Reduced MHC variation in a threatened tuatara species

The relationship between neutral and adaptive genetic diversity is important to understand in assessing the implications of a population bottleneck. Fitness-related genes, such as those of the major histocompatibility complex (MHC), may be influenced by selection, and so retain diversity even when it is lost at neutral markers. We measured MHC class I variation in an archaic reptile species Sphenodon guntheri [North Brother Island (NBI) tuatara], which naturally occurs on one 4 ha island in Cook Strait, New Zealand, and has low levels of microsatellite diversity. MHC variation in S. guntheri was compared with microsatellite DNA variation, and with MHC variation in a large population of Sphenodon punctatus (Cook Strait tuatara) on Stephens Island. The NBI population shows significantly decreased levels of genetic diversity compared with the Stephens Island population. Only three different MHC sequences and three genotypes were found on NBI, compared with 15 sequences and 21 genotypes in a similar sample size from Stephens Island. Two sequences appear to be unique to the NBI population. The assortment of sequence variants into genotypes suggests strong gametic disequilibrium between two MHC class I loci in S. guntheri , and only two haplotypes that were present in Hardy–Weinberg proportions were identified. MHC diversity in NBI tuatara appears to be largely influenced by genetic drift, consistent with a recent population bottleneck. This may compromise the ability of this population to respond to novel disease threats.     

Genome‐wide analysis of TNF‐alpha response in pigs challenged with porcine circovirus 2b

Tumor necrosis factor alpha (TNF‐α) is a pro‐inflammatory cytokine with a role in activating adaptive immunity to viral infections. By inhibiting the capacity of plasmacytoid dendritic cells to produce interferon‐α and TNF‐α, porcine circovirus 2 (PCV2) limits the maturation of myeloid dendritic cells and impairs their ability to recognize viral and bacterial antigens. Previously, we reported QTL for viremia and immune response in PCV2‐infected pigs. In this study, we analyzed phenotypic and genetic relationships between TNF‐α protein levels, a potential indicator of predisposition to PCV2 co‐infection, and PCV2 susceptibility. Following experimental challenge with PCV2b, TNF‐α reached the peak at 21 days post‐infection (dpi), at which time a difference was observed between pigs that expressed extreme variation in viremia and growth (P < 0.10). A genome‐wide association study (n = 297) revealed that genotypes of 56 433 SNPs explained 73.9% of the variation in TNF‐α at 21 dpi. Major SNPs were identified on SSC8, SSC10 and SSC14. Haplotypes based on SNPs from a SSC8 (9 Mb) 1‐Mb window were associated with variation in TNF‐α (P < 0.02), IgG (P = 0.05) and IgM (P < 0.13) levels at 21 dpi. Potential overlap of regulatory mechanisms was supported by the correlations between genomic prediction values of TNF‐α and PCV2 antibodies (21 dpi, r > 0.22), viremia (14–21 dpi, P > 0.29) and viral load (r = 0.31, P < 0.0001). Characterization of the QTL regions uncovered genes that could influence variation in TNF‐α levels as well as T‐ and B‐cell development, which can affect disease susceptibility.     

Risk modulation of GSTM1–GSTT1 interactions to head and neck cancer in tobacco users

Tobacco use and environmental air pollution are the established etiological factors in head and neck cancer (HNC) progression. Nevertheless, not all the inhabitants with high usage of tobacco from the same polluted locality are suffering with HNC and this is due to the existence of factors like inter-individual genetic polymorphisms, life time exposure to tobacco and the rate of xenobiotic metabolism enzyme (XME) activity. The present study investigates the polymorphic genotypes of the most important XME, glutathione-S-transferase Mu 1 (GST M1) and Theta 1 (GST T1) as the risk modulator to HNC among tobacco-habituated inhabitants of Saurashtra in Gujarat, a region in western India. A population based case–control study was done in 252 HNC patients and 504 healthy controls. Blood samples were collected from the subjects and investigated for polymorphic genotypes of GST M1 and GST T1. Estimation of the odds of risks was done by logistic regressions. Among the subjects with high usage of tobacco, M1 not null-T1 null genotypes presence was found as risk reducing factor to HNC with 0.334 folds (95 % CI; 0.170–0.659). The presence of M1 null-T1 not null genotypes was found with susceptibility to HNC among the subjects with no habit of tobacco chewing, adjusted odds ratio (AOR) 3.170 (1.128–8.913) and no habit of smoking, AOR of 2.544 (1.094–5.963). The present study reveals the finding of significantly increased risk to HNC by interactions of GST M1 null-GST T1 not null polymorphic genotypes among the subjects with nil or less tobacco usage shed some light for the insights of biomarker application in early detection of HNC.     

V‐antigen homologs in pathogenic gram‐negative bacteria

Gram‐negative bacteria cause many types of infections in animals from fish and shrimps to humans. Bacteria use Type III secretion systems (TTSSs) to translocate their toxins directly into eukaryotic cells. The V‐antigen is a multifunctional protein required for the TTSS in Yersinia and Pseudomonas aeruginosa. V‐antigen vaccines and anti‐V‐antigen antisera confer protection against Yersinia or P. aeruginosa infections in animal models. The V‐antigen forms a pentameric cap structure at the tip of the Type III secretory needle; this structure, which has evolved from the bacterial flagellar cap structure, is indispensable for toxin translocation. Various pathogenic gram‐negative bacteria such as Photorhabdus luminescens, Vibrio spp., and Aeromonas spp. encode homologs of the V‐antigen. Because the V‐antigens of pathogenic gram‐negative bacteria play a key role in toxin translocation, they are potential therapeutic targets for combatting bacterial virulence. In the USA and Europe, these vaccines and specific antibodies against V‐antigens are in clinical trials investigating the treatment of Yersinia or P. aeruginosa infections. Pathogenic gram‐negative bacteria are of great interest because of their ability to infect fish and shrimp farms, their potential for exploitation in biological terrorism attacks, and their ability to cause opportunistic infections in humans. Thus, elucidation of the roles of the V‐antigen in the TTSS and mechanisms by which these functions can be blocked is critical to facilitating the development of improved anti‐V‐antigen strategies.     

Rapid Antiretroviral Therapy Initiation for Women in an HIV-1 Prevention Clinical Trial Experiencing Primary HIV-1 Infection during Pregnancy or Breastfeeding

During an HIV-1 prevention clinical trial in East Africa, we observed 16 cases of primary HIV-1 infection in women coincident with pregnancy or breastfeeding. Nine of eleven pregnant women initiated rapid combination antiretroviral therapy (ART), despite having CD4 counts exceeding national criteria for ART initiation; breastfeeding women initiated ART or replacement feeding. Rapid ART initiation during primary HIV-1 infection during pregnancy and breastfeeding is feasible in this setting.     

Sample Size Determination for Grouped Exponential Observations: A Cost Function Approach

Calculating the required sample size for a desired power at a given type I error level, we often assume that we know the exact time of all subject responses whenever they occur during our study period. It is very common, however, in practice that we only monitor subjects periodically and, therefore, we know only whether responses occur or not during an interval. This paper includes a quantitative discussion of the effect resulting from data grouping or interval censoring on the required sample size when we have two treatment groups. Furthermore, with the goal of exploring the optimum in the number of subjects, the number of examinations per subject for test responses, and the total length of a study time period, this paper also provides a general guideline about how to determine these to minimize the total cost of a study for a desired power at a given α-level. A specified linear cost function that incorporates the costs of obtaining subjects, periodic examinations for test responses of subjects, and the total length of a study period, is assumed, primarily for illustrative purpose.