Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Smart homes and their users:a systematic analysis and key challenges

Published research on smart homes and their users is growing exponentially, yet a clear understanding of who these users are and how they might use smart home technologies is missing from a field being overwhelmingly pushed by technology developers. Through a systematic analysis of peer-reviewed literature on smart homes and their users, this paper takes stock of the dominant research themes and the linkages and disconnects between them. Key findings within each of nine themes are analysed, grouped into three: (1) views of the smart home-functional, instrumental, socio-technical; (2) users and the use of the smart home-prospective users, interactions and decisions, using technologies in the home; and (3) challenges for realising the smart home-hardware and software, design, domestication. These themes are integrated into an organising framework for future research that identifies the presence or absence of cross-cutting relationships between different understandings of smart homes and their users. The usefulness of the organising framework is illustrated in relation to two major concerns-privacy and control-that have been narrowly interpreted to date, precluding deeper insights and potential solutions. Future research on smart homes and their users can benefit by exploring and developing cross-cutting relationships between the research themes identified

Naturally Occurring Osmolyte, Trehalose Induces Functional Conformation in an Intrinsically Disordered Activation Domain of Glucocorticoid Receptor

Intrinsically disordered (ID) regions are frequently found in the activation domains of many transcription factors including nuclear hormone receptors. It is believed that these ID regions promote molecular recognition by creating large surfaces suitable for interactions with their specific protein binding partners, which is a critical component of gene regulation by transcription factors. It has been hypothesized that conditional folding of these activation domains may be a prerequisite for their efficient interaction with specific coregulatory proteins, and subsequent transcriptional activity leading to the regulation of target gene(s). In this study, we tested whether a naturally occurring osmolyte, trehalose can promote functionally ordered conformation in glucocorticoid receptor's major activation function domain, AF1, which is found to exist as an ID protein, and requires an efficient interaction with coregulatory proteins for optimal activity. Our data show that trehalose induces an ordered conformation in AF1 such that its interaction with steroid receptor coactivator-1 (SRC-1), a critical coregulator of glucocorticoid receptor's activity, is greatly enhanced

Trapped in the prison of the mind: notions of climate-induced (im)mobility decision-making and wellbeing from an urban informal settlement in Bangladesh

The concept of Trapped Populations has until date mainly referred to people ‘trapped’ in environmentally high-risk rural areas due to economic constraints. This article attempts to widen our understanding of the concept by investigating climate-induced socio-psychological immobility and its link to Internally Displaced People’s (IDPs) wellbeing in a slum of Dhaka. People migrated here due to environmental changes back on Bhola Island and named the settlement Bhola Slum after their home. In this way, many found themselves ‘immobile’ after having been mobile—unable to move back home, and unable to move to other parts of Dhaka, Bangladesh, or beyond. The analysis incorporates the emotional and psychosocial aspects of the diverse immobility states. Mind and emotion are vital to better understand people’s (im)mobility decision-making and wellbeing status. The study applies an innovative and interdisciplinary methodological approach combining Q-methodology and discourse analysis (DA). This mixed-method illustrates a replicable approach to capture the complex state of climate-induced (im)mobility and its interlinkages to people’s wellbeing. People reported facing non-economic losses due to the move, such as identity, honour, sense of belonging and mental health. These psychosocial processes helped explain why some people ended up ‘trapped’ or immobile. The psychosocial constraints paralysed them mentally, as well as geographically. More empirical evidence on how climate change influences people’s wellbeing and mental health will be important to provide us with insights in how to best support vulnerable people having faced climatic impacts, and build more sustainable climate policy frameworks

Membrane Partitioning: “Classical” and “Nonclassical” Hydrophobic Effects

The free energy of transfer of nonpolar solutes from water to lipid bilayers is often dominated by a large negative enthalpy rather than the large positive entropy expected from the hydrophobic effect. This common observation has led to the idea that membrane partitioning is driven by the “nonclassical” hydrophobic effect. We examined this phenomenon by characterizing the partitioning of the well-studied peptide melittin using isothermal titration calorimetry (ITC) and circular dichroism (CD). We studied the temperature dependence of the entropic (−TΔS) and enthalpic (ΔH) components of free energy (ΔG) of partitioning of melittin into lipid membranes made of various mixtures of zwitterionic and anionic lipids. We found significant variations of the entropic and enthalpic components with temperature, lipid composition and vesicle size but only small changes in ΔG (entropy–enthalpy compensation). The heat capacity associated with partitioning had a large negative value of about −0.5 kcal mol−1 K−1. This hallmark of the hydrophobic effect was found to be independent of lipid composition. The measured heat capacity values were used to calculate the hydrophobic-effect free energy ΔGhΦ, which we found to dominate melittin partitioning regardless of lipid composition. In the case of anionic membranes, additional free energy comes from coulombic attraction, which is characterized by a small effective peptide charge due to the lack of additivity of hydrophobic and electrostatic interactions in membrane interfaces [Ladokhin and White J Mol Biol 309:543–552, 2001]. Our results suggest that there is no need for a special effect—the nonclassical hydrophobic effect—to describe partitioning into lipid bilayers

Zircon ages in granulite facies rocks: decoupling from geochemistry above 850 °C?

Granulite facies rocks frequently show a large spread in their zircon ages, the interpretation of which raises questions: Has the isotopic system been disturbed? By what process(es) and conditions did the alteration occur? Can the dates be regarded as real ages, reflecting several growth episodes? Furthermore, under some circumstances of (ultra-)high-temperature metamorphism, decoupling of zircon U–Pb dates from their trace element geochemistry has been reported. Understanding these processes is crucial to help interpret such dates in the context of the P–T history. Our study presents evidence for decoupling in zircon from the highest grade metapelites (> 850 °C) taken along a continuous high-temperature metamorphic field gradient in the Ivrea Zone (NW Italy). These rocks represent a well-characterised segment of Permian lower continental crust with a protracted high-temperature history. Cathodoluminescence images reveal that zircons in the mid-amphibolite facies preserve mainly detrital cores with narrow overgrowths. In the upper amphibolite and granulite facies, preserved detrital cores decrease and metamorphic zircon increases in quantity. Across all samples we document a sequence of four rim generations based on textures. U–Pb dates, Th/U ratios and Ti-in-zircon concentrations show an essentially continuous evolution with increasing metamorphic grade, except in the samples from the granulite facies, which display significant scatter in age and chemistry. We associate the observed decoupling of zircon systematics in high-grade non-metamict zircon with disturbance processes related to differences in behaviour of non-formula elements (i.e. Pb, Th, U, Ti) at high-temperature conditions, notably differences in compatibility within the crystal structure

Defining the road map to a UK national lung cancer screening programme

Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries

Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells

Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging

Development of an Orthotopic Human Pancreatic Cancer Xenograft Model Using Ultrasound Guided Injection of Cells

Mice have been employed as models of cancer for over a century, providing significant advances in our understanding of this multifaceted family of diseases. In particular, orthotopic tumor xenograft mouse models are emerging as the preference for cancer research due to increased clinical relevance over subcutaneous mouse models. In the current study, we developed orthotopic pancreatic cancer xenograft models in mice by a minimally invasive method, ultrasound guided injection (USGI) comparable to highly invasive surgical orthotopic injection (SOI) methods. This optimized method prevented injection complications such as recoil of cells through the injection canal or leakage of cells out of the pancreas into the peritoneal cavity. Tumor growth was monitored in vivo and quantified by ultrasound imaging weekly, tumors were also detected by in vivo fluorescence imaging using a tumor targeted molecular probe. The mean tumor volumes for the USGI and SOI models after 2 weeks of tumor growth were 205 mm3 and 178 mm3 respectively. By USGI of human pancreatic cancer cell lines, human orthotopic pancreatic cancer xenografts were established. Based on ultrasound imaging, the orthotopic human pancreatic cancer xenograft take rate was 100% for both human pancreatic cancer cell lines used, MiaPaCa-2 and Su86.86, with mean tumor volumes of 28 mm3and 30 mm3. We demonstrated that this USGI method is feasible, reproducible, facile, minimally invasive and improved compared to the highly-invasive SOI method for establishing orthotopic pancreatic tumor xenograft models suitable for molecular imaging

A Participatory Return-to-Work Intervention for Temporary Agency Workers and Unemployed Workers Sick-Listed Due to Musculoskeletal Disorders: Results of a Randomized Controlled Trial

Introduction Within the labour force workers without an employment contract represent a vulnerable group. In most cases, when sick-listed, these workers have no workplace/employer to return to. Therefore, the aim of this study was to evaluate the effectiveness on return-to-work of a participatory return-to-work program compared to usual care for unemployed workers and temporary agency workers, sick-listed due to musculoskeletal disorders. Methods The workers, sick-listed for 2–8 weeks due to musculoskeletal disorders, were randomly allocated to the participatory return-to-work program (n = 79) or to usual care (n = 84). The new program is a stepwise procedure aimed at making a consensus-based return-to-work plan, with the possibility of a temporary (therapeutic) workplace. Outcomes were measured at baseline, 3, 6, 9 and 12 months. The primary outcome measure was time to sustainable first return-to-work. Secondary outcome measures were duration of sickness benefit, functional status, pain intensity, and perceived health. Results The median duration until sustainable first return-to-work was 161 days in the intervention group, compared to 299 days in the usual care group. The new return-to-work program resulted in a non-significant delay in RTW during the first 90 days, followed by a significant advantage in RTW rate after 90 days (hazard ratio of 2.24 [95% confidence interval 1.28–3.94] P = 0.005). No significant differences were found for the measured secondary outcomes. Conclusions The newly developed participatory return-to-work program seems to be a promising intervention to facilitate work resumption and reduce work disability among temporary agency workers and unemployed workers, sick-listed due to musculoskeletal disorders