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41.
Kurt G. Pike Karine Malagu Marc G. Hummersone Keith A. Menear Heather M.E. Duggan Sylvie Gomez Niall M.B. Martin Linette Ruston Sarah L. Pass Martin Pass 《Bioorganic & medicinal chemistry letters》2013,23(5):1212-1216
The optimization of a potent and highly selective series of dual mTORC1 and mTORC2 inhibitors is described. An initial focus on improving cellular potency whilst maintaining or improving other key parameters, such as aqueous solubility and margins over hERG IC50, led to the discovery of the clinical candidate AZD8055 (14). Further optimization, particularly aimed at reducing the rate of metabolism in human hepatocyte incubations, resulted in the discovery of the clinical candidate AZD2014 (21). 相似文献
42.
Cécile Echalier Soultan Al-Halifa Aude Kreiter Christine Enjalbal Pierre Sanchez Luisa Ronga Karine Puget Pascal Verdié Muriel Amblard Jean Martinez Gilles Subra 《Amino acids》2013,45(6):1395-1403
Despite correct purity of crude peptides prepared on trityl resin by Fmoc/tBu microwave assisted solid phase peptide synthesis, surprisingly, lower yields than those expected were obtained while preparing C-terminal acid peptides. This could be explained by cyclization/cleavage through diketopiperazine formation during the second amino acid deprotection and third amino acid coupling. However, we provide here evidence that this is not the case and that this yield loss was due to high temperature promoted hydrolysis of the 2-chlorotrityl ester, yielding premature cleavage of the C-terminal acid peptides. 相似文献
43.
Karine Loridon Concetta Burgarella Nathalie Chantret Frédéric Martins Jérôme Gouzy Jean‐Marie Prospéri Joëlle Ronfort 《Molecular ecology resources》2013,13(1):84-95
Extensive genomic resources are available in the model legume Medicago truncatula. Here, we present the discovery and design of the first array of single‐nucleotide polymorphism (SNP) markers in M. truncatula through large‐scale Sanger resequencing of genomic fragments spanning the genome, in a diverse panel of 16 M. truncatula accessions. Both anonymous fragments and fragments targeting candidate genes for flowering phenology and symbiosis were surveyed for nucleotide variation in almost 230 kb of unique genomic regions. A set of 384 SNP markers was designed for an Illumina's GoldenGate assay, genotyped on a collection of 192 inbred lines (CC192) representing the geographical range of the species and used to survey the diversity of two natural populations. Finally, 86% of the tested SNPs were of high quality and exhibited polymorphism in the CC192 collection. Even at the population level, we detected polymorphism for more than 50% of the selected SNPs. Analysis of the allele frequency spectrum in the CC192 showed a reduced ascertainment bias, mostly limited to very rare alleles (frequency <0.01). The substantial polymorphism detected at the species and population levels, the high marker quality and the potential to survey large samples of individuals make this set of SNP markers a valuable tool to improve our understanding of the effect of demographic and selective factors that shape the natural genetic diversity within the selfing species Medicago truncatula. 相似文献
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Chantelle J. Giesbrecht Norm O’Rourke Olga Leonova Verena Strehlau Karine Paquet Fidel Vila-Rodriguez William J. Panenka G. William MacEwan Geoffrey N. Smith Allen E. Thornton William G. Honer 《PloS one》2016,11(3)
Rates of psychopathology are elevated in marginalized and unstably housed persons, underscoring the need for applicable clinical measures for these populations. The Positive and Negative Syndrome Scale (PANSS) is a clinical instrument principally developed for use in schizophrenia to identify the presence and severity of psychopathology symptoms. The current study investigates whether a reliable and valid PANSS factor structure emerges in a marginally housed, heterogeneous sample recruited from the Downtown Eastside of Vancouver where substance use disorders and psychiatric illness are pervasive. Participants (n = 270) underwent structured clinical assessments including the PANSS and then were randomly assigned to either exploratory (EFA) or confirmatory factor analytic (CFA) subsamples. EFA pointed to a novel three factor PANSS. This solution was supported by CFA. All retained items (28 out of 30) load significantly upon hypothesized factors and model goodness of fit analyses are in the acceptable to good range. Each of the three first-order factor constructs, labeled Psychosis/Disorganized, Negative Symptoms/Hostility, and Insight/Awareness, contributed significantly to measurement of a higher-order psychopathology construct. Further, the latent structure of this 3-factor solution appears temporally consistent over one-year. This PANSS factor structure appears valid and reliable for use in persons with multimorbidity, including substance use disorders. The structure is somewhat distinct from existing solutions likely due to the unique characteristics of this marginally housed sample. 相似文献
46.
Karine Bibeau Benoit Sicotte Mélanie Béland Menakshi Bhat Louis Gaboury Réjean Couture Jean St-Louis Michèle Brochu 《PloS one》2016,11(1)
Lower maternal plasma volume expansion was found in idiopathic intrauterine growth restriction (IUGR) but the link remains to be elucidated. An animal model of IUGR was developed by giving a low-sodium diet to rats over the last week of gestation. This treatment prevents full expansion of maternal circulating volume and the increase in uterine artery diameter, leading to reduced placental weight compared to normal gestation. We aimed to verify whether this is associated with reduced remodeling of uteroplacental circulation and placental hypoxia. Dams were divided into two groups: IUGR group and normal-fed controls. Blood velocity waveforms in the main uterine artery were obtained by Doppler sonography on days 14, 18 and 21 of pregnancy. On day 22 (term = 23 days), rats were sacrificed and placentas and uterine radial arteries were collected. Diameter and myogenic response of uterine arteries supplying placentas were determined while expression of hypoxia-modulated genes (HIF-1α, VEGFA and VEGFR2), apoptotic enzyme (Caspase -3 and -9) and glycogen cells clusters were measured in control and IUGR term-placentas. In the IUGR group, impaired blood velocity in the main uterine artery along with increased resistance index was observed without alteration in umbilical artery blood velocity. Radial uterine artery diameter was reduced while myogenic response was increased. IUGR placentas displayed increased expression of hypoxia markers without change in the caspases and increased glycogen cells in the junctional zone. The present data suggest that reduced placental and fetal growth in our IUGR model may be mediated, in part, through reduced maternal uteroplacental blood flow and increased placental hypoxia. 相似文献
47.
Magnus Simonsson Mélanie Court Johan Bergholm Damien Lemarchand Stephen Hillier 《Biogeochemistry》2016,129(1-2):77-91
Clay minerals and K feldspars were evaluated as sources of K in a Norway spruce stand (Picea abies (L.) Karst.) from the Skogaby experimental forest in southwest Sweden. The soil, developed in a Quaternary glacial till, has only 3–5% clay, and more than 95% of its K resides in feldspars. Ratios of K/Rb were assessed in interlayers of 2:1 clay minerals (extracted with hot (100 °C) 2 M HCl), biomass and the forest floor. These compartments had similarly low K/Rb ratios, whereas K feldspars were significantly poorer in Rb. A fractionation model indicated preferential retention of Rb in the biomass and forest floor, due to stronger adsorption of Rb than K in the humus, as well as preferential uptake of K from the exchange complex in the mineral soil. Preferential uptake of K may result from weaker adsorption of K by the cation exchanger, or preference for dissolved K over Rb by the roots. A quantitative mineralogical analysis revealed that loss from micas may account for half of the Holocene loss of K from the soil, which was approximately 22 Mg ha?1. Exceptionally low K/Rb ratios in HCl extracts of the upper 60 cm of the profile indicated extensive loss of K from mica in the parent material and re-fixation of K and Rb at lower ratios. The results indicate that fixation in and release from clay minerals may be prominent in the cycling of K, even in a soil that is poor in clay minerals. 相似文献
48.
Gaëlle Lentini David J. Dubois Bohumil Maco Dominique Soldati‐Favre Karine Frnal 《Traffic (Copenhagen, Denmark)》2019,20(8):583-600
To efficiently enter host cells, apicomplexan parasites such as Toxoplasma gondii rely on an apical complex composed of tubulin‐based structures as well as two sets of secretory organelles named micronemes and rhoptries. The trafficking and docking of these organelles to the apical pole of the parasite is crucial for the discharge of their contents. Here, we describe two proteins typically associated with microtubules, Centrin 2 (CEN2) and Dynein Light Chain 8a (DLC8a), that are required for efficient host cell invasion. CEN2 localizes to four different compartments, and remarkably, conditional depletion of the protein occurs in stepwise manner, sequentially depleting the protein pools from each location. This phenomenon allowed us to discern the essential function of the apical pool of CEN2 for microneme secretion, motility, invasion and egress. DLC8a localizes to the conoid, and its depletion also perturbs microneme exocytosis in addition to the apical docking of the rhoptry organelles, causing a severe defect in host cell invasion. Phenotypic characterization of CEN2 and DLC8a indicates that while both proteins participate in microneme secretion, they likely act at different steps along the cascade of events leading to organelle exocytosis. 相似文献
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Valérian Meline Wesley Delage Chrystelle Brin Camille Li-Marchetti Daniel Sochard Matthieu Arlat Céline Rousseau Armelle Darrasse Martial Briand Guillaume Lebreton Perrine Portier Marion Fischer-Le Saux Karine Durand Marie-Agnès Jacques Etienne Belin Tristan Boureau 《Molecular Plant Pathology》2019,20(1):33-50
Cases of emergence of novel plant-pathogenic strains are regularly reported that reduce the yields of crops and trees. However, the molecular mechanisms underlying such emergence are still poorly understood. The acquisition by environmental non-pathogenic strains of novel virulence genes by horizontal gene transfer has been suggested as a driver for the emergence of novel pathogenic strains. In this study, we tested such an hypothesis by transferring a plasmid encoding the type 3 secretion system (T3SS) and four associated type 3 secreted proteins (T3SPs) to the non-pathogenic strains of Xanthomonas CFBP 7698 and CFBP 7700, which lack genes encoding T3SS and any previously known T3SPs. The resulting strains were phenotyped on Nicotiana benthamiana using chlorophyll fluorescence imaging and image analysis. Wild-type, non-pathogenic strains induced a hypersensitive response (HR)-like necrosis, whereas strains complemented with T3SS and T3SPs suppressed this response. Such suppression depends on a functional T3SS. Amongst the T3SPs encoded on the plasmid, Hpa2, Hpa1 and, to a lesser extent, XopF1 collectively participate in suppression. Monitoring of the population sizes in planta showed that the sole acquisition of a functional T3SS by non-pathogenic strains impairs growth inside leaf tissues. These results provide functional evidence that the acquisition via horizontal gene transfer of a T3SS and four T3SPs by environmental non-pathogenic strains is not sufficient to make strains pathogenic. In the absence of a canonical effector, the sole acquisition of a T3SS seems to be counter-selective, and further acquisition of type 3 effectors is probably needed to allow the emergence of novel pathogenic strains. 相似文献