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Daniel F. Gudbjartsson Hilma Holm Olafur S. Indridason Gudmar Thorleifsson Vidar Edvardsson Patrick Sulem Femmie de Vegt Frank C. H. d'Ancona Martin den Heijer Leifur Franzson Thorunn Rafnar Kristleifur Kristjansson Unnur S. Bjornsdottir Gudmundur I. Eyjolfsson Lambertus A. Kiemeney Augustine Kong Runolfur Palsson Unnur Thorsteinsdottir Kari Stefansson 《PLoS genetics》2010,6(7)
Chronic kidney disease (CKD) is a worldwide public health problem that is associated with substantial morbidity and mortality. To search for sequence variants that associate with CKD, we conducted a genome-wide association study (GWAS) that included a total of 3,203 Icelandic cases and 38,782 controls. We observed an association between CKD and a variant with 80% population frequency, rs4293393-T, positioned next to the UMOD gene (GeneID: 7369) on chromosome 16p12 (OR = 1.25, P = 4.1×10−10). This gene encodes uromodulin (Tamm-Horsfall protein), the most abundant protein in mammalian urine. The variant also associates significantly with serum creatinine concentration (SCr) in Icelandic subjects (N = 24,635, P = 1.3×10−23) but not in a smaller set of healthy Dutch controls (N = 1,819, P = 0.39). Our findings validate the association between the UMOD variant and both CKD and SCr recently discovered in a large GWAS. In the Icelandic dataset, we demonstrate that the effect on SCr increases substantially with both age (P = 3.0×10−17) and number of comorbid diseases (P = 0.008). The association with CKD is also stronger in the older age groups. These results suggest that the UMOD variant may influence the adaptation of the kidney to age-related risk factors of kidney disease such as hypertension and diabetes. The variant also associates with serum urea (P = 1.0×10−6), uric acid (P = 0.0064), and suggestively with gout. In contrast to CKD, the UMOD variant confers protection against kidney stones when studied in 3,617 Icelandic and Dutch kidney stone cases and 43,201 controls (OR = 0.88, P = 5.7×10−5). 相似文献
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Ultrasonography is a fast, accurate, and non–invasive method to determine the sex of cod ( Gadus morhua ). In this study it was used on 788 farmed cod ranging in age from 1 to 6 yr. Accuracy of sex determination was over 95% for fish subjected to Ultrasonography from October to April. 相似文献
126.
Interaction between transmembrane TNF and TNFR1/2 mediates the activation of monocytes by contact with T cells 总被引:1,自引:0,他引:1
Rossol M Meusch U Pierer M Kaltenhäuser S Häntzschel H Hauschildt S Wagner U 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(6):4239-4248
Monocytes and monocytic cells produce proinflammatory cytokines upon direct cell contact with activated T cells. In the autoimmune disease rheumatoid arthritis, the pivotal role of TNF-alpha implies that the interaction between transmembrane TNF-alpha (mTNF) and the TNF receptors (TNFR1 and TNFR2) might participate in the T cell contact-dependent activation of monocytes. Accordingly, treatment of rheumatoid arthritis by administration of a TNF-alpha-blocking Ab was found to significantly decrease TNF-alpha production by monocytes. Several lines of evidence indicated that signaling through TNFR1/2 and through mTNF (reverse signaling) is involved in TNF-alpha production by monocytes after T cell contact: 1) blocking mTNF on activated T cells leads to a significant reduction in TNF-alpha production; 2) down-regulation of TNFR1/2 on monocytes by transfection with small interfering RNA results in diminished TNF-alpha production; 3) blocking or down-regulating TNFR2 on activated T cells inhibits TNF-alpha production, indicating that mTNF on the monocyte surface mediates signaling; 4) ligation of mTNF on monocytes by surface TNFR2 transfected into resting T cells induces TNF-alpha production due to reverse signaling by mTNF; and 5) ligation of mTNF on monocytes by a soluble TNFR2:Ig receptor construct induces TNF-alpha production due to reverse signaling. In conclusion, we identified mTNF and TNFR1/2 as interaction partners contributing to TNF-alpha production in monocytes. Both pathways initiated by mTNF-TNFR interaction are likely to be inhibited by treatment with anti-TNF-alpha Abs. 相似文献
127.
Hansen RK Christensen C Korshunova I Kriebel M Burkarth N Kiselyov VV Olsen M Ostergaard S Holm A Volkmer H Walmod PS Berezin V Bock E 《Journal of neurochemistry》2007,103(4):1396-1407
A combinatorial library of undecapeptides was produced and utilized for the isolation of peptide binding to the fibronectin type 3 modules (F3I–F3II) of the neural cell adhesion molecule (NCAM). The isolated peptides were sequenced and produced as dendrimers. Two of the peptides (denoted ENFIN2 and ENFIN11) were confirmed to bind to F3I–F3II of NCAM by surface plasmon resonance. The peptides induced neurite outgrowth in primary cerebellar neurons and PC12E2 cells, but had no apparent neuroprotective properties. NCAM is known to activate different intracellular pathways, including signaling through the fibroblast growth factor receptor, the Src-related non-receptor tyrosine kinase Fyn, and heterotrimeric G-proteins. Interestingly, neurite outgrowth stimulated by ENFIN2 and ENFIN11 was independent of signaling through fibroblast growth factor receptor and Fyn, but could be inhibited with pertussis toxin, an inhibitor of certain heterotrimeric G-proteins. Neurite outgrowth induced by trans- homophilic NCAM was unaffected by the peptides, whereas knockdown of NCAM completely abrogated ENFIN2- and ENFIN11-induced neuritogenesis. These observations suggest that ENFIN2 and ENFIN11 induce neurite outgrowth in an NCAM-dependent manner through G-protein-coupled signal transduction pathways. Thus, ENFIN2 and ENFIN11 may be valuable for exploring this particular type of NCAM-mediated signaling. 相似文献
128.
Wickramarachchi T Illeperuma RJ Perera L Bandara S Holm I Longacre S Handunnetti SM Udagama-Randeniya PV 《International journal for parasitology》2007,37(2):199-208
We report here, for the first time, a comparison of naturally acquired antibody responses to the 42 and 19 kDa C-terminal processing products of Plasmodium vivax Merozoite Surface Protein-1 assayed by ELISA using p42 and p19 baculovirus-derived recombinant proteins, respectively. Test populations comprised patients with microscopy confirmed acute P. vivax infections from two regions endemic for vivax malaria where low transmission and unstable malaria conditions prevail, and a non-endemic urban area, in Sri Lanka. The antibody prevalence to the two proteins, both at the individual and population levels, tend to respond more to p42 than to p19 in all test areas, where >14% of individuals preferentially recognized p42, compared with <2% for p19. In patients with no previous exposure to malaria, 21% preferentially recognized p42, whereas none exclusively recognized p19. A significantly lower prevalence of anti-p19 IgM, but not anti-p42 IgM, was observed among residents from endemic areas compared with their non-endemic counterparts. Individuals from both endemic areas produced significantly less anti-p19 IgM compared with anti-p42 IgM. IgG1 was the predominant IgG isotype for both antigens in all individuals. With increasing exposure to malaria in both endemic areas, anti-p19 antibody responses were dominated by the functionally important IgG1 and IgG3 isotypes, with a concurrent reduction in IgM that was lacking in the non-endemic residents. This antibody switch was also reflected for PvAMA-1 as we previously reported with the identical battery of sera. In contrast, the antibody switch for p42 was restricted to endemic residents with more extensive exposure. These results suggest that an IgM-dominated antibody response against the p42 polymorphic region in endemic residents may interfere with the development of an IgG-dominated "protective" isotype shift to p19, that may complicate vaccine development. 相似文献
129.
Cohn RD van Erp C Habashi JP Soleimani AA Klein EC Lisi MT Gamradt M ap Rhys CM Holm TM Loeys BL Ramirez F Judge DP Ward CW Dietz HC 《Nature medicine》2007,13(2):204-210
Skeletal muscle has the ability to achieve rapid repair in response to injury or disease. Many individuals with Marfan syndrome (MFS), caused by a deficiency of extracellular fibrillin-1, exhibit myopathy and often are unable to increase muscle mass despite physical exercise. Evidence suggests that selected manifestations of MFS reflect excessive signaling by transforming growth factor (TGF)-beta (refs. 2,3). TGF-beta is a known inhibitor of terminal differentiation of cultured myoblasts; however, the functional contribution of TGF-beta signaling to disease pathogenesis in various inherited myopathic states in vivo remains unknown. Here we show that increased TGF-beta activity leads to failed muscle regeneration in fibrillin-1-deficient mice. Systemic antagonism of TGF-beta through administration of TGF-beta-neutralizing antibody or the angiotensin II type 1 receptor blocker losartan normalizes muscle architecture, repair and function in vivo. Moreover, we show TGF-beta-induced failure of muscle regeneration and a similar therapeutic response in a dystrophin-deficient mouse model of Duchenne muscular dystrophy. 相似文献
130.
Alkaline copper quaternary (ACQ) Type D is one of several compounds currently being used as a chemical preservative to treat wood for prevention of rot and decay. As wood weathers naturally, human exposure to ACQ might occur through dermal contact or incidental ingestion of residues from the wood surface. To understand any potential for health risks from the use of ACQ-treated wood, a health-based evaluation was undertaken on the primary components of ACQ, which are copper, didecyl dimethyl ammonium carbonate, 2-methyl-4-isothiazolin-3-one, and 5-chloro-2-methyl-4-isothiazolin-3-one. For these components, there are no formalized toxicity values in USEPA's Integrated Risk Information System, although extensive toxicity data are available in the scientific literature. Therefore, health-based toxicity benchmarks were derived from a review of existing toxicity data. The exposure assessment was based on methods developed by the Consumer Product Safety Commission in their evaluation of the potential for children's exposure to arsenic from wood treated with chromated copper arsenate. This approach entailed wipe testing the surface of treated wood to determine the amount of chemical that might be removed from the wood, and estimating the amount of chemical that a child might contact via the dermal route or incidental ingestion through hand-to-mouth activities. All calculated exposure estimates were well below toxicity benchmarks. 相似文献