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The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes 1 , 2 . Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site 3 . MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies 4 . Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies 5 and Parkinson’s disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces—whereas silencing MAPT-AS1 expression increases—neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1 . These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs 6 , with particular relevance for proteostasis in neurodegeneration. The natural antisense transcript MAPT-AS1 interferes with translation of mRNA transcript into tau protein in the brain and may represent a general mechanism for controlling levels of intrinsically disordered proteins, with particular relevance for neurodegeneration.

In cross-platform analyses of 174 metabolites, we identify 499 associations ( P  < 4.9 × 10 −10 ) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights. A large-scale genome-wide meta-analysis conducted across different platforms identifies genetic loci regulating levels of circulating metabolites.

Insights into the architecture and stoichiometry of membrane complexes have grown with advances in cryo–electron microscopy and native mass spectroscopy. However, most of these studies are not in the context of native membrane. Chorev et al. released intact membrane complexes directly from native lipid membrane vesicles into a mass spectrometer. They analyzed components of the Escherichia coli inner and outer membranes and the bovine mitochondrial inner membrane. For several identified complexes, they found a stoichiometry that differs from published results and, in some cases, confirmed interactions that could not be characterized structurally. Science , this issue p. 829 Mass spectra reveal the composition of complexes ejected directly from native cellular membrane environments. Membrane proteins reside in lipid bilayers and are typically extracted from this environment for study, which often compromises their integrity. In this work, we ejected intact assemblies from membranes, without chemical disruption, and used mass spectrometry to define their composition. From Escherichia coli outer membranes, we identified a chaperone-porin association and lipid interactions in the β-barrel assembly machinery. We observed efflux pumps bridging inner and outer membranes, and from inner membranes we identified a pentameric pore of TonB, as well as the protein-conducting channel SecYEG in association with F 1 F O adenosine triphosphate (ATP) synthase. Intact mitochondrial membranes from Bos taurus yielded respiratory complexes and fatty acid–bound dimers of the ADP (adenosine diphosphate)/ATP translocase (ANT-1). These results highlight the importance of native membrane environments for retaining small-molecule binding, subunit interactions, and associated chaperones of the membrane proteome.

Meteorological and hydrological hazards present challenges to people and ecosystems worldwide, but the limited length of observational data means that the possible extreme range is not fully understood. Here, a large ensemble of climate model data is combined with a simple grid-based hydrological model to assess unprecedented but plausible hydrological extremes in the current climate across England. Two case studies are selected – dry (summer 2022) and wet (autumn 2023) – with the hydrological model initialised from known conditions and then run forward for several months using the large climate ensemble. The modelling chain provides a large set of plausible events including extremes outside the range from use of observed data, with the lowest flows around 28 % lower on average for the summer 2022 drought study and the highest flows around 42 % higher on average for the autumn 2023 flood study. The temporal evolution and spatial dependence of extremes are investigated, including the potential timescale of the recovery of flows to normal levels and the chance of persistent extremes. Being able to plan for such events could help improve the resilience of water supply systems to drought and improve flood risk management and incident response.

ObjectivesThe Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation.MethodsThe literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC).ResultsNo revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97).ConclusionThe ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions.

Cotadutide is a dual glucagon-like peptide 1 and glucagon receptor agonist under development for the treatment of non-alcoholic steatohepatitis and type 2 diabetes mellitus (T2DM) and chronic kidney disease. Non-alcoholic steatohepatitis is a complex disease with no approved pharmacotherapies, arising from an underlying state of systemic metabolic dysfunction in association with T2DM and obesity. Cotadutide has been shown to improve glycaemic control, body weight, lipids, liver fat, inflammation and fibrosis. We conducted a two-part, randomized phase 2a trial in men and women with overweight or obesity diagnosed with T2DM to evaluate the efficacy and safety of cotadutide compared with placebo and liraglutide. The primary endpoints were change from baseline to day 28 of treatment in postprandial hepatic glycogen (part A) and to day 35 of treatment in fasting hepatic glycogen (part B) with cotadutide versus placebo. Secondary endpoints in part B were changes in fasting hepatic glycogen with cotadutide versus the mono glucagon-like peptide 1 receptor agonist, liraglutide, and change in hepatic fat fraction. The trial met its primary endpoint. We showed that cotadutide promotes greater reductions in liver glycogen and fat compared with placebo and liraglutide. Safety and tolerability findings with cotadutide were comparable to those of previous reports. Thus, this work provides evidence of additional benefits of cotadutide that could be attributed to glucagon receptor engagement. Our results suggest that cotadutide acts on the glucagon receptor in the human liver to promote glycogenolysis and improve the metabolic health of the liver. ClinicalTrials.gov registration: NCT03555994 . In a two-part randomized phase 2a trial in men and women with overweight or obesity and type 2 diabetes mellitus, cotadutide promoted greater reductions in liver glycogen and fat than placebo and liraglutide.

Dementia care requires a wide range of knowledge and skills delivered by both unpaid care partners and health and social care providers. In Ontario, Canada, no systematic framework currently aligns educational content with dementia care competencies. This gap risks the effectiveness of dementia-related education and care delivery. Therefore, this study protocol describes our approach to achieve consensus on the behavioural statements that describe the core competencies required of care partners, health and social care providers involved in dementia care. We will use a two-round modified Delphi method with expert panellists from two groups: (1) care partners with experience caring for someone living with dementia and (2) interprofessional health and social care providers working with people living with dementia. We will purposively recruit up to 80 panellists (40 per group). Panellists will assess standardized behavioural competency statements derived from earlier study phases, rating them on importance and measurability using a nine-point Likert scale. Round 1 will include opportunities for panellists to suggest new statements. Statements reaching ≥70% agreement (rated 7–9 on a 9-point Likert scale) and demonstrating a narrow interquartile range (IQR ≤ 2) will advance to Round 2. In the second round, a higher consensus threshold (≥80%) and stability in ratings (median shift ≤1 point) will determine final inclusion. Qualitative feedback through open-ended questions will be analyzed alongside quantitative results to refine the statements. Findings will support the development of a consensus-based Dementia Care Competency Framework to guide evidence-based educational initiatives and care delivery across settings. This inclusive approach will provide a model for ensuring both lived experience and clinical expertise shape the future of dementia care education in Canada and beyond.

Background: Early warning tools identify patients at risk of deterioration in hospitals. Electronic medical records in hospitals offer real-time data and the opportunity to automate early warning tools and provide real-time, dynamic risk estimates. Objective: This review describes published studies on the development, validation, and implementation of tools for predicting patient deterioration in general wards in hospitals. Methods: An electronic database search of peer reviewed journal papers from 2008-2020 identified studies reporting the use of tools and algorithms for predicting patient deterioration, defined by unplanned transfer to the intensive care unit, cardiac arrest, or death. Studies conducted solely in intensive care units, emergency departments, or single diagnosis patient groups were excluded. Results: A total of 46 publications were eligible for inclusion. These publications were heterogeneous in design, setting, and outcome measures. Most studies were retrospective studies using cohort data to develop, validate, or statistically evaluate prediction tools. The tools consisted of early warning, screening, or scoring systems based on physiologic data, as well as more complex algorithms developed to better represent real-time data, deal with complexities of longitudinal data, and warn of deterioration risk earlier. Only a few studies detailed the results of the implementation of deterioration warning tools. Conclusions: Despite relative progress in the development of algorithms to predict patient deterioration, the literature has not shown that the deployment or implementation of such algorithms is reproducibly associated with improvements in patient outcomes. Further work is needed to realize the potential of automated predictions and update dynamic risk estimates as part of an operational early warning system for inpatient deterioration.

Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P(2df) = 10(-6), GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10(-7)) but not in light coffee-drinkers. The a priori Replication hypothesis that \"Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers\" was confirmed: OR(Replication) = 0.59, P(Replication) = 10(-3); OR(Pooled) = 0.51, P(Pooled) = 7×10(-8). Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10(-3)), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10(-13)). Imputation revealed a block of SNPs that achieved P(2df)<5×10(-8) in GWAIS, and OR = 0.41, P = 3×10(-8) in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.

West Africa and its semi-arid Sahelian region are one of the world’s most vulnerable regions to climate change with a history of extreme climate variability. There is still considerable uncertainty as to how projected climate change will affect precipitation at local and regional scales and the consequent impact on river flows and water resources across West Africa. Here, we aim to address this uncertainty by configuring a regional-scale hydrological model to West Africa. The model (hydrological modelling framework for West Africa—HMF-WA) simulates spatially consistent river flows on a 0.1° × 0.1° grid (approximately 10 km × 10 km) continuously across the whole domain and includes estimates of anthropogenic water use, wetland inundation, and local hydrological features such as endorheic regions. Regional-scale hydrological simulations driven by observed weather data are assessed against observed flows before undertaking an analysis of the impact of projected future climate scenarios from the CMIP5 on river flows up to the end of the twenty-first century. The results indicate that projected future changes in river flows are highly spatially variable across West Africa, particularly across the Sahelian region where the predicted changes are more pronounced. The study shows that median peak flows are projected to decrease by 23% in the west (e.g. Senegal) and increase by 80% in the eastern region (e.g. Chad) by the 2050s. The projected reductions in river flows in western Sahel lead to future droughts and water shortages more likely, while in the eastern Sahel, projected increases lead to future frequent floods.