Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn(−/−);SMN2(tg/0);SMN1(SC)). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms

Solastalgia mediates between bushfire impact and mental health outcomes: A study of Australia\u27s 2019–2020 bushfire season

In 2019–2020, Australia experienced an unprecedented bushfire season that caused widespread environmental destruction across the continent, and especially to its south-east corner. Over two studies, we examine mental health outcomes of individuals impacted by bushfire, drawing on the concept of solastalgia – the sense of distress arising from unwanted environmental change – as a potential explanation for the mental health consequences of bushfire. In Study 1, we surveyed 2084 residents from the Australian Capital Territory and surrounding regions directly after the bushfire season. Participants were asked about exposure to the 2019–2020 bushfires, and to a previous regional fire of significance, experience of solastalgia, and five mental health indicators. In Study 2, we broaden our focus to all of Australia, and administer our measures with a nationally representative sample six months after the conclusion of the bushfire season (N = 1477). In both studies, we find the severity of reported bushfire impact is significantly associated with mental health, such that greater impact predicts poorer outcomes. Moreover, we find the experience of solastalgia mediates the relationship between bushfire impact and mental health and wellbeing. Experiencing solastalgia is a partial, but important, mechanism for understanding the impact of bushfire exposure on mental health and wellbeing. Importantly, people not directly impacted by a bushfire event also experience solastalgia and subsequent poorer mental health outcomes following bushfires. We suggest that future measurements of the impact of abrupt environmental change events, including bushfires, consider the role of solastalgia and localised environmental contexts in shaping the mental health impacts to the population

Transcriptome signatures of wastewater effluent exposure in larval zebrafish vary with seasonal mixture composition in an effluent-dominated stream

Wastewater treatment plant (WWTP) effluent-dominated streams provide critical habitat for aquatic and terrestrial organisms but also continually expose them to complex mixtures of pharmaceuticals that can potentially impair growth, behavior, and reproduction. Currently, few biomarkers are available that relate to pharmaceutical-specific mechanisms of action. In the experiment reported in this paper, zebrafish (Danio rerio) embryos at two developmental stages were exposed to water samples from three sampling sites (0.1 km upstream of the outfall, at the effluent outfall, and 0.1 km below the outfall) during base-flow conditions from two months (January and May) of a temperate-region effluent-dominated stream containing a complex mixture of pharmaceuticals and other contaminants of emerging concern. RNA-sequencing identified potential biological impacts and biomarkers of WWTP effluent exposure that extend past traditional markers of endocrine disruption. Transcriptomics revealed changes to a wide range of biological functions and pathways including cardiac, neurological, visual, metabolic, and signaling pathways. These transcriptomic changes varied by developmental stage and displayed sensitivity to variable chemical composition and concentration of effluent, thus indicating a need for stage-specific biomarkers. Some transcripts are known to be associated with genes related to pharmaceuticals that were present in the collected samples. Although traditional biomarkers of endocrine disruption were not enriched in either month, a high estrogenicity signal was detected upstream in May and implicates the presence of unidentified chemical inputs not captured by the targeted chemical analysis. This work reveals associations between bioeffects of exposure, stage of development, and the composition of chemical mixtures in effluent-dominated surface water. The work underscores the importance of measuring effects beyond the endocrine system when assessing the impact of bioactive chemicals in WWTP effluent and identifies a need for non-targeted chemical analysis when bioeffects are not explained by the targeted analysis

The Brief Solastalgia Scale: A Psychometric Evaluation and Revision

Witnessing degradation and loss to one’s home environment can cause the negative emotional experience of solastalgia. We review the psychometric properties of the 9-item Solastalgia subscale from the Environmental Distress Scale (Higginbotham et al. (EcoHealth 3:245–254, 2006)). Using data collected from three large, independent, adult samples (N = 4229), who were surveyed soon after the 2019/20 Australian bushfires, factor analyses confirmed the scale’s unidimensionality, while analyses derived from Item Response Theory highlighted the poor psychometric performance and redundant content of specific items. Consequently, we recommend a short-form scale consisting of five items. This Brief Solastalgia Scale (BSS) yielded excellent model fit and internal consistency in both the initial and cross-validation samples. The BSS and its parent version provide very similar patterns of associations with demographic, health, life satisfaction, climate emotion, and nature connectedness variables. Finally, multi-group confirmatory factor analysis demonstrated comparable construct architecture (i.e. configural, metric, and scalar invariance) across validation samples, gender categories, and age. As individuals and communities increasingly confront and cope with climate change and its consequences, understanding related emotional impacts is crucial. The BSS promises to aid researchers, decision makers, and practitioners to understand and support those affected by negative environmental change

Strong chemical tagging with APOGEE: 21 candidate star clusters that have dissolved across the Milky Way disc

Chemically tagging groups of stars born in the same birth cluster is a major goal of spectroscopic surveys. To investigate the feasibility of such strong chemical tagging, we perform a blind chemical tagging experiment on abundances measured from APOGEE survey spectra. We apply a density-based clustering algorithm to the eight dimensional chemical space defined by [Mg/Fe], [Al/Fe], [Si/Fe], [K/Fe], [Ti/Fe], [Mn/Fe], [Fe/H], and [Ni/Fe], abundances ratios which together span multiple nucleosynthetic channels. In a high quality sample of 182,538 giant stars, we detect twenty-one candidate clusters with more than fifteen members. Our candidate clusters are more chemically homogeneous than a population of non-member stars with similar [Mg/Fe] and [Fe/H], even in abundances not used for tagging. Group members are consistent with having the same age and fall along a single stellar-population track in logg vs. Teff space. Each group's members are distributed over multiple kpc, and the spread in their radial and azimuthal actions increases with age. We qualitatively reproduce this increase using N-body simulations of cluster dissolution in Galactic potentials that include transient winding spiral arms. Observing our candidate birth clusters with high-resolution spectroscopy in other wavebands to investigate their chemical homogeneity in other nucleosynthetic groups will be essential to confirming the efficacy of strong chemical tagging. Our initially spatially-compact but now widely dispersed candidate clusters will provide novel limits on chemical evolution and orbital diffusion in the Galactic disc, and constraints on star formation in loosely-bound groups.Comment: 15 pages, 9 figures, accepted by MNRA

Clinical and cost effectiveness of single stage compared with two stage revision for hip prosthetic joint infection (INFORM):pragmatic, parallel group, open label, randomised controlled trial

OBJECTIVES: To determine whether patient reported outcomes improve after single stage versus two stage revision surgery for prosthetic joint infection of the hip, and to determine the cost effectiveness of these procedures. DESIGN: Pragmatic, parallel group, open label, randomised controlled trial. SETTING: High volume tertiary referral centres or orthopaedic units in the UK (n=12) and in Sweden (n=3), recruiting from 1 March 2015 to 19 December 2018. PARTICIPANTS: 140 adults (aged ≥18 years) with a prosthetic joint infection of the hip who required revision (65 randomly assigned to single stage and 75 to two stage revision). INTERVENTIONS: A computer generated 1:1 randomisation list stratified by hospital was used to allocate participants with prosthetic joint infection of the hip to a single stage or a two stage revision procedure. MAIN OUTCOME MEASURES: The primary intention-to-treat outcome was pain, stiffness, and functional limitations 18 months after randomisation, measured by the Western Ontario and McMasters Universities Osteoarthritis Index (WOMAC) score. Secondary outcomes included surgical complications and joint infection. The economic evaluation (only assessed in UK participants) compared quality adjusted life years and costs between the randomised groups. RESULTS: The mean age of participants was 71 years (standard deviation 9) and 51 (36%) were women. WOMAC scores did not differ between groups at 18 months (mean difference 0.13 (95% confidence interval -8.20 to 8.46), P=0.98); however, the single stage procedure was better at three months (11.53 (3.89 to 19.17), P=0.003), but not from six months onwards. Intraoperative events occurred in five (8%) participants in the single stage group and 20 (27%) in the two stage group (P=0.01). At 18 months, nine (14%) participants in the single stage group and eight (11%) in the two stage group had at least one marker of possible ongoing infection (P=0.62). From the perspective of healthcare providers and personal social services, single stage revision was cost effective with an incremental net monetary benefit of £11 167 (95% confidence interval £638 to £21 696) at a £20 000 per quality adjusted life years threshold (£1.0; $1.1; €1.4). CONCLUSIONS: At 18 months, single stage revision compared with two stage revision for prosthetic joint infection of the hip showed no superiority by patient reported outcome. Single stage revision had a better outcome at three months, fewer intraoperative complications, and was cost effective. Patients prefer early restoration of function, therefore, when deciding treatment, surgeons should consider patient preferences and the cost effectiveness of single stage surgery. TRIAL REGISTRATION: ISRCTN registry ISRCTN10956306.RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.Unknow