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Age at onset in two common neurodegenerative diseases is genetically controlled 总被引:17,自引:1,他引:16 下载免费PDF全文
Li YJ Scott WK Hedges DJ Zhang F Gaskell PC Nance MA Watts RL Hubble JP Koller WC Pahwa R Stern MB Hiner BC Jankovic J Allen FA Goetz CG Mastaglia F Stajich JM Gibson RA Middleton LT Saunders AM Scott BL Small GW Nicodemus KK Reed AD Schmechel DE Welsh-Bohmer KA Conneally PM Roses AD Gilbert JR Vance JM Haines JL Pericak-Vance MA 《American journal of human genetics》2002,70(4):985-993
To identify genes influencing age at onset (AAO) in two common neurodegenerative diseases, a genomic screen was performed for AAO in families with Alzheimer disease (AD; n=449) and Parkinson disease (PD; n=174). Heritabilities between 40%–60% were found in both the AD and PD data sets. For PD, significant evidence for linkage to AAO was found on chromosome 1p (LOD = 3.41). For AD, the AAO effect of APOE (LOD = 3.28) was confirmed. In addition, evidence for AAO linkage on chromosomes 6 and 10 was identified independently in both the AD and PD data sets. Subsequent unified analyses of these regions identified a single peak on chromosome 10q between D10S1239 and D10S1237, with a maximum LOD score of 2.62. These data suggest that a common gene affects AAO in these two common complex neurodegenerative diseases. 相似文献
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The erythrocyte surface sialic acid concentration of clinically healthy mongrel and exotic (Alsatian i.e. German shepherd and Terrier) breeds of dogs was analyzed in order to determine their role in the genetic resistance of these
breeds of dogs to diseases that cause anaemia. The mean erythrocyte surface sialic acid (ESA) concentration was 57.08 ± 1.67,
34.50 ± 2.30 and 20.20 ± 3.54 mg/dl for Mongrel, Alsatian (German shepherd) and Terrier breeds of dogs, respectively, on acid
hydrolysis. The mean values of ESA obtained following enzymic hydrolysis of haemoglobin-free erythrocyte membranes using Clostridium chauvoei (Jakari strain) sialidase were 49.08 ± 0.41, 30.97 ± 1.82 and 18.64 ± 0.75 mg/dl for Mongrel, Alsatian (German shepherd)
and Terrier dogs respectively. When Trypanosoma vivax sialidase was used the ESA values obtained were 50.81 ± 0.37, 41.70 ± 0.94 and 19.65 + 0.65 mg/dl for Mongrel, Alsatian
(German shepherd) and Terrier breeds of dogs respectively. This represents a statistically significant difference (P < 0.001) between the mean ESA concentration of all the breeds of dogs investigated in this study. The higher mean ESA concentration
in Mongrel dogs, compared to the exotic breeds may be responsible for their resistance to disease conditions, whose aetiologic
agents produce neuraminidase and also cause anaemia. 相似文献
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Nicodemus KK Kolachana BS Vakkalanka R Straub RE Giegling I Egan MF Rujescu D Weinberger DR 《Human genetics》2007,120(6):889-906
Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome
associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal
cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of
inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent
case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression
to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia
susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs
in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found
in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects
for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect
statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant
main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic
models may improve replication of psychiatric candidate gene studies. 相似文献
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Tu Z Aird KM Bitler BG Nicodemus JP Beeharry N Xia B Yen TJ Zhang R 《Developmental cell》2011,21(6):1077-1091
Here, we report a cell-intrinsic mechanism by which oncogenic RAS promotes senescence while predisposing cells to senescence bypass by allowing for secondary hits. We show that oncogenic RAS inactivates the BRCA1 DNA repair complex by dissociating BRCA1 from chromatin. This event precedes senescence-associated cell cycle exit and coincides with the accumulation of DNA damage. Downregulation of BRIP1, a physiological partner of BRCA1 in the DNA repair pathway, triggers BRCA1 chromatin dissociation. Conversely, ectopic BRIP1 rescues BRCA1 chromatin dissociation and suppresses RAS-induced senescence and the DNA damage response. Significantly, cells undergoing senescence do not exhibit a BRCA1-dependent DNA repair response when exposed to DNA damage. Overall, our study provides a molecular basis by which oncogenic RAS promotes senescence. Because DNA damage has the potential to produce additional "hits" that promote senescence bypass, our findings may also suggest one way a small minority of cells might bypass senescence and contribute to cancer development. 相似文献
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Nicodemus KK 《Briefings in bioinformatics》2011,12(4):369-373
A recent study examined the stability of rankings from random forests using two variable importance measures (mean decrease accuracy (MDA) and mean decrease Gini (MDG)) and concluded that rankings based on the MDG were more robust than MDA. However, studies examining data-specific characteristics on ranking stability have been few. Rankings based on the MDG measure showed sensitivity to within-predictor correlation and differences in category frequencies, even when the number of categories was held constant, and thus may produce spurious results. The MDA measure was robust to these data characteristics. Further, under strong within-predictor correlation, MDG rankings were less stable than those using MDA. 相似文献
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Di Girolamo N Indoh I Jackson N Wakefield D McNeil HP Yan W Geczy C Arm JP Tedla N 《Journal of immunology (Baltimore, Md. : 1950)》2006,177(4):2638-2650
Mast cells are key effectors in the pathogenesis of inflammatory and tissue destructive diseases such as rheumatoid arthritis (RA). These cells contain specialized secretory granules loaded with bioactive molecules including cytokines, growth factors, and proteases that are released upon activation. This study investigated the regulation of matrix metalloproteinase MMP-9 (gelatinase B) in human mast cells by cytokines that are known to be involved in the pathogenesis of RA. Immunohistochemical staining of synovial tissue showed abundant expression of MMP-9 by synovial tissue mast cells in patients with RA but not in normal controls. The expression, activity, and production of MMP-9 in mast cells was confirmed by RT-PCR, zymography, and Western blotting using cord blood-derived human mast cells (CB-HMC). Treatment of CB-HMC with TNF-alpha significantly increased the expression of MMP-9 mRNA and up-regulated the activity of MMP-9 in a time- and dose-dependent manner. By contrast, IFN-gamma inhibited MMP-9 mRNA and protein expression. The cytokine-mediated regulation of MMP-9 was also apparent in the human mast cell line (HMC-1) and in mouse bone marrow-derived mast cells. Furthermore, TNF-alpha significantly increased the invasiveness of CB-HMC across Matrigel-coated membranes while the addition of IFN-gamma, rTIMP-1, or pharmacological MMP inhibitors significantly reduced this process. These observations suggest that MMP-9 is not a stored product in mast cells but these cells are capable of producing this enzyme under inflammatory conditions that may facilitate the migration of mast cell progenitors to sites of inflammation and may also contribute to local tissue damage. 相似文献
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C F Nicodemus S Avraham K F Austen S Purdy J Jablonski R L Stevens 《The Journal of biological chemistry》1990,265(10):5889-5896
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S Avraham K F Austen C F Nicodemus M C Gartner R L Stevens 《The Journal of biological chemistry》1989,264(28):16719-16726