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91.
Christel Thauvin-Robinet Martine Auclair Laurence Duplomb Martine Caron-Debarle Magali Avila Judith St-Onge Martine Le?Merrer Bernard Le?Luyer Delphine Héron Michèle Mathieu-Dramard Pierre Bitoun Jean-Michel Petit Sylvie Odent Jeanne Amiel Damien Picot Virginie Carmignac Julien Thevenon Patrick Callier Martine Laville Yves Reznik Cédric Fagour Marie-Laure Nunes Jacqueline Capeau Olivier Lascols Frédéric Huet Laurence Faivre Corinne Vigouroux Jean-Baptiste Rivière 《American journal of human genetics》2013,93(1):141-149
Short stature, hyperextensibility of joints and/or inguinal hernia, ocular depression, Rieger anomaly, and teething delay (SHORT) syndrome is a developmental disorder with an unknown genetic cause and hallmarks that include insulin resistance and lack of subcutaneous fat. We ascertained two unrelated individuals with SHORT syndrome, hypothesized that the observed phenotype was most likely due to de novo mutations in the same gene, and performed whole-exome sequencing in the two probands and their unaffected parents. We then confirmed our initial observations in four other subjects with SHORT syndrome from three families, as well as 14 unrelated subjects presenting with syndromic insulin resistance and/or generalized lipoatrophy associated with dysmorphic features and growth retardation. Overall, we identified in nine affected individuals from eight families de novo or inherited PIK3R1 mutations, including a mutational hotspot (c.1945C>T [p.Arg649Trp]) present in four families. PIK3R1 encodes the p85α, p55α, and p50α regulatory subunits of class IA phosphatidylinositol 3 kinases (PI3Ks), which are known to play a key role in insulin signaling. Functional data from fibroblasts derived from individuals with PIK3R1 mutations showed severe insulin resistance for both proximal and distal PI3K-dependent signaling. Our findings extend the genetic causes of severe insulin-resistance syndromes and provide important information with respect to the function of PIK3R1 in normal development and its role in human diseases, including growth delay, Rieger anomaly and other ocular affections, insulin resistance, diabetes, paucity of fat, and ovarian cysts. 相似文献
92.
Annelies De Paepe Sylvie De Buck Jonah Nolf Els Van Lerberge Ann Depicker 《The Plant journal : for cell and molecular biology》2013,75(1):172-184
Random T–DNA integration into the plant host genome can be problematic for a variety of reasons, including potentially variable transgene expression as a result of different integration positions and multiple T–DNA copies, the risk of mutating the host genome and the difficulty of stacking well‐defined traits. Therefore, recombination systems have been proposed to integrate the T–DNA at a pre‐selected site in the host genome. Here, we demonstrate the capacity of the ?C31 integrase (INT) for efficient targeted T–DNA integration. Moreover, we show that the iterative site‐specific integration system (ISSI), which combines the activities of the CRE recombinase and INT, enables the targeting of genes to a pre‐selected site with the concomitant removal of the resident selectable marker. To begin, plants expressing both the CRE and INT recombinase and containing the target attP site were constructed. These plants were supertransformed with a T–DNA vector harboring the loxP site, the attB sites, a selectable marker and an expression cassette encoding a reporter protein. Three out of the 35 transformants obtained (9%) showed transgenerational site‐specific integration (SSI) of this T–DNA and removal of the resident selectable marker, as demonstrated by PCR, Southern blot and segregation analysis. In conclusion, our results show the applicability of the ISSI system for precise and targeted Agrobacterium‐mediated integration, allowing the serial integration of transgenic DNA sequences in plants. 相似文献
93.
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
94.
Timothy A. Stammers René Coulombe Martin Duplessis Gulrez Fazal Alexandre Gagnon Michel Garneau Sylvie Goulet Araz Jakalian Steven LaPlante Jean Rancourt Bounkham Thavonekham Dominik Wernic George Kukolj Pierre L. Beaulieu 《Bioorganic & medicinal chemistry letters》2013,23(24):6879-6885
Optimization efforts on the anthranilic acid-based Thumb Pocket 2 HCV NS5B polymerase inhibitors 1 and 2 resulted in the identification of multiple structural elements that contributed to improved cell culture potency. The additive effect of these elements resulted in compound 46, an inhibitor with enzymatic (IC50) and cell culture (EC50) potencies of less than 100 nanomolar. 相似文献
95.
Vincent P. Alibu Sylvie Daunes Claudius D’Silva 《Bioorganic & medicinal chemistry letters》2013,23(15):4351-4353
A series of glutathione derivatives 1–4, modified at the N,S and/or COOH sites, with in vitro antitrypanosomal activity were tested against bloodstream form Trypanosoma brucei 247 wild type and a T. b. brucei 247 strain over-expressing the multiple drug resistance protein (MRPA) by 50–100x to assess the susceptibility of these compounds to resistance by the TbMRP protein. Of the compounds tested, only compound 1 inhibited both bloodstream form T. brucei and T. bruceiMRPA, with a resistance factor of 1.4, indicating it to be an inhibitor of this protein and proteins acting in synergy with the transporter, whilst 2 & 3 and its derivatives showed reduced inhibitory activity against T. bruceiMRPA, indicating them to be substrates and susceptible to resistance. 相似文献
96.
Jeffrey Gardner Tze-Hei Yong Sylvie A. Pitcher Michael P. Hoffmann 《Biocontrol Science and Technology》2013,23(4):367-380
Trichogramma ostriniae was imported into the USA from China and it continues to be evaluated as a biological control agent against the European corn borer and other lepidopteran pest species. A natural enemy's ability to overwinter is a facet of its biology with important ramifications for biological control and non-target effects. Thus, studies were conducted to examine the ability of the introduced egg parasitoid to survive over winters in central New York State. Eggs of Ostrinia nubilalis, Ephestia kuehniella, Trichoplusia ni, Helicoverpa zea and Utetheisa ornatrix were subjected to parasitism by adult T. ostriniae and then placed out of doors and exposed to winter conditions. For trials initiated in 2003 and 2004, the adult parental wasps were exposed to a diapause-inducing photoperiod and temperature regime in the laboratory; in 2010, parental wasps were conditioned out of doors and prior to the onset of winter conditions. Emergence of their progeny was monitored over time by taking aliquots of parasitised eggs, and holding them under warm conditions until emergence was complete. The level of wasp emergence generally displayed a decline followed by gradual increase until spring. Levels of overwintering ranged from 1% for O. nubilalis to 76% for E. kuehniella, and logistic regression indicated that the odds of overwintering was dependent on the year, host species, time out of doors and varied over exposure time depending on host. The potential to overwinter in New York was further confirmed by positive identification of T. ostriniae from naturally occurring O. nubilalis eggs collected from field sites where augmentative releases had been made in previous years. 相似文献
97.
Stimulation of native microbial populations in soil by the addition of small amounts of secondary carbon sources (cosubstrates) and its effect on the degradation and theoretical mineralization of DDT [l,l,l-trichloro-2,2-bis(p-chlorophenyl)ethane] and its main metabolites, DDD and DDE, were evaluated. Microbial activity in soil polluted with DDT, DDE and DDD was increased by the presence of phenol, hexane and toluene as cosubstrates. The consumption of DDT was increased from 23 % in a control (without cosubstrate) to 67, 59 and 56 % in the presence of phenol, hexane and toluene, respectively. DDE was completely removed in all cases, and DDD removal was enhanced from 67 % in the control to ~86 % with all substrates tested, except for acetic acid and glucose substrates. In the latter cases, DDD removal was either inhibited or unchanged from the control. The optimal amount of added cosubstrate was observed to be between 0.64 and 2.6 mg C $ {\text{g}}^{ - 1}_{\text{dry soil}} $ . The CO2 produced was higher than the theoretical amount for complete cosubstrate mineralization indicating possible mineralization of DDT and its metabolites. Bacterial communities were evaluated by denaturing gradient gel electrophoresis, which indicated that native soil and the untreated control presented a low bacterial diversity. The detected bacteria were related to soil microorganisms and microorganisms with known biodegradative potential. In the presence of toluene a bacterium related to Azoarcus, a genus that includes species capable of growing at the expense of aromatic compounds such as toluene and halobenzoates under denitrifying conditions, was detected. 相似文献
98.
Background
Insulin-like growth factor binding proteins (IGFBPs) are six related secreted proteins that share IGF-dependent and -independent functions. If the former functions begin to be well described, the latter are somewhat more difficult to investigate and to characterize. At the cellular level, IGFBPs were shown to modulate numerous processes including cell growth, differentiation and apoptosis. However, the molecular mechanisms implicated remain largely unknown. We previously demonstrated that IGFBP-3, but not IGFBP-1 or IGFBP-5, increase intracellular calcium concentration in MCF-7 cells (Ricort J-M et al. (2002) FEBS lett 527: 293–297).Methodology/Principal Findings
We perform a global analysis in which we studied, by two different approaches, the binding of each IGFBP isoform (i.e., IGFBP-1 to -6) to the surface of two different cellular models, MCF-7 breast adenocarcinoma cells and C2 myoblast proliferative cells, as well as the IGFBP-induced increase of intracellular calcium concentration. Using both confocal fluorescence microscopy and flow cytometry analysis, we showed that all IGFBPs bind to MCF-7 cell surface. By contrast, only four IGFBPs can bind to C2 cell surface since neither IGFBP-2 nor IGFBP-4 were detected. Among the six IGFBPs tested, only IGFBP-1 did not increased intracellular calcium concentration whatever the cellular model studied. By contrast, IGFBP-2, -3, -4 and -6, in MCF-7 cells, and IGFBP-3, -5 and -6, in C2 proliferative cells, induce a rapid and transient increase in intracellular free calcium concentration. Moreover, IGFBP-2 and -3 (in MCF-7 cells) and IGFBP-5 (in C2 cells) increase intracellular free calcium concentration by a pertussis toxin sensitive signaling pathway.Conclusions
Our results demonstrate that IGFBPs are able to bind to cell surface and increase intracellular calcium concentration. By characterizing the IGFBPs-induced cell responses and intracellular couplings, we highlight the cellular specificity and complexity of the IGF-independent actions of these IGF binding proteins. 相似文献99.
Papa Makhtar Drame Abdoulaye Diallo Anne Poinsignon Olayide Boussari Stephanie Dos Santos Vanessa Machault Richard Lalou Sylvie Cornelie Jean-Yves LeHesran Franck Remoue 《PloS one》2013,8(6)
Standard entomological methods for evaluating the impact of vector control lack sensitivity in low-malaria-risk areas. The detection of human IgG specific to Anopheles gSG6-P1 salivary antigen reflects a direct measure of human–vector contact. This study aimed to assess the effectiveness of a range of vector control measures (VCMs) in urban settings by using this biomarker approach. The study was conducted from October to December 2008 on 2,774 residents of 45 districts of urban Dakar. IgG responses to gSG6-P1 and the use of malaria VCMs highly varied between districts. At the district level, specific IgG levels significantly increased with age and decreased with season and with VCM use. The use of insecticide-treated nets, by drastically reducing specific IgG levels, was by far the most efficient VCM regardless of age, season or exposure level to mosquito bites. The use of spray bombs was also associated with a significant reduction of specific IgG levels, whereas the use of mosquito coils or electric fans/air conditioning did not show a significant effect. Human IgG response to gSG6-P1 as biomarker of vector exposure represents a reliable alternative for accurately assessing the effectiveness of malaria VCM in low-malaria-risk areas. This biomarker tool could be especially relevant for malaria control monitoring and surveillance programmes in low-exposure/low-transmission settings. 相似文献
100.
Chao-Wu Xiao Carla M. Wood Eleonora Swist Reiko Nagasaka Kurtis Sarafin Claude Gagnon Lois Fernandez Sylvie Faucher Hong-Xing Wu Laura Kenney Walisundera M. N. Ratnayake 《PloS one》2016,11(1)