A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region

In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A --> G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 x 10(-10).     

Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) 相似文献   

Human body temperature and new approaches to constructing temperature-sensitive bacterial vaccines

Many of the live human and animal vaccines that are currently in use are attenuated by virtue of their temperature-sensitive (TS) replication. These vaccines are able to function because they can take advantage of sites in mammalian bodies that are cooler than the core temperature, where TS vaccines fail to replicate. In this article, we discuss the distribution of temperature in the human body, and relate how the temperature differential can be exploited for designing and using TS vaccines. We also examine how one of the coolest organs of the body, the skin, contains antigen-processing cells that can be targeted to provoke the desired immune response from a TS vaccine. We describe traditional approaches to making TS vaccines, and highlight new information and technologies that are being used to create a new generation of engineered TS vaccines. We pay particular attention to the recently described technology of substituting essential genes from Arctic bacteria for their homologues in mammalian pathogens as a way of creating TS vaccines.     

Vegetation response to prescribed fire in Dinosaur National Monument

Much of western North America is dominated by dense, monotypic, late seral stands of big sagebrush ( Artemisia tridentata Nutt.). These stands often have depauperate understories with limited species richness, diversity, and herbaceous cover. The National Park Service at Dinosaur National Monument, Colorado, is using both strategic and natural prescribed fire in Wyoming big sagebrush ( Artemisia tridentata ssp. wyomingensis Beetle and Young) communities to foster intra-community (α -scale) and landscape diversity. This study analyzed an accumulated foliar cover data set between paired burn and control areas on 6 different sites during the last 20 years. Across the monitoring period, mean total vegetation cover of all combined sites was 44% control and 42% burn. Total vegetation cover in burn areas was higher than or equal to paired control areas within 2-3 years post-burn. Shrubs were essentially eliminated in burn areas, but perennial grass cover was 10-35% higher. Mean number of species on all sites and years combined was 17 control and 18 burn. Species richness was different on only 1 site-year, Dry Woman 1995 ( P = 0.001, 15 control, 9 burn). Species similarity by site and between treatments ranged from 44% to 75%. Differences in Shannon-Weiner diversity index values between paired sites occurred in 6 of 20 years ( P < 0.05). Index value differences on these 6 sites were due to a large annual grass component in burn areas. Prescribed burning successfully shifted late successional sagebrushdominated communities to earlier herbaceous-dominated successional stages without lowering total vegetation cover, while maintaining -scale diversity and species richness.     

MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis

The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans.     

A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrugresistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.     

Protein deprivation causes reversible impariment of mucosal immune response to cholera toxoid/toxin in rat gut

Scretory antibodies may be the major defence against mucosal infections, especially those due to viruses and non-invasive pathogens such as Vibrio cholerae and toxinogenic Escherichia coli. The high incidence of mucosal infections in malnourished protein-deficient children may result from defective antibody production, but evidence for this is conflicting. We report here that protein deficiency markedly impairs the mucosal immune reponse to cholera toxiod/toxin (CT), a protein antigen, in rats and that this impairment is rapidly reversed by refeeding.