The Cell and Molecular Biology of Neurodegenerative Diseases: An Overview

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Germline variation in ADAMTSL1 is associated with prognosis following breast cancer treatment in young women

To identify genetic variants associated with breast cancer prognosis we conduct a meta-analysis of overall survival (OS) and disease-free survival (DFS) in 6042 patients from four cohorts. In young women, breast cancer is characterized by a higher incidence of adverse pathological features, unique gene expression profiles and worse survival, which may relate to germline variation. To explore this hypothesis, we also perform survival analysis in 2315 patients agedPeer reviewe

Evaluation of a complex intervention (Engager) for prisoners with common mental health problems, near to and after release: study protocol for a randomised controlled trial.

INTRODUCTION: The 'Engager' programme is a 'through-the-gate' intervention designed to support prisoners with common mental health problems as they transition from prison back into the community. The trial will evaluate the clinical and cost-effectiveness of the Engager intervention. METHODS AND ANALYSIS: The study is a parallel two-group randomised controlled trial with 1:1 individual allocation to either: (a) the Engager intervention plus standard care (intervention group) or (b) standard care alone (control group) across two investigation centres (South West and North West of England). Two hundred and eighty prisoners meeting eligibility criteria will take part. Engager is a person-centred complex intervention delivered by practitioners and aimed at addressing offenders' mental health and social care needs. It comprises one-to-one support for participants prior to release from prison and for up to 20 weeks postrelease. The primary outcome is change in psychological distress measured by the Clinical Outcomes in Routine Evaluation-Outcome Measure at 6 months postrelease. Secondary outcomes include: assessment of subjective met/unmet need, drug and alcohol use, health-related quality of life and well-being-related quality of life measured at 3, 6 and 12 months postrelease; change in objective social domains, drug and alcohol dependence, service utilisation and perceived helpfulness of services and change in psychological constructs related to desistence at 6 and 12 months postrelease; and recidivism at 12 months postrelease. A process evaluation will assess fidelity of intervention delivery, test hypothesised mechanisms of action and look for unintended consequences. An economic evaluation will estimate the cost-effectiveness. ETHICS AND DISSEMINATION: This study has been approved by the Wales Research Ethics Committee 3 (ref: 15/WA/0314) and the National Offender Management Service (ref: 2015-283). Findings will be disseminated to commissioners, clinicians and service users via papers and presentations. TRIAL REGISTRATION NUMBER: ISRCTN11707331; Pre-results

The aggradation of alluvial fans in response to monsoon variability over the last 400 ka in the Hajar Mountains, south-east Arabia

The preservation and interpretation of past external forcings within sedimentary archives can be complicated. Marine proxy records show that, throughout the Mid-Late Quaternary, monsoon rainfall in south-east Arabia has varied at precessional timescales (∼ 23 ka). By contrast, terrestrial environmental records from the region, such as speleothems and palaeolake sequences, generally only capture rainfall variability at eccentricity (∼ 100 ka) timescales and geomorphological archives rarely record events over multiple glacial cycles. Previous work has suggested that the alluvial fan systems of the Hajar Mountains record aggradation coincident with precessional peaks because of more northerly Indian Ocean Summer Monsoon (IOSM) rainfall, relative to present. However, the alluvial record is complex: there is a growing body of ‘anomalous’ aggradation age data from periods of precessional minima and it is spatially uneven, mainly being derived from fans at either the northern- or southern-most extents of the western side of the mountains. We present optically stimulated luminescence (OSL) ages of alluvial aggradation from new sites in the central portion of the western and eastern sides of the Hajar mountains. Sedimentary units that show evidence of more sustained flow conditions, such as coarse conglomerate deposition and the development of thick floodplain deposits, typically date to periods of higher IOSM rainfall at precessional timescales. Sites where there is evidence of deposition under more ephemeral flow conditions, like today, yield ages corresponding to precessional minima. We synthesise these data with similarly interpreted alluvial and lacustrine deposits from across the region, employing a hierarchical clustering approach to generate clusters of ages representing periods of increased hydrological activity. This objective approach to regional chronological data suggests that ten periods of more sustained hydrological activity are evidenced across the Hajar region, broadly aligning to precessional and eccentricity peaks over the last 400 ka. These clusters show that Hajar fans predominately aggrade because of increasing rainfall over their catchments, with the central ages of clusters often aligning with the onset of precessional forcing. Hajar alluvial systems preserve important records of Quaternary climate variability over long timescales in an arid region where terrestrial records are scarce due to preservation issues

The pharmacological regulation of cellular mitophagy

Small molecules are pharmacological tools of considerable value for dissecting complex biological processes and identifying potential therapeutic interventions. Recently, the cellular quality-control process of mitophagy has attracted considerable research interest; however, the limited availability of suitable chemical probes has restricted our understanding of the molecular mechanisms involved. Current approaches to initiate mitophagy include acute dissipation of the mitochondrial membrane potential (ΔΨm) by mitochondrial uncouplers (for example, FCCP/CCCP) and the use of antimycin A and oligomycin to impair respiration. Both approaches impair mitochondrial homeostasis and therefore limit the scope for dissection of subtle, bioenergy-related regulatory phenomena. Recently, novel mitophagy activators acting independently of the respiration collapse have been reported, offering new opportunities to understand the process and potential for therapeutic exploitation. We have summarized the current status of mitophagy modulators and analyzed the available chemical tools, commenting on their advantages, limitations and current applications

Re‐analysis of late Quaternary dust mass accumulation rates in Serbia using new luminescence chronology for loess–palaeosol sequence at Surduk

Despite numerous palaeoenvironmental investigations of loess–palaeosol sequences across the Carpathian Basin, well‐dated high‐resolution records are scarce. This paper presents a new high‐resolution chronology for the loess‐palaeosol sequence at Surduk (Serbia), based on optically stimulated luminescence (quartz) and post‐infrared infrared stimulated luminescence (polymineral) dating. The presented record spans 53–19 ka, with primary loess deposition occurring after 52±2 ka, and differs from previously published chronologies that relied on less precise and now superseded dating protocols. Based on the new chronology, mass accumulation rates (MAR s) for Surduk were constructed and compared with sites in the Carpathian Basin. The results demonstrate that accumulation periods across this area are not consistent in timing or rates. The high‐resolution dating strategy identifies a disturbance in sediment deposition that occurred after 45±2 ka and implies that site contains a hiatus. Finally, we show samples that failed routine dose recovery and preheat plateau tests, and had low fast ratios. Supported by bulk sample geochemical analysis it is proposed that a potential abrupt source shift, during the Last Glacial Maximum, may be the cause of the anomalous luminescence behaviour

Women's secure hospital care pathways in practice: a qualitative analysis of clinicians views in England and Wales

BACKGROUND: In England and Wales women form a small but significant group within the wider, largely male, secure hospital population. Secure hospitals are designed to assess and treat individuals with both mental health problems and significant criminal behaviour. The theoretical approach to the care of secure hospital women is increasingly informed by a grasp of gender-specific issues. However, there is a lack of evidence on the adequacy of current structures and processes of care delivery. METHODS: This qualitative study explores the nature and quality of care pathways for women in low and medium secure hospital beds by eliciting participants' views of factors enhancing or impeding care. Beds are publicly funded and provided either by the National Health Service (NHS) or the Independent Sector (IS). Participants from both sectors were local experts (40 Consultant Psychiatrists, 7 Service Managers) who were well placed to describe their immediate health environment. RESULTS: Evidence from the study indicates that participants were focused on the physical relocation of women to less secure conditions, even though many women do not readily achieve this.Participants were alert to potential conflicts between ideal care and affordable care. Ideal care was compromised by the absence of suitable local services (beds or community placements), curtailed episodes of care and changes of care team. It was promoted by an awareness of the specific needs of women, continuity of care and support for teams unfamiliar with women's needs. CONCLUSION: Future service design must address these challenges in care delivery, incorporating a better understanding of and response to the ways the system can echo women's experiences of trauma and their negative attachment histories. Specifically, critical transitions in care must not be allowed to further reinforce the discontinuity, failure and rejection experienced by individual women earlier in their lives

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Comparing the Importance of Iodine and Isoprene on Tropospheric Photochemistry

Isoprene, arguably the most studied biogenically emitted gas, is thought to have a large impact on tropospheric composition. Other naturally emitted species have been considered to play a less important role. Here the GEOS-Chem model is used to compare the impacts of isoprene and iodine emissions on present-day tropospheric composition. Removing isoprene emissions leads to a 3.4 burden, a smaller absolute change than the 5.9+0.60.05 whereas isoprene has a substantial impact on both (−4.34.2. Isoprene emissions and chemistry are seen as essential for tropospheric chemistry models, but iodine is often not. We suggest that iodine should receive greater attention in model development and experimental research to allow improved predictions of past, present, and future tropospheric O3

Genome-wide association study of germline variants and breast cancer-specific mortality.

BackgroundWe examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.MethodsMeta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).ResultsWe did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.ConclusionsWe uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients