Specialised information processing deficits and distinct metabolomics profiles following TM-domain disruption of Nrg1

While there is considerable genetic and pathologic evidence for an association between neuregulin 1 (NRG1) dysregulation and schizophrenia, the underlying molecular and cellular mechanisms remain unclear. Mutant mice containing disruption of the transmembrane (TM) domain of the NRG1 gene constitute a heuristic model for dysregulation of NRG1-ErbB4 signalling in schizophrenia. The present study focused on specialised behavioural and characterisation of hitherto un-characterised information processing phenotypes in this mutant line. Using a mass spectrometry-based metabolomics approach, we also quantified levels of unique metabolites in brain. Across two different sites and protocols, Nrg1 mutants demonstrated deficits in pre-pulse inhibition, a measure of sensorimotor gating that is disrupted in schizophrenia; these deficits were partially reversed by acute treatment with second-, but not first-, generation antipsychotic drugs. However, Nrg1 mutants did not show a specific deficit in latent inhibition, a measure of selective attention that is also disrupted in schizophrenia. In contrast, in the ‘what-where-when’ cognitive paradigm, Nrg1 mutants displayed sex-specific (males only) disruption of ‘what-when’ performance, indicative of impaired episodic memory. Differential metabolomic profiling revealed that these behavioural phenotypes were accompanied, most prominently, by alterations in lipid metabolism pathways. This study is the first to associate these novel physiological mechanisms, previously independently identified as being abnormal in schizophrenia, with disruption of NRG1 function. These data suggest novel mechanisms by which compromised neuregulin function from birth might lead to schizophrenia-relevant behavioural changes in adulthood

Geographical and temporal distribution of SARS-CoV-2 clades in the WHO European Region, January to June 2020

We show the distribution of SARS-CoV-2 genetic clades over time and between countries and outline potential genomic surveillance objectives. We applied three available genomic nomenclature systems for SARS-CoV-2 to all sequence data from the WHO European Region available during the COVID-19 pandemic until 10 July 2020. We highlight the importance of real-time sequencing and data dissemination in a pandemic situation. We provide a comparison of the nomenclatures and lay a foundation for future European genomic surveillance of SARS-CoV-2.Peer reviewe

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: A systematic analysis for the Global Burden of Disease Study 2015

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods: We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings: Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation: Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding: Bill & Melinda Gates Foundation

Upper Paleozoic to Jurassic accretionary complex of the Cache Creek Terrane, central British Columbia

International audienceUpper Paleozoic to Lower Jurassic oceanic rocks of the Cache Creek Terrane near Fort St. lames, in central British Columbia, form a semi-organized thrust imbricated complex cut by steeply dipping striking faults. The terrane consists of Tezzeron succession, Cache Creek Complex and Sitlika Assemblage. Tezzeron succession and lhe sedimentary rocks of the Sitlika assemblage appear to be derived from trench fill sediments wilh a volcanic arc provenance during the Upper Triassic to Lower Jurassic. Cache Creek Complex and the volcanic rocks of Sitlika assemblage were derived from an ocean plate active from Late Carboniferous to Early Jurassic time. The floor of the present accretionary complex consists mainly of Permian to Lower Jurassic greywacke, ribbon cbert and minor limestone. Onto these rocks are thrust ophiolitic successions, ocean island and plateau ultramafite, basalt, and limestone, and mixed arc and oceanic basalt. Some of these units are thrust onto trench fill sequences of the Tezzcron and Sitlika. Unlike a mélange, these thrust sheets have some regional consistency and form orogen parallel belts wilhin the Cache Creek Terrane. In the eastern part of the complex, Triassic blueschist metamorphic rocks appear to form thrust slivers within the regionally lower parts of the complex that include the trench fill successions. These thrust sheet units were amalgamated prior to 165 Ma, as they are truncated by plutons of that age. They must have formed at least in part after the youngest of the sedimentary successions. Toarcian (-190Ma) and incorporate subduction generated blueschist wedges of Triassic age

Upper Paleozoic to Jurassic accretionary complex of the Cache Creek Terrane, central British Columbia

International audienceUpper Paleozoic to Lower Jurassic oceanic rocks of the Cache Creek Terrane near Fort St. lames, in central British Columbia, form a semi-organized thrust imbricated complex cut by steeply dipping striking faults. The terrane consists of Tezzeron succession, Cache Creek Complex and Sitlika Assemblage. Tezzeron succession and lhe sedimentary rocks of the Sitlika assemblage appear to be derived from trench fill sediments wilh a volcanic arc provenance during the Upper Triassic to Lower Jurassic. Cache Creek Complex and the volcanic rocks of Sitlika assemblage were derived from an ocean plate active from Late Carboniferous to Early Jurassic time. The floor of the present accretionary complex consists mainly of Permian to Lower Jurassic greywacke, ribbon cbert and minor limestone. Onto these rocks are thrust ophiolitic successions, ocean island and plateau ultramafite, basalt, and limestone, and mixed arc and oceanic basalt. Some of these units are thrust onto trench fill sequences of the Tezzcron and Sitlika. Unlike a mélange, these thrust sheets have some regional consistency and form orogen parallel belts wilhin the Cache Creek Terrane. In the eastern part of the complex, Triassic blueschist metamorphic rocks appear to form thrust slivers within the regionally lower parts of the complex that include the trench fill successions. These thrust sheet units were amalgamated prior to 165 Ma, as they are truncated by plutons of that age. They must have formed at least in part after the youngest of the sedimentary successions. Toarcian (-190Ma) and incorporate subduction generated blueschist wedges of Triassic age