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121.
Erik Ziegler Ariane Foret Laura Mascetti Vincenzo Muto Anahita Le Bourdiec-Shaffii Johan Stender Evelyne Balteau Vinciane Dideberg Vincent Bours Pierre Maquet Christophe Phillips 《PloS one》2013,8(7)
Brain-derived neurotrophic factor (BDNF) modulates the pruning of synaptically silent axonal arbors. The Met allele of the BDNF gene is associated with a reduction in the neurotrophin''s activity-dependent release. We used diffusion-weighted imaging to construct structural brain networks for 36 healthy subjects with known BDNF genotypes. Through permutation testing we discovered clear differences in connection strength between subjects carrying the Met allele and those homozygotic for the Val allele. We trained a Gaussian process classifier capable of identifying the subjects'' allelic group with 86% accuracy and high predictive value. In Met carriers structural connectivity was greatly increased throughout the forebrain, particularly in connections corresponding to the anterior and superior corona radiata as well as corticothalamic and corticospinal projections from the sensorimotor, premotor, and prefrontal portions of the internal capsule. Interhemispheric connectivity was also increased via the corpus callosum and anterior commissure, and extremely high connectivity values were found between inferior medial frontal polar regions via the anterior forceps. We propose that the decreased availability of BDNF leads to deficits in axonal maintenance in carriers of the Met allele, and that this produces mesoscale changes in white matter architecture. 相似文献
122.
Vincent M Gallay J Jamin N Garrigos M de Foresta B 《Biochimica et biophysica acta》2007,1768(3):538-552
The human multidrug resistance protein MRP1 (or ABCC1) is one of the most important members of the large ABC transporter family, in terms of both its biological (tissue defense) and pharmacological functions. Many studies have investigated the function of MRP1, but structural data remain scarce for this protein. We investigated the structure and dynamics of predicted transmembrane fragment 17 (TM17, from Ala(1227) to Ser(1251)), which contains a single Trp residue (W(1246)) involved in MRP1 substrate specificity and transport function. We synthesized TM17 and a modified peptide in which Ala(1227) was replaced by a charged Lys residue. Both peptides were readily solubilized in dodecylmaltoside (DM) or dodecylphosphocholine (DPC) micelles, as membrane mimics. The interaction of these peptides with DM or DPC micelles was studied by steady-state and time-resolved Trp fluorescence spectroscopy, including experiments in which Trp was quenched by acrylamide or by two brominated analogs of DM. The secondary structure of these peptides was determined by circular dichroism. Overall, the results obtained indicated significant structuring ( approximately 50% alpha-helix) of TM17 in the presence of either DM or DPC micelles as compared to buffer. A main interfacial location of TM17 is proposed, based on significant accessibility of Trp(1246) to brominated alkyl chains of DM and/or acrylamide. The comparison of various fluorescence parameters including lambda(max), lifetime distributions and Trp rotational mobility with those determined for model fluorescent transmembrane helices in the same detergents is also consistent with the interfacial location of TM17. We therefore suggest that TM17 intrinsic properties may be insufficient for its transmembrane insertion as proposed by the MRP1 consensus topological model. This insertion may also be controlled by additional constraints such as interactions with other TM domains and its position in the protein sequence. The particular pattern of behavior of this predicted transmembrane peptide may be the hallmark of a fragment involved in substrate transport. 相似文献
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125.
Epidermal growth factor receptor and notch pathways participate in the tumor suppressor function of gamma-secretase 总被引:1,自引:0,他引:1
Li T Wen H Brayton C Das P Smithson LA Fauq A Fan X Crain BJ Price DL Golde TE Eberhart CG Wong PC 《The Journal of biological chemistry》2007,282(44):32264-32273
Gamma-secretase, a unique aspartyl protease, is required for the regulated intramembrane proteolysis of Notch and APP, pathways that are implicated, respectively, in the pathogenesis of cancer and Alzheimer disease. However, the mechanism whereby reduction of gamma-secretase causes tumors such as squamous cell carcinoma (SCC) remains poorly understood. Here, we demonstrate that gamma-secretase functions in epithelia as a tumor suppressor in an enzyme activity-dependent manner. Notch signaling is down-regulated and epidermal growth factor receptor (EGFR) is activated in SCC caused by genetic reduction of gamma-secretase. Moreover, the level of EGFR is inversely correlated with the level of gamma-secretase in fibroblasts, suggesting that the up-regulation of EGFR stimulates hyperproliferation in epithelia of mice with genetic reduction of gamma-secretase. Supporting this notion is our finding that the proliferative response of fibroblasts lacking gamma-secretase activity is more sensitive when challenged by either EGF or an inhibitor of EGFR as ompared with wild type cells. Interestingly, the up-regulation of EGFR is independent of Notch signaling, suggesting that the EGFR pathway functions in parallel with Notch in the tumorigenesis of SCC. Collectively, our results establish a novel mechanism linking the EGFR pathway to the tumor suppressor role of gamma-secretase and that mice with genetic reduction of gamma-secretase represent an excellent rodent model for clarifying pathogenesis of SCC and for testing therapeutic strategy to ameliorate this type of human cancer. 相似文献
126.
Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach 总被引:5,自引:0,他引:5
127.
Manuel B.?MoralesEmail author Vincent?Bretagnolle Beatriz?Arroyo 《Biodiversity and Conservation》2005,14(13):3135-3150
Stochastic computer simulations are used to evaluate the sensitivity of Little bustard population parameters, estimating the
survival probabilities of the seven endangered Little bustard populations of central-western France for which conservation
actions are currentlybeing or have been implemented. Different scenarios of parameter compensation for those nuclei to establish
parameter levels assuring population viability are discussed. Adult survival, productivity per female, initial population
size and carrying capacity were the most sensitive parameters in a hypothetical, isolated population. Juvenile survival also
affected population survival, although its sensitivity was lower. Sex ratio did not have a linear effect on population survival,
but probability of extinction increased for extreme values. Productivity per female and initial population size, varied strongly
among the populations studied, determining their average time of extinction and growth rate. When a metapopulation scenario
was simulated, the survival probabilities of each population and the metapopulations stayed close to 1.0 if no mortality was
associated to migration. When mortality during migration was included in the simulations, the metapopulation's probability
of survival significantly decreased under 90%. This approach may help managers to correctly address conservation measures
and design effective strategies, which should be directed mainly to improve productivity, enhance female survival, and minimise
mortality during migration (e.g. promoting insect-rich nesting substrates, avoiding female killing and nest destruction at
harvesting, reducing the risk of collision with powerlines, or controlling poaching). 相似文献
128.
Marinaki AM Champion M Kurian MA Simmonds HA Marie S Vincent MF van den Berghe G Duley JA Fairbanks LD 《Nucleosides, nucleotides & nucleic acids》2004,23(8-9):1231-1233
A deficiency of adenylosuccinate lyase (ASDL) is characterised by the accumulation of SAICAriboside (SAICAr) and succinyladenosine (S-Ado) in body fluids. The severity of the clinical presentation correlates with a low S-Ado/SAICAr ratio in body fluids. We report the first British case of ADSL deficiency. The patient presented at 14 days with a progressive neonatal encephalopathy and seizures. There was marked axial and peripheral hypotonia. Brain MRI showed widespread white matter changes. She died at 4 weeks of age. Concentrations of SAICAr and SAdo were markedly elevated in urine, plasma and CSF and the SAdo/SAICAr ratio was low, consistent with the severe phenotype. The patient was compound heterozygous for 2 novel ADSL mutations; c.9 G>C (A3P) and c.572 C>T (R190X). 相似文献
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