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61.
Daly JW 《Cellular and molecular life sciences : CMLS》2007,64(16):2153-2169
Caffeine, widely consumed in beverages, and many xanthine analogs have had a major impact on biomedical research. Caffeine
and various analogs, the latter designed to enhance potency and selectivity toward specific biological targets, have played
key roles in defining the nature and role of adenosine receptors, phosphodiesterases, and calcium release channels in physiological
processes. Such xanthines and other caffeine-inspired heterocycles now provide important research tools and potential therapeutic
agents for intervention in Alzheimer’s disease, asthma, cancer, diabetes, and Parkinson’s disease. Such compounds also have
activity as analgesics, antiinflammatories, antitussives, behavioral stimulants, diuretics/natriuretics, and lipolytics. Adverse
effects can include anxiety, hypertension, certain drug interactions, and withdrawal symptoms.
Received 31 January 2007; received after revision 7 April 2007; accepted 26 April 2007 相似文献
62.
Rioux JD Xavier RJ Taylor KD Silverberg MS Goyette P Huett A Green T Kuballa P Barmada MM Datta LW Shugart YY Griffiths AM Targan SR Ippoliti AF Bernard EJ Mei L Nicolae DL Regueiro M Schumm LP Steinhart AH Rotter JI Duerr RH Cho JH Daly MJ Brant SR 《Nature genetics》2007,39(5):596-604
We present a genome-wide association study of ileal Crohn disease and two independent replication studies that identify several new regions of association to Crohn disease. Specifically, in addition to the previously established CARD15 and IL23R associations, we identified strong and significantly replicated associations (combined P < 10(-10)) with an intergenic region on 10q21.1 and a coding variant in ATG16L1, the latter of which was also recently reported by another group. We also report strong associations with independent replication to variation in the genomic regions encoding PHOX2B, NCF4 and a predicted gene on 16q24.1 (FAM92B). Finally, we demonstrate that ATG16L1 is expressed in intestinal epithelial cell lines and that functional knockdown of this gene abrogates autophagy of Salmonella typhimurium. Together, these findings suggest that autophagy and host cell responses to intracellular microbes are involved in the pathogenesis of Crohn disease. 相似文献
63.
Plenge RM Cotsapas C Davies L Price AL de Bakker PI Maller J Pe'er I Burtt NP Blumenstiel B DeFelice M Parkin M Barry R Winslow W Healy C Graham RR Neale BM Izmailova E Roubenoff R Parker AN Glass R Karlson EW Maher N Hafler DA Lee DM Seldin MF Remmers EF Lee AT Padyukov L Alfredsson L Coblyn J Weinblatt ME Gabriel SB Purcell S Klareskog L Gregersen PK Shadick NA Daly MJ Altshuler D 《Nature genetics》2007,39(12):1477-1482
To identify susceptibility alleles associated with rheumatoid arthritis, we genotyped 397 individuals with rheumatoid arthritis for 116,204 SNPs and carried out an association analysis in comparison to publicly available genotype data for 1,211 related individuals from the Framingham Heart Study. After evaluating and adjusting for technical and population biases, we identified a SNP at 6q23 (rs10499194, approximately 150 kb from TNFAIP3 and OLIG3) that was reproducibly associated with rheumatoid arthritis both in the genome-wide association (GWA) scan and in 5,541 additional case-control samples (P = 10(-3), GWA scan; P < 10(-6), replication; P = 10(-9), combined). In a concurrent study, the Wellcome Trust Case Control Consortium (WTCCC) has reported strong association of rheumatoid arthritis susceptibility to a different SNP located 3.8 kb from rs10499194 (rs6920220; P = 5 x 10(-6) in WTCCC). We show that these two SNP associations are statistically independent, are each reproducible in the comparison of our data and WTCCC data, and define risk and protective haplotypes for rheumatoid arthritis at 6q23. 相似文献
64.
Guilt beyond a reasonable doubt 总被引:10,自引:0,他引:10
65.
Common variants in WFS1 confer risk of type 2 diabetes 总被引:10,自引:0,他引:10
Sandhu MS Weedon MN Fawcett KA Wasson J Debenham SL Daly A Lango H Frayling TM Neumann RJ Sherva R Blech I Pharoah PD Palmer CN Kimber C Tavendale R Morris AD McCarthy MI Walker M Hitman G Glaser B Permutt MA Hattersley AT Wareham NJ Barroso I 《Nature genetics》2007,39(8):951-953
We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes. 相似文献
66.
Replicating genotype-phenotype associations 总被引:1,自引:0,他引:1
NCI-NHGRI Working Group on Replication in Association Studies Chanock SJ Manolio T Boehnke M Boerwinkle E Hunter DJ Thomas G Hirschhorn JN Abecasis G Altshuler D Bailey-Wilson JE Brooks LD Cardon LR Daly M Donnelly P Fraumeni JF Freimer NB Gerhard DS Gunter C Guttmacher AE Guyer MS Harris EL Hoh J Hoover R Kong CA Merikangas KR Morton CC Palmer LJ Phimister EG Rice JP Roberts J Rotimi C Tucker MA Vogan KJ Wacholder S Wijsman EM Winn DM Collins FS 《Nature》2007,447(7145):655-660
67.
68.
P. R. Nemeth K. Daly S. Erde J. D. Wood 《Cellular and molecular life sciences : CMLS》1985,41(2):259-261
Summary Intracellular recording methods were used to investigate the action of methylene blue on electrical behavior of myenteric neurons in guinea pig small intestine. The neurophysiological studies were done in parallel with studies on contractile activity of the intestinal musculature. Methylene blue depolarized the membranes, increased the input resistance, augmented excitability and reduced postspike hyperpolarizing potentials in AH/Type 2 myenteric neurons. These effects, with the exception of suppression of postspike hyperpolarization, were reversed by exposure to elevated calcium. The mechanism of action of methylene blue appeared to be suppression of calcium-dependent potassium conductance in the neuronal membranes. The neuronal action of methylene blue was manifest as a release of excitatory neurontransmitter substances with evoked contraction of the small intestinal longitudinal muscle. 相似文献
69.
Zusammenfassung Es wird eine einfache, schnelle und empfindliche Methode zur Isolierung und Identifizierung von Analgetica mittels der Dünnschichtchromatographie beschrieben. Die Methode ist zur Charakterisierung dieser Stoffe im Harn und für toxikologische, forensische und Stoffwechseluntersuchungen brauchbar. 相似文献
70.
Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression 总被引:51,自引:0,他引:51
Kuehl P Zhang J Lin Y Lamba J Assem M Schuetz J Watkins PB Daly A Wrighton SA Hall SD Maurel P Relling M Brimer C Yasuda K Venkataramanan R Strom S Thummel K Boguski MS Schuetz E 《Nature genetics》2001,27(4):383-391
Variation in the CYP3A enzymes, which act in drug metabolism, influences circulating steroid levels and responses to half of all oxidatively metabolized drugs. CYP3A activity is the sum activity of the family of CYP3A genes, including CYP3A5, which is polymorphically expressed at high levels in a minority of Americans of European descent and Europeans (hereafter collectively referred to as 'Caucasians'). Only people with at least one CYP3A5*1 allele express large amounts of CYP3A5. Our findings show that single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and CYP3A5*6 that cause alternative splicing and protein truncation result in the absence of CYP3A5 from tissues of some people. CYP3A5 was more frequently expressed in livers of African Americans (60%) than in those of Caucasians (33%). Because CYP3A5 represents at least 50% of the total hepatic CYP3A content in people polymorphically expressing CYP3A5, CYP3A5 may be the most important genetic contributor to interindividual and interracial differences in CYP3A-dependent drug clearance and in responses to many medicines. 相似文献