On the use of sibling recurrence risks to select environmental factors liable to interact with genetic risk factors

Gene–environment interactions are likely to be involved in the susceptibility to multifactorial diseases but are difficult to detect. Available methods usually concentrate on some particular genetic and environmental factors. In this paper, we propose a new method to determine whether a given exposure is susceptible to interact with unknown genetic factors. Rather than focusing on a specific genetic factor, the degree of familial aggregation is used as a surrogate for genetic factors. A test comparing the recurrence risks in sibs according to the exposure of indexes is proposed and its power is studied for varying values of model parameters. The Exposed versus Unexposed Recurrence Analysis (EURECA) is valuable for common diseases with moderate familial aggregation, only when the role of exposure has been clearly outlined. Interestingly, accounting for a sibling correlation for the exposure increases the power of EURECA. An application on a sample ascertained through one index affected with type 2 diabetes is presented where gene–environment interactions involving obesity and physical inactivity are investigated. Association of obesity with type 2 diabetes is clearly evidenced and a potential interaction involving this factor is suggested in Hispanics (P=0.045), whereas a clear gene–environment interaction is evidenced involving physical inactivity only in non-Hispanic whites (P=0.028). The proposed method might be of particular interest before genetic studies to help determine the environmental risk factors that will need to be accounted for to increase the power to detect genetic risk factors and to select the most appropriate samples to genotype.     

Genetic structure and variability of virus populations in cross-protected grapevines superinfected by Grapevine fanleaf virus

Recombination was assessed in a vineyard site in which grapevines cross-protected with mild strains GHu of Grapevine fanleaf virus (GFLV) or Ta of Arabis mosaic virus (ArMV) were superinfected with GFLV field isolates following transmission by the nematode vector Xiphinema index. The genetic structure and variability within RNA2 of isolates from grapevines co-infected with GFLV field isolates and either GFLV-GHu or ArMV-Ta were characterized to identify intra- and interspecies recombinants. Sequence analysis and phylogenetic relationships inferred intraspecies recombination among GFLV field isolates but not between field isolates and GFLV-GHu. SISCAN analysis confirmed a mosaic structure for two GFLV field isolates for which recombination sites were located in the movement protein and coat protein genes. One of the recombinants was found in eight grapevines that were in close spatial proximity within the vineyard site, suggesting its transmission by X. index. No interspecies recombination was detected between GFLV field isolates and ArMV-Ta. Altogether, our findings suggest that mild protective strains GFLV-GHu and ArMV-Ta did not assist the emergence of viable recombinants to detectable level during a 12-year cross-protection trial. To our knowledge, this is the first extensive characterization of the genetic structure and variability of virus isolates in cross-protected plants.     

Post-PKS Tailoring Steps of the Spiramycin Macrolactone Ring in Streptomyces ambofaciens

Spiramycins are clinically important 16-member macrolide antibiotics produced by Streptomyces ambofaciens. Biosynthetic studies have established that the earliest lactonic intermediate in spiramycin biosynthesis, the macrolactone platenolide I, is synthesized by a type I modular polyketide synthase (PKS). Platenolide I then undergoes a series of post-PKS tailoring reactions yielding the final products, spiramycins I, II, and III. We recently characterized the post-PKS glycosylation steps of spiramycin biosynthesis in S. ambofaciens. We showed that three glycosyltransferases, Srm5, Srm29, and Srm38, catalyze the successive attachment of the three carbohydrates mycaminose, forosamine, and mycarose, respectively, with the help of two auxiliary proteins, Srm6 and Srm28. However, the enzymes responsible for the other tailoring steps, namely, the C-19 methyl group oxidation, the C-9 keto group reduction, and the C-3 hydroxyl group acylation, as well as the timing of the post-PKS tailoring reactions, remained to be established. In this study, we show that Srm13, a cytochrome P450, catalyzes the oxidation of the C-19 methyl group into a formyl group and that Srm26 catalyzes the reduction of the C-9 keto group, and we propose a timeline for spiramycin-biosynthetic post-PKS tailoring reactions.     

Virtual Partner Interaction (VPI): Exploring Novel Behaviors via Coordination Dynamics

Inspired by the dynamic clamp of cellular neuroscience, this paper introduces VPI—Virtual Partner Interaction—a coupled dynamical system for studying real time interaction between a human and a machine. In this proof of concept study, human subjects coordinate hand movements with a virtual partner, an avatar of a hand whose movements are driven by a computerized version of the Haken-Kelso-Bunz (HKB) equations that have been shown to govern basic forms of human coordination. As a surrogate system for human social coordination, VPI allows one to examine regions of the parameter space not typically explored during live interactions. A number of novel behaviors never previously observed are uncovered and accounted for. Having its basis in an empirically derived theory of human coordination, VPI offers a principled approach to human-machine interaction and opens up new ways to understand how humans interact with human-like machines including identification of underlying neural mechanisms.     

Bacterial adhesion to conventional hydrogel and new silicone-hydrogel contact lens materials

Background As bacterial adhesion to contact lenses may contribute to the pathogenesis of keratitis, the aim of our study was to investigate in vitro adhesion of clinically relevant bacteria to conventional hydrogel (standard HEMA) and silicone-hydrogel contact lenses using a bioluminescent ATP assay. Methods Four types of unworn contact lenses (Etafilcon A, Galyfilcon A, Balafilcon A, Lotrafilcon B) were incubated with Staphylococcus epidermidis (two different strains) and Pseudomonas aeruginosa suspended in phosphate buffered saline (PBS). Lenses were placed with the posterior surface facing up and were incubated in the bacterial suspension for 4 hours at 37°C. Bacterial binding was then measured and studied by bioluminescent ATP assay. Six replicate experiments were performed for each lens and strain. Results Adhesion of all species of bacteria to standard HEMA contact lenses (Etafilcon A) was found to be significantly lower than that of three types of silicone-hydrogel contact lenses, whereas Lotrafilcon B material showed the highest level of bacterial binding. Differences between species in the overall level of adhesion to the different types of contact lenses were observed. Adhesion of P. aeruginosa was typically at least 20 times greater than that observed with both S. epidermidis strains. Conclusions Conventional hydrogel contact lenses exhibit significantly lower bacterial adhesion in vitro than silicone-hydrogel ones. This could be due to the greater hydrophobicity but also to the higher oxygen transmissibility of silicone–hydrogel lenses. A minor part of this work was presented at the 2006 CLAO Congress.     

Cancer risk associated with household exposure to chloroform

Chloroform (CHCl3) the trihalomethane most prevalent in drinking water, is a proven animal carcinogen and a suspected human carcinogen. Consequently, standards have been issued by health authorities to limit its concentration in drinking water. These limits are based solely on ingestion, without taking into account inhalation and skin contact. Exposure to CHCl3 was assessed for 18 men (age: mean 38 years; range 23-51) following a 10-min shower in their respective residences located in the Quebec City region (Canada). CHCl3 concentration was measured in alveolar air samples collected before, immediately after, and 15 min and 30 min following the shower. Indoor air and water concentrations were determined concomitantly. Mean CHCl3 concentrations in the air of the shower stall and in water were respectively 147 microg/m3 (SD = 56.2 microg/m3) and 20.1 microg/L (SD = 9.0 microg/L). Water concentrations were comparable to those documented in a large proportion of distribution networks in Canada. The mean increase in alveolar air CHCl3 concentration (deltaCHCIALV) at the end of the shower was 33 microg/m3 (SD = 14.7 microg/m3). A multiple-regression analysis revealed that deltaCHCl3ALV values were only associated with chloroform concentration in air of the shower stall. DeltaCHCl3ALV were described using a physiologically based pharmacokinetic (PBPK) model. This model was then used to estimate concentrations of CHCl3 metabolites bound to liver and kidney macromolecules following a shower, and also according to exposure scenarios that integrate drinking-water ingestion and air inhalation. The concentration predicted in the liver following a worst-case exposure scenario was 0.41 microg CHCl3 equivalents/kg of tissue, some 6,000 times lower than the lowest concentration that did not increase the incidence of hepatic tumors in laboratory animals. Data indicate that for this range of exposure the safety margin appears therefore considerable with respect to the potential carcinogenic effect of household exposure to CHCl3.