enzymes in M. tuberculosis

Increased 15-PGDH expression leads to dysregulated resolution responses in stromal cells from patients with chronic tendinopathy

S.G.D. is a recipient of an Oxford UCB Prize Fellowship in Biomedical Research and also received funding from Arthritis Research UK (grant no: 20506). Arthritis Research UK also supported UO (program grant 20522). J.D. received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343). J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z). Research at NDORMS, University of Oxford is supported through the National Institute for Health Research (NIHR) Oxford Musculoskeletal Biomedical Research Centre (BRC)

Stress Corrosion Cracking Study of Aluminum Alloys Using Electrochemical Noise Analysis

Stress corrosion cracking studies of aluminum alloys AA2219, AA8090, and AA5456 in heat-treated and non heat-treated condition were carried out using electrochemical noise technique with various applied stresses. Electrochemical noise time series data (corrosion potential vs. time) was obtained for the stressed tensile specimens in 3.5% NaCl aqueous solution at room temperature (27 degrees C). The values of drop in corrosion potential, total corrosion potential, mean corrosion potential, and hydrogen overpotential were evaluated from corrosion potential versus time series data. The electrochemical noise time series data was further analyzed with rescaled range (R/S) analysis proposed by Hurst to obtain the Hurst exponent. According to the results, higher values of the Hurst exponents with increased applied stresses showed more susceptibility to stress corrosion cracking as confirmed in case of alloy AA 2219 and AA8090

Design and Evaluation of Liposomal Formulation of Pilocarpine Nitrate

Prolonged release drug delivery system of pilocarpine nitrate was made by optimizing thin layer film hydration method. Egg phosphatidylcholine and cholesterol were used to make multilamellar vesicles. Effects of charges over the vesicles were studied by incorporating dicetylphosphate and stearylamine. Various factors, which may affect the size, shape, encapsulation efficiency and release rate, were studied. Liposomes in the size range 0.2 to 1 µm were obtained by optimizing the process. Encapsulation efficiency of neutral, positive and negatively charged liposomes were found to be 32.5, 35.4 and 34.2 percent, respectively. In vitro drug release rate was studied on specially designed model. Biological response in terms of reduction in intraocular pressure was observed on rabbit eyes. Pilocarpine nitrate liposomes were lyophilized and stability studies were conducted

Inkk Trial - Intraoperative ketamine for perioperative pain management following total knee endoprosthetic replacement in oncology: a double-blinded randomized trial.

BACKGROUND: There has been a growing interest in the use of ketamine following orthopedic surgeries. We hypothesized that low dose intravenous ketamine during surgery would help in mobilization following total knee replacement (TKR) in oncology patients as assessed by the timed to up and go (TUG) test at 72 hours post-surgery. Our secondary objectives were to compare the opioid requirement at the end of 72 hours, pain scores, satisfaction with pain management, adverse effects, range of joint movement achieved in the post-operative period and the functional recovery at the end of 1 month. METHODS: After the ethics commitee approval, registration of the trial with the Clinical Trial Registry - India (CTRI), and informed consent, this double-blinded trial was conducted. Using computer generated randomization chart, an independent team randomized the patients into ketamine group which received at induction, a ketamine bolus dose of 0.5 mg.kg-1 before the incision followed by 10 µg.kg-1min-1 infusion which was maintained intraoperatively till skin closure and the saline group received an equivalent volume of saline. Postoperatively, patient controlled morphine pumps were attached and the pain score with morphine usage were recorded for 72 hours. The TUG tests and range of motion were assessed by the physiotherapists until 72 hours. RESULTS: Fifty-two patients were enrolled in the trial. Demographics were comparable. No significant intraoperative hemodynamic changes and post-operative adverse events were noted between the groups. A decrease in the TUG test, along with decreased opioid usage with a better range of movements was noted in the ketamine group, but this was not statistically significant. Day of discharge, patient satisfaction score, and functional recovery assessed by Oxford Knee Score (OKS) were comparable between the groups. CONCLUSION: In conclusion, low dose intraoperative ketamine infusion does not provide clinical benefit in perioperative pain management and postoperative rehabilitation following total knee endoprosthetic replacement in oncology

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Not AvailableAgriculture,the way of life, has advanced from ploughing soil with a stone fitted on a tree-branch drawn by a horse, to monitoring the entire filed with artificial intelligence and drone technology. Thus, the dimension of it has changed a lot during last couple of decades. Agriculture is not confined managing soils only rather understating what actually the factors going on behind producing the ultimate product, yield. Many new tools like biotechnology, nano-technology, machine learning in agriculture and so on have got their massive importance in the advancement of agriculture. Recently, climate change is one of the burgeoning issues in the agricultural sector. It is a big challenge to the scientists and the policy makers to develop a better resilient agriculture under changing climatic scenario. So, advanced agriculture must consider this aspect as well. Biotic stresses due to weeds, insect and diseases are highly responsible to reduce the crop yield. Better understanding the science behind these stresses and development of their management strategies accordingly is also very much needful. Now a days, horticulture sector has emerged out as an important and highly income generating option to the farmers. This particular sector of agriculture has got its advancement a lot in the recent past creating huge employment generations in the nation. A slogan called ‘waste to wealth’ is very much trendy now. In the agricultural sector, nothing is waste actually. The so called waste of agriculture mainly consists of crop residues which can be converted into wealth. In the light of advancement one must not overlook the goal of sustainable agricultural development. Any advancement must be nature and biodiversity saving. All these are the milieu of editing a book entitled, ‘Advanced Agriculture’ which includes the recent advances of agricultural sciences covering the aforementioned topics.Not Availabl