Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei‐like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

Genetic correlations and genome-wide associations of cortical structure in general population samples of 22824 adults

Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging

Geological history of the Winchcombe meteorite - A new cm Chrondrite fall

Introduction: The Mighei-like (CM) carbonaceous chondrites are the largest class of hydrated meteorites, representing collisionally derived fragments of water-rich asteroids [1,2]. Most (>95%) are breccias, whose clasts sample a range of aqueous alteration extents [3]. They can therefore act as “snapshots” recording the progression of fluidrock interaction on the CM parent body. Conversely, analysis of the material between clasts (termed cataclastic matrix) provides an opportunity to study the post-hydration history of the CM parent body, specifically its fragmentation and re-accretion. Here, we investigate both aspects of the CM chondrites’ geological history through study of the newly recovered fall: Winchcombe [4, 5]. Methods: Sixteen polished sections with a total area of 190 mm2 were generated for this work. They were studied under scanning electron microscopy (SEM) using backscattered electron (BSE) imaging, energy dispersive X-ray spectroscopy (EDX) and electron microprobe analysis (EMPA). These sections sample the two largest masses (the main mass [320 g] and the agricultural field stone [152 g]) recovered from the Winchcombe strewn field [4]. Results: Winchcombe is a breccia, composed of lithological clasts held within a cataclastic matrix. We identified eight distinct lithologies. Their aqueous alteration extents vary between intensely altered CM2.0 and moderately altered CM2.6 [6]. Although no lithology dominates, three rock types represent >70% of the studied area. Several lithologies contain abundant tochilinite-cronstedtite intergrowths (TCIs). Type-II forms with zoned textures are most common, typically they have Fe-rich rims (“FeO”/SiO2 wt.%: 1-5) and Mg-rich cores (“FeO”/SiO2 wt.%: < 1), however, forms with hollow cores or cores containing a mix of phyllosilicate and calcite or phyllosilciates and anhydrous silicate are also found. The cataclastic matrix represents ~15% of the studied area. It has a coarse, heterogenous texture and includes abundant subangular fragments. Fragments include the full range of CM chondrite components (e.g. Fe-sulphides, whole chondrules with or without fine-grained rims, olivine and pyroxene grains, serpentine, carbonate grains, TCI clusters, as well as coherent blocks of fine-grained matrix). The cataclastic matrix is, therefore, a complex mix of components, with both heavily altered and mildly altered phases found in close association. Another striking feature is the apparent low abundance (< 3 area%) of identifiable whole chondrules. Discussion and conclusions: Our data suggest that both anhydrous silicates and carbonates (T1a calcites) act as precursor phases for type-II TCI formation. Cross-cutting relationships allow the sequence of mineralization to be reconstructed. Initially, inward dissolution by Fe-rich and S-rich fluids forms rims composed of intermixed tochilinite and cronstedtite. In the intermediate stages of type-II TCI formation, further dissolution continues without concurrent precipitation, resulting in the formation of hollow structures. These voids were later infilled, most often by Mg-rich phyllosilicates. As alteration advanced, early-formed secondary phases became unstable and were either dissolved (e.g. T1a calcites) or chemically altered (e.g. TCI rims). The presence of numerous lithological clasts with variable aqueous alteration extents and abrupt boundaries found in close juxtaposition indicates that the cataclastic matrix formed by the deposition of fines, alongside larger fragments (the clasts), on or near the surface of the parent asteroid. Furthermore, the composition of the cataclastic matrix is consistent with formation by fragmentation and mixing of debris derived from the entire clast population. The cataclastic matrix is, therefore, interpreted as an impact-derived fallback breccia. Analysis of grain size and texture suggests that disruption of the original parent asteroid responded by intergranular fracture at grain sizes <100 μm, while larger phases, such as whole chondrules, splintered apart. Re-accretion formed a poorly lithified rubble-pile body. During atmospheric entry, the meteoroid broke apart with new fractures preferentially cutting through the weaker cataclastic matrix and thereby separating the Winchcombe meteoroid into its component- lithological clasts. Thus, the strength of the cataclastic matrix imparts a significant control on the survival of CM chondrite meteoroids. References: [1] McSween, 1979. GCA, 43:1761-1770. [2] Suttle et al. 2021. GCA, 299:219-256. [3] Bischoff, et al. 2017, 80th MetSoc. (Abstr.#6089), [4] Meteoritical Bulletin Database, Winchcombe entry (available at: https://www.lpi.usra.edu/meteor/metbull.php?code=74388). [5] Daly et al., (this meeting). [6] Rubin et al. 2007,GCA, 71:2361-2382

The Winchcombe meteorite—A regolith breccia from a rubble pile CM chondrite asteroid

The Winchcombe meteorite is a CM chondrite breccia composed of eight distinct lithological units plus a cataclastic matrix. The degree of aqueous alteration varies between intensely altered CM2.0 and moderately altered CM2.6. Although no lithology dominates, three heavily altered rock types (CM2.1–2.3) represent >70 area%. Tochilinite–cronstedtite intergrowths (TCIs) are common in several lithologies. Their compositions can vary significantly, even within a single lithology, which can prevent a clear assessment of alteration extent if only TCI composition is considered. We suggest that this is due to early alteration under localized geochemical microenvironments creating a diversity of compositions and because later reprocessing was incomplete, leaving a record of the parent body's fluid history. In Winchcombe, the fragments of primary accretionary rock are held within a cataclastic matrix (~15 area%). This material is impact‐derived fallback debris. Its grain size and texture suggest that the disruption of the original parent asteroid responded by intergranular fracture at grain sizes <100 μm, while larger phases, such as whole chondrules, splintered apart. Re‐accretion formed a poorly lithified body. During atmospheric entry, the Winchcombe meteoroid broke apart with new fractures preferentially cutting through the weaker cataclastic matrix and separating the breccia into its component clasts. The strength of the cataclastic matrix imparts a control on the survival of CM chondrite meteoroids. Winchcombe's unweathered state and diversity of lithologies make it an ideal sample for exploring the geological history of the CM chondrite group

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Dissecting the Shared Genetic Architecture of Suicide Attempt, Psychiatric Disorders, and Known Risk Factors

Background Suicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders. Methods We conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors. Results Two loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged. Conclusions Our results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.Peer reviewe

Brecciation at the grain scale within the lithologies of the Winchcombe Mighei-like carbonaceous chondrite

The Mighei‐like carbonaceous (CM) chondrites have been altered to various extents by water–rock reactions on their parent asteroid(s). This aqueous processing has destroyed much of the primary mineralogy of these meteorites, and the degree of alteration is highly heterogeneous at both the macroscale and nanoscale. Many CM meteorites are also heavily brecciated juxtaposing clasts with different alteration histories. Here we present results from the fine‐grained team consortium study of the Winchcombe meteorite, a recent CM chondrite fall that is a breccia and contains eight discrete lithologies that span a range of petrologic subtypes (CM2.0–2.6) that are suspended in a cataclastic matrix. Coordinated multitechnique, multiscale analyses of this breccia reveal substantial heterogeneity in the extent of alteration, even in highly aqueously processed lithologies. Some lithologies exhibit the full range and can comprise nearly unaltered coarse‐grained primary components that are found directly alongside other coarse‐grained components that have experienced complete pseudomorphic replacement by secondary minerals. The preservation of the complete alteration sequence and pseudomorph textures showing tochilinite–cronstedtite intergrowths are replacing carbonates suggest that CMs may be initially more carbonate rich than previously thought. This heterogeneity in aqueous alteration extent is likely due to a combination of microscale variability in permeability and water/rock ratio generating local microenvironments as has been established previously. Nevertheless, some of the disequilibrium mineral assemblages observed, such as hydrous minerals juxtaposed with surviving phases that are typically more fluid susceptible, can only be reconciled by multiple generations of alteration, disruption, and reaccretion of the CM parent body at the grain scale

The genetics of the mood disorder spectrum:genome-wide association analyses of over 185,000 cases and 439,000 controls

Background Mood disorders (including major depressive disorder and bipolar disorder) affect 10-20% of the population. They range from brief, mild episodes to severe, incapacitating conditions that markedly impact lives. Despite their diagnostic distinction, multiple approaches have shown considerable sharing of risk factors across the mood disorders. Methods To clarify their shared molecular genetic basis, and to highlight disorder-specific associations, we meta-analysed data from the latest Psychiatric Genomics Consortium (PGC) genome-wide association studies of major depression (including data from 23andMe) and bipolar disorder, and an additional major depressive disorder cohort from UK Biobank (total: 185,285 cases, 439,741 controls; non-overlapping N = 609,424). Results Seventy-three loci reached genome-wide significance in the meta-analysis, including 15 that are novel for mood disorders. More genome-wide significant loci from the PGC analysis of major depression than bipolar disorder reached genome-wide significance. Genetic correlations revealed that type 2 bipolar disorder correlates strongly with recurrent and single episode major depressive disorder. Systems biology analyses highlight both similarities and differences between the mood disorders, particularly in the mouse brain cell-types implicated by the expression patterns of associated genes. The mood disorders also differ in their genetic correlation with educational attainment – positive in bipolar disorder but negative in major depressive disorder. Conclusions The mood disorders share several genetic associations, and can be combined effectively to increase variant discovery. However, we demonstrate several differences between these disorders. Analysing subtypes of major depressive disorder and bipolar disorder provides evidence for a genetic mood disorders spectrum