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141.
OPCML at 11q25 is epigenetically inactivated and has tumor-suppressor function in epithelial ovarian cancer 总被引:12,自引:0,他引:12
142.
Late Cretaceous sediments from the Western Interior of North America yield exceptionally well preserved fossils that serve as proxies for the rapidly changing climate preceding the Cretaceous/Tertiary boundary (about 67-65 Myr ago). Here we reconstruct the ontogenetic history of a Maastrichtian-age fish, Vorhisia vulpes, by using the carbon, oxygen and strontium isotope ratios of four aragonite otoliths collected from the Fox Hills Formation of South Dakota. Individuals of V. vulpes spawned in brackish water (about 70-80% seawater) and during their first year migrated to open marine waters of the Western Interior Seaway, where they remained for 3 years before returning to the estuary, presumably to spawn and die. The mean delta(18)O from the marine growth phase of V. vulpes yields a seawater temperature of 18 degrees C, which is consistent with leaf physiognomy and general-circulation-model temperature estimates for the Western Interior during the latest Maastrichtian. 相似文献
143.
Hidden complexity in the mechanical properties of titin 总被引:2,自引:0,他引:2
Williams PM Fowler SB Best RB Toca-Herrera JL Scott KA Steward A Clarke J 《Nature》2003,422(6930):446-449
Individual molecules of the giant protein titin span the A-bands and I-bands that make up striated muscle. The I-band region of titin is responsible for passive elasticity in such muscle, and contains tandem arrays of immunoglobulin domains. One such domain (I27) has been investigated extensively, using dynamic force spectroscopy and simulation. However, the relevance of these studies to the behaviour of the protein under physiological conditions was not established. Force studies reveal a lengthening of I27 without complete unfolding, forming a stable intermediate that has been suggested to be an important component of titin elasticity. To develop a more complete picture of the forced unfolding pathway, we use mutant titins--certain mutations allow the role of the partly unfolded intermediate to be investigated in more depth. Here we show that, under physiological forces, the partly unfolded intermediate does not contribute to mechanical strength. We also propose a unified forced unfolding model of all I27 analogues studied, and conclude that I27 can withstand higher forces in muscle than was predicted previously. 相似文献
144.
分析了我国企业在安全教育中存在的问题,介绍了山西铝厂安全教育市场化改革的实践和效果,指明了市场化是企业安全教育发展的新趋向,同时也是企业技术教育和管理培训改革的新趋向。 相似文献
145.
Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus 总被引:1,自引:0,他引:1
Lee-Kirsch MA Gong M Chowdhury D Senenko L Engel K Lee YA de Silva U Bailey SL Witte T Vyse TJ Kere J Pfeiffer C Harvey S Wong A Koskenmies S Hummel O Rohde K Schmidt RE Dominiczak AF Gahr M Hollis T Perrino FW Lieberman J Hübner N 《Nature genetics》2007,39(9):1065-1067
TREX1 acts in concert with the SET complex in granzyme A-mediated apoptosis, and mutations in TREX1 cause Aicardi-Goutières syndrome and familial chilblain lupus. Here, we report monoallelic frameshift or missense mutations and one 3' UTR variant of TREX1 present in 9/417 individuals with systemic lupus erythematosus but absent in 1,712 controls (P = 4.1 x 10(-7)). We demonstrate that two mutant TREX1 alleles alter subcellular targeting. Our findings implicate TREX1 in the pathogenesis of SLE. 相似文献
146.
Guo DC Pannu H Tran-Fadulu V Papke CL Yu RK Avidan N Bourgeois S Estrera AL Safi HJ Sparks E Amor D Ades L McConnell V Willoughby CE Abuelo D Willing M Lewis RA Kim DH Scherer S Tung PP Ahn C Buja LM Raman CS Shete SS Milewicz DM 《Nature genetics》2007,39(12):1488-1493
The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC alpha-actin (encoded by ACTA2) and the beta-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta. 相似文献
147.
Cabral WA Chang W Barnes AM Weis M Scott MA Leikin S Makareeva E Kuznetsova NV Rosenbaum KN Tifft CJ Bulas DI Kozma C Smith PA Eyre DR Marini JC 《Nature genetics》2007,39(3):359-365
A recessive form of severe osteogenesis imperfecta that is not caused by mutations in type I collagen has long been suspected. Mutations in human CRTAP (cartilage-associated protein) causing recessive bone disease have been reported. CRTAP forms a complex with cyclophilin B and prolyl 3-hydroxylase 1, which is encoded by LEPRE1 and hydroxylates one residue in type I collagen, alpha1(I)Pro986. We present the first five cases of a new recessive bone disorder resulting from null LEPRE1 alleles; its phenotype overlaps with lethal/severe osteogenesis imperfecta but has distinctive features. Furthermore, a mutant allele from West Africa, also found in African Americans, occurs in four of five cases. All proband LEPRE1 mutations led to premature termination codons and minimal mRNA and protein. Proband collagen had minimal 3-hydroxylation of alpha1(I)Pro986 but excess lysyl hydroxylation and glycosylation along the collagen helix. Proband collagen secretion was moderately delayed, but total collagen secretion was increased. Prolyl 3-hydroxylase 1 is therefore crucial for bone development and collagen helix formation. 相似文献
148.
Sun L Rommens JM Corvol H Li W Li X Chiang TA Lin F Dorfman R Busson PF Parekh RV Zelenika D Blackman SM Corey M Doshi VK Henderson L Naughton KM O'Neal WK Pace RG Stonebraker JR Wood SD Wright FA Zielenski J Clement A Drumm ML Boëlle PY Cutting GR Knowles MR Durie PR Strug LJ 《Nature genetics》2012,44(5):562-569
Variants associated with meconium ileus in cystic fibrosis were identified in 3,763 affected individuals by genome-wide association study (GWAS). Five SNPs at two loci near SLC6A14 at Xq23-24 (minimum P = 1.28 × 10(-12) at rs3788766) and SLC26A9 at 1q32.1 (minimum P = 9.88 × 10(-9) at rs4077468) accounted for ~5% of phenotypic variability and were replicated in an independent sample of affected individuals (n = 2,372; P = 0.001 and 0.0001, respectively). By incorporating the knowledge that disease-causing mutations in CFTR alter electrolyte and fluid flux across surface epithelium into a hypothesis-driven GWAS (GWAS-HD), we identified associations with the same SNPs in SLC6A14 and SLC26A9 and established evidence for the involvement of SNPs in a third solute carrier gene, SLC9A3. In addition, GWAS-HD provided evidence of association between meconium ileus and multiple genes encoding constituents of the apical plasma membrane where CFTR resides (P = 0.0002; testing of 155 apical membrane genes jointly and in replication, P = 0.022). These findings suggest that modulating activities of apical membrane constituents could complement current therapeutic paradigms for cystic fibrosis. 相似文献
149.
Manning AK Hivert MF Scott RA Grimsby JL Bouatia-Naji N Chen H Rybin D Liu CT Bielak LF Prokopenko I Amin N Barnes D Cadby G Hottenga JJ Ingelsson E Jackson AU Johnson T Kanoni S Ladenvall C Lagou V Lahti J Lecoeur C Liu Y Martinez-Larrad MT Montasser ME Navarro P Perry JR Rasmussen-Torvik LJ Salo P Sattar N Shungin D Strawbridge RJ Tanaka T van Duijn CM An P de Andrade M Andrews JS Aspelund T Atalay M Aulchenko Y Balkau B Bandinelli S Beckmann JS Beilby JP Bellis C Bergman RN Blangero J 《Nature genetics》2012,44(6):659-669
Recent genome-wide association studies have described many loci implicated in type 2 diabetes (T2D) pathophysiology and β-cell dysfunction but have contributed little to the understanding of the genetic basis of insulin resistance. We hypothesized that genes implicated in insulin resistance pathways might be uncovered by accounting for differences in body mass index (BMI) and potential interactions between BMI and genetic variants. We applied a joint meta-analysis approach to test associations with fasting insulin and glucose on a genome-wide scale. We present six previously unknown loci associated with fasting insulin at P < 5 × 10(-8) in combined discovery and follow-up analyses of 52 studies comprising up to 96,496 non-diabetic individuals. Risk variants were associated with higher triglyceride and lower high-density lipoprotein (HDL) cholesterol levels, suggesting a role for these loci in insulin resistance pathways. The discovery of these loci will aid further characterization of the role of insulin resistance in T2D pathophysiology. 相似文献
150.
Recent studies, including two in this issue, report heterozygous missense mutations in the U2AF1 and SF3B1 genes that encode spliceosome subunits. U2AF1 is frequently mutated in myeloid hematopoietic malignancies, especially in myelodysplastic syndrome (MDS), and SF3B1 is frequently mutated in both MDS and chronic lymphocytic leukemia (CLL). 相似文献