Early-life adversity increases morphine tolerance and persistent inflammatory hypersensitivity through upregulation of δ opioid receptors in mice

Supported by a NIAA (BJA/RCoA) grant WKR0-2017-0066 and WKR0-2019-0067 awarded to T. G. Hales. C. Sneddon and A. Bakina were supported by MRC DTP studentships. S. Singleton and T. G. Hales were supported by a UKRI and vs Arthritis Grant: MR/W002566/1.Exposure to severely stressful events during childhood is associated with poor health outcomes in later life, including chronic pain and substance use disorder. However, the mediators and mechanisms are unclear. We investigated the impact of a well-characterized mouse model of early-life adversity, fragmented maternal care (FC) between postnatal day 2 and 9, on nociception, inflammatory hypersensitivity, and responses to morphine. Male and female mice exposed to FC exhibited prolonged basal thermal withdrawal latencies and decreased mechanical sensitivity. In addition, morphine had reduced potency in mice exposed to FC and their development of tolerance to morphine was accelerated. Quantitative PCR analysis in several brain regions and the spinal cords of juvenile and adult mice revealed an impact of FC on the expression of genes encoding opioid peptide precursors and their receptors. These changes included enhanced abundance of δ opioid receptor transcript in the spinal cord. Acute inflammatory hypersensitivity (induced by hind paw administration of complete Freund's adjuvant) was unaffected by exposure to FC. However, after an initial recovery of mechanical hypersensitivity, there was a reappearance in mice exposed to FC by day 15, which was not seen in control mice. Changes in nociception, morphine responses, and hypersensitivity associated with FC were apparent in males and females but were absent from mice lacking δ receptors or β-arrestin2. These findings suggest that exposure to early-life adversity in mice enhances δ receptor expression leading to decreased basal sensitivity to noxious stimuli coupled with accelerated morphine tolerance and enhanced vulnerability to persistent inflammatory hypersensitivity.Publisher PDFPeer reviewe

Fermion Production in the Background of Minkowski Space Classical Solutions in Spontaneously Broken Gauge Theory

We investigate fermion production in the background of Minkowski space solutions to the equations of motion of $SU(2)$ gauge theory spontaneously broken via the Higgs mechanism. First, we attempt to evaluate the topological charge $Q$ of the solutions. We find that for solutions $Q$ is not well-defined as an integral over all space-time. Solutions can profitably be characterized by the (integer-valued) change in Higgs winding number $\Delta N_H$. We show that solutions which dissipate at early and late times and which have nonzero $\Delta N_H$ must have at least the sphaleron energy. We show that if we couple a quantized massive chiral fermion to a classical background given by a solution, the number of fermions produced is $\Delta N_H$, and is not related to $Q$.Comment: Version to be published. Argument showing that the topological charge of solutions is undefined has been strengthened and clarified. Conclusions unchange

The transcription factor PPARα is overexpressed and is associated with a favourable prognosis in IDH-wildtype primary glioblastoma

© 2016 John Wiley & Sons Ltd Aims: PPARα agonists are in current clinical use as hypolipidaemic agents and show significant antineoplastic effects in human glioblastoma models. To date however, the expression of PPARα in large-scale glioblastoma datasets has not been examined. We aimed to investigate the expression of the transcription factor PPARα in primary glioblastoma, the relationship between PPARα expression and patients’ clinicopathological features and other molecular markers associated with gliomagenesis. Methods and results: With protein immunoblotting techniques and reverse transcription quantitative real-time PCR, PPARα was found to be significantly overexpressed in glioblastoma compared with control brain tissue (P = 0.032 and P = 0.005). PPARA gene expression was found to be enriched in the classical glioblastoma subtype within The Cancer Genome Atlas (TCGA) dataset. Although not associated with overall survival when assessed by immunohistochemistry, cross-validation with the TCGA dataset and multivariate analyses identified PPARA gene expression as an independent prognostic marker for overall survival (P = 0.042). Finally, hierarchical clustering revealed novel, significant associations between high PPARA expression and a putative set of glioblastoma molecular mediators including EMX2, AQP4, and NTRK2. Conclusions: PPARα is overexpressed in primary glioblastoma and high PPARA expression functions as an independent prognostic marker in the glioblastoma TCGA dataset. Further studies are required to explore genetic associations with high PPARA expression and to analyse the predictive role of PPARα expression in glioblastoma models in response to PPARα agonists

Healthcare workers' perceptions and attitudes towards the UK's COVID-19 vaccination programme: a rapid qualitative appraisal

OBJECTIVES: While there is research relating to perceptions of vaccines among healthcare workers (HCWs), the evidence base in relation to COVID-19 remains limited. The aim of this study was to explore HCWs' perceptions and attitudes towards vaccines and the COVID-19 vaccination programme in the UK, including their expectations and views on promoting vaccination to others. DESIGN: This study was designed as a rapid qualitative appraisal, integrating data from a review of UK policies and guidance on COVID-19 vaccination with data from in-depth semistructured telephone interviews with frontline HCWs in the UK. Data were analysed using framework analysis. PARTICIPANTS: Interviews were carried out with a purposive sample of HCWs from two large London-based hospital Trusts (n=24) and 24 government policies, and guidelines on the vaccination programme were reviewed. RESULTS: The level of uncertainty about the long-term safety of vaccines and efficacy against mutant strains made it difficult for HCWs to balance the benefits against the risks of vaccination. HCWs felt that government decisions on vaccine rollout had not been supported by evidence-based science, and this impacted their level of trust and confidence in the programme. The spread of misinformation online also impacted HCWs' attitudes towards vaccination, particularly among junior level and black, Asian and minority ethnic (BAME) HCWs. Most HCWs felt encouraged to promote vaccination to their patients, and the majority said they would advocate vaccination or engage in conversations about vaccination with others when relevant. CONCLUSION: In order to improve HCWs' trust and confidence in the UK's COVID-19 vaccination programme, there needs to be clarity about what is known and not known about the vaccines and transparency around the evidence-base supporting government decisions on vaccine rollout. Effort is also needed to dispel the spread of vaccine-related misinformation online and to address specific concerns, particularly among BAME and junior-level HCWs

Healthcare workers’ perceptions and attitudes towards the UK’s COVID-19 vaccination programme: a rapid qualitative appraisal

Objectives While there is research relating to perceptions of vaccines among healthcare workers (HCWs), the evidence base in relation to COVID-19 remains limited. The aim of this study was to explore HCWs’ perceptions and attitudes towards vaccines and the COVID-19 vaccination programme in the UK, including their expectations and views on promoting vaccination to others. Design This study was designed as a rapid qualitative appraisal, integrating data from a review of UK policies and guidance on COVID-19 vaccination with data from in-depth semistructured telephone interviews with frontline HCWs in the UK. Data were analysed using framework analysis. Participants Interviews were carried out with a purposive sample of HCWs from two large London-based hospital Trusts (n=24) and 24 government policies, and guidelines on the vaccination programme were reviewed. Results The level of uncertainty about the long-term safety of vaccines and efficacy against mutant strains made it difficult for HCWs to balance the benefits against the risks of vaccination. HCWs felt that government decisions on vaccine rollout had not been supported by evidence-based science, and this impacted their level of trust and confidence in the programme. The spread of misinformation online also impacted HCWs’ attitudes towards vaccination, particularly among junior level and black, Asian and minority ethnic (BAME) HCWs. Most HCWs felt encouraged to promote vaccination to their patients, and the majority said they would advocate vaccination or engage in conversations about vaccination with others when relevant. Conclusion In order to improve HCWs’ trust and confidence in the UK’s COVID-19 vaccination programme, there needs to be clarity about what is known and not known about the vaccines and transparency around the evidence-base supporting government decisions on vaccine rollout. Effort is also needed to dispel the spread of vaccine-related misinformation online and to address specific concerns, particularly among BAME and junior-level HCWs

The 2015 Global Climate Legislation Study: a review of climate change legislation in 99 countries: summary for policy-makers

This report summarises the main insights from the 2015 Global Climate Legislation Study. It is the fifth edition in a series dating back to 2010 (Townshend et al., 2011). The 2015 edition covers 98 countries plus the EU, up from 66 in 2014, which together account for 93 per cent of global greenhouse gas emissions. The study is intended as a source of information for legislators, researchers and policy-makers. It is hoped that parliaments considering climate change legislation will benefit from the growing body of experience reflected in the study. Facilitating knowledge exchange among parliamentarians was one of the primary motivations behind the Climate Legislation Study when the series was conceived by the Grantham Research Institute, LSE and GLOBE International in 2010. Since then there have been many examples of parliamentarians learning from, and being inspired by, each other through forums such as GLOBE and the Inter-Parliamentary Union – the two co-sponsors of the 2015 study

Denial of long-term issues with agriculture on tropical peatlands will have devastating consequences

Non peer reviewe

SARS-CoV-2 Omicron is an immune escape variant with an altered cell entry pathway

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant