Aseismic fracturing and cataclasis involving reaction softening within core material from the Cajon Pass Drill Hole

Cataclastic deformation features in crystalline rocks from the Cajon Pass drill hole, located some 4 km NE of the San Andreas fault trace in southern California, appear to have developed at slow strain rates. There is no clear evidence of seismic deformation. Most of the observed structures and microstructures are inferred to have formed during pre-Pliocene distributed deformation, before the San Andreas fault became active in this area. Extension fractures are filled by laumontite which increases in grain size from a fine amorphous habit to coarser prismatic crystals unidirectionally across fractures and does not generally display crack-seal textures. Fragments within fractures were derived from adjacent grains without rotation or shear. Fracture opening and cementation were therefore synchronous and slow. Fluids were present at all times during fracture opening, but there was no repeated hydrofracturing after fracture formation. However pore fluid pressures probably stayed close to the least principal stress (σ3) during subsequent fracture growth. Plagioclase compositions in all fractured areas change from oligoclase to albite or anorthite as a consequence of albitization and laumontization. Particle size distributions in dilational areas, and in extension and in shear fracture fillings, show that alteration of the major phase, plagioclase, is the fundamental process of grain size reduction in a variety of rock types. Cataclastic stresses and strain rates were controlled by alteration reaction rates in a coupled process that is a form of transformation-modified deformation. Fracturing leading to weakening was assisted by stresses due to the 60% volume increase accompanying in situ laumontization of plagioclase and by stress corrosion and subcritical crack growth facilitated by alteration. Deformation was also enhanced by replacement of plagioclase by weaker laumontite. Such dilatant cataclasis is consistent with fluid pressure levels having remained high during deformation with effective least principal compressive stress close to zero. This transformation-modified deformation at low temperatures (90° < T < 250°C) may be a common process in feldspar-rich rocks. The structures and microstructures described here could be used to distinguish the products of slow and fast Cataclastic deformation

Genetic determinants of risk in pulmonary arterial hypertension:international genome-wide association studies and meta-analysis

Background: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13 × 10 –15 ) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65 × 10 –20 ) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69 × 10 –12 ; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to &gt;13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR. </p

Abstracts from the 20th International Symposium on Signal Transduction at the Blood-Brain Barriers

https://deepblue.lib.umich.edu/bitstream/2027.42/138963/1/12987_2017_Article_71.pd

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility