Investigation of the Verhaar scheme for predicting acute aquatic toxicity: improving predictions obtained from Toxtree ver. 2.6

Assessment of the potential of compounds to cause harm to the aquatic environment is an integral part 8 of the REACH legislation. To reduce the number of vertebrate and invertebrate animals required for 9 this analysis alternative approaches have been promoted. Category formation and read-across have 10 been applied widely to predict toxicity. A key approach to grouping for environmental toxicity is the 11 Verhaar scheme which uses rules to classify compounds into one of four mechanistic categories. 12 These categories provide a mechanistic basis for grouping and any further predictive modelling. A 13 computational implementation of the Verhaar scheme is available in Toxtree v2.6. The work 14 presented herein demonstrates how modifications to the implementation of Verhaar between version 15 1.5 and 2.6 of Toxtree have improved performance by reducing the number of incorrectly classified 16 compounds. However, for the datasets used in this analysis, version 2.6 classifies more compounds as 17 outside of the domain of the model. Further amendments to the classification rules have been 18 implemented here using a post-processing filter encoded as a KNIME workflow. This results in fewer 19 compounds being classified as outside of the model domain, further improving the predictivity of the 20 scheme. The utility of the modification described herein is demonstrated through building quality, 21 mechanism-specific Quantitative Structure Activity Relationship (QSAR) models for the compounds 22 within specific mechanistic categories

Adverse Outcome Pathway (AOP) Informed Modeling of Aquatic Toxicology: QSARs, Read-Across, and Interspecies Verification of Modes of Action.

Alternative approaches have been promoted to reduce the number of vertebrate and invertebrate animals required for the assessment of the potential of compounds to cause harm to the aquatic environment. A key philosophy in the development of alternatives is a greater understanding of the relevant adverse outcome pathway (AOP). One alternative method is the fish embryo toxicity (FET) assay. Although the trends in potency have been shown to be equivalent in embryo and adult assays, a detailed mechanistic analysis of the toxicity data has yet to be performed; such analysis is vital for a full understanding of the AOP. The research presented herein used an updated implementation of the Verhaar scheme to categorize compounds into AOP-informed categories. These were then used in mechanistic (quantitative) structure-activity relationship ((Q)SAR) analysis to show that the descriptors governing the distinct mechanisms of acute fish toxicity are capable of modeling data from the FET assay. The results show that compounds do appear to exhibit the same mechanisms of toxicity across life stages. Thus, this mechanistic analysis supports the argument that the FET assay is a suitable alternative testing strategy for the specified mechanisms and that understanding the AOPs is useful for toxicity prediction across test systems

Taxonomic and geographic bias in 50 years of research on the behaviour and ecology of galagids

Identifying knowledge gaps and taxonomic and geographic bias in the literature is invaluable for guiding research towards a more representative understanding of animal groups. Galagids are nocturnal African primates and, for many species, detailed information on their behaviour and ecology is unavailable. To identify gaps and bias in the literature we reviewed published peer-reviewed research articles on galagid behaviour and ecology over a 50-year period from January 1971 to December 2020. Using the Web of Science and Google Scholar databases, we identified 758 articles, assessed 339 full texts for eligibility and included 211 in the review. Species of Otolemur have been extensively researched in comparison to other genera (78.2% of studies; Euoticus: 13.3% of studies; Galago: 66.4% of studies; Galagoides: 20.9% of studies; Paragalago: 22.3% of studies; Sciurocheirus: 15.2% of studies). The most common category of research was physiology (55.0% of studies), followed by behavioural ecology (47.4% of studies), and fewer studies were on genetics and taxonomy (16.1% of studies) and habitat and distribution (14.2% of studies). Text mining revealed that the word ‘behaviour’ was the most common word used in abstracts and keywords, and few words were related to ecology. Negative binomial regression revealed that mean body mass and geographic range size were significant positive predictors of the total number of scientific outputs on each species. Research on wild populations was carried out in only 24 (60%) of the 40 countries galagids are thought to inhabit. Studies were undertaken in locations with lower mean annual temperatures and higher human population densities over warmer and less populated areas. We encourage a more equal sampling effort both taxonomically and geographically that in particular addresses the paucity of research on smaller species and those with restricted ranges. Research on in situ populations, especially in warmer and remote areas, is urgently needed, particularly in West, Central and some Southern African countries

Ensuring confidence in predictions: A scheme to assess the scientific validity of in silico models

The use of in silico tools within the drug development process to predict a wide range of properties including absorption, distribution, metabolism, elimination and toxicity has become increasingly important due to changes in legislation and both ethical and economic drivers to reduce animal testing. Whilst in silico tools have been used for decades there remains reluctance to accept predictions based on these methods particularly in regulatory settings. This apprehension arises in part due to lack of confidence in the reliability, robustness and applicability of the models. To address this issue we propose a scheme for the verification of in silico models that enables end users and modellers to assess the scientific validity of models in accordance with the principles of good computer modelling practice. We report here the implementation of the scheme within the Innovative Medicines Initiative project “eTOX” (electronic toxicity) and its application to the in silico models developed within the frame of this project

Sleeping Site Selection in the Nocturnal Northern Lesser Galago (Galago senegalensis) Supports Antipredator and Thermoregulatory Hypotheses

© 2019, The Author(s). Sleep is an important and time-consuming activity, during which animals may be particularly vulnerable. Selecting a suitable sleeping site is therefore essential for an individual’s fitness. Here we test the importance of antipredator and thermoregulatory hypotheses for the sleeping site preference of a nocturnal primate, the Northern lesser galago (Galago senegalensis), in Northern Tanzania. During June to August of 2015 and 2016 we conducted daily surveys of sleeping sites to record the number of galagos and their location within the sleeping tree, and used focal follows to record when galagos reached and left sleeping sites. We collected vegetation data for sleeping sites (N = 47) and matched controls, and placed data loggers in sleeping (N = 14) and control locations to compare temperature and humidity. Sleeping group sizes were similar to that of G. senegalensis in The Gambia, and the mean proportion of visits in which galagos were present at each site was 27 ± SD 25%. Galagos slept on branches (N = 29), nests (N = 6), palm leaves (N = 6), and in tree cavities (N = 1). Palm leaves have not been previously recorded as regular sleeping sites for galagos and were overrepresented relative to their occurrence in the habitat. Random forest classification analysis revealed that galagos sleep in areas with greater canopy cover and connectivity, greater mid-level vegetation cover, higher tree density, and a greater number of Acacia trees. Sleeping locations had significantly lower mean temperatures but greater mean humidity than control locations. Our findings support predator avoidance and thermoregulation as drivers of nesting behavior. In particular, the characteristics of galago sleeping sites correspond well to those expected for protection from aerial predators, while those related to protection from terrestrial predators seem to play a minor role

Inattentive Consumers in Markets for Services

In an experiment on markets for services, we find that consumers are likely to stick to default tariffs and achieve suboptimal outcomes. We find that inattention to the task of choosing a better tariff is likely to be a substantial problem in addition to any task and tariff complexity effect. The institutional setup on which we primarily model our experiment is the UK electricity and gas markets, and our conclusion is that the new measures by the UK regulator Ofgem to improve consumer outcomes are likely to be of limited impact

Potassium homeostasis and management of dyskalemia in kidney diseases: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward. In sum, we provide here our conference deliberations on potassium homeostasis in health and disease, guidance for evaluation and management of dyskalemias in the context of kidney diseases, and research priorities in each of the above areas

Temperature- and thickness-dependent elastic moduli of polymer thin films

The mechanical properties of polymer ultrathin films are usually different from those of their counterparts in bulk. Understanding the effect of thickness on the mechanical properties of these films is crucial for their applications. However, it is a great challenge to measure their elastic modulus experimentally with in situ heating. In this study, a thermodynamic model for temperature- (T) and thickness (h)-dependent elastic moduli of polymer thin films Ef(T,h) is developed with verification by the reported experimental data on polystyrene (PS) thin films. For the PS thin films on a passivated substrate, Ef(T,h) decreases with the decreasing film thickness, when h is less than 60 nm at ambient temperature. However, the onset thickness (h*), at which thickness Ef(T,h) deviates from the bulk value, can be modulated by T. h* becomes larger at higher T because of the depression of the quenching depth, which determines the thickness of the surface layer δ

Isolation and characterization of resident endogenous c-Kit⁺ cardiac stem cells from the adult mouse and rat heart

This protocol describes the isolation of endogenous c-Kit (also known as CD117)-positive (c-Kit⁺), CD45-negative (CD45⁻) cardiac stem cells (eCSCs) from whole adult mouse and rat hearts. The heart is enzymatically digested via retrograde perfusion of the coronary circulation, resulting in rapid and extensive breakdown of the whole heart. Next, the tissue is mechanically dissociated further and cell fractions are separated by centrifugation. The c-Kit⁺ CD45⁻ eCSC population is isolated by magnetic-activated cell sorting technology and purity and cell numbers are assessed by flow cytometry. This process takes ∼4 h for mouse eCSCs or 4.5 h for rat eCSCs. We also describe how to characterize c-Kit⁺ CD45⁻ eCSCs. The c-Kit⁺ CD45⁻eCSCs exhibit the defining characteristics of stem cells: they are self-renewing, clonogenic and multipotent. This protocol also describes how to differentiate eCSCs into three main cardiac lineages: functional, beating cardiomyocytes, smooth muscle, and endothelial cells. These processes take 17-20 d