Review of dose setting for the extended one-generation reproductive toxicity studies (OECD TG 443): Considerations on ECHA's dose level selection recommendations.

During 2020, The European Chemicals Agency (ECHA) began evaluating the OECD Test Guideline 443: Extended One Generation Reproductive Toxicity Study (EOGRTS) to analyze specific aspects related to study design, conduct and toxicological findings. A significant outcome of this ECHA evaluation focused on adequate dose level selection. Subsequently, ECHA published recommendations for DART studies, however, these recommendations seemingly do not align with the principles of the 3Rs, animal welfare or human safety goals, specifically, regarding three aspects. First, the requirement to segregate testing for sexual function and fertility from the ability to produce normally developing offspring increases the risk of inadequate identification of postnatal hazards for development and sexual function and fertility, therefore failing human health protection goals. Second, the current ECHA high-dose level setting recommendations for EOGRTS exceed the MTD (Maximum Tolerated Dose), and therefore compromise the interpretation of the biological response relative to the intrinsic effect of the chemical under evaluation. Third, the combination of these aspects will result in an increase in the number of animals tested, increasing animal welfare concerns. This paper reflects the consensus of subject matter experts, professional, and scientific societies who have authored and signed on to this statement. The signatories encourage ECHA to adopt a revised science-driven approach to the dose selection criteria that strikes a balance between regulatory vigilance and scientific pragmatism.

The visual coupling between neighbours explains local interactions underlying human 'flocking'.

Patterns of collective motion in bird flocks, fish schools and human crowds are believed to emerge from local interactions between individuals. Most 'flocking' models attribute these local interactions to hypothetical rules or metaphorical forces and assume an omniscient third-person view of the positions and velocities of all individuals in space. We develop a visual model of collective motion in human crowds based on the visual coupling that governs pedestrian interactions from a first-person embedded viewpoint. Specifically, humans control their walking speed and direction by cancelling the average angular velocity and optical expansion/contraction of their neighbours, weighted by visibility (1 - occlusion). We test the model by simulating data from experiments with virtual crowds and real human 'swarms'. The visual model outperforms our previous omniscient model and explains basic properties of interaction: 'repulsion' forces reduce to cancelling optical expansion, 'attraction' forces to cancelling optical contraction and 'alignment' to cancelling the combination of expansion/contraction and angular velocity. Moreover, the neighbourhood of interaction follows from Euclid's Law of perspective and the geometry of occlusion. We conclude that the local interactions underlying human flocking are a natural consequence of the laws of optics. Similar perceptual principles may apply to collective motion in other species.

Impacts of additional noise on the social interactions of a cooperatively breeding fish.

Anthropogenic noise is a global pollutant known to affect the behaviour of individual animals in all taxa studied. However, there has been relatively little experimental testing of the effects of additional noise on social interactions between conspecifics, despite these forming a crucial aspect of daily life for most species. Here, we use established paradigms to investigate how white-noise playback affects both group defensive actions against an intruder and associated within-group behaviours in a model fish species, the cooperatively breeding cichlid Neolamprologus pulcher. Additional noise did not alter defensive behaviour, but did result in changes to within-group behaviour. Both dominant and subordinate females, but not the dominant male, exhibited less affiliation and showed a tendency to produce more submissive displays to groupmates when there was additional noise compared with control conditions. Thus, our experimental results indicate the potential for anthropogenic noise to affect social interactions between conspecifics and emphasize the possibility of intraspecific variation in the impacts of this global pollutant.

CRISPR-RT: a web application for designing CRISPR-C2c2 crRNA with improved target specificity.

Summary: CRISPR-Cas systems have been successfully applied in genome editing. Recently, the CRISPR-C2c2 system has been reported as a tool for RNA editing. Here we describe CRISPR-RT (CRISPR RNA-Targeting), the first web application to help biologists design crRNAs with improved target specificity for the CRISPR-C2c2 system. CRISPR-RT allows users to set up a wide range of parameters, making it highly flexible for current and future research in CRISPR-based RNA editing. CRISPR-RT covers major model organisms and can be easily extended to cover other species. CRISPR-RT will empower researchers in RNA editing. Availability and implementation: Freely available at http://bioinfolab.miamioh.edu/CRISPR-RT. Contact: liangc@miamioh.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Water Adsorption Isotherms on Fly Ash from Several Sources.

In this study, horizontal attenuated total reflection (HATR) Fourier-transform infrared (FT-IR) spectroscopy was combined with quartz crystal microbalance (QCM) gravimetry to investigate the adsorption isotherms of water on fly ash, a byproduct of coal combustion in power plants. Because of composition variability with the source region, water uptake was studied at room temperature as a function of relative humidity (RH) on fly ash from several regions: United States, India, The Netherlands, and Germany. The FT-IR spectra show water features growth as a function of RH, with water absorbing on the particle surface in both an ordered (ice-like) and a disordered (liquid-like) structure. The QCM data was modeled using the Brunauer, Emmett, and Teller (BET) adsorption isotherm model. The BET model was found to describe the data well over the entire range of RH, showing that water uptake on fly ash takes place mostly on the surface of the particle, even for poorly combusted samples. In addition, the source region and power-plant efficiency play important roles in the water uptake and ice nucleation (IN) ability of fly ash. The difference in the observed water uptake and IN behavior between the four samples and mullite (3Al2O3·2SiO2), the aluminosilicate main component of fly ash, is attributed to differences in composition and the density of OH binding sites on the surface of each sample. A discussion is presented on the RH required to reach monolayer coverage on each sample as well as a comparison between surface sites of fly ash samples and enthalpies of adsorption of water between the samples and mullite.

Vigabatrin-induced CNS changes in juvenile rats: Induction, progression and recovery of myelin-related changes.

The purpose of this study was to expand on the knowledge previously published on the central nervous system effects of Vigabatrin in juvenile animals. By employing extended sectioning of the brain and by using four different tissue staining techniques it is demonstrated that oral administration of Vigabatrin to juvenile rats (treatment periods of post-natal day (PND) 4-7, 7-14 or 14-30) will cause histological CNS changes at dose levels of 15 and 50mg/kg/day, but not at a dose level of 5mg/kg/day. No evidence of neuronal degeneration or gliosis was seen at any stage of treatment. Consistent with previous reports microvacuolation, as well as effects on myelination and on oligodendrocytes were recorded. The present study expands on these findings and demonstrates that the variation in the location of the vigabatrin-induced lesions in the juvenile rat brain (both neuropil vacuolation and reduction of myelin) appears to be consistent with the process of myelination: In the youngest animals (PND 4-7) myelination occurs mainly in the hind brain (medulla oblongata and pons) where neuropil vacuolations is recorded. In animals dosed during PNDs 7-14 or during PNDs 14-30, the first changes were found in the thalamus. It seems likely that the earlier stages of myelination are more vulnerable to treatment related effects and the swollen oligodendrocytes seen as the initial change in the thalamus in animals treated during PNDs 4-7 and 7-14 represents an early stage in the development of the myelin lesion which is seen later as neuropil vacuolation.

Behavioral counseling after screening for alcohol misuse in primary care: a systematic review and meta-analysis for the U.S. Preventive Services Task Force.

BACKGROUND: Alcohol misuse, which includes the full spectrum from risky drinking to alcohol dependence, is a leading cause of preventable death in the United States. PURPOSE: To evaluate the benefits and harms of behavioral counseling interventions for adolescents and adults who misuse alcohol. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Library, CINAHL, PsycINFO, International Pharmaceutical Abstracts, and reference lists of published literature (January 1985 through January 2012, limited to English-language articles). STUDY SELECTION: Controlled trials at least 6 months' duration that enrolled persons with alcohol misuse identified by screening in primary care settings and evaluated behavioral counseling interventions. DATA EXTRACTION: One reviewer extracted data and a second checked accuracy. Two independent reviewers assigned quality ratings and graded the strength of the evidence. DATA SYNTHESIS: The 23 included trials generally excluded persons with alcohol dependence. The best evidence was for brief (10- to 15-minute) multicontact interventions. Among adults receiving behavioral interventions, consumption decreased by 3.6 drinks per week from baseline (weighted mean difference, 3.6 drinks/wk [95% CI, 2.4 to 4.8 drinks/wk]; 10 trials; 4332 participants), 12% fewer adults reported heavy drinking episodes (risk difference, 0.12 [CI, 0.07 to 0.16]; 7 trials; 2737 participants), and 11% more adults reported drinking less than the recommended limits (risk difference, 0.11 [CI, 0.08 to 0.13]; 9 trials; 5973 participants) over 12 months compared with control participants (moderate strength of evidence). Evidence was insufficient to draw conclusions about accidents, injuries, or alcohol-related liver problems. Trials enrolling young adults or college students showed reduced consumption and fewer heavy drinking episodes (moderate strength of evidence). Little or no evidence of harms was found. LIMITATIONS: Results may be biased to the null because the behavior of control participants could have been affected by alcohol misuse assessments. In addition, evidence is probably inapplicable to persons with alcohol dependence and selective reporting may have occurred. CONCLUSION: Behavioral counseling interventions improve behavioral outcomes for adults with risky drinking. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Dried blood spot bioanalysis: an evaluation of techniques and opportunities for reduction and refinement in mouse and juvenile rat toxicokinetic studies.

Toxicokinetic investigations are an essential component of nonclinical toxicology studies and generally rely on bioanalysis of plasma samples, which requires relatively large volumes of blood and, often, additional numbers of animals. Dried blood spot (DBS) analysis can substantially reduce the volume of blood needed and, therefore, presents a particular opportunity for reducing animal use in studies involving small animals; an approach consistent with industry objectives to reduce animal use and refine methods that are minimally invasive and improve animal welfare. Investigations using mice and juvenile rats indicate that implementation of DBS technology can reduce the number of animals used, and data are as good as those derived from whole blood in terms of AUC, drug-concentration-over-time curves, quantitation, accuracy, variability, and precision. These factors, and the improved data quality arising from less reliance on composite data, suggest that DBS analysis should be considered from the early stages of nonclinical development.