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151.
Jeff A. O'Meara Christopher T. Lemke Cédrickx Godbout George Kukolj Lisette Lagacé Beno?t Moreau Diane Thibeault Peter W. White Montse Llinàs-Brunet 《The Journal of biological chemistry》2013,288(8):5673-5681
Although optimizing the resistance profile of an inhibitor can be challenging, it is potentially important for improving the long term effectiveness of antiviral therapy. This work describes our rational approach toward the identification of a macrocyclic acylsulfonamide that is a potent inhibitor of the NS3-NS4A proteases of all hepatitis C virus genotypes and of a panel of genotype 1-resistant variants. The enhanced potency of this compound versus variants D168V and R155K facilitated x-ray determination of the inhibitor-variant complexes. In turn, these structural studies revealed a complex molecular basis of resistance and rationalized how such compounds are able to circumvent these mechanisms. 相似文献
152.
153.
Johann B?hm Frédéric Chevessier André?Maues De?Paula Catherine Koch Shahram Attarian Claire Feger Daniel Hanta? Pascal Laforêt Karima Ghorab Jean-Michel Vallat Michel Fardeau Dominique Figarella-Branger Jean Pouget Norma?B. Romero Marc Koch Claudine Ebel Nicolas Levy Martin Krahn Bruno Eymard Marc Bartoli Jocelyn Laporte 《American journal of human genetics》2013,92(2):271-278
Tubular aggregates are regular arrays of membrane tubules accumulating in muscle with age. They are found as secondary features in several muscle disorders, including alcohol- and drug-induced myopathies, exercise-induced cramps, and inherited myasthenia, but also exist as a pure genetic form characterized by slowly progressive muscle weakness. We identified dominant STIM1 mutations as a genetic cause of tubular-aggregate myopathy (TAM). Stromal interaction molecule 1 (STIM1) is the main Ca2+ sensor in the endoplasmic reticulum, and all mutations were found in the highly conserved intraluminal Ca2+-binding EF hands. Ca2+ stores are refilled through a process called store-operated Ca2+ entry (SOCE). Upon Ca2+-store depletion, wild-type STIM1 oligomerizes and thereby triggers extracellular Ca2+ entry. In contrast, the missense mutations found in our four TAM-affected families induced constitutive STIM1 clustering, indicating that Ca2+ sensing was impaired. By monitoring the calcium response of TAM myoblasts to SOCE, we found a significantly higher basal Ca2+ level in TAM cells and a dysregulation of intracellular Ca2+ homeostasis. Because recessive STIM1 loss-of-function mutations were associated with immunodeficiency, we conclude that the tissue-specific impact of STIM1 loss or constitutive activation is different and that a tight regulation of STIM1-dependent SOCE is fundamental for normal skeletal-muscle structure and function. 相似文献
154.
We characterize lichen flora of Slovakia based on the review of recent studies published since 1998, point at selected lichen taxa described for science from this territory and outline main geographical elements and other important groups. We annex critically revised and updated checklist of lichens of Slovakia, which includes 1,628 species. As a result of intensive field work the number of species increased by 142 new species since the last version of checklist published 15 years ago, 26 species were excluded. 相似文献
155.
Anne Décor Chantal Grand-Maître Oliver Hucke Jeff O’Meara Cyrille Kuhn Léa Constantineau -Forget Christian Brochu Eric Malenfant Mégan Bertrand-Laperle Josée Bordeleau Elise Ghiro Marc Pesant Gulrez Fazal Vida Gorys Michael Little Colette Boucher Sylvain Bordeleau Pascal Turcotte Annick Gauthier 《Bioorganic & medicinal chemistry letters》2013,23(13):3841-3847
We describe here the design, synthesis and biological evaluation of antiviral compounds acting against human rhinovirus (HRV). A series of aminothiazoles demonstrated pan-activity against the HRV genotypes screened and productive structure–activity relationships. A comprehensive investigational library was designed and performed allowing the identification of potent compounds with lower molecular weight and improved ADME profile. 31d-1, 31d-2, 31f showed good exposures in CD-1 mice. The mechanism of action was discovered to be a host target: the lipid kinase phosphatidylinositol 4-kinase III beta (PI4KIIIß). The identification of the pan-HRV active compound 31f combined with a structurally distinct literature compound T-00127-HEV1 allowed the assessment of target related tolerability of inhibiting this kinase for a short period of time in order to prevent HRV replication. 相似文献
156.
Caroline L. Côté Pierre‐Alexandre Gagnaire Vincent Bourret Guy Verreault Martin Castonguay Louis Bernatchez 《Molecular ecology》2013,22(7):1763-1776
We performed population genetic analyses on the American eel (Anguilla rostrata) with three main objectives. First, we conducted the most comprehensive analysis of neutral genetic population structure to date to revisit the null hypothesis of panmixia in this species. Second, we used this data to provide the first estimates of contemporary effective population size (Ne) and to document temporal variation in effective number of breeders (Nb) in American eel. Third, we tested for statistical associations between temporal variation in the North Atlantic Oscillation (NAO), the effective number of breeders and two indices of recruit abundance. A total of 2142 eels from 32 sampling locations were genotyped with 18 microsatellite loci. All measures of differentiation were essentially zero, and no evidence for significant spatial or temporal genetic differentiation was found. The panmixia hypothesis should thus be accepted for this species. Nb estimates varied by a factor of 23 among 12 cohorts, from 473 to 10 999. The effective population size Ne was estimated at 10 532 (95% CI, 9312–11 752). This study also showed that genetically based demographic indices, namely Nb and allelic richness (Ar), can be used as surrogates for the abundance of breeders and recruits, which were both shown to be positively influenced by variation during high (positive) NAO phases. Thus, long‐term genetic monitoring of American glass eels at several sites along the North American Atlantic coast would represent a powerful and efficient complement to census monitoring to track demographic fluctuations and better understand their causes. 相似文献
157.
Michal Tichý Radek Pohl Eva Tloušt’ová Jan Weber Gina Bahador Yu-Jen Lee Michal Hocek 《Bioorganic & medicinal chemistry》2013,21(17):5362-5372
Two series of new 4-aminopyrimido[4,5-b]indole ribonucleosides bearing phenyl or hetaryl group at position 5 or 6 have been prepared by Suzuki or Stille cross-coupling reactions employing X-Phos ligand with (het)arylboronic acids or stannanes. A series of 4-substituted nucleosides has been also prepared by Pd-catalyzed cross-couplings or nucleophilic substitution. Some of these compounds displayed moderate antiviral activities against HCV and dengue viruses. 相似文献
158.
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159.
Alina Vîlcan Ioan Tăut Liviu Holonec Lucica Mihalte Radu E. Sestras 《Trees - Structure and Function》2013,27(3):697-705
A wide range of pests and diseases attacks larch, and over 3 years in an orchard in north-western Romania, the most frequently occurring were larch needle disease (Hypodermella laricis), the case-bearer (Coleophora laricella) and woolly adelgid (Adelges laricis) insects. Their attack on seven larch clones obtained through selection from different geographic populations from Romania was studied. To evaluate the attack intensity, four branches per tree were analysed in the upper, middle and lower third of the crowns in all cardinal directions. According to the position in the crown, a high attack intensity by H. laricis was recorded on the branches in the north direction. A high intensity of C. laricella attack was registered on the upper third of the crown, especially in the east, west and south directions. A positive relationship was identified between the damaged sprouts caused by the C. laricella and A. laricis attack. The differences among the reaction of the clones and the heritability coefficients illustrated that the response to the attacks had a strong genetic determinism, with resistance being clearly influenced by genotype. In addition to the identification of gene sources that are useful for larch breeding, this study offers technical information about the potential to develop efficient treatments based on the attacks on the tree crowns. 相似文献
160.
Many recent studies have suggested that the majority of animal-pollinated plants have a higher diversity of pollinators than that expected according to their pollination syndrome. This broad generalization, often based on pollination web data, has been challenged by the fact that some floral visitors recorded in pollination webs are ineffective pollinators. To contribute to this debate, and to obtain a contrast between visitors and pollinators, we studied insect and bird visitors to virgin flowers of Hypoestes aristata in the Bamenda Highlands, Cameroon. We observed the flowers and their visitors for 2-h periods and measured the seed production as a metric of reproductive success. We determined the effects of individual visitors using 2 statistical models, single-visit data that were gathered for more frequent visitor species, and frequency data. This approach enabled us to determine the positive as well as neutral or negative impact of visitors on H. aristata’s reproductive success. We found that (i) this plant is not generalized but rather specialized; although we recorded 15 morphotaxa of visitors, only 3 large bee species seemed to be important pollinators; (ii) the carpenter bee Xylocopa cf. inconstans was both the most frequent and the most effective pollinator; (iii) the honey bee Apis mellifera acted as a nectar thief with apparent negative effects on the plant reproduction; and (iv) the close relationship between H. aristata and carpenter bees was in agreement with the large-bee pollination syndrome of this plant. Our results highlight the need for studies detecting the roles of individual visitors. We showed that such an approach is necessary to evaluate the pollination syndrome hypothesis and create relevant evolutionary and ecological hypotheses. 相似文献