The biological and structural characterization of Mycobacterium tuberculosis UvrA provides novel insights into its mechanism of action

Mycobacterium tuberculosis is an extremely well adapted intracellular human pathogen that is exposed to multiple DNA damaging chemical assaults originating from the host defence mechanisms. As a consequence, this bacterium is thought to possess highly efficient DNA repair machineries, the nucleotide excision repair (NER) system amongst these. Although NER is of central importance to DNA repair in M. tuberculosis, our understanding of the processes in this species is limited. The conserved UvrABC endonuclease represents the multi-enzymatic core in bacterial NER, where the UvrA ATPase provides the DNA lesion-sensing function. The herein reported genetic analysis demonstrates that M. tuberculosis UvrA is important for the repair of nitrosative and oxidative DNA damage. Moreover, our biochemical and structural characterization of recombinant M. tuberculosis UvrA contributes new insights into its mechanism of action. In particular, the structural investigation reveals an unprecedented conformation of the UvrB-binding domain that we propose to be of functional relevance. Taken together, our data suggest UvrA as a potential target for the development of novel anti-tubercular agents and provide a biochemical framework for the identification of small-molecule inhibitors interfering with the NER activity in M. tuberculosis.

Antithyroid drugs and their analogues: synthesis, structure, and mechanism of action

Thyroid hormones are essential for the development and differentiation of all cells of the human body. They regulate protein, fat, and carbohydrate metabolism. In this Account, we discuss the synthesis, structure, and mechanism of action of thyroid hormones and their analogues. The prohormone thyroxine (14) is synthesized on thyroglobulin by thyroid peroxidase (TPO), a heme enzyme that uses iodide and hydrogen peroxide to perform iodination and phenolic coupling reactions. The monodeiodination of T4 to 3,3',5-triiodothyronine (13) by selenium-containing deiodinases (ID-1, ID-2) is a key step in the activation of thyroid hormones. The type 3 deiodinase (ID-3) catalyzes the deactivation of thyroid hormone in a process that removes iodine selectively from the tyrosyl ring of T4 to produce 3,3',5'-triiodothyronine (rT3). Several physiological and pathological stimuli influence thyroid hormone synthesis. The overproduction of thyroid hormones leads to hyperthyroidism, which is treated by antithyroid drugs that either inhibit the thyroid hormone biosynthesis and/or decrease the conversion of T4 to T3. Antithyroid drugs are thiourea-based compounds, which indude propylthiouracil (PTU), methimazole (MM I), and carbimazole (CBZ). The thyroid gland actively concentrates these heterocyclic compounds against a concentration gradient Recently, the selenium analogues of PTU, MMI, and CBZ attracted significant attention because the selenium moiety in these compounds has a higher nucleophilicity than that of the sulfur moiety. Researchers have developed new methods for the synthesis of the selenium compounds. Several experimental and theoretical investigations revealed that the selone (C=Se) in the selenium analogues is more polarized than the thione (C=S) in the sulfur compounds, and the selones exist predominantly in their zwitterionic forms. Although the thionamide-based antithyroid drugs have been used for almost 70 years, the mechanism of their action is not completely understood. Most investigations have revealed that MMI and PTU irreversibly inhibit TPO. PTU, MTU, and their selenium analogues also inhibit ID-1, most likely by reacting with the selenenyl iodide intermediate. The good ID-1 inhibitory activity of Pill and its analogues can be ascribed to the presence of the -N(H)-C(=O)- functionality that can form hydrogen bonds with nearby amino add residues in the selenenyl sulfide state. In addition to the TPO and ID-1 inhibition, the selenium analogues are very good antioxidants. In the presence of cellular reducing agents such as GSH, these compounds catalytically reduce hydrogen peroxide. They can also efficiently scavenge peroxynitrite, a potent biological oxidant and nitrating agent.

2-(4-Chlorobenzyl)-6-arylimidazo2,1-b]1,3,4]thiadiazoles: Synthesis, cytotoxic activity and mechanism of action

The cytotoxic activity of a new series of 2-(4'-chlorobenzyl)-5,6-disubstituted imidazo2,1-b]1,3,4]wthiadiazoles against different human and murine cancer cell lines is reported. Among the tested compounds, two derivatives namely 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo2,1-1)]1,3,4]th iadiazole-5-carbaldehyde 4i and 2-(4-chlorobenzyl)-6-(2-oxo-2H-chromen-3-ypimidazo2,1-1)]1,3,4]thi adiazol-5-yl thiocyanate 5i emerged as the most potent against all the cell lines. To investigate the mechanism of action, we selected compounds 4i for cell cycle study, analysis of mitochondrial membrane potential and Annexin V-FITC flow cytometric analysis and DNA fragmentation assay. Results showed that 4i induced cytotoxicity by inducing apoptosis without arresting the cell cycle. (C) 2014 Elsevier Masson SAS. All rights reserved.

Comparison of systems of biological indication approved during the course of the joint Anglo-Soviet investigations held under the auspices of the Institute of Hydrobiology of the Academy of Sciences of the Ukrainian SSR

In accordance with the plan for joint Anglo-Soviet scientific and technical collaboration on environmental problems, the comparative evaluation of systems of hydrobiological analysis of the surface water quality started in 1977 at the Regional Laboratory of the Severn-Trent Water Authority in Nottingham were continued in the spring of 1978. The investigations were carried out under the auspices of the Institute of Hydrobiology of the Academy of Sciences of the Ukrainian SSR. Hydrobiological and hydrochemical samples were collected by Soviet and British specialists from the Kiev reservoir and the rivers Dnieper, Sozh, Desna and Snov. The samples were processed on the expedition ships and in the Laboratory for the Hydrobiology of Small Water Bodies of the Institute of Hydrobiology of the Academy of Sciences of the Ukrainian SSR. The possible approved methods to be adopted were evaluated from the samples using the phytoperiphyton, phytoplankton, zooplankton and zoobenthos against a background of hydrochemical characteristics. The study concludes that weather conditions complicated the work on testing the systems of biological indication of water quality and made it inadvisable to use those methods of comparison which were used when similar work was carried out in Nottingham.

Resveratrol: Anti-Obesity Mechanisms of Action

Resveratrol is a non-flavonoid polyphenol which belongs to the stilbenes group and is produced naturally in several plants in response to injury or fungal attack. Resveratrol has been recently reported as preventing obesity. The present review aims to compile the evidence concerning the potential mechanisms of action which underlie the anti-obesity effects of resveratrol, obtained either in cultured cells lines and animal models. Published studies demonstrate that resveratrol has an anti-adipogenic effect. A good consensus concerning the involvement of a down-regulation of C/EBPa and PPAR. in this effect has been reached. Also, in vitro studies have demonstrated that resveratrol can increase apoptosis in mature adipocytes. Furthermore, different metabolic pathways involved in triacylglycerol metabolism in white adipose tissue have been shown to be targets for resveratrol. Both the inhibition of de novo lipogenesis and adipose tissue fatty acid uptake mediated by lipoprotein lipase play a role in explaining the reduction in body fat which resveratrol induces. As far as lipolysis is concerned, although this compound per se seems to be unable to induce lipolysis, it increases lipid mobilization stimulated by beta-adrenergic agents. The increase in brown adipose tissue thermogenesis, and consequently the associated energy dissipation, can contribute to explaining the body-fat lowering effect of resveratrol. In addition to its effects on adipose tissue, resveratrol can also acts on other organs and tissues. Thus, it increases mitochondriogenesis and consequently fatty acid oxidation in skeletal muscle and liver. This effect can also contribute to the body-fat lowering effect of this molecule.

Esporte como experiência : uma análise fenomenológico-pragmática da Constituição do jogo coletivo

O objetivo desse trabalho é compreender a ação humana nos jogos esportivos coletivos. Os jogos em questão são aqueles que são disputados em interações conduzidas pelos jogadores em ações simultâneas mutuamente referidas que envolvem o corpo em um mesmo ambiente ? geralmente esportes com bola, como o futebol, o basquetebol e o voleibol, entre outros. A perspectiva adotada nos conduziu no sentido de compreender a ação no curso da experiência de jogar, uma experiência comumente retratada por praticantes como uma experiência desafiadora, excitante, arrebatadora e autêntica. A realização da ação adequada à lógica dos eventos no sentido de propiciar o alcance das metas e objetivos propostos pelo jogo aos jogadores e à sua equipe, com uma organização e sentido de desafio, conduz e ordena todo o curso da experiência competitiva até o fim da partida ocasionando aquela experiência. Como isso é possível? Para tentar entender como ação e experiência se articulam em uma vivência singular, distinta das demais, na prática dos esportes coletivos, devemos compreender toda a ordem presente na própria constituição do desafio que caracteriza todo o jogo ? uma ordem prática que confere ao ser um impulso contínuo e arrebatador à ação. O jogo, desse modo, é apresentado aqui como um mundo a que corresponde toda uma ordem de existência. Esse mundo, em relação ao qual um modo agonistico de ser se alinha, é ordenado por um conjunto de regras que determina a forma lógica básica da prática competitiva. No modo como foi subjetivada e incorporada pelos jogadores em suas competências, essa forma ordena as interações permitindo que uma dinâmica competitiva real se desdobre fluentemente entre eles numa mesma corrente simultânea e sequencial de eventos que envolvem a todos, sendo vivenciada por cada um no mesmo tempo e no mesmo espaço de uma experiência competitiva nossa. Essa forma se apresenta como ordem de uma mesma realidade contínua, presente tanto numa dimensão predominante espacial e corporal da experiência, envolvendo objetos físicos, no tempo imediato; quanto numa dimensão predominantemente temporal, onde se situa um espaço relacional no qual segue se definindo quem está melhor ou pior e, ao final, o vencedor e o perdedor da partida. Nesse mundo dos jogos agonísticos, ambas as dimensões se mantêm articuladas por mecanismos de definição, acumulação e objetivação numérica dos eventos (como o placar) que são programados para funcionar de acordo com um princípio integrador de justiça, baseados em critérios de excelência e competitividade ? mecanismos cujas operações bem inter-relacionadas devem definir o melhor a cada partida, conferindo à realidade vivenciável nesse mundo um sentido de unidade e completude próprias de uma experiência singular.

The cost of action: CRM investment in the Philippines

Knowing the cost of investment in coastal resources management (CRM) is important especially in understanding the cost of undertaking one and ascertaining whether the outcomes are worth the money spent. In the Philippines, various CRM projects have already been initiated and no studies have tried to account for the total level of investment. This paper provides an estimate of money spent or invested on CRM in the Philippines and examines the investment per km2 of coral reefs.