Rapid screening of environmental chemicals for estrogen receptor binding capacity.

Over the last few years, an increased awareness of endocrine disrupting chemicals (EDCs) and their potential to affect wildlife and humans has produced a demand for practical screening methods to identify endocrine activity in a wide range of environmental and industrial chemicals. While it is clear that in vivo methods will be required to identify adverse effects produced by these chemicals, in vitro assays can define particular mechanisms of action and have the potential to be employed as rapid and low-cost screens for use in large scale EDC screening programs. Traditional estrogen receptor (ER) binding assays are useful for characterizing a chemical's potential to be an estrogen-acting EDC, but they involve displacement of a radioactive ligand from crude receptor preparations at low temperatures. The usefulness of these assays for realistically determining the ER binding interactions of weakly estrogenic environmental and industrial compounds that have low aqueous solubility is unclear. In this report, we present a novel fluorescence polarization (FP) method that measures the capacity of a competitor chemical to displace a high affinity fluorescent ligand from purified, recombinant human ER-[alpha] at room temperature. The ER-[alpha] binding interactions generated for 15 natural and synthetic compounds were found to be similar to those determined with traditional receptor binding assays. We also discuss the potential to employ this FP technology to binding studies involving ER-ss and other receptors. Thus, the assay introduced in this study is a nonradioactive receptor binding method that shows promise as a high throughput screening method for large-scale testing of environmental and industrial chemicals for ER binding interactions

Magnetorheological landing gear: 2. Validation using experimental data

Aircraft landing gears are subjected to a wide range of excitation conditions with conflicting damping requirements. A novel solution to this problem is to implement semi-active damping using magnetorheological (MR) fluids. In part 1 of this contribution, a methodology was developed that enables the geometry of a flow mode MR valve to be optimized within the constraints of an existing passive landing gear. The device was designed to be optimal in terms of its impact performance, which was demonstrated using numerical simulations of the complete landing gear system. To perform the simulations, assumptions were made regarding some of the parameters used in the MR shock strut model. In particular, the MR fluid's yield stress, viscosity, and bulk modulus properties were not known accurately. Therefore, the present contribution aims to validate these parameters experimentally, via the manufacture and testing of an MR shock strut. The gas exponent, which is used to model the shock strut's nonlinear stiffness, is also investigated. In general, it is shown that MR fluid property data at high shear rates are required in order to accurately predict performance prior to device manufacture. Furthermore, the study illustrates how fluid compressibility can have a significant influence on the device time constant, and hence on potential control strategies

Developing and Implementing a Sustainable, Integrated Weed Management Program for herbicide-resistant Poa annua in turfgrass

The ability of Poa annua L. to adapt to most turfgrass environments extends to its ability to develop resistance to commonly used herbicides. Herbicide resistant P. annua is of almost epidemic proportions. The loss of once viable chemical-based treatments pushes practitioners towards more expensive, and often less effective, control strategies. This management guide focuses on integrated weed management (IWM) practices for P. annua control and herbicide resistance—what it is and how to overcome it. Also discussed are resistance mechanisms and documentation of common occurrences of field-level resistance within much of the United States. Finally, a summary of some of the social and economic constraints that practitioners face in the implementation of IWM strategies for P. annua is discussed

Insights Into Patients' Experience With Type 1 Diabetes: Exit Interviews From Phase III Studies of Sotagliflozin

Purpose: The purpose of this study was to conduct qualitative participant interviews to provide context to the meaningfulness of improvements in end points seen in 2 large-scale Phase III sotagliflozin trials in participants with type 1 diabetes. Methods: Participants were eligible for an interview if they had exited one of the clinical trials within the previous 12 months. Participants were recruited by investigators at the clinical trial sites, and interviews were conducted by independent interviewers by telephone in accordance with a semistructured interview guide. Both interviewers and participants were blinded to treatment assignment. Qualitative analysis was conducted using ATLAS-ti version 7.5, and descriptive statistics were computed and summarized. Findings: Across 3 countries, 41 participants were interviewed. Difficulty maintaining blood glucose within a desired range, described by participants as lack of blood glucose “stability,” was the most concerning symptom that they reported, wanting to see it improved during the clinical trial because it negatively impacted their physical, mental, and emotional lives. Participants who reported symptom improvement also reported a positive psychosocial impact while taking the clinical trial medication. All participants who monitored ketones described themselves as being “pretty confident” to “very confident” that they could avoid diabetic ketoacidosis by monitoring both ketone levels and understanding the physical signs and symptoms of hyperglycemia. Implications: Improvements in glucose stability and control were important to participants with type 1 diabetes, as these improvements were correlated with improvements in the participants' lives. ClinicalTrials.gov identifiers: NCT02384941; NCT02421510

Initial locomotor sensitivity to cocaine varies widely among inbred mouse strains: Initial locomotor sensitivity to cocaine in inbred mice

Initial sensitivity to psychostimulants can predict subsequent use and abuse in humans. Acute locomotor activation in response to psychostimulants is commonly used as an animal model of initial drug sensitivity and has been shown to have a substantial genetic component. Identifying the specific genetic differences that lead to phenotypic differences in initial drug sensitivity can advance our understanding of the processes that lead to addiction. Phenotyping inbred mouse strain panels are frequently used as a first step for studying the genetic architecture of complex traits. We assessed locomotor activation following a single, acute 20 mg/kg dose of cocaine (COC) in males from 45 inbred mouse strains and observed significant phenotypic variation across strains indicating a substantial genetic component. We also measured levels of COC, the active metabolite, norcocaine and the major inactive metabolite, benzoylecgonine, in plasma and brain in the same set of inbred strains. Pharmacokinetic (PK) and behavioral data were significantly correlated, but at a level that indicates that PK alone does not account for the behavioral differences observed across strains. Phenotypic data from this reference population of inbred strains can be utilized in studies aimed at examining the role of psychostimulant-induced locomotor activation on drug reward and reinforcement and to test theories about addiction processes. Moreover, these data serve as a starting point for identifying genes that alter sensitivity to the locomotor stimulatory effects of COC