Comparative Analysis Of Zebrafish And Planarian Model Systems For Developmental Neurotoxicity Screens Using An 87-Compound Library

There is a clear need to establish and validate new methodologies to more quickly and efficiently screen chemicals for potential toxic effects, particularly on development. The emergence of alternative animal systems for rapid toxicology screens presents valuable opportunities to evaluate how systems complement each other. In this article, we compare a chemical library of 87-compounds in two such systems, developing zebrafish and freshwater planarians, by screening for developmental neurotoxic effects. We show that the systems’ toxicological profiles are complementary to each other, with zebrafish yielding more detailed morphological endpoints and planarians more behavioral endpoints. Overall, zebrafish was more sensitive to this chemical library, yielding 86/87 hits, compared to 50/87 hits in planarians. The difference in sensitivity could not be attributed to molecular weight, Log Kow or the bioconcentration factor. Of the 87 chemicals, 28 had previously been evaluated in mammalian developmental neuro- (DNT), neuro- or developmental toxicity studies. Of the 28, 20 were hits in the planarian, and 27 were hits in zebrafish. Eighteen of the 28 had previously been identified as DNT hits in mammals and were highly associated with activity in zebrafish and planarian behavioral assays in this study. Only 1 chemical (out of 28) was a false negative in both zebrafish and planarian systems. Differences in endpoint coverage and system sensitivity illustrate the value of a dual systems approach to rapidly query a large chemical-bioactivity space and provide weight-of-evidence for prioritization of chemicals for further testing

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

Studying Planarian Regeneration Aboard The International Space Station Within The Student Space Flight Experimental Program

The growing possibilities of space travel are quickly moving from science fiction to reality. However, to realize the dream of long-term space travel, we must understand how these conditions affect biological and physiological processes. Planarians are master regenerators, famous for their ability to regenerate from very small parts of the original animal. Understanding how this self-repair works may inspire regenerative therapies in humans. Two studies conducted aboard the International Space Station (ISS) showed that planarian regeneration is possible in microgravity. One study reported no regenerative defects, whereas the other study reported behavioral and microbiome alterations post-space travel and found that 1 of 15 planarians regenerated a Janus head, suggesting that microgravity exposure may not be without consequences. Given the limited number of studies and specimens, further microgravity experiments are necessary to evaluate the effects of microgravity on planarian regeneration. Such studies, however, are generally difficult and expensive to conduct. We were fortunate to be sponsored by the Student Spaceflight Experiment Program (SSEP) to investigate how microgravity affects regeneration of the planarian species Dugesia japonica on the ISS. While we were unable to successfully study planarian regeneration within the experimental constraints of our SSEP Mission, we systematically analyzed the cause for the failed experiment, leading us to propose a modified protocol. This work thus opens the door for future experiments on the effects of microgravity on planarian regeneration on SSEP Missions as well as for more advanced experiments by professional researchers

The Effect of Resistance Training on Telomere Length in Women Recovering from Breast Cancer

The purpose of this exploratory analysis was to examine the effects of resistance training (RT) on leukocyte telomere length in breast cancer survivors. Samples from 33 breast cancer survivors were analysed following a 16-week RT or usual care intervention (RT: n = 19, control: n = 14). The RT group performed supervised exercise three times per week. Leukocyte telomere length was assessed before and after training using quantitative PCR. Changes in telomere length were analysed using ANCOVA, with the change score being the dependent variable, and the baseline value the covariate. Effect sizes (ES) were calculated via partial eta squared. We found a non-statistically significant change in telomere length, and a small associated ES in the RT group compared to the control group for change in telomere length (p = 0.78, ES = 0.003). Our exploratory study demonstrates that a 16-week RT intervention does not have a significant effect on telomere length in women recovering from breast cancer. Therefore, RT is a safe intervention that does not accelerate biological ageing

Would You Choose to be Happy? Tradeoffs Between Happiness and the Other Dimensions of Life in a Large Population Survey

A large literature documents the correlates and causes of subjective well-being, or happiness. But few studies have investigated whether people choose happiness. Is happiness all that people want from life, or are they willing to sacrifice it for other attributes, such as income and health? Tackling this question has largely been the preserve of philosophers. In this article, we find out just how much happiness matters to ordinary citizens. Our sample consists of nearly 13,000 members of the UK and US general populations. We ask them to choose between, and make judgments over, lives that are high (or low) in different types of happiness and low (or high) in income, physical health, family, career success, or education. We find that people by and large choose the life that is highest in happiness but health is by far the most important other concern, with considerable numbers of people choosing to be healthy rather than happy. We discuss some possible reasons for this preference

Null infinity waveforms from extreme-mass-ratio inspirals in Kerr spacetime

We describe the hyperboloidal compactification for Teukolsky equations in Kerr spacetime. We include null infinity on the numerical grid by attaching a hyperboloidal layer to a compact domain surrounding the rotating black hole and the orbit of an inspiralling point particle. This technique allows us to study, for the first time, gravitational waveforms from large- and extreme-mass-ratio inspirals in Kerr spacetime extracted at null infinity. Tests and comparisons of our results with previous calculations establish the accuracy and efficiency of the hyperboloidal layer method.Comment: 14 pages, 7 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

Absorbing boundary conditions for the Westervelt equation

The focus of this work is on the construction of a family of nonlinear absorbing boundary conditions for the Westervelt equation in one and two space dimensions. The principal ingredient used in the design of such conditions is pseudo-differential calculus. This approach enables to develop high order boundary conditions in a consistent way which are typically more accurate than their low order analogs. Under the hypothesis of small initial data, we establish local well-posedness for the Westervelt equation with the absorbing boundary conditions. The performed numerical experiments illustrate the efficiency of the proposed boundary conditions for different regimes of wave propagation