Exposure reconstruction for reducing uncertainty in risk assessment: example using MTBE biomarkers and a simple pharmacokinetic model

Adverse health risks from environmental agents are generally related to average (long-term) exposures. Because a given individual's contact with a pollutant is highly variable and dependent on activity patterns, local sources and exposure pathways, simple 'snapshot' measurements of surrounding environmental media may not accurately assign the exposure level. Furthermore, susceptibility to adverse effects from contaminants is considered highly variable in the population so that even similar environmental exposure levels may result in differential health outcomes in different individuals. The use of biomarker measurements coupled to knowledge of rates of uptake, metabolism and elimination has been suggested as a remedy for reducing this type of uncertainty. To demonstrate the utility of such an approach, we invoke results from a series of controlled human exposure tests and classical first-order rate kinetic calculations to estimate how well spot measurements of methyl tertiary butyl ether and the primary metabolite, tertiary butyl alcohol, can be expected to predict different hypothetical scenarios of previous exposures. We found that blood and breath biomarker measurements give similar results and that the biological damping effect of the metabolite production gives more stable estimates of previous exposure. We also explore the value of a potential urinary biomarker, 2-hydroxyisobutyrate suggested in the literature. We find that individual biomarker measurements are a valuable tool in reconstruction of previous exposures and that a simple pharmacokinetic model can identify the time frames over which an exogenous chemical and the related chemical biomarker are useful. These techniques could be applied to broader ranges of environmental contaminants to assess cumulative exposure risks if ADME (Absorption, Distribution, Metabolization and Excretion) is understood and systemic biomarkers can be measured.     

Birth-death symmetry in the evolution of a social trait

Studies of the evolution of a social trait often make ecological assumptions (of population structure, life history), and thus a trait can be studied many different times with different assumptions. Here, I consider a Moran model of continuous reproduction and use an inclusive fitness analysis to investigate the relationships between fecundity or survival selection and birth-death (BD) or death-birth (DB) demography on the evolution of a social trait. A simple symmetry obtains: fecundity (respectively survival) effects under BD behave the same as survival (respectively fecundity) effects under DB. When these results are specialized to a homogeneous population, greatly simplified conditions for a positive inclusive fitness effect are obtained in both a finite and an infinite population. The results are established using the elegant formalism of mathematical group theory and are illustrated with an example of a finite population arranged in a cycle with asymmetric offspring dispersal.     

Nav1.5 mutations linked to dilated cardiomyopathy phenotypes

Na_v1.5 dysfunctions are commonly linked to rhythms disturbances that include type 3 long QT syndrome (LQT3), Brugada syndrome (BrS), sick sinus syndrome (SSS) and conduction defects. Recently, this channel protein has been also linked to structural heart diseases such as dilated cardiomyopathy (DCM).     

Prenatal stress decreases Bdnf expression and increases methylation of Bdnf exon IV in rats

There is ample evidence that exposure to stress during gestation increases the risk of the offspring to develop mood disorders. Brain-derived neurotrophic factor (Bdnf) plays a critical role during neuronal development and is therefore a prime candidate to modulate neuronal signaling in adult offspring of rat dams that were stressed during gestation. In the current study, we tested the hypothesis that alterations in Bdnf expression in prenatally stressed (PNS) offspring are mediated by changes in DNA methylation in exons IV and VI of the Bdnf gene. We observed decreased Bdnf expression in the amygdala and hippocampus of prenatally stressed rats both at weaning and in adulthood. This decrease in Bdnf expression was accompanied by increased DNA methylation in Bdnf exon IV in the amygdala and hippocampus, suggesting that PNS-induced reduction in Bdnf expression may, at least in part, be mediated by increased DNA methylation of Bdnf exon IV. Expression of DNA methyltransferases (Dnmt) 1 and 3a was increased in PNS rats in the amygdala and hippocampus. Our data suggest that PNS induces decreases in Bdnf expression that may at least in part be mediated by increased DNA methylation of Bdnf exon IV.     

Are we underestimating the genetic variances of dimorphic traits?

Populations often contain discrete classes or morphs (e.g., sexual dimorphisms, wing dimorphisms, trophic dimorphisms) characterized by distinct patterns of trait expression. In quantitative genetic analyses, the different morphs can be considered as different environments within which traits are expressed. Genetic variances and covariances can then be estimated independently for each morph or in a combined analysis. In the latter case, morphs can be considered as separate environments in a bivariate analysis or entered as fixed effects in a univariate analysis. Although a common approach, we demonstrate that the latter produces downwardly biased estimates of additive genetic variance and heritability unless the quantitative genetic architecture of the traits concerned is perfectly correlated between the morphs. This result is derived for four widely used quantitative genetic variance partitioning methods. Given that theory predicts the evolution of genotype‐by‐environment (morph) interactions as a consequence of selection favoring different trait combinations in each morph, we argue that perfect correlations between the genetic architectures of the different morphs are unlikely. A sampling of the recent literature indicates that the majority of researchers studying traits expressed in different morphs recognize this and do estimate morph‐specific quantitative genetic architecture. However, ca. 16% of the studies in our sample utilized only univariate, fixed‐effects models. We caution against this approach and recommend that it be used only if supported by evidence that the genetic architectures of the different morphs do not differ.     

我国不同地区烟蚜种群生殖特征研究

研究了我国4个地区3种生活史类型的烟蚜在烟草上的种群繁殖特征,并用Weibull模型对种群存活特征和生殖特征进行了分析。结果表明:25±1℃、14L:10D、70%±10%RH条件下,长春地区烟蚜的生殖前期和产仔高峰日分别为大于等于7d和第11d,而南京、湖南郴州和河南宜阳烟蚜的生殖前期和产仔高峰日分别为小于7d和第9d。烟蚜种群的R0、T和rm在同一地区不同体色之间以及不同地区同一体色之间均存在有差异显著性,平均寿命仅在不同地区的红色烟蚜和褐色烟蚜中有显著性差异,在黄绿色之间差异均不显著。     

Optimum reproduction and dispersal strategies of a clonal plant in a metapopulation: a simulation study with Hieracium pilosella

Clonal spread is favoured in many plants at the expense of seed production in order to expand rapidly into open habitats or to occupy space by forming dense patches. However, for the dynamics of a population in a patchy landscape seed dispersal remains important even for clonal plants. We used a spatially explicit individual-based metapopulation model to examine the consequences of two trade-offs in Hieracium pilosella L: first, between vegetative and sexual reproduction, and second, between short and far-distance dispersal of seeds. Our main question was, what are the environmental conditions that cause a mixed strategy of vegetative and sexual reproduction to be optimal. The model was parameterised with field data on local population dynamics of H. pilosella. Patch dynamics were given firstly by disturbance events that opened patches in a matrix of a clonal grass that were colonisable for H. pilosella, and secondly by the gradual disappearance of H. pilosella patches due to the expanding grass. Simulations revealed opposing selection pressures on traits determined by the two trade-offs. Vegetative reproduction is favoured by local dynamics, i.e. the need for maintenance and expansion of established populations, whereas seed production is favoured by the necessity to colonise empty habitats. Similar pressures act on the proportion of seeds dispersed over short and far distances. Optimum reproductive and dispersal strategies depended on habitat quality (determined by seedling establishment probability), the fraction of dispersed seeds, and the fraction of seeds lost on unsuitable ground. Under habitat conditions supporting moderate to low seedling establishment, between 20% and 40% of reproductive effort in H. pilosella should be devoted to sexual reproduction with at least 10% of the seeds dispersed over distances suitable to attain empty patches. We conclude that in a spatially heterogeneous landscape sexual seed production in a clonal plant is advantageous even at the expense of local vegetative growth.     

Animal models for basic and translational research in reconstructive transplantation

Reconstructive transplantation represents a bona fide option for select patients with devastating tissue loss, which could better restore the appearance, anatomy, and function than any other conventional treatment currently available. Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the potential side effects of chronic multidrug immunosuppression. Thus, any reconstructive measures to improve these non‐life‐threatening conditions must address a delicate balance of risks and benefits. Today, several exciting novel therapeutic strategies, such as the implementation of cellular therapies including bone marrow or stem cells that integrate the concepts of immune regulation with those of nerve regeneration, are on the horizon. The development of reliable and reproducible small andlarge animal models is essential for the study of the unique immunological and biological aspects of vascularized composite allografts and to translate such novel immunoregulatory and tolerance‐inducing strategies and therapeutic concepts from the bench to bedside. This review provides an overview of the multitude of small and largeanimal models that have been particularly designed for basicand translational research related to reconstructive transplantation. (Part C) 96:39–50, 2012. © 2012 Wiley Periodicals, Inc.     

Quantitative metrics of overlaps in Grinnellian niches: advances and possible drawbacks

Aim Studies of environmental niche shift/niche conservatism that are based on species distribution modelling require a quantification of niche purity and potential overlap. Although various metrics have been proposed for this task, no comparisons of their performance are available yet that express the linearity of range shifts and error‐proneness. Herein, we assess the performance of six niche overlap metrics using three sister pairs of plethodontid salamanders as well as artificial species to test for linearity of overlap curves, impacts of varying potential distribution sizes and study area sizes. Location North America, artificial environments. Methods Species distribution models for the salamanders were performed with Maxent , and artificial species were created in the R environment. Potential distributions of species with varying range sizes and extents of the study area were compared using the Bray–Curtis distance BC, Schoener's D, two different modifications of the Hellinger distance I_mod, I_cor, Pianka's O and Horn's R. Niche overlaps in ecological space were compared using linear discriminant analyses based on principal components. Results Simulations of niche overlaps revealed strong variations in the performance of the niche overlap metrics. In artificial species, BC and D performed best, followed by O, R and I_cor, but the modified Hellinger distance I_mod showed a nonlinear slope and a truncated range. Furthermore, the simulations suggest that, in proportionally small potential distributions on large grids, an inclusion of a high proportion of grid cells with low occurrence probabilities representing background noise may bias assessments of niche overlaps. Main conclusions Both the salamander examples and simulations suggest that Schoener's D and the Bray–Curtis distance BC are best suited to compute niche overlaps from potential distributions derived from species distribution models. However, like all analysed metrics, both D and BC are seriously affected by the inclusion of high numbers of grid cells where the species are probably absent, i.e. with low occurrence probabilities. Therefore, pre‐processing to eliminate background noise in the potential distribution grids is highly recommended.