Single-cell profiling of Anopheles gambiae spermatogenesis defines the onset of meiotic silencing and premeiotic overexpression of the X chromosome

Understanding development and genetic regulation in the Anopheles gambiae germline is essential to engineer effective genetic control strategies targeting this malaria mosquito vector. These include targeting the germline to induce sterility or using regulatory sequences to drive transgene expression for applications such as gene drive. However, only very few germline-specific regulatory elements have been characterised with the majority showing leaky expression. This has been shown to considerably reduce the efficiency of current genetic control strategies, which rely on regulatory elements with more tightly restricted spatial and/or temporal expression. Meiotic silencing of the sex chromosomes limits the flexibility of transgene expression to develop effective sex-linked genetic control strategies. Here, we build on our previous study, dissecting gametogenesis into four distinct cell populations, using single-cell RNA sequencing to define eight distinct cell clusters and associated germline cell–types using available marker genes. We reveal overexpression of X-linked genes in a distinct cluster of pre-meiotic cells and document the onset of meiotic silencing of the X chromosome in a subcluster of cells in the latter stages of spermatogenesis. This study provides a comprehensive dataset, characterising the expression of distinct cell types through spermatogenesis and widening the toolkit for genetic control of malaria mosquitoes

Planum temporale asymmetry in people who stutter

Previous studies have reported that the planum temporale - a language-related structure that normally shows a leftward asymmetry - had reduced asymmetry in people who stutter (PWS) and reversed asymmetry in those with severe stuttering. These findings are consistent with the theory that altered language lateralization may be a cause or consequence of stuttering. Here, we re-examined these findings in a larger sample of PWS. We evaluated planum temporale asymmetry in structural MRI scans obtained from 67 PWS and 63 age-matched controls using: 1) manual measurements of the surface area; 2) voxel-based morphometry to automatically calculate grey matter density. We examined the influences of gender, age, and stuttering severity on planum temporale asymmetry. The size of the planum temporale and its asymmetry were not different in PWS compared with Controls using either the manual or the automated method. Both groups showed a significant leftwards asymmetry on average (about one-third of PWS and Controls showed rightward asymmetry). Importantly, and contrary to previous reports, the degree of asymmetry was not related to stuttering severity. In the manual measurements, women who stutter had a tendency towards rightwards asymmetry but men who stutter showed the same degree of leftwards asymmetry as male Controls. In the automated measurements, Controls showed a significant increase in leftwards asymmetry with age but this relationship was not observed in PWS. We conclude that reduced planum temporale asymmetry is not a prominent feature of the brain in PWS and that the asymmetry is unrelated to stuttering severity. [Abstract copyright: Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Single-cell profiling of mosquito spermatogenesis defines the onset of meiotic silencing and pre-meiotic overexpression of the X chromosome.

Understanding development and genetic regulation in the Anopheles gambiae germline is essential to engineer effective genetic control strategies targeting this malaria mosquito vector. These include targeting the germline to induce sterility or using regulatory sequences to drive transgene expression for applications such as gene drive. However, only very few germline-specific regulatory elements have been characterised with the majority showing leaky expression. This has been shown to considerably reduce the efficiency of current genetic control strategies, which rely on regulatory elements with more tightly restricted spatial and/or temporal expression. Meiotic silencing of the sex chromosomes limits the flexibility of transgene expression to develop effective sex-linked genetic control strategies. Here, we build on our previous study, dissecting gametogenesis into four distinct cell populations, using single-cell RNA sequencing to define eight distinct cell clusters and associated germline cell–types using available marker genes. We reveal overexpression of X-linked genes in a distinct cluster of pre-meiotic cells and document the onset of meiotic silencing of the X chromosome in a subcluster of cells in the latter stages of spermatogenesis. This study provides a comprehensive dataset, characterising the expression of distinct cell types through spermatogenesis and widening the toolkit for genetic control of malaria mosquitoes

Single-cell profiling of mosquito spermatogenesis defines the onset of meiotic silencing and pre-meiotic overexpression of the X chromosome.

Understanding development and genetic regulation in the Anopheles gambiae germline is essential to engineer effective genetic control strategies targeting this malaria mosquito vector. These include targeting the germline to induce sterility or using regulatory sequences to drive transgene expression for applications such as gene drive. However, only very few germline-specific regulatory elements have been characterised with the majority showing leaky expression. This has been shown to considerably reduce the efficiency of current genetic control strategies, which rely on regulatory elements with more tightly restricted spatial and/or temporal expression. Meiotic silencing of the sex chromosomes limits the flexibility of transgene expression to develop effective sex-linked genetic control strategies. Here, we build on our previous study, dissecting gametogenesis into four distinct cell populations, using single-cell RNA sequencing to define eight distinct cell clusters and associated germline cell–types using available marker genes. We reveal overexpression of X-linked genes in a distinct cluster of pre-meiotic cells and document the onset of meiotic silencing of the X chromosome in a subcluster of cells in the latter stages of spermatogenesis. This study provides a comprehensive dataset, characterising the expression of distinct cell types through spermatogenesis and widening the toolkit for genetic control of malaria mosquitoes

Loneliness as an active ingredient in preventing or alleviating youth anxiety and depression : a critical interpretative synthesis incorporating principles from rapid realist reviews

Loneliness is a relatively common problem in young people (14-24 years) and predicts the onset of depression and anxiety. Interventions to reduce loneliness thus have significant potential as active ingredients in strategies to prevent or alleviate anxiety and depression among young people. Previous reviews have focused on quantitative evidence and have not examined potential mechanisms that could be targets for intervention strategies. To build on this work, in this review we aimed to combine qualitative and quantitative evidence with stakeholder views to identify interventions that appear worth testing for their potential effectiveness in reducing loneliness, anxiety and depression in young people aged 14-24 years, and provide insights into the potential mechanisms of action. We conducted a Critical Interpretative Synthesis, a systematic review method that iteratively synthesises qualitative and quantitative evidence and is explicitly focused on building theory through a critical approach to the evidence that questions underlying assumptions. Literature searches were performed using nine databases, and eight additional databases were searched for theses and grey literature. Charity and policy websites were searched for content relevant to interventions for youth loneliness. We incorporated elements of Rapid Realistic Review approaches by consulting with young people and academic experts to feed into search strategies and the resulting conceptual framework, in which we aimed to set out which interventions appear potentially promising in terms of theoretical and empirical underpinnings and which fit with stakeholder views. We reviewed effectiveness data and quality ratings for the included randomised controlled trials only. Through synthesising 27 studies (total participants n = 105,649; range 1-102,072 in different studies) and grey literature, and iteratively consulting with stakeholders, a conceptual framework was developed. A range of Intrapersonal (e.g. therapy that changes thinking and behaviour), Interpersonal (e.g. improving social skills), and Social Strategies (e.g. enhancing social support, and providing opportunities for social contact) seem worth testing further for their potential to help young people address loneliness, thereby preventing or alleviating depression and/or anxiety. Such strategies should be co-designed with young people and personalised to fit individual needs. Plausible mechanisms of action are facilitating sustained social support, providing opportunities for young people to socialise with peers who share similar experiences, and changing thinking and behaviour, for instance through building positive attitudes to themselves and others. The most convincing evidence of effectiveness was found in support of Intrapersonal Strategies: two randomised controlled studies quality-rated as good found decreases in loneliness associated with different forms of therapy (Cognitive Behavioural Therapy or peer network counselling), although power calculations were not reported, and effect sizes were small or missing. Strategies to address loneliness and prevent or alleviate anxiety and depression need to be co-designed and personalised. Promising elements to incorporate into these strategies are social support, including from peers with similar experiences, and psychological therapy.Funding Agencies|UKRI [ES/S004440/1]</p