Bayesian population receptive field modeling in human somatosensory cortex

Somatosensation is fundamental to our ability to sense our body and interact with the world. Our body is continuously sampling the environment using a variety of receptors tuned to different features, and this information is routed up to primary somatosensory cortex. Strikingly, the spatial organization of the peripheral receptors in the body are well maintained, with the resulting representation of the body in the brain being referred to as the somatosensory homunculus. Recent years have seen considerable advancements in the field of high-resolution fMRI, which have enabled an increasingly detailed examination of the organization and properties of this homunculus. Here we combined advanced imaging techniques at ultra-high field (7T) with a recently developed Bayesian population receptive field (pRF) modeling framework to examine pRF properties in primary somatosensory cortex. In each subject, vibrotactile stimulation of the fingertips (i.e., the peripheral mechanoreceptors) modulated the fMRI response along the post-central gyrus and these signals were used to estimate pRFs. We found the pRF center location estimates to be in accord with previous work as well as evidence of other properties in line with the underlying neurobiology. Specifically, as expected from the known properties of cortical magnification, we find a larger representation of the index finger compared to the other stimulated digits (middle, index, little). We also show evidence that the little finger is marked by the largest pRF sizes, and that pRF size increases from anterior to posterior regions of S1. The ability to estimate somatosensory pRFs in humans provides an unprecedented opportunity to examine the neural mechanisms underlying somatosensation and is critical for studying how the brain, body, and environment interact to inform perception and action

Correction of ATM mutations in iPS cells from two ataxia-telangiectasia patients restores DNA damage and oxidative stress responses

Patients with ataxia-telangiectasia (A-T) lack a functional ATM kinase protein and exhibit defective repair of DNA double strand breaks (DSB) and response to oxidative stress. We show that CRISPR/Cas9-assisted gene correction combined with piggyBac transposon-mediated excision of the selection cassette enables seamless restoration of functional ATM alleles in induced pluripotent stem cells from an A-T patient carrying compound heterozygous exonic missense/frameshift mutations, and from a patient with a homozygous splicing acceptor mutation of an internal coding exon. We show that the correction of one allele restores expression of ~ 50% of full-length ATM protein and ameliorates DNA damage-induced activation (auto-phosphorylation) of ATM and phosphorylation of its downstream targets KAP-1 and H2AX. Restoration of ATM function also normalises radiosensitivity, mitochondrial ROS production, and oxidative stress-induced apoptosis levels in A-T iPSC lines, demonstrating that restoration of a single ATM allele is sufficient to rescue key ATM functions. Our data further show that, despite the absence of a functional ATM kinase, homology-directed repair and seamless correction of a pathogenic ATM mutation is possible. The isogenic pairs of A-T and gene-corrected iPSCs described here constitute valuable tools for elucidating the role of ATM in ageing and A-T pathogenesis

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation

Funder: British Heart Foundation (BHF); doi: https://doi.org/10.13039/501100000274Funder: Cardiac Society of Australia and New Zealand (CSANZ); doi: https://doi.org/10.13039/501100001173Funder: Société Française de Cardiologie (French Society of Cardiology); doi: https://doi.org/10.13039/501100005630Funder: Heart and Stroke Foundation of Canada (Heart and Stroke Foundation); doi: https://doi.org/10.13039/100004411Funder: Mayo Clinic; doi: https://doi.org/10.13039/100000871Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

Nat Genet

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

Genome-wide association meta-analysis of spontaneous coronary artery dissection identifies risk variants and genes related to artery integrity and tissue-mediated coagulation.

Spontaneous coronary artery dissection (SCAD) is an understudied cause of myocardial infarction primarily affecting women. It is not known to what extent SCAD is genetically distinct from other cardiovascular diseases, including atherosclerotic coronary artery disease (CAD). Here we present a genome-wide association meta-analysis (1,917 cases and 9,292 controls) identifying 16 risk loci for SCAD. Integrative functional annotations prioritized genes that are likely to be regulated in vascular smooth muscle cells and artery fibroblasts and implicated in extracellular matrix biology. One locus containing the tissue factor gene F3, which is involved in blood coagulation cascade initiation, appears to be specific for SCAD risk. Several associated variants have diametrically opposite associations with CAD, suggesting that shared biological processes contribute to both diseases, but through different mechanisms. We also infer a causal role for high blood pressure in SCAD. Our findings provide novel pathophysiological insights involving arterial integrity and tissue-mediated coagulation in SCAD and set the stage for future specific therapeutics and preventions

UQ Open Science Conference 2018

This is a collection of resources and presentations for the Open Science Conference held at the University of Queensland, 24-25 September 201