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91.
Biancalana V Caron O Gallati S Baas F Kress W Novelli G D'Apice MR Lagier-Tourenne C Buj-Bello A Romero NB Mandel JL 《Human genetics》2003,112(2):135-142
X-linked myotubular myopathy is characterised by neonatal hypotonia, muscle weakness and respiratory distress in affected males, leading often to early death, although prolonged survival is observed in milder forms, or as a result of prolongation of ventilation support. It is caused by mutations in the MTM1 gene, which encodes a phosphatase called myotubularin, which has been highly conserved during evolution, down to yeasts ( S. cerevisiae and S. pombe). To date, 251 mutations have been identified in unrelated families, corresponding to 158 different disease-associated mutations, which are widespread throughout the gene. We have found additional mutations in 77 patients, including 35 novel ones. We identified a missense mutation N180K in a 67-year-old grandfather (the oldest known patient with an MTM1 mutation), previously suspected to have autosomal centronuclear myopathy, and in his two grandsons also mildly affected. Mild and moderate phenotypes associated with novel missense mutations and with a translation initiation defect mutation are discussed, as well as severe phenotypes associated with particular novel mutations. With the present report, 192 different mutations in the MTM1 gene have been described in 328 families. The spectrum of mutations is now enlarged from the very severe classic neonatal phenotype to very mild phenotype allowing survival to the age of 67 years. 相似文献
92.
Guianvarc'h D Fourrey JL Maurisse R Sun JS Benhida R 《Bioorganic & medicinal chemistry》2003,11(13):2751-2759
We report herein on the synthesis, the incorporation into triplex forming oligonucleotides (TFO) and the recognition properties of a series of synthetic nucleosides designed for the specific recognition of an inverted A x T base pair in a pyrimidine triple helix motif. These analogues were designed on the basis of the results obtained with our previously reported compounds S and B(t), in order to define a structure-stability relationship. We report also on the chemical nature effect of the bases flanking S in the case of S-containing TFOs, in order to get further informations about the recognition process within the A x TxS triplet. This study establishes guidelines for the conception of more potent analogues for the recognition of both A x T and G x C inverted base pairs. 相似文献
93.
Enantiopure nitrogen mustards which mimic (L)-carnitine framework are prepared by a multi-step synthesis from the (R)-di-tert-butyl malate and their antitumor properties evaluated. 相似文献
94.
HIV-1 entry into T-cells is not dependent on CD4 and CCR5 localization to sphingolipid-enriched,detergent-resistant,raft membrane domains 总被引:11,自引:0,他引:11
Percherancier Y Lagane B Planchenault T Staropoli I Altmeyer R Virelizier JL Arenzana-Seisdedos F Hoessli DC Bachelerie F 《The Journal of biological chemistry》2003,278(5):3153-3161
The contribution of raft domains to human immunodeficiency virus (HIV) 1 entry was assessed. In particular, we asked whether the CD4 and CCR5 HIV-1 receptors need to associate with sphingolipid-enriched, detergent-resistant membrane domains (rafts) to allow viral entry into primary and T-cell lines. Based on Triton X-100 solubilization and confocal microscopy, CD4 was shown to distribute partially to rafts. In contrast, CCR5 did not associate with rafts and localized in nonraft plasma membrane domains. HIV-1-receptor partitioning remained unchanged upon viral adsorption, suggesting that viral entry probably takes place outside rafts. To directly investigate this possibility, we targeted CD4 to nonraft domains of the membrane by preventing CD4 palmitoylation and interaction with p56(lck). Directed mutagenesis of both targeting signals significantly prevented association of CD4 with rafts, but did not suppress the HIV-1 receptor function of CD4. Collectively, these results strongly suggest that the presence of HIV-1 receptors in rafts is not required for viral infection. We show, however, that depleting plasma membrane cholesterol inhibits HIV-1 entry. We therefore propose that cholesterol modulates the HIV-1 entry process independently of its ability to promote raft formation. 相似文献
95.
Myocardial ischemia and increased heart work modulate the phosphorylation state of eukaryotic elongation factor-2 总被引:11,自引:0,他引:11
Horman S Beauloye C Vertommen D Vanoverschelde JL Hue L Rider MH 《The Journal of biological chemistry》2003,278(43):41970-41976
Protein synthesis, in particular peptide chain elongation, is an energy-consuming biosynthetic process. AMP-activated protein kinase (AMPK) is a key regulatory enzyme involved in cellular energy homeostasis. Therefore, we tested the hypothesis that, as in liver, it could mediate the inhibition of protein synthesis by oxygen deprivation in heart by modulating the phosphorylation of eukaryotic elongation factor-2 (eEF2), which becomes inactive in its phosphorylated form. In anoxic cardiomyocytes, AMPK activation was associated with an inhibition of protein synthesis and an increase in phosphorylation of eEF2. Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), did not mimic the effect of oxygen deprivation to inhibit protein synthesis in cardiomyocytes or lead to eEF2 phosphorylation in perfused hearts, suggesting that AMPK activation did not inhibit mTOR/p70 ribosomal protein S6 kinase (p70S6K) signaling. Human recombinant eEF2 kinase (eEF2K) was phosphorylated by AMPK in a time- and AMP-dependent fashion, and phosphorylation led to eEF2K activation, similar to that observed in extracts from ischemic hearts. In contrast, increasing the workload resulted in a dephosphorylation of eEF2, which was rapamycin-insensitive, thus excluding a role for mTOR in this effect. eEF2K activity was unchanged by increasing the workload, suggesting that the decrease in eEF2 phosphorylation could result from the activation of an eEF2 phosphatase. 相似文献
96.
Zarev S Bonnefont-Rousselot D Jedidi I Cosson C Couturier M Legrand A Beaudeux JL Thérond P 《Archives of biochemistry and biophysics》2003,420(1):68-78
The aim of our study was to determine, as a function of [Cu(2+)]/[LDL] ratios (0.5 and 0.05) and of oxidation phases, the extent of LDL oxidation by assessing the lipid and apo B oxidation products. The main results showed that: (i) kinetics of conjugated diene formation presented four phases for Cu(2+)/LDL ratio of 0.5 and two phases for [Cu(2+)]/[LDL] ratio of 0.05; (ii) oxidation product formation (cholesteryl ester and phosphatidylcholine hydroperoxides, apo B carbonyl groups) occurred early in the presence of endogenous antioxidants, under both copper oxidation conditions; (iii) apo B carbonylated fragments appeared when antioxidants were totally consumed at [Cu(2+)]/[LDL] ratio of 0.5; and (iv) antioxidant concentrations were stable, oxysterol formation was negligible, and no carbonylated fragment was detected at [Cu(2+)]/[LDL] ratio of 0.05. Depending on the copper/LDL ratio, oxidized LDL differ greatly in the nature of lipid peroxidation product and the degree of apo B fragmentation. 相似文献
97.
Mapping the microtubule binding regions of calponin 总被引:3,自引:0,他引:3
The smooth muscle basic calponin interacts with F-actin and inhibits the actomyosin ATPase in a calmodulin or phosphorylation modulated manner. It also binds in vitro to microtubules and its acidic isoform, present in nonmuscle cells, and co-localizes with microfilaments and microtubules in cultured neurons. To assess the physiological significance and the molecular basis of the calponin-microtubule interaction, we have first studied the solution binding of recombinant acidic calponin to microtubules using quantitative cosedimentation analyses. We have also characterized, for the first time, the ability of both calponin isoforms to induce the inhibition of the microtubule-stimulated ATPase activity of the cytoskeletal, kinesin-related nonclaret dysjunctional motor protein (ncd) and the abolition of this effect by calcium calmodulin. This property makes calponin a potent inhibitor of all filament-activated motor ATPases and, therefore, a potential regulatory factor of many motor-based biological events. By combining the enzymatic measurements of the ncd-microtubules system with various in vitro binding assays employing proteolytic, recombinant and synthetic fragments of basic calponin, we further unambiguously identified the interaction of microtubules at two distinct calponin sites. One is inhibitory and resides in the segment 145-182, which also binds F-actin and calmodulin. The other one is noninhibitory, specific for microtubules, and is located on the COOH-terminal repeat-containing region 183-292. Finally, quantitative fluorescence studies of the binding of basic calponin to the skeletal pyrenyl F-actin in the presence of microtubules did not reveal a noticeable competition between the two sets of filaments for calponin. This result implies that calponin undergoes a concomitant binding to both F-actin and microtubules by interaction at the former site with actin and at the second site with microtubules. Thus, in the living cells, calponin could potentially behave as a cross-linking protein between the two major cytoskeletal filaments. 相似文献
98.
Rosu F De Pauw E Guittat L Alberti P Lacroix L Mailliet P Riou JF Mergny JL 《Biochemistry》2003,42(35):10361-10371
The telomeric G-rich single-stranded DNA can adopt in vitro an intramolecular quadruplex structure, which has been shown to directly inhibit telomerase activity. The reactivation of this enzyme in immortalized and most cancer cells suggests that telomerase is a relevant target in oncology, and telomerase inhibitors have been proposed as new potential anticancer agents. In this paper, we have analyzed the selectivity of four ethidium derivatives and ethidium itself toward different G-quadruplex species, with electrospray mass spectrometry and competitive equilibrium dialysis and evaluated their inhibitory properties against telomerase. A selectivity profile may be obtained through electrospray ionization mass spectrometry (ESI-MS), which is in fair agreement with competitive equilibrium dialysis data. It also provides unambiguous data on the number of binding sites per nucleic acid (maximal number of two ethidium derivatives per quadruplex, in agreement with external stacking). Our experiments also demonstrate that one compound (4) is the most active and selective G-quadruplex ligand within this series and the most selective telomerase inhibitor in a modified TRAP-G4 assay. 相似文献
99.
Stability of the I-motif structure is related to the interactions between phosphodiester backbones
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The i-motif DNA tetrameric structure is formed of two parallel duplexes intercalated in a head-to-tail orientation, and held together by hemiprotonated cytosine pairs. The four phosphodiester backbones forming the structure define two narrow and wide grooves. The short interphosphate distances across the narrow groove induce a strong repulsion which should destabilize the tetramer. To investigate this point, molecular dynamics simulations were run on the [d(C2)]4 and [d(C4)]4 tetramers in 3'E and 5'E topologies, for which the interaction of the phosphodiester backbones through the narrow groove is different. The analysis of the simulations, using the Molecular Mechanics Generalized Born Solvation Area and Molecular Mechanics Poisson-Boltzmann Solvation Area approaches, shows that it is the van der Waals energy contribution which displays the largest relative difference between the two topologies. The comparison of the solvent-accessible area of each topology reveals that the sugar-sugar interactions account for the greater stability of the 3'E topology. This stresses the importance of the sugar-sugar contacts across the narrow groove which, enforcing the optimal backbone twisting, are essential to the base stacking and the i-motif stability. Tighter interactions between the sugars are observed in the case of N-type sugar puckers. 相似文献
100.
High yield regioselective monobenzyloxycarbonylation of secondary alcohols in glycopyranoside series
The regioselective monobenzyloxycarbonylation of secondary alcohols in methyl 6-O-(4-methoxytrityl)-alpha-D-manno-, gluco- and galactopyranoside has been achieved in high yields (74-85%) by using benzyl chloroformate in the presence of 4-dimethylaminopyridine and/or 1,4-diazabicyclo[2.2.2]octane. 相似文献