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91.
High Functional Diversity in Mycobacterium tuberculosis Driven by Genetic Drift and Human Demography
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Ruth Hershberg Mikhail Lipatov Peter M Small Hadar Sheffer Stefan Niemann Susanne Homolka Jared C Roach Kristin Kremer Dmitri A Petrov Marcus W Feldman Sebastien Gagneux 《PLoS biology》2008,6(12)
Mycobacterium tuberculosis infects one third of the human world population and kills someone every 15 seconds. For more than a century, scientists and clinicians have been distinguishing between the human- and animal-adapted members of the M. tuberculosis complex (MTBC). However, all human-adapted strains of MTBC have traditionally been considered to be essentially identical. We surveyed sequence diversity within a global collection of strains belonging to MTBC using seven megabase pairs of DNA sequence data. We show that the members of MTBC affecting humans are more genetically diverse than generally assumed, and that this diversity can be linked to human demographic and migratory events. We further demonstrate that these organisms are under extremely reduced purifying selection and that, as a result of increased genetic drift, much of this genetic diversity is likely to have functional consequences. Our findings suggest that the current increases in human population, urbanization, and global travel, combined with the population genetic characteristics of M. tuberculosis described here, could contribute to the emergence and spread of drug-resistant tuberculosis. 相似文献
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Sebastien L'hoste Abderrahmen Chargui Radia Belfodil Christophe Duranton Isabelle Rubera Baharia Mograbi Chantal Poujeol Michel Tauc Philippe Poujeol 《Free radical biology & medicine》2009,46(8):1017-1031
The aim of this study was to characterize the role of CFTR during Cd2+-induced apoptosis. For this purpose primary cultures and cell lines originated from proximal tubules (PCT) of wild-type cftr+/+ and cftr?/? mice were used. In cftr+/+ cells, the application of Cd2+ (5 μM) stimulated within 8 min an ERK1/2-activated CFTR-like Cl? conductance sensitive to CFTRinh-172. Thereafter Cd2+ induced an apoptotic volume decrease (AVD) within 6 h followed by caspase-3 activation and apoptosis. The early increase in CFTR conductance was followed by the activation of volume-sensitive outwardly rectifying (VSOR) Cl? and TASK2 K+ conductances. By contrast, cftr?/? cells exposed to Cd2+ were unable to develop VSOR currents, caspase-3 activity, and AVD process and underwent necrosis. Moreover in cftr+/+ cells, Cd2+ enhanced reactive oxygen species (ROS) production and induced a 50% decrease in total glutathione content (major ROS scavenger in PCT). ROS generation and glutathione decrease depended on the presence of CFTR, since they did not occur in the presence of CFTRinh-172 or in cftr?/? cells. Additionally, Cd2+ exposure accelerates effluxes of fluorescent glutathione S-conjugate in cftr+/+ cells. Our data suggest that CFTR could modulate ROS levels to ensure apoptosis during Cd2+ exposure by modulating the intracellular content of glutathione. 相似文献
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Danit Atias Khalil Abu-Rabeah Sebastien Herrmann Julia Frenkel Dorith Tavor Serge Cosnier Robert S. Marks 《Biosensors & bioelectronics》2009,24(12):3683-3687
Herein the development of an alternative optic-conductive fiber configuration applied for the construction of biosensing platforms. This new approach is based on applying the chemical polymerization of pyrrole onto the surface of polymethyl metacrylate (PMMA) fibers to create a polymer—a conductive surface, onto which an additional photoactive polypyrrole-benzophenone (PpyBz) film is electrochemically generated upon the fiber surface. Irradiation of the benzophenone groups embedded in the Ppy films with UV radiation (350 nm) formed active radicals that allowed the covalent attachment of the desired bioreceptors. Characterization of the amperometric biosensing matrix was accomplished by using a model Urease (Urs) through electrochemical impedance spectroscopy (EIS) and amperometry. Both techniques have shown a low charge transfer resistance (340 kΩ) and a high sensitivity (12.3 μA mM−1 cm−2). Thereafter, the construction of an optical biosensing matrix based on horseradish peroxidase (HRP) production of photons was carried out. The high signal to noise (S/N) ratio (1600) indicated clearly that this approach can serve as a new platform to replace glass optical fibers based on biosensors. 相似文献
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Sebastien Jacquet Xiaoke Yin Pierre Sicard James Clark Gajen S. Kanaganayagam Manuel Mayr Michael S. Marber 《Molecular & cellular proteomics : MCP》2009,8(12):2687-2699
Acute myocardial infarction (AMI) is a common cause of death for which effective treatments are available provided that diagnosis is rapid. The current diagnostic gold standards are circulating cardiac troponins I and T. However, their slow release delays diagnosis, and their persistence limits their utility in the identification of reinfarction. The aim was to identify candidate biomarkers of AMI. Isolated mouse hearts were perfused with oxygenated protein-free buffer, and coronary effluent was collected after ischemia or during matched normoxic perfusion. Effluents were analyzed using proteomics approaches based on one- or two-dimensional initial separation. Of the 459 proteins identified after ischemia with one-dimensional separation, 320 were not detected in the control coronary effluent. Among these were all classic existing biomarkers of AMI. We also identified the cardiac isoform of myosin-binding protein C in its full-length form and as a 40-kDa degradation product. This protein was not detected in the other murine organs examined, increased markedly with even trivial myocardial infarction, and could be detected in the plasma after myocardial infarction in vivo, a profile compatible with a biomarker of AMI. Two-dimensional fluorescence DIGE of ischemic and control coronary effluents identified more than 200 asymmetric spots verified by swapping dyes. Once again existing biomarkers of injury were confirmed as well as posttranslational modifications of antioxidant proteins such as peroxiredoxins. Perfusing hearts with protein-free buffers provides a platform of graded ischemic injury that allows detailed analysis of protein release and identification of candidate cardiac biomarkers like myosin-binding protein C.Acute myocardial infarction (AMI)1 is a common cause of death for which effective treatments are available provided that the condition is rapidly diagnosed. The modern diagnosis of AMI relies on the rise and fall of a specific serum biomarker accompanied by an appropriate circumstance such as chest pain or revascularization. In this accepted paradigm, the diagnosis cannot be ruled in or ruled out without the definite presence or definite absence of a serum biomarker. The ideal biomarker of cardiac injury should be cardiac specific and released rapidly after myocardial injury in direct proportion to the extent of damage. Furthermore, the biomarker should have a high sensitivity and specificity (1). Several biomarkers of AMI have been described in the literature, but only a few, none of which are ideal, have found their way into routine clinical practice. For example, CK-MB starts to increase 4–8 h after coronary artery occlusion and returns to base line within 2–3 days (2). However, its use is limited by its presence in skeletal muscle and normal serum and by sensitivity of the assay to interference, causing some to question its utility (3). Myoglobin is another cytoplasmic protein found in cardiac and skeletal, but not smooth, muscle. It is released even earlier within 1–2 h of AMI and peaks within 5–6 h (2). Unfortunately, any injury to skeletal muscle also causes elevated levels of myoglobin, reducing specificity. Fatty acid-binding proteins (FABPs) are small (15-kDa) cytoplasmic proteins expressed in all tissues with active fatty acid metabolism. Among the nine proteins, heart-specific FABP (H-FABP) is found in heart but also kidney, brain, skeletal muscle, and placenta (4). Following acute myocardial infarction, H-FABP can be detected within 20 min and peaks at 4 h, considerably faster even than CK/CK-MB in the same patient cohort. Although H-FABP concentrations in normal plasma are low, they are known to rise nonspecifically during physical exertion (without a troponin rise), kidney injury, and stroke (5).The most specific and sensitive cardiac proteins released after acute myocardial infarction are cardiac troponins I and T. Both troponins I and T are released slowly, peaking ∼18 h after myocardial infarction, and remain elevated for 7–10 days (2). This slow release is likely the result of their relatively inaccessible cellular location compared with CK-MB, myoglobin, and H-FABP. Troponins regulate the physical interaction of actin and myosin and thus are found almost entirely associated within the crystalline structure of the sarcomere of striated muscle cells (6). The troponin complex is composed of three forms: I, T, and C. Troponins I and T exist as cardiac specific isoforms with epitopes that differ from the corresponding skeletal isoforms. In addition, the absent or extremely low normal circulating levels of troponin provide the greatest dynamic range of any of the currently available biomarkers (7). Although there is no doubt troponins have revolutionized the detection and management of patients with AMI (8), they do have disadvantages. The slow release of troponin delays diagnosis and the initiation of specific treatments that could salvage heart tissue in those in whom it is raised. Similarly, patients in whom it is absent and who are ultimately reassured and discharged are admitted to the hospital unnecessarily. Furthermore, the persistence of troponins limits their utility in the diagnosis of reinfarction.It is therefore widely accepted that there is a need for new biomarkers that can diagnose AMI earlier during its natural history and/or that have a short plasma half-life, allowing use in diagnosis and quantification of reinfarction. The purpose of this study was to use the platform of the crystalloid perfused mouse hearts to perform a systematic proteomics analysis of the coronary effluent after minimal AMI to identify new potential biomarkers (9). 相似文献
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Hepcidin was originally identified as a liver-expressed antimicrobial peptide but further studies have shown that it also
has a key role in iron homeostasis. The NMR structure of the synthetic peptides reveal a distorted beta-sheet containing 4
disulphide bridges, with an unusual vicinal disulphide bridge which has been suggested to be functionally significant. In
this study, we report the presence of co-purified iron with the urine-purified 20 and 25 residue hepcidins. Since the published
structure does not allow metal binding, the interaction of hepcidin with metals was investigated for other possible structural
conformations by threading its primary sequence onto existing 3D folds. Several alignments were obtained and the best scores
were used to build a 3D model of hepcidin containing one atom of iron. The new 3D structure, that contains only reduced Cys
residues, is completely different from the solved structure of the synthetic peptide. Although the model presented here shows
only one metal bound to the peptide, the binding of several metal atoms cannot be excluded from such a short flexible peptide.
The co-purification of iron with both peptides, together with our 3D model, suggest a conformational polymorphism for hepcidin,
reminiscent of the iron regulatory proteins IRPs. 相似文献
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Zmitek K Stavber S Zupan M Bonnet-Delpon D Charneau S Grellier P Iskra J 《Bioorganic & medicinal chemistry》2006,14(23):7790-7795
The oxidative system H2O2/fluorinated alcohol (TFE, HFIP) was used for direct acid- and MeReO3-catalyzed synthesis of 1,2,4,5-tetraoxanes from cyclic (C6, C7, and C12) and acyclic ketones. The influence of ring size and alkyl chain length were studied and antimalarial activities of synthetic 3,3,6,6-tetraalkyl-1,2,4,5-tetraoxanes were determined. Variations in their antimalarial activities were significant, although they share similar electrochemical properties of the peroxide bond. 相似文献
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Taurin S Sandbo N Qin Y Browning D Dulin NO 《The Journal of biological chemistry》2006,281(15):9971-9976