Multi-Behavioral Endpoint Testing Of An 87-Chemical Compound Library In Freshwater Planarians

There is an increased recognition in the field of toxicology of the value of medium-to-high-throughput screening methods using in vitro and alternative animal models. We have previously introduced the asexual freshwater planarian Dugesia japonica as a new alternative animal model and proposed that it is particularly well-suited for the study of developmental neurotoxicology. In this paper, we discuss how we have expanded and automated our screening methodology to allow for fast screening of multiple behavioral endpoints, developmental toxicity, and mortality. Using an 87-compound library provided by the National Toxicology Program (NTP), consisting of known and suspected neurotoxicants, including drugs, flame retardants, industrial chemicals, polycyclic aromatic hydrocarbons (PAHs), pesticides and presumptive negative controls, we further evaluate the benefits and limitations of the system for medium-throughput screening, focusing on the technical aspects of the system. We show that, in the context of this library, planarians are the most sensitive to pesticides with 16/16 compounds causing toxicity and the least sensitive to PAHs, with only 5/17 causing toxicity. Furthermore, while none of the presumptive negative controls were bioactive in adult planarians, 2/5, acetaminophen and acetylsalicylic acid, were bioactive in regenerating worms. Notably, these compounds were previously reported as developmentally toxic in mammalian studies. Through parallel screening of adults and developing animals, planarians are thus a useful model to detect such developmental-specific effects, which was observed for 13 chemicals in this library. We use the data and experience gained from this screen to propose guidelines for best practices when using planarians for toxicology screens

Hyperboloidal evolution of test fields in three spatial dimensions

We present the numerical implementation of a clean solution to the outer boundary and radiation extraction problems within the 3+1 formalism for hyperbolic partial differential equations on a given background. Our approach is based on compactification at null infinity in hyperboloidal scri fixing coordinates. We report numerical tests for the particular example of a scalar wave equation on Minkowski and Schwarzschild backgrounds. We address issues related to the implementation of the hyperboloidal approach for the Einstein equations, such as nonlinear source functions, matching, and evaluation of formally singular terms at null infinity.Comment: 10 pages, 8 figure

A nonstationary form of the range refraction parabolic equation and its application as an artificial boundary condition for the wave equation in a waveguide

The time-dependent form of Tappert's range refraction parabolic equation is derived using Daletskiy-Krein formula form noncommutative analysis and proposed as an artificial boundary condition for the wave equation in a waveguide. The numerical comparison with Higdon's absorbing boundary conditions shows sufficiently good quality of the new boundary condition at low computational cost.Comment: 12 pages, 9 figure

Mode signature and stability for a Hamiltonian model of electron temperature gradient turbulence

Stability properties and mode signature for equilibria of a model of electron temperature gradient (ETG) driven turbulence are investigated by Hamiltonian techniques. After deriving the infinite families of Casimir invariants, associated with the noncanonical Poisson bracket of the model, a sufficient condition for stability is obtained by means of the Energy-Casimir method. Mode signature is then investigated for linear motions about homogeneous equilibria. Depending on the sign of the equilibrium "translated" pressure gradient, stable equilibria can either be energy stable, i.e.\ possess definite linearized perturbation energy (Hamiltonian), or spectrally stable with the existence of negative energy modes (NEMs). The ETG instability is then shown to arise through a Kre\u{\i}n-type bifurcation, due to the merging of a positive and a negative energy mode, corresponding to two modified drift waves admitted by the system. The Hamiltonian of the linearized system is then explicitly transformed into normal form, which unambiguously defines mode signature. In particular, the fast mode turns out to always be a positive energy mode (PEM), whereas the energy of the slow mode can have either positive or negative sign

On Krein-like theorems for noncanonical Hamiltonian systems with continuous spectra: application to Vlasov-Poisson

The notions of spectral stability and the spectrum for the Vlasov-Poisson system linearized about homogeneous equilibria, f_0(v), are reviewed. Structural stability is reviewed and applied to perturbations of the linearized Vlasov operator through perturbations of f_0. We prove that for each f_0 there is an arbitrarily small delta f_0' in W^{1,1}(R) such that f_0+delta f_0$is unstable. When$f_0$ is perturbed by an area preserving rearrangement, f_0 will always be stable if the continuous spectrum is only of positive signature, where the signature of the continuous spectrum is defined as in previous work. If there is a signature change, then there is a rearrangement of f_0 that is unstable and arbitrarily close to f_0 with f_0' in W^{1,1}. This result is analogous to Krein's theorem for the continuous spectrum. We prove that if a discrete mode embedded in the continuous spectrum is surrounded by the opposite signature there is an infinitesimal perturbation in C^n norm that makes f_0 unstable. If f_0 is stable we prove that the signature of every discrete mode is the opposite of the continuum surrounding it.Comment: Submitted to the journal Transport Theory and Statistical Physics. 36 pages, 12 figure

Reconstruction Mechanism of FCC Transition-Metal (001) Surfaces

The reconstruction mechanism of (001) fcc transition metal surfaces is investigated using a full-potential all-electron electronic structure method within density-functional theory. Total-energy supercell calculations confirm the experimental finding that a close-packed quasi-hexagonal overlayer reconstruction is possible for the late 5$d$-metals Ir, Pt, and Au, while it is disfavoured in the isovalent 4$d$ metals (Rh, Pd, Ag). The reconstructive behaviour is driven by the tensile surface stress of the unreconstructed surfaces; the stress is significantly larger in the 5$d$ metals than in 4$d$ ones, and only in the former case it overcomes the substrate resistance to the required geometric rearrangement. It is shown that the surface stress for these systems is due to $d$ charge depletion from the surface layer, and that the cause of the 4th-to-5th row stress difference is the importance of relativistic effects in the 5$d$ series.Comment: RevTeX 3.0, 12 pages, 1 PostScript figure available upon request] 23 May 199

Planarian Cholinesterase: Molecular And Functional Characterization Of An Evolutionarily Ancient Enzyme To Study Organophosphorus Pesticide Toxicity

The asexual freshwater planarian Dugesia japonica has emerged as a medium-throughput alternative animal model for neurotoxicology. We have previously shown that D. japonica are sensitive to organophosphorus pesticides (OPs) and characterized the in vitro inhibition profile of planarian cholinesterase (DjChE) activity using irreversible and reversible inhibitors. We found that DjChE has intermediate features of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Here, we identify two candidate genes (Djche1 and Djche2) responsible for DjChE activity. Sequence alignment and structural homology modeling with representative vertebrate AChE and BChE sequences confirmed our structural predictions, and show that both DjChE enzymes have intermediate sized catalytic gorges and disrupted peripheral binding sites. Djche1 and Djche2 were both expressed in the planarian nervous system, as anticipated from previous activity staining, but with distinct expression profiles. To dissect how DjChE inhibition affects planarian behavior, we acutely inhibited DjChE activity by exposing animals to either an OP (diazinon) or carbamate (physostigmine) at 1 µM for 4 days. Both inhibitors delayed the reaction of planarians to heat stress. Simultaneous knockdown of both Djche genes by RNAi similarly resulted in a delayed heat stress response. Furthermore, chemical inhibition of DjChE activity increased the worms’ ability to adhere to a substrate. However, increased substrate adhesion was not observed in Djche1/Djche2 (RNAi) animals or in inhibitor-treated day 11 regenerates, suggesting this phenotype may be modulated by other mechanisms besides ChE inhibition. Together, our study characterizes DjChE expression and function, providing the basis for future studies in this system to dissect alternative mechanisms of OP toxicity