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71.
Scotet V Barton DE Watson JB Audrézet MP McDevitt T McQuaid S Shortt C De Braekeleer M Férec C Le Maréchal C 《Human mutation》2003,22(1):105
This study aims to compare the spectrum of the mutations identified in the gene responsible for cystic fibrosis in three cohorts of patients of Celtic origin from Brittany and Ireland. It included 389 patients from Brittany, 631 from Dublin and 139 from Cork. The CFTR gene analysis relied on the detection of the most common mutations, followed by a complete gene scanning using DGGE or D-HPLC. High mutation detection rates were obtained in each cohort: 99.6%, 96.8%, and 96.0% respectively. A high frequency of the c.1652_1655 del3 mutation (F508del: 74.8% to 81.3%) and of the "Celtic" mutation (c.1784G>A (G551D): 3.7% to 9.7%) was observed in each population. Apart from this, the mutation spectrums differed. In Brittany, the most common abnormalities were: c.1078delT (3.6%), c.4041C>G (N1303K: 1.4%), c.2670G>A (W846X(2): 1.0%) and c.1717-1G>A (1.0%), whereas in the cohort of Dublin, the main mutations were: c.482G>A (R117H: 3.0%), c.1811G>C (R560T: 2.4%) and c.621+1G>T (1.7%). Finally, in the Cork area, only the c.482G>A mutation (R117H) reached a frequency of 1%. Two previously-unreported mutations were identified in the Dublin cohort: c.2623-2A>G and c.3446T>G (M1105R). This collaborative study highlights the similarities of the CFTR alleles in the Breton and Irish populations, but also the disparities that exist between these populations, despite their common origin. Each population has its own history, with its mixture of founder effects and genetic drifts, which are at the origin of the current mutation distribution. The molecular study of the CFTR gene provides new tools for retracing European populations' histories. 相似文献
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73.
Eun Joo Song Shannon L. Werner Jakob Neubauer Frank Stegmeier Julie Aspden Donald Rio J. Wade Harper Stephen J. Elledge Marc W. Kirschner Michael Rape 《Genes & development》2010,24(13):1434-1447
The spliceosome, a dynamic assembly of proteins and RNAs, catalyzes the excision of intron sequences from nascent mRNAs. Recent work has suggested that the activity and composition of the spliceosome are regulated by ubiquitination, but the underlying mechanisms have not been elucidated. Here, we report that the spliceosomal Prp19 complex modifies Prp3, a component of the U4 snRNP, with nonproteolytic K63-linked ubiquitin chains. The K63-linked chains increase the affinity of Prp3 for the U5 snRNP component Prp8, thereby allowing for the stabilization of the U4/U6.U5 snRNP. Prp3 is deubiquitinated by Usp4 and its substrate targeting factor, the U4/U6 recycling protein Sart3, which likely facilitates ejection of U4 proteins from the spliceosome during maturation of its active site. Loss of Usp4 in cells interferes with the accumulation of correctly spliced mRNAs, including those for α-tubulin and Bub1, and impairs cell cycle progression. We propose that the reversible ubiquitination of spliceosomal proteins, such as Prp3, guides rearrangements in the composition of the spliceosome at distinct steps of the splicing reaction. 相似文献
74.
Stewart TL Roschger P Misof BM Mann V Fratzl P Klaushofer K Aspden R Ralston SH 《Calcified tissue international》2005,77(2):113-118
Previous work identified a G/T polymorphism affecting a Sp1 binding site in a regulatory region of the COLIA1 gene that predisposes to osteoporotic fractures by affecting bone strength through mechanisms that are partly independent
of differences in bone mineral density (BMD). To clarify the mechanisms by which COLIA1 Sp1 alleles influence bone strength we used quantitative backscattered electron imaging (qBEI) to characterize bone mineralization
in biopsy samples from subjects of different COLIA1 genotype and studied the ability of osteoblast-like cells cultured from subjects of different genotypes to form mineralized
bone nodules. The qBEI analysis showed a significant (P = 0.014) reduction in mineralization in bone biopsies from G/T heterozygotes (n = 6) compared with G/G homozygotes (n = 7) and a significant increase in heterogeneity of mineralization (P = 0.017). The in vitro studies showed that osteoblasts derived from G/T heterozygotes (n = 5) were significantly less able to produce mineralized bone nodules than G/G homozygotes (n = 10) at all time-points examined (P < 0.0001). We conclude that carriage of the COLIA1 Sp1 “T” allele is associated with an impaired ability of osteoblast-like cells to form mineralized bone nodules in vitro and with abnormalities of bone mineralization in vivo. This suggests that the increased bone fragility in carriers of the COLIA1 Sp1 allele may result in part from defects in bone mineralization.
T.L.S. and P.R. contributed equally. 相似文献
75.
Plumb MS Aspden RM 《Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society》2005,13(12):417-1091
OBJECTIVE: To investigate the biosynthetic response of elderly human femoral head articular cartilage to mechanical stimulation in vitro and its variation with site. METHOD: Full-depth cartilage biopsies of articular cartilage were removed from defined sites on 10 femoral heads from patients aged 68-95 years. Cartilage explants were subjected to either static or cyclic (2s on/2s off) loading in unconfined compression at a stress of 1MPa for 24h, or no load. Metabolic activity was assessed by adding medium containing (35)S-sulphate and (3)H-leucine during the last 4h of loading and measuring the incorporated radioisotope. Matrix composition was measured in terms of the amounts of collagen, sulphated glycosaminoglycans (GAG) and water content. RESULTS: Loading of elderly human articular cartilage at 1MPa significantly inhibited incorporation of (35)S-sulphate (P=0.023) into cartilage explants. Pairwise comparisons showed that the difference in incorporation was only for static loading (43% decrease compared to unloaded) (P<0.05). (3)H-leucine incorporation appeared to follow the same trends but neither static nor cyclic load was significantly different from control (P=0.31). Significant topographical variation was found for % GAG wet and GAG:collagen but not water content, % GAG dry or collagen. Isotope incorporation rates were in the order anterior>superior>posterior. CONCLUSION: Static loading inhibits matrix biosynthesis in elderly human cartilage, and cyclic loading is not stimulatory. This is in contrast to previous studies on young bovine tissue where cyclic loading is stimulatory. 相似文献
76.
Simpson R Williams G Petroeschevsky A Best T Morgan G Denison L Hinwood A Neville G Neller A 《Australian and New Zealand journal of public health》2005,29(3):205-212
OBJECTIVE: To examine the short-term health effects of air pollution on daily mortality in four Australian cities (Brisbane, Melbourne, Perth and Sydney), where more than 50% of Australians reside. METHODS: The study used a similar protocol to APHEA2 (Air Pollution and Health: A European Approach) study and derived single-city and pooled estimates. RESULTS: The results derived from the different approaches for the 1996-99 period showed consistent results for different statistical models used. There were significant effects on total mortality, (RR = 1.0284 per 1 unit increase in nephelometry [10(-4).m(-1)], RR = 1.0011 per 1ppb increase in NO2), and on respiratory mortality (RR = 1.0022 per 1ppb increase in O3). No significant differences between cities were found, but the NO2 and particle effects may refer to the same impacts. Meta-analyses carried out for three cities yielded estimates for the increase in the daily total number of deaths of 0.2% (-0.8% to 1.2%) for a 10 microg/m3 increase in PM10 concentration, and 0.9% (-0.7% to 2.5%) for a 10 microg/m3 increase in PM2.5 concentration. CONCLUSIONS: Air pollutants in Australian cities have significant effects on mortality. 相似文献
77.
Tran T Fernandes DJ Schuliga M Harris T Landells L Stewart AG 《British journal of pharmacology》2005,145(1):123-131
For a subpopulation of asthmatics, symptoms persist even with high doses of glucocorticoids. Glucocorticoids reduce the levels of the proinflammatory and fibrogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF) produced by human cultured airway smooth muscle (ASM). We have contrasted the effects of a synthetic glucocorticoid, dexamethasone, on thrombin- and IL-1alpha-stimulated GM-CSF production in human ASM cells. Although IL-1alpha stimulated three-fold higher levels of GM-CSF mRNA and protein compared to thrombin, dexamethasone concentration-dependently reduced IL-1alpha-stimulated GM-CSF more potently and to a greater extent than the response to thrombin. This pattern of glucocorticoid regulation was also observed at the GM-CSF mRNA level and was reproduced with other glucocorticoids such as fluticasone propionate. IL-1alpha and thrombin stimulated NF-kappa B-dependent luciferase expression equally. Dexamethasone treatment reduced luciferase expression stimulated by both IL-1alpha and thrombin. The GM-CSF mRNA half life was markedly prolonged by IL-1alpha compared to thrombin. This IL-1alpha-induced GM-CSF mRNA stability was prevented by either dexamethasone or the p38(MAPK) inhibitor, SB203580, neither of which influenced GM-CSF mRNA stability in thrombin-treated cells. Dexamethasone inhibited p38(MAPK) phosphorylation in IL-1alpha-stimulated ASM, whereas thrombin does not stimulate p38(MAPK) phosphorylation. These data suggest that the mechanism underlying the greater potency and efficacy of glucocorticoids in reducing GM-CSF synthesis stimulated by IL-1alpha depends on inhibition of the involvement of p38(MAPK)-induced increases in GM-CSF message stability. 相似文献
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79.
For many years articular cartilage has been the focus of research aimed at improving understanding of and treatment for osteoarthritis. Although much is known about the tissue, research has had little success in elucidating the pathogenesis of generalised osteoarthritis. A new hypothesis is required. Substantial changes in many tissues, including bone, muscle, ligaments, and joint capsule, as well as cartilage, are increasingly recognised in this disease, and not all these changes are localised to the affected joints. There is also a well established link with obesity. These observations, the common origins of the mesenchymal cells that maintain these tissues, and the possible role of neuroendocrine factors that can regulate bone mass, result in the hypothesis that systemic factors that include altered lipid metabolism could explain the diversity of physiological changes in generalised osteoarthritis. If proven, this hypothesis could have important implications for a new approach to pharmacological intervention in the early stages of the disease. 相似文献