Silicon isotopes in an Archaean migmatite confirm seawater silicification of TTG sources

Funding: This work was made possible by PhD funding to MM by the University of St Andrews School of Earth and Environmental Sciences and the Handsel scheme, in addition to NERC grant NE/R002134/1 to PS.Unraveling ancient melting processes is key to understanding how the earliest, tonalite-trondhjemite-granodiorite (TTG)-dominated continental crust formed from partial melting of amphibolite. Application of silicon isotope analysis to ancient crust reveals that Archaean TTGs exhibit consistently high Si isotope values (δ30Si) compared to modern granitoids, attributed to seawater-derived silica introduced by either (a) partial melting of variably silicified basalts or (b) assimilation of authigenic silica-rich marine lithologies in the melt source. However, both mechanisms can introduce highly variable δ30Si, conflicting with the strikingly consistent δ30Si compositions of Archaean TTGs. This study investigates an alternative model, whereby the distinct mineralogy and chemistry of TTG melt sources impart a distinct silicon isotope composition to the melt, compared with “modern” granitoids. We measured δ30Si in component parts (melanosome and leucosome) of an Archaean (2.7 Ga) mafic migmatite and coeval amphibolites and mafic granulites from the Kapuskasing uplift, Canada, to explore how Si isotopes fractionate during incipient TTG melt formation. Our data reveal leucosome (i.e., melt) exhibits consistently high δ30Si values compared to a relatively isotopically lighter melanosome (i.e., residuum). We also derive inter-mineral silicon isotope fractionation factors for mineral separates that agree well with those of ab initio estimates for the same minerals and show that the magnitude of equilibrium fractionation between TTG source rock and melt replicates that in Phanerozoic granitoids. We conclude the effects of magmatic differentiation on δ30Si have remained consistent throughout Earth history, meaning that Archaean TTGs must require a source isotopically heavier than unaltered basalt, as reflected by our amphibolites and mafic migmatite components. The consistently heavy δ30Si of seawater through Earth history, and the high SiO2 content of amphibolites relative to coeval leucosome-free granulites in our study area, imply seawater silicification is the source of the observed high δ30Si. Thus, the consistently heavy Si isotope compositions measured in Archaean melt products define a unique aspect of ancient crust formation: that of the silicification of TTG source rock, implying the intrinsic involvement of a primeval hydrosphere.Publisher PDFPeer reviewe

Scotland Registry for Ankylosing Spondylitis (SIRAS) – Protocol

Funding SIRAS was funded by unrestricted grants from Pfizer and AbbVie. The project was reviewed by both companies, during the award process, for Scientific merit, to ensure that the design did not compromise patient safety, and to assess the global regulatory implications and any impact on regulatory strategy.Publisher PD

Collaborative Leadership Is Key for Maine’s Forest Products Industry

The forest products industry is economically, socially, culturally, and environmentally important to Maine. Thus, Maine’s future economy depends greatly on the leadership in this industry. Effective leadership grows out of understanding the changes that are taking place in the industry and finding innovative ways to address unexpected challenges and emerging opportunities. During times of change, many industry leaders settle for maintaining the status quo. The forest products industry in Maine, however, is systematically assessing the ways the landscape is changing. Rather than continuing on the same path, the industry is gathering insights that could lead to a vibrant, but perhaps different, future. What we report here is an innovative process that actively solicits insights reflecting the diverse perspectives of those who work in different subsectors of the industry. What is emerging is evidence of the importance of collective leadership that brings together different areas of knowledge. We report on the process, the emerging findings, and the implications for leadership in moving forward

Glycine transport inhibitors for the treatment of pain.

Opioids, local anesthetics, anticonvulsant drugs, antidepressants, and non-steroidal anti-inflammatory drugs (NSAIDs) are used to provide pain relief but they do not provide adequate pain relief in a large proportion of chronic pain patients and are often associated with unacceptable side effects. Inhibitory glycinergic neurotransmission is impaired in chronic pain states, and this provides a novel target for drug development. Inhibitors of the glycine transporter 2 (GlyT2) enhance inhibitory neurotransmission and show particular promise for the treatment of neuropathic pain. N-arachidonyl-glycine (NAGly) is an endogenous lipid that inhibits glycine transport by GlyT2 and also shows potential as an analgesic, which may be further exploited in drug development. In this review we discuss the role of glycine neurotransmission in chronic pain and future prospects for the use of glycine transport inhibitors in the treatment of pain.NHMRC Grant: 104596

Care-experienced cHildren and young peoples Interventions to improve Mental health and wEll-being outcomes: Systematic review (CHIMES) protocol

Introduction The mental health and well-being of children and young people who have been in care (ie, care-experienced) are a priority. There are a range of interventions aimed at addressing these outcomes, but the international evidence-base remains ambiguous. There is a paucity of methodologically robust systematic reviews of intervention effectiveness, with few considering the contextual conditions under which evaluations were conducted. This is important in understanding the potential transferability of the evidence-base across contexts. The present systematic review will adopt a complex systems perspective to synthesise evidence reporting evaluations of mental health and well-being interventions for care-experienced children and young people. It will address impact, equity, cost-effectiveness, context, implementation and acceptability. Stakeholder consultation will prioritise a programme theory, and associated intervention, that may progress to further development and evaluation in the UK. Methods and analysis We will search 16 bibliographic databases from 1990 to June 2020. Supplementary searching will include citation tracking, author recommendation, and identification of evidence clusters relevant to included evaluations. The eligible population is children and young people (aged ≤25 years) with experience of being in care. Outcomes are (1) mental, behavioural or neurodevelopmental disorders; (2) subjective well-being; (3) self-harm; suicidal ideation; suicide. Study quality will be appraised with methodologically appropriate tools. We will construct a taxonomy of programme theories and intervention types. Thematic synthesis will be used for qualitative data reporting context, implementation and acceptability. If appropriate, meta-analysis will be conducted with outcome and economic data. Convergent synthesis will be used to integrate syntheses of qualitative and quantitative data. Ethics and dissemination We have a comprehensive strategy for engagement with care-experienced children and young people, carers and social care professionals. Dissemination will include academic and non-academic publications and conference presentations. Ethical approval from Cardiff University’s School of Social Sciences REC will be obtained if necessary

Mutation detection in cholestatic patients using microarray resequencing of ATP8B1 and ABCB11

© 2013 McKay KE et al. Background: Neonatal cholestasis is a common presentation of childhood liver diseases and can be a feature of various conditions including disorders of bile acid biogenesis and transport, various inborn errors of metabolism and perinatal infections. Some inherited metabolic diseases can be easily screened using biochemical assays, however many can only be accurately diagnosed by DNA sequencing. Fluorescent capillary Sanger sequencing (FS) is the gold standard method used by clinical laboratories for genetic diagnosis of many inherited conditions; however, it does have limitations. Recently microarray resequencing (MR) has been introduced into research and clinical practice as an alternative method for genetic diagnosis of heterogeneous conditions. In this report we compared the accuracy of mutation detection for MR with FS in a group of patients with 'low-normal' gamma glutamyl transpeptidase (gGT) cholestasis without known molecular diagnoses. Methods: 29 patient DNA samples were tested for mutations in the ATP8B1 and ABCB11 genes using both FS and MR. Other known causes of "low gGT cholestasis such as ARC syndrome and bile acid biosynthesis disorders were excluded. Results: Mutations were identified in 13/29 samples. In 3/29 samples FS and MR gave discordant results: MR had a false positive rate of 3.4% and a false negative rate of 7%. Conclusions: The major advantage of MR over FS is that multiple genes can be screened in one experiment, allowing rapid and cost-effective diagnoses. However, we have demonstrated that MR technology is limited in sensitivity. We therefore recommend that MR be used as an initial evaluation, with FS deployed when genetic and clinical or histopathological findings are discordant

Huntington’s disease age at motor onset is modified by the tandem hexamer repeat in TCERG1

Huntington’s disease is caused by an expanded CAG tract in HTT. The length of the CAG tract accounts for over half the variance in age at onset of disease, and is influenced by other genetic factors, mostly implicating the DNA maintenance machinery. We examined a single nucleotide variant, rs79727797, on chromosome 5 in the TCERG1 gene, previously reported to be associated with Huntington’s disease and a quasi-tandem repeat (QTR) hexamer in exon 4 of TCERG1 with a central pure repeat. We developed a method for calling perfect and imperfect repeats from exome-sequencing data, and tested association between the QTR in TCERG1 and residual age at motor onset (after correcting for the effects of CAG length in the HTT gene) in 610 individuals with Huntington’s disease via regression analysis. We found a significant association between age at onset and the sum of the repeat lengths from both alleles of the QTR (p = 2.1 × 10−9), with each added repeat hexamer reducing age at onset by one year (95% confidence interval [0.7, 1.4]). This association explained that previously observed with rs79727797. The association with age at onset in the genome-wide association study is due to a QTR hexamer in TCERG1, translated to a glutamine/alanine tract in the protein. We could not distinguish whether this was due to cis-effects of the hexamer repeat on gene expression or of the encoded glutamine/alanine tract in the protein. These results motivate further study of the mechanisms by which TCERG1 modifies onset of HD

Bone marrow-derived and resident liver macrophages display unique transcriptomic signatures but similar biological functions

Abstract: Background and aims: Kupffer cells (KCs), the resident tissue macrophages of the liver, play a crucial role in the clearance of pathogens and other particulate materials that reach the systemic circulation. Recent studies have identified KCs as a yolk sac-derived resident macrophage population that is replenished independently of monocytes in the steady state. Although it is now established that following local tissue injury, bone-marrow derived monocytes may infiltrate the tissue and differentiate into macrophages, the extent to which newly differentiated macrophages functionally resemble the KCs they have replaced has not been extensively studied. Methods and results: Here we show using intravital microscopy, morphometric analysis and gene expression profiling that bone marrow derived “KCs” accumulating as a result of genotoxic injury resemble, but are not identical to their yolk-sac (YS) counterparts. An ion homeostasis gene signature, including genes associated with scavenger receptor function and extracellular matrix deposition, allows discrimination between these two KC populations. Reflecting the differential expression of scavenger receptors, YS-derived KCs were more effective at accumulating Ac-LDL, whereas surprisingly they were poorer than BM-derived KCs when assessed for uptake of a range of bacterial pathogens. The two KC populations were almost indistinguishable in regard to i) response to LPS challenge, ii) phagocytosis of effete RBCs and iii) their ability to contain infection and direct granuloma formation against Leishmania donovani, a KC-tropic intracellular parasite. Conclusions: BM-derived KCs differentiate locally to resemble YS-derived KC in most but not all respects, with implications for models of infectious diseases, liver injury and bone marrow transplantation. In addition, the gene signature we describe adds to the tools available for distinguishing KC subpopulations based on their ontology

Mental health and wellbeing interventions for care-experienced children and young people: Systematic review and synthesis of process evaluations

Background The mental health and well-being of care-experienced children and young people remains a concern. Despite a range of interventions, the existing evidence base is limited in scope, with a reliance on standalone outcome evaluations which limits understanding of how contextual factors influence implementation and acceptability. The Care-experienced cHildren and young people’s Interventions to improve Mental health and wEll-being outcomes Systematic review (CHIMES) aimed to synthesise evidence of intervention theory, outcome, process and economic effectiveness. This paper reports the process evaluation synthesis, exploring how system factors facilitate and inhibit implementation and acceptability of mental health and wellbeing interventions for care-experienced children and young people. Methods Sixteen databases and 22 websites were searched between 2020 and 2022 for studies published from 1990 and May 2022. This was supplemented with contacting experts in the field, citation tracking, screening of relevant systematic reviews and stakeholder consultations. We drew on framework synthesis of qualitative data and incorporated a systems lens, taking account of contextual influences across socio-ecological domains. Quality appraisal assessed reliability and usefulness. Confidence in synthesised findings was assessed with the GRADE-CERQual tool. We report the review in accordance with relevant elements of both the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA), and the Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) checklist. Results Searches retrieved 15,068 unique study reports, and 23 of these were eligible for process evaluation synthesis, reporting on sixteen interventions. Studies were published between 2003 and 2021. Nine interventions were from the UK and Ireland, six interventions were from the USA, and one was from Australia. They were largely classified as interpersonal, where the aim was to modify carer-child relationships. Five key context factors were identified that supported and prohibited intervention delivery: (1) lack of system resources; (2) intervention burden, which encompasses the time, cognitive, and emotional burden associated with implementation and participation; (3) interprofessional relationships between health and social care professionals; (4) care-experienced young people’s identity; and (5) carer identity. Conclusion We identified several supportive and restrictive factors across social and health care systems that may impact intervention implementation and acceptability. Key implications include: the importance of involving diverse stakeholders in intervention development and delivery; the need to better resource and support those involved in interventions, particularly training and support for carers; and ensuring future evaluations integrate process evaluations in order to optimise interventions