Genetic architecture of subcortical brain structures in 38,851 individuals

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease

Atrial fibrillation genetic risk differentiates cardioembolic stroke from other stroke subtypes

AbstractObjectiveWe sought to assess whether genetic risk factors for atrial fibrillation can explain cardioembolic stroke risk.MethodsWe evaluated genetic correlations between a prior genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously-validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors.ResultsWe observed strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson’s r=0.77 and 0.76, respectively, across SNPs with p &lt; 4.4 × 10−4 in the prior AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio (OR) per standard deviation (sd) = 1.40, p = 1.45×10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per sd = 1.07, p = 0.004), but no other primary stroke subtypes (all p &gt; 0.1).ConclusionsGenetic risk for AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.</jats:sec

Methyl methacrylate and respiratory sensitization: A Critical review

Methyl methacrylate (MMA) is a respiratory irritant and dermal sensitizer that has been associated with occupational asthma in a small number of case reports. Those reports have raised concern that it might be a respiratory sensitizer. To better understand that possibility, we reviewed the in silico, in chemico, in vitro, and in vivo toxicology literature, and also epidemiologic and occupational medicine reports related to the respiratory effects of MMA. Numerous in silico and in chemico studies indicate that MMA is unlikely to be a respiratory sensitizer. The few in vitro studies suggest that MMA has generally weak effects. In vivo studies have documented contact skin sensitization, nonspecific cytotoxicity, and weakly positive responses on local lymph node assay; guinea pig and mouse inhalation sensitization tests have not been performed. Cohort and cross-sectional worker studies reported irritation of eyes, nose, and upper respiratory tract associated with short-term peaks exposures, but little evidence for respiratory sensitization or asthma. Nineteen case reports described asthma, laryngitis, or hypersensitivity pneumonitis in MMA-exposed workers; however, exposures were either not well described or involved mixtures containing more reactive respiratory sensitizers and irritants.The weight of evidence, both experimental and observational, argues that MMA is not a respiratory sensitizer

Testing the Fill-and-Spill Model ofSubsurface Lateral Flow Using GroundPenetrating Radar and Dye Tracing

Preferential flow (PF), which bypasses large portions of the soil or subsurface matrix, is critical in the transport of water and dissolved constituents in the unsaturated zone. To test the &ldquo;fill-and-spill&rdquo; model of hillslope hydrology that describes the generation and pattern of downslope lateral PF after storms, we used dye tracer and time-lapse, ground-penetrating radar (GPR) on a forested hillslope in the Susquehanna&ndash;Shale Hills Critical Zone Observatory. We injected 50 L of water mixed with Brilliant Blue dye (4 g L⁻&sup1;) into a shallow trench cut perpendicular to the slope and used GPR to monitor the tracer downslope across a 1.0- by 2.0-m grid. The site was then excavated to the soil&ndash;saprock interface and photographed to document the dye pathways. We observed vertical dye fingering near the infiltration trench. Downslope lateral PF at the soil&ndash;saprock boundary was limited to ~0.40 m, which is evidence that the soil&ndash;saprock interface did not fill-and-spill. The extent, depth, and direction of the downslope PF indicated by GPR generally matched the dye staining patterns in the excavation, but the resolution of the 800-MHz GPR antenna was insufficient to distinguish small fingers of dye. A revised filland- spill model was proposed for this site that incorporates the PF through fractured saprock before water encounters fresh bedrock surface. This study demonstrates that GPR integrated with dye tracer infiltration can provide a useful means of testing hillslope hydrological hypotheses and unraveling the complexity of PF at the hillslope scale in a field setting

A Positioning and Data Logging System for Surface Geophysical Surveys

The Ultrasonic Ranging and Data System (USRADS) developed at ORNL is being adapted to work with two commercially available geophysical instruments: a magnetometer and an EM31 terrain conductivity meter. Geophysical surveys have proven an important preliminary step in investigating hazardous waste sites. Magnetometers and terrain conductivity meters are used to locate buried drums, trenches, conductive contaminant plumes and map regional changes in geology. About half the field time of a typical geophysical investigation is spent surveying the position of the grid points at which the measurements will be made. Additional time is lost and errors may be made recording instrument values in field notebooks and transcribing the data to a computer. Developed for gamma radiation surveys, the USRAD system keeps track of the surveyor's position automatically by triangulating on an ultrasonic transmitter carried in a backpack. The backpack also contains a radio transmitter that sends the instrument's reading coincident with the ultrasonic pulse. The surveyor's position and the instrument's reading are recorded by a portable computer which can plot the data to check the survey's progress. Electronic files are stored in a form compatible with AutoCAD to speed report writing. 7 refs., 3 figs

Advanced ground penetrating radar signal processing techniques

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SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.

There is pressing urgency to understand the pathogenesis of the severe acute respiratory syndrome coronavirus clade 2 (SARS-CoV-2), which causes the disease COVID-19. SARS-CoV-2 spike (S) protein binds angiotensin-converting enzyme 2 (ACE2), and in concert with host proteases, principally transmembrane serine protease 2 (TMPRSS2), promotes cellular entry. The cell subsets targeted by SARS-CoV-2 in host tissues and the factors that regulate ACE2 expression remain unknown. Here, we leverage human, non-human primate, and mouse single-cell RNA-sequencing (scRNA-seq) datasets across health and disease to uncover putative targets of SARS-CoV-2 among tissue-resident cell subsets. We identify ACE2 and TMPRSS2 co-expressing cells within lung type II pneumocytes, ileal absorptive enterocytes, and nasal goblet secretory cells. Strikingly, we discovered that ACE2 is a human interferon-stimulated gene (ISG) in vitro using airway epithelial cells and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection