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91.
92.
Sylvain Hanein Mathilde Garcia Lucas Fares-Taie Valérie Serre Yves De Keyzer Thierry Delaveau Isabelle Perrault Nathalie Delphin Sylvie Gerber Alain Schmitt Jean-Marc Masse Arnold Munnich Josseline Kaplan Frédéric Devaux Jean-Michel Rozet 《Biochimica et Biophysica Acta (BBA)/General Subjects》2013
Background
Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.Methods
A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.Results
TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.Conclusions
TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.General significance
Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins. 相似文献93.
Variations in genomic DNA methylation during the long-term in vitro proliferation of oil palm embryogenic suspension cultures 总被引:1,自引:0,他引:1
Alain Rival Pascal Ilbert Axel Labeyrie Esperanza Torres Sylvie Doulbeau Aline Personne Stéphane Dussert Thierry Beulé Tristan Durand-Gasselin James W. Tregear Estelle Jaligot 《Plant cell reports》2013,32(3):359-368
Key message
The long-term proliferation of embryogenic cell suspensions of oil palm is associated with changes in both genomic methylation rates and embryogenic capacities.Abstract
In the aim of exploring the relationship between epigenetic stability and the long-term in vitro proliferation of plant tissues, we have studied changes in genomic DNA methylation levels in embryogenic suspensions of oil palm (Elaeis guineensis Jacq.). Five embryogenic callus lines were obtained from selected hybrid seeds and then proliferated as suspension cultures. Each clonal line obtained from a single genotype was subdivided into three independent subclonal lines. Once established, cultures proliferated for 12 months and genomic DNA was sampled at 4 months intervals for the estimation of global DNA methylation rates through high performance liquid chromatography (HPLC) quantitation of deoxynucleosides. Our results show that in vitro proliferation induces DNA hypermethylation in a time-dependent fashion. Moreover, this trend is statistically significant in several clonal lines and shared between subclonal lines originating from the same genotype. Interestingly, the only clonal line undergoing loss of genomic methylation in the course of proliferation has been found unable to generate somatic embryos. We discuss the possible implications of genome-wide DNA methylation changes in proliferating cells with a view to the maintenance of genomic and epigenomic stability. 相似文献94.
Sylvie Fainzang 《Culture, medicine and psychiatry》2013,37(3):488-504
The concept of medicalization has given rise to considerable discussion in the social sciences, focusing especially on the extension of medicine’s jurisdiction and its hold over our bodies through the reduction of social phenomena to individual biological pathologies. However, the process leading to medical treatment may start when individuals engage in self-medication and thus practice “self-medicalization.” But, can we apply to this concept the same type of analysis as the first and see merely the individual’s replication of the social control mechanisms to which he/she usually falls victim? This article aims to demonstrate that the medicalization individuals practice on themselves takes on a completely different meaning to that practiced by the medical profession. Empirical data collected in France show that self-medicalization, which may involve treating a problem medically when doctors believe it to be of a non-medical nature, can be an attempt by individuals to furnish a social explanation for their somatic problems and experiences. In this article, I examine the social and political significance of this phenomenon. 相似文献
95.
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
96.
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
97.
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
98.
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
99.
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
100.
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