Dislocation structures and the role of grain boundaries in cyclically deformed Ni micropillars

Transmission electron microscopy and finite element-based dislocation simulations were combined to study the development of dislocation microstructures after cyclic deformation of single crystal and bicrystal Ni micropillars oriented for multi-slip. A direct correlation between large accumulation of plastic strain and the presence of dislocation cell walls in the single crystal micropillars was observed, while the presence of the grain boundary hampered the formation of wall-like structures in agreement with a smaller accumulated plastic strain. Automated crystallographic orientation and nanostrain mapping using transmission electron microscopy revealed the presence of lattice heterogeneities associated to the cell walls including long range elastic strain fields. By combining the nanostrain mapping with an inverse modelling approach, information about dislocation density, line orientation and Burgers vector direction was derived, which is not accessible otherwise in such dense dislocation structures. Simulations showed that the image forces associated with the grain boundary in this specific bicrystal configuration have only a minor influence on dislocation behavior. Thus, the reduced occurrence of “mature” cell walls in the bicrystal can be attributed to the available volume, which is too small to accommodate cell structures

Estimation of toxicity of chemical mixtures through modeling of chemical interactions.

The Agency for Toxic Substances and Disease Registry (ATSDR), in collaboration with the Dutch Organization for Applied Scientific Research (TNO) Nutrition and Food Research Institute, is conducting studies to evaluate the role of chemical interactions in the expression of toxicity from low-level exposure to combinations of chemicals. The goal of this collaborative effort is to use a weight-of-evidence (WOE) approach to estimate joint toxicity of some simple chemical mixtures and to compare the estimations with test results from animal toxicity studies. The WOE approach uses individual chemical dose-response assessments and algorithms that incorporate various assumptions regarding potential chemical interactions. Qualitative evaluations were prepared for binary combinations of chemicals for the effect of butyl hydroxyanisole on di(2-ethylhexyl)phthalate, the effect of stannous chloride on Cd chloride (CdCl2), and the effect of CdCl2 on loperamide. Analyses of these evaluations and their comparison with the conclusions of laboratory animal experiments indicate that the WOE approach can be used to estimate qualitatively the joint toxicity of such simple mixtures. To further test the utility of the WOE approach, qualitative and semiquantitative evaluations were prepared for two chemical mixtures--one with similarly acting halogenated aliphatics (trichloroethylene, tetrachloroethylene, hexachloro-1,3-butadiene[HCBD], and 1,1,2-trichloro-3,3,3-trifluoropropene [TCTFP]) and the other with dissimilarly acting nephrotoxic components (mercuric chloride, lysinolalanine, D-limonene, and HCBD). These two sets of data were used to estimate the overall toxicities of the mixtures using the WOE algorithm for the mixture. The comparison of the results of the estimated toxicity with experimentally determined toxicity of the mixture of similarly acting nephrotoxicants demonstrated that the WOE approach correctly adjusted for the observed interactions in experimental animal studies. However, this was not true for the mixture of dissimilarly acting nephrotoxicants. This could be attributed to the fact that WOE evaluations are based on dose additivity that postulates that all chemicals in a given mixture act in the same way--by the same mechanism--and differ only in their potencies. In these cases the WOE approach evaluations, based on consideration of common mechanisms for simple chemical mixtures, can lead to better estimates of joint toxicity of chemical mixtures than the default assumption of dose additivity. The results also show that the WOE evaluations should be target-organ specific because none of the models tested could approximate the observed responses in organs other than the target organs in the laboratory animal studies

Blumenols as shoot markers of root symbiosis with arbuscular mycorrhizal fungi.

High-through-put (HTP) screening for functional arbuscular mycorrhizal fungi (AMF)-associations is challenging because roots must be excavated and colonization evaluated by transcript analysis or microscopy. Here we show that specific leaf-metabolites provide broadly applicable accurate proxies of these associations, suitable for HTP-screens. With a combination of untargeted and targeted metabolomics, we show that shoot accumulations of hydroxy- and carboxyblumenol C-glucosides mirror root AMF-colonization in Nicotiana attenuata plants. Genetic/pharmacologic manipulations indicate that these AMF-indicative foliar blumenols are synthesized and transported from roots to shoots. These blumenol-derived foliar markers, found in many di- and monocotyledonous crop and model plants (Solanum lycopersicum, Solanum tuberosum, Hordeum vulgare, Triticum aestivum, Medicago truncatula and Brachypodium distachyon), are not restricted to particular plant-AMF interactions, and are shown to be applicable for field-based QTL mapping of AMF-related genes

Pests, pesticide use and alternative options in European maize production: current status and future prospects

Political efforts are made in the European Union (EU) to reduce pesticide use and to increase the implementation of integrated pest management (IPM). Within the EU project ENDURE, research priorities on pesticide reduction are defined. Using maize, one of the most important crops in Europe, as a case study, we identified the most serious weeds, arthropod pests, and fungal diseases as well as classes and amounts of pesticides applied. Data for 11 European maize growing regions were collected from databases, publications and expert estimates. Silage maize dominates in northern Europe and grain production in central and southern Europe. Crop rotations range from continuous growing of maize over several years to well-planned rotation systems. Weeds, arthropod pests and fungal diseases cause economic losses in most regions, even though differences exist between northern countries and central and southern Europe. Several weed and arthropod species cause increasing problems, illustrating that the goal of reducing chemical pesticide applications is challenging. Pesticides could potentially be reduced by the choice of varieties including genetically modified hybrids, cultural control including crop rotation, biological control, optimized application techniques for chemicals, and the development of more specific treatments. However, restrictions in the availability of alternative pest control measures, farm organization, and the training and knowledge of farmers need to be overcome before the adoption of environmentally friendly pest control strategies can reduce chemical pesticides in an economically competitive way. The complex of several problems that need to be tackled simultaneously and the link between different control measures demonstrates the need for IPM approaches, where pest control is seen in the context of the cropping system and on a regional scale. Multicriteria assessments and decision support systems combined with pest monitoring programs may help to develop region-specific and sustainable strategies that are harmonized within a EU framework

Increased maternal and fetal cholesterol efflux capacity and placental cyp27a1 expression in pre-eclampsia

Preeclampsia is a pregnancy-specific condition that leads to increased cardiovascular risk in later life. A decrease in cholesterol efflux capacity is linked to CVD. We hypothesized that in preeclampsia there would be a disruption of maternal/fetal plasma to efflux cholesterol, as well as differences in the concentrations of both placental sterol 27-hydroxylase (CYP27A1) and apoA1 binding protein (AIBP). Total, HDL-, and ABCA1-mediated cholesterol effluxes were performed with maternal and fetal plasma from women with preeclampsia and normotensive controls (both n = 17). apoA1 and apoE were quantified by chemiluminescence, and 27-hydroxycholesterol (27-OHC) by GC-MS. Immunohistochemistry was used to determine placental expression/localization of CYP27A1, AIBP, apoA1, apoE, and SRB1. Maternal and fetal total and HDL-mediated cholesterol efflux capacities were increased in preeclampsia (by 10–20%), but ABCA1-mediated efflux was decreased (by 20–35%; P < 0.05). Maternal and fetal apoE concentrations were higher in preeclampsia. Fetal plasma 27-OHC levels were decreased in preeclamptic samples (P < 0.05). Placental protein expression of both CYP27A1 and AIBP were localized around fetal vessels and significantly increased in preeclampsia (P = 0.04). Placental 27-OHC concentrations were also raised in preeclampsia (P < 0.05). Increased HDL-mediated cholesterol efflux capacity and placental CYP27A1/27-OHC could be a rescue mechanism in preeclampsia, to remove cholesterol from cells to limit lipid peroxidation and increase placental angiogenesis

Meeting Report: Validation of Toxicogenomics-Based Test Systems: ECVAM–ICCVAM/NICEATM Considerations for Regulatory Use

This is the report of the first workshop “Validation of Toxicogenomics-Based Test Systems” held 11–12 December 2003 in Ispra, Italy. The workshop was hosted by the European Centre for the Validation of Alternative Methods (ECVAM) and organized jointly by ECVAM, the U.S. Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM), and the National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative Toxicological Methods (NICEATM). The primary aim of the workshop was for participants to discuss and define principles applicable to the validation of toxicogenomics platforms as well as validation of specific toxicologic test methods that incorporate toxicogenomics technologies. The workshop was viewed as an opportunity for initiating a dialogue between technologic experts, regulators, and the principal validation bodies and for identifying those factors to which the validation process would be applicable. It was felt that to do so now, as the technology is evolving and associated challenges are identified, would be a basis for the future validation of the technology when it reaches the appropriate stage. Because of the complexity of the issue, different aspects of the validation of toxicogenomics-based test methods were covered. The three focus areas include a) biologic validation of toxicogenomics-based test methods for regulatory decision making, b) technical and bioinformatics aspects related to validation, and c) validation issues as they relate to regulatory acceptance and use of toxicogenomics-based test methods. In this report we summarize the discussions and describe in detail the recommendations for future direction and priorities

An update on the strategies in multicomponent activity monitoring within the phytopharmaceutical field

<p>Abstract</p> <p>Background</p> <p>To-date modern drug research has focused on the discovery and synthesis of single active substances. However, multicomponent preparations are gaining increasing importance in the phytopharmaceutical field by demonstrating beneficial properties with respect to efficacy and toxicity.</p> <p>Discussion</p> <p>In contrast to single drug combinations, a botanical multicomponent therapeutic possesses a complex repertoire of chemicals that belong to a variety of substance classes. This may explain the frequently observed pleiotropic bioactivity spectra of these compounds, which may also suggest that they possess novel therapeutic opportunities. Interestingly, considerable bioactivity properties are exhibited not only by remedies that contain high doses of phytochemicals with prominent pharmaceutical efficacy, but also preparations that lack a sole active principle component. Despite that each individual substance within these multicomponents has a low molar fraction, the therapeutic activity of these substances is established via a potentialization of their effects through combined and simultaneous attacks on multiple molecular targets. Although beneficial properties may emerge from such a broad range of perturbations on cellular machinery, validation and/or prediction of their activity profiles is accompanied with a variety of difficulties in generic risk-benefit assessments. Thus, it is recommended that a comprehensive strategy is implemented to cover the entirety of multicomponent-multitarget effects, so as to address the limitations of conventional approaches.</p> <p>Summary</p> <p>An integration of standard toxicological methods with selected pathway-focused bioassays and unbiased data acquisition strategies (such as gene expression analysis) would be advantageous in building an interaction network model to consider all of the effects, whether they were intended or adverse reactions.</p

A framework for integrated environmental health impact assessment of systemic risks

Traditional methods of risk assessment have provided good service in support of policy, mainly in relation to standard setting and regulation of hazardous chemicals or practices. In recent years, however, it has become apparent that many of the risks facing society are systemic in nature – complex risks, set within wider social, economic and environmental contexts. Reflecting this, policy-making too has become more wide-ranging in scope, more collaborative and more precautionary in approach. In order to inform such policies, more integrated methods of assessment are needed. Based on work undertaken in two large EU-funded projects (INTARESE and HEIMTSA), this paper reviews the range of approaches to assessment now in used, proposes a framework for integrated environmental health impact assessment (both as a basis for bringing together and choosing between different methods of assessment, and extending these to more complex problems), and discusses some of the challenges involved in conducting integrated assessments to support policy

Hydrogeologic Monitoring at University of Minnesota Outreach, Research and Educational Park (UMore Park), 2011

The mining of the gravel resource and subsequent development at the University of Minnesota Outreach, Research and Educational Park (UMore Park) may potentially impact the groundwater quality at, and around UMore Park. In order to provide a pre-mining baseline against which to monitor potential water quality changes, monitoring of water quality in selected monitoring wells began in 2009 (Anger and Alexander, 2010.) Anger and Alexander (2010) reviews the previous work defining the hydrogeology of the UMore Park site and installing the existing monitoring wells. This report updates and Anger and Alexander (2010) with monitoring data obtained through June 2011