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排序方式: 共有643条查询结果,搜索用时 13 毫秒
391.
Bender A Krishnan KJ Morris CM Taylor GA Reeve AK Perry RH Jaros E Hersheson JS Betts J Klopstock T Taylor RW Turnbull DM 《Nature genetics》2006,38(5):515-517
Here we show that in substantia nigra neurons from both aged controls and individuals with Parkinson disease, there is a high level of deleted mitochondrial DNA (mtDNA) (controls, 43.3% +/- 9.3%; individuals with Parkinson disease, 52.3% +/- 9.3%). These mtDNA mutations are somatic, with different clonally expanded deletions in individual cells, and high levels of these mutations are associated with respiratory chain deficiency. Our studies suggest that somatic mtDNA deletions are important in the selective neuronal loss observed in brain aging and in Parkinson disease. 相似文献
392.
CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer 总被引:19,自引:0,他引:19
Weisenberger DJ Siegmund KD Campan M Young J Long TI Faasse MA Kang GH Widschwendter M Weener D Buchanan D Koh H Simms L Barker M Leggett B Levine J Kim M French AJ Thibodeau SN Jass J Haile R Laird PW 《Nature genetics》2006,38(7):787-793
Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors. 相似文献
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395.
Lee HJ Jang SH Kim H Yoon JH Chung KC 《Cellular and molecular life sciences : CMLS》2012,69(19):3301-3315
Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of neuronal death in PD is largely unknown, but several genetic loci, including PTEN-induced putative kinase 1 (PINK1), have been linked to early onset autosomal recessive forms of familial PD. PINK1 encodes a serine/threonine kinase, which phosphorylates several substrates and consequently leads to cell protection against apoptosis induced by various stresses. In addition, research has shown that inflammation largely contributes to the pathogenesis of PD, but the functional link between PINK1 and PD-linked neuroinflammation remains poorly understood. Therefore, in the present study, we investigated the functional role of PINK1 in interleukin (IL)-1β-mediated inflammatory signaling. We show that PINK1 specifically binds to TRAF6 and TAK1, and facilitates the autodimerization and autoubiquitination of TRAF6. PINK1 also enhances the association between TRAF6 and TAK1, phosphorylates TAK1, and stimulates polyubiquitination of TAK1. Furthermore, PINK1 leads to the potentiation of IL-1β-mediated NF-κB activity and cytokine production. These findings suggest that PINK1 positively regulates two key molecules, TRAF6 and TAK1, in the IL-1β-mediated signaling pathway, consequently up-regulating their downstream inflammatory events. 相似文献
396.
Taal HR St Pourcain B Thiering E Das S Mook-Kanamori DO Warrington NM Kaakinen M Kreiner-Møller E Bradfield JP Freathy RM Geller F Guxens M Cousminer DL Kerkhof M Timpson NJ Ikram MA Beilin LJ Bønnelykke K Buxton JL Charoen P Chawes BL Eriksson J Evans DM Hofman A Kemp JP Kim CE Klopp N Lahti J Lye SJ McMahon G Mentch FD Müller-Nurasyid M O'Reilly PF Prokopenko I Rivadeneira F Steegers EA Sunyer J Tiesler C Yaghootkar H;Cohorts for Heart Aging Research in Genetic Epidemiology Consortium 《Nature genetics》2012,44(5):532-538
To identify genetic variants associated with head circumference in infancy, we performed a meta-analysis of seven genome-wide association studies (GWAS) (N = 10,768 individuals of European ancestry enrolled in pregnancy and/or birth cohorts) and followed up three lead signals in six replication studies (combined N = 19,089). rs7980687 on chromosome 12q24 (P = 8.1 × 10(-9)) and rs1042725 on chromosome 12q15 (P = 2.8 × 10(-10)) were robustly associated with head circumference in infancy. Although these loci have previously been associated with adult height, their effects on infant head circumference were largely independent of height (P = 3.8 × 10(-7) for rs7980687 and P = 1.3 × 10(-7) for rs1042725 after adjustment for infant height). A third signal, rs11655470 on chromosome 17q21, showed suggestive evidence of association with head circumference (P = 3.9 × 10(-6)). SNPs correlated to the 17q21 signal have shown genome-wide association with adult intracranial volume, Parkinson's disease and other neurodegenerative diseases, indicating that a common genetic variant in this region might link early brain growth with neurological disease in later life. 相似文献
397.
Cho YS Chen CH Hu C Long J Ong RT Sim X Takeuchi F Wu Y Go MJ Yamauchi T Chang YC Kwak SH Ma RC Yamamoto K Adair LS Aung T Cai Q Chang LC Chen YT Gao Y Hu FB Kim HL Kim S Kim YJ Lee JJ Lee NR Li Y Liu JJ Lu W Nakamura J Nakashima E Ng DP Tay WT Tsai FJ Wong TY Yokota M Zheng W Zhang R Wang C So WY Ohnaka K Ikegami H Hara K Cho YM Cho NH Chang TJ Bao Y Hedman ÅK Morris AP McCarthy MI;DIAGRAM Consortium;MuTHER Consortium Takayanagi R Park KS Jia W Chuang LM Chan JC Maeda S Kadowaki T Lee JY Wu JY 《Nature genetics》2012,44(1):67-72
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, which is involved in pancreatic beta cell development and insulin gene expression, is known for its association with fasting glucose levels. The evidence of an association with T2D for PEPD and HNF4A has been shown in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings, derived from an east Asian population, provide new perspectives on the etiology of T2D. 相似文献
398.
399.
Aitman TJ Critser JK Cuppen E Dominiczak A Fernandez-Suarez XM Flint J Gauguier D Geurts AM Gould M Harris PC Holmdahl R Hubner N Izsvák Z Jacob HJ Kuramoto T Kwitek AE Marrone A Mashimo T Moreno C Mullins J Mullins L Olsson T Pravenec M Riley L Saar K Serikawa T Shull JD Szpirer C Twigger SN Voigt B Worley K 《Nature genetics》2008,40(5):516-522
The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research. 相似文献
400.
Low-density lipoprotein receptor-mediated endocytosis of PEGylated nanoparticles in rat brain endothelial cells 总被引:4,自引:0,他引:4
Kim HR Gil S Andrieux K Nicolas V Appel M Chacun H Desmaële D Taran F Georgin D Couvreur P 《Cellular and molecular life sciences : CMLS》2007,64(3):356-364
Poly(methoxypolyethyleneglycol cyanoacrylate-co-hexadecylcyanoacrylate) (PEG-PHDCA) nanoparticles have demonstrated their
capacity to diffuse through the blood-brain barrier after intravenous administration. However, the mechanism of transport
of these nanoparticles into brain has not yet been clearly elucidated. The development of a model of rat brain endothelial
cells (RBEC) in culture has allowed investigations into this mechanism. A study of the intracellular trafficking of nanoparticles
by cell fractionation and confocal microscopy showed that nanoparticles are internalized by the endocytic pathway. Inhibition
of the caveolae-mediated pathway by preincubation with filipin and nystatin did not modify the cellular uptake of the nanoparticles.
In contrast, chlorpromazine and NaN3 pretreatment, which interferes with clathrin and energy-dependent endocytosis, caused a significant decrease of nanoparticle
internalization. Furthermore, cellular uptake experiments with nanoparticles preincubated with apolipoprotein E and blocking
of low-density lipoprotein receptors (LDLR) clearly suggested that the LDLR-mediated pathway was involved in the endocytosis
of PEGPHDCA nanoparticles by RBEC.
Received 1 September 2006; received after revision 4 December 2006; accepted 18 December 2006 相似文献