Background/hypothesis HLA, INS, PTPN22 and CTLA4 are considered to be confirmed type 1 diabetes susceptibility genes. HLA, PTPN22 and CTLA4 are known to be involved in immune regulation. Few studies ...have systematically investigated the joint effect of multiple genetic variants. We evaluated joint effects of the four established genes on the risk of childhood-onset type 1 diabetes. Methods We genotyped 421 nuclear families, 1,331 patients and 1,625 controls for polymorphisms of HLA-DRB1, -DQA1 and -DQB1, the insulin gene (INS, -23 HphI), CTLA4 (JO27_1) and PTPN22 (Arg620Trp). Results The joint effect of HLA and PTPN22 on type 1 diabetes risk was significantly less than multiplicative in the case-control data, but a multiplicative model could not be rejected in the trio data. All other two-way gene-gene interactions fitted multiplicative models. The high-risk HLA genotype conferred a very high risk of type 1 diabetes (OR 20.6, using the neutral-risk HLA genotype as reference). When including also intermediate-risk HLA genotypes together with risk genotypes at the three non-HLA loci, the joint odds ratio was 61 (using non-risk genotypes at all loci as reference). Conclusion Most established susceptibility genes seem to act approximately multiplicatively with other loci on the risk of disease except for the joint effect of HLA and PTPN22. The joint effect of multiple susceptibility loci conferred a very high risk of type 1 diabetes, but applies to a very small proportion of the general population. Using multiple susceptibility genotypes compared with HLA genotype alone seemed to influence the prediction of disease only marginally.
The high radiation fields around the production target and the beam dump in the fragment separator at the Rare Isotope Accelerator requires that radiation resistant magnets be used. Because large ...apertures and high gradients are required for the quadrupoles and similar demanding requirements for the dipole and sextupoles, resistive coils are difficult to justify. The radiation heating of any materials at liquid helium temperatures also requires that superconducting versions of the magnets have low cold-masses. The final optical design has taken the practical magnets limits into account and sizes and fields adjusted to what is believed to be achievable with technology that is possible with sufficient R&D. Designs with higher obtainable current densities and having good radiation tolerances that use superconducting coils are presented, as well as the radiation transport calculations that drive the material parameters.
Avalanche photodiodes (APDs) are used in short- and mid-wave infrared applications such as optical communication, LIDAR and 3D imaging 1 due to their internal gain, which improves the signal to noise ...ratio (SNR). However, the multiplication gain ( M ) gives rise to excess noise, caused by the stochastic nature of impact ionization, which can significantly degrade the SNR of APDs. The excess noise is quantitatively measured by excess noise factor, F(M) that is expressed by McIntyre's local field theory 1 , F(M) = kM + (1-k)2-(1/M) where k is the ratio of the impact ionization coefficients for electrons and holes. According to the equation above, the low excess noise factor in APDs can be attained by a low k value.
In humans, cardiovascular disease begins in young adulthood and is more prevalent in males than females. However, little is known about vascular function during transition to adulthood in males. The ...aim of this study was to define changes in production of endothelium-derived nitric oxide (NO) and coronary arterial responses during puberty. Plasma was collected from juvenile (2-3 mo of age) and adult (5-6 mo of age) male pigs (n = 8/group) for measurement of NO, and aortic endothelial cells were collected for measurement of mRNA and protein for endothelial NO synthase (eNOS). Although plasma NO was higher in juvenile (67.0 +/- 25.6 microM) than in adult (15.0 +/- 7.1 microM) male pigs, eNOS protein was similar in both groups. However, levels of mRNA for eNOS were lower in aortic endothelial cells from juvenile pigs. In rings of coronary arteries suspended in organ chambers for measurement of isometric force and contracted with PGF2alpha, relaxations to an alpha2-adrenergic agonist were significantly inhibited by indomethacin only in juvenile pigs EC50 (-log M), 6.7 +/- 0.3 with indomethacin and 7.7 +/- 0.3 under control conditions. NG-monomethyl-l-arginine (l-NMMA) inhibited relaxations in both groups. On the contrary, in the presence of indomethacin, relaxations to bradykinin were inhibited by l-NMMA only in arteries from adult pigs EC50 (-log M), 8.9 +/- 0.3 with indomethacin and 8.6 +/- 0.3 with addition of l-NMMA. These results suggest that hormonal changes associated with sexual maturity may affect posttranscriptional and/or translational regulation of eNOS protein and result in lower plasma NO in adult male pigs. In addition, endothelium-derived inhibitory cyclooxygenase products seem to predominate in juveniles.
To support pre-conceptual research and development for rare isotope beam production via projectile fragmentation at the Rare-Isotope Accelerator facility or similar next-generation exotic beam ...facilities, the interactions between primary beams and beryllium and liquid-lithium production targets in the fragment pre- separator area were simulated using the Monte-Carlo radiation transport code PHITS. The purpose of this simulation is to determine the magnitude of the radiation fields in the pre-separator area so that levels of hadron flux and energy deposition can be obtained. It was of particular interest to estimate the maximum radiation doses to magnet coils and other components such as the electromagnetic pump for a liquid-lithium loop, and to estimate component lifetimes.
Yields of neutron-rich and other ions in the region of 10≤
Z≤30, produced by a 30
MeV/u
136Xe
24+ beam on a thick
natC target, are presented. The ions were collected and identified with the ...University of Michigan 7-Tesla solenoid device `BigSol' at 1.36
Tm. The yields are sufficient to make feasible gamma- and/or beta-decay studies of lifetimes and nuclear structure at the solenoid's focal position, or alternately with the fragments transported away for low-background studies. Small but usable amounts of ions close to or including the most n-rich ions produced anywhere to-date are produced and it is shown that if particle-by-particle identification is not continuously required, that the yields may be increased by over two orders of magnitude.
In a pooled analysis of samples from ten autoimmune diseases, Surolia et al. identified 12 distinct nonsynonymous SIAE risk variant genotypes present in 24 of 923 affected persons (2.60%) versus 2 of ...648 controls (0.31%; P = 0.0002; odds ratio of 8.6) that the authors considered to be "functionally defective SIAE alleles" because they result in defects in either esterase activity or secretion1.
Vascular function changes following loss of ovarian hormones in women at menopause and in experimental animals following surgical ovariectomy. Little is known about changes in vascular function ...during hormonal transition from sexual immaturity (juvenile) to sexual maturity. Therefore, experiments were designed to determine effects of natural puberty on vascular function in female pigs. Tissue was studied from eight juvenile (2-3 mo) and eight adult (5-6 mo) female pigs. Plasma nitric oxide (NO) was measured, and mRNA for endothelium-derived NO synthase (eNOS) and eNOS protein were determined in aortic endothelial cells. Rings of coronary arteries were suspended for measurement of isometric force in organ chambers. Serum 17beta-estradiol levels were comparable in the two groups, whereas the arithmetic mean of progesterone levels was about two-thirds lower in adults compared with juvenile pigs. Plasma NO was significantly higher in juveniles compared with adults, but mRNA and protein for eNOS were comparable. In coronary arteries, an alpha2-adrenergic agonist caused greater endothelium-dependent relaxations in rings from juvenile compared with adult pigs. Relaxations to bradykinin were similar in arteries from both groups, but inhibition of NO reduced relaxations only in arteries from juvenile pigs. Relaxations from NO were greater in arteries from adult compared with juvenile female pigs. In conclusion, coronary arterial endothelial and smooth muscle responses are selectively modulated at puberty in female pigs. At maturity, plasma NO is reduced and sensitivity of the smooth muscle to exogenous NO is increased. Posttranscriptional regulation of eNOS protein may explain differences in NO bioavailability in juvenile pigs.
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