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991.
Andrew M. Thompson Adrian Blaser Brian D. Palmer Robert F. Anderson Sujata S. Shinde Delphine Launay Eric Chatelain Louis Maes Scott G. Franzblau Baojie Wan Yuehong Wang Zhenkun Ma William A. Denny 《Bioorganic & medicinal chemistry letters》2017,27(11):2583-2589
As part of a quest for backups to the antitubercular drug pretomanid (PA-824), we investigated the unexplored 6-nitro-2,3-dihydroimidazo[2,1-b][1,3]-thiazoles and related -oxazoles. The nitroimidazothiazoles were prepared in high yield from 2-bromo-4-nitroimidazole via heating with substituted thiiranes and diisopropylethylamine. Equivalent examples of these two structural classes provided broadly comparable MICs, with 2-methyl substitution and extended aryloxymethyl side chains preferred; albeit, S-oxidised thiazoles were ineffective for tuberculosis. Favourable microsomal stability data for a biaryl thiazole (45) led to its assessment in an acute Mycobacterium tuberculosis mouse model, alongside the corresponding oxazole (48), but the latter proved to be more efficacious. In vitro screening against kinetoplastid diseases revealed that nitroimidazothiazoles were inactive versus leishmaniasis but showed interesting activity, superior to that of the nitroimidazooxazoles, against Chagas disease. Overall, “thio-delamanid” (49) is regarded as the best lead. 相似文献
992.
Lara Massai Luigi Messori Nicola Micale Tanja Schirmeister Louis Maes Dolores Fregona Maria Agostina Cinellu Chiara Gabbiani 《Biometals》2017,30(2):313-320
Gold compounds form a new class of promising metal-based drugs with a number of potential therapeutic applications, particularly in the fields of anticancer and antimicrobial treatments. Previous research revealed that a group of structurally diverse gold compounds cause conspicuous inhibition of the protease activities of the human proteasome. Given the pharmacological importance of protease inhibition, the present study further explored whether these gold compounds might inhibit a few other proteases that are accepted druggable targets for disease treatment. In particular, four distinct cysteine proteases were considered here: cathepsin B and L that play a primary role in tumor-cell invasion and metastasis; rhodesain, the major cathepsin L-like cysteine protease of Trypanosoma brucei rhodesiense and CPB2.8ΔCTE, a Leishmania mexicana mature cysteine protease. Based on the encouraging results obtained for some of the tested gold compounds on the two parasitic cysteine proteases, especially against CPB2.8ΔCTE, with IC50s in the micromolar range, we next evaluated whether those gold compounds might contrast effectively the growth of the respective protozoa and indeed important antiprotozoal properties were disclosed; on the other hand a certain lack of selectivity was highlighted. Also, no direct or clear correlation could be established between the in vitro antiprotozoal properties and the level of protease inhibition. The implications of these results are discussed in relation to possible pharmaceutical applications. 相似文献
993.
Mycobacterium tuberculosis, the etiological agent of human tuberculosis, harbours five ESAT‐6/type VII secretion (ESX/T7S) systems. The first esx gene clusters were identified during the genome‐sequencing project of M. tuberculosis H37Rv. Follow‐up studies revealed additional genes playing important roles in ESX/T7S systems. Among the latter genes, one can find those that encode Pro‐Glu (PE) and Pro‐Pro‐Glu (PPE) proteins as well as a gene cluster that is encoded >260 kb upstream of the esx‐1 locus and encodes ESX‐1 secretion‐associated proteins EspA (Rv3616c), EspC (Rv3615c) and EspD (Rv3614c). The espACD cluster has been suggested to have an important function in ESX‐1 secretion since EspA‐EspC and EsxA–EsxB are mutually co‐dependent on each other for secretion. However, the molecular mechanism of this co‐dependence and interaction between the substrates remained unknown. In this issue of Molecular Microbiology, Lou and colleagues show that EspC forms high‐molecular weight polymerization complexes that resemble selected components of type II, III and/or IV secretion systems of Gram‐negative bacteria. Indeed, EspC‐multimeric complexes form filamentous structures that could well represent a secretion needle of ESX‐1 type VII secretion systems. This exciting observation opens new avenues for research to discover and characterize ESX/T7S components and elucidates the co‐dependence of EsxA/B secretion with EspA/C. 相似文献
994.
Louis Bernatchez Maren Wellenreuther Cristián Araneda David T. Ashton Julia M.I. Barth Terry D. Beacham Gregory E. Maes Jann T. Martinsohn Kristina M. Miller Kerry A. Naish Jennifer R. Ovenden Craig R. Primmer Ho Young Suk Nina O. Therkildsen Ruth E. Withler 《Trends in ecology & evolution》2017,32(9):665-680
995.
996.
Animal movement in the absence of predation: environmental drivers of movement strategies in a partial migration system 下载免费PDF全文
Guillaume Bastille‐Rousseau James P. Gibbs Charles B. Yackulic Jacqueline L. Frair Fredy Cabrera Louis‐Philippe Rousseau Martin Wikelski Franz Kümmeth Stephen Blake 《Oikos》2017,126(7):1004-1019
Animal movement strategies including migration, dispersal, nomadism, and residency are shaped by broad‐scale spatial‐temporal structuring of the environment, including factors such as the degrees of spatial variation, seasonality and inter‐annual predictability. Animal movement strategies, in turn, interact with the characteristics of individuals and the local distribution of resources to determine local patterns of resource selection with complex and poorly understood implications for animal fitness. Here we present a multi‐scale investigation of animal movement strategies and resource selection. We consider the degree to which spatial variation, seasonality, and inter‐annual predictability in resources drive migration patterns among different taxa and how movement strategies in turn shape local resource selection patterns. We focus on adult Galapagos giant tortoises Chelonoidis spp. as a model system since they display many movement strategies and evolved in the absence of predators of adults. Specifically, our analysis is based on 63 individuals among four taxa tracked on three islands over six years and almost 106 tortoise re‐locations. Tortoises displayed a continuum of movement strategies from migration to sedentarism that were linked to the spatio‐temporal scale and predictability of resource distributions. Movement strategies shaped patterns of resource selection. Specifically, migratory individuals displayed stronger selection toward areas where resources were more predictable among years than did non‐migratory individuals, which indicates a selective advantage for migrants in seasonally structured, more predictable environments. Our analytical framework combines large‐scale predictions for movement strategies, based on environmental structuring, with finer‐scale analysis of space‐use. Integrating different organizational levels of analysis provides a deeper understanding of the eco‐evolutionary dynamics at play in the emergence and maintenance of migration and the critical role of resource predictability. Our results highlight that assessing the potential benefits of differential behavioral responses first requires an understanding of the interactions among movement strategies, resource selection and individual characteristics. 相似文献
997.
998.
999.
Robert P. Favier Bart Spee Louis C. Penning Bas Brinkhof Jan Rothuizen 《Mammalian genome》2005,16(6):460-463
The recently discovered locus for copper toxicosis (CT) in Bedlington terriers (BT) has a 13-kb deletion enveloping the 187-bp exon-2 of the MURR1 gene. This MURR1 gene is not only involved with biliary copper excretion but also associated with HIV-1 replication. The microsatellite C04107 lying in an intron of the MURR1 gene is highly associated with the disease but shows haplotype diversity. The only solid molecular test for the disease is by showing the deletion in exon-2 in cDNA in liver tissue; this test is not robust on RNA from peripheral leukocytes because of their low MURR1 expression level. Because of these drawbacks, we developed a new quantitative PCR (Q-PCR) protocol. Here we show that the MURR1 exon-2/exon-3 ratio measured by Q-PCR on genomic DNA correlates perfectly with the microsatellite marker and with RT-PCR data from blood samples, buccal swabs, and liver biopsies. In view of the important role of MURR1 in cells of many tissues, this new test has a wide range of applications in comparative biomedical research. Furthermore, Q-PCR on DNA may be a new tool in general to analyze mutations that cannot be approached by standard methods.Robert P. Favier and Bart Spee contributed equally to this work. 相似文献
1000.
The mechanisms of longevity have been the subject of investigations for a number of years. Although the role of genetic factors is generally acknowledged, important questions persist regarding the relative impact of environmental exposures, lifestyle characteristics, and genes. The BALSAC population register offers a unique opportunity to study longevity from an intergenerational and genealogical point of view. Individuals from the Saguenay-Lac-St-Jean population who died at age 90 or older between 1950 and 1974 were selected from this database (n?=?576), along with a control group of individuals born in the same period who died between 50 and 75 years of age. For these subjects and controls, spouses’ ages at death and parental ages at death and at their birth were investigated using regression analysis. Genealogical reconstructions were carried out for each individual, and various analyses were performed on both groups. Both fathers’ and mothers’ mean ages at death were significantly higher among the longer-lived cases than among controls whereas spouses’ ages at death and parental ages at birth had no effect. Regression analysis confirmed the positive effect of both fathers’ and mothers’ age at death. Mean kinship coefficients for the parents’ generations displayed significant differences, indicating that kinship was higher among subjects than controls (this effect was stronger among the oldest 10% of the subjects). Frequencies and genetic contributions of ancestors were very similar for the two groups, and none of these ancestors appeared more likely to have introduced genetic variants involved in longevity patterns in this French Canadian population. 相似文献