Atrial fibrillation variant-to-gene prioritization through cross-ancestry eQTL and single-nucleus multiomic analyses.

Atrial fibrillation (AF) is the most common arrhythmia in the world. Human genetics can provide strong AF therapeutic candidates, but the identification of the causal genes and their functions remains challenging. Here, we applied an AF fine-mapping strategy that leverages results from a previously published cross-ancestry genome-wide association study (GWAS), expression quantitative trait loci (eQTLs) from left atrial appendages (LAAs) obtained from two cohorts with distinct ancestry, and a paired RNA sequencing (RNA-seq) and ATAC sequencing (ATAC-seq) LAA single-nucleus assay (sn-multiome). At nine AF loci, our co-localization and fine-mapping analyses implicated 14 genes. Data integration identified several candidate causal AF variants, including rs7612445 at GNB4 and rs242557 at MAPT. Finally, we showed that the repression of the strongest AF-associated eQTL gene, LINC01629, in human embryonic stem cell-derived cardiomyocytes using CRISPR inhibition results in the dysregulation of pathways linked to genes involved in the development of atrial tissue and the cardiac conduction system.

Major cell-types in multiomic single-nucleus datasets impact statistical modeling of links between regulatory sequences and target genes.

Epigenomic profiling, including ATACseq, is one of the main tools used to define enhancers. Because enhancers are overwhelmingly cell-type specific, inference of their activity is greatly limited in complex tissues. Multiomic assays that probe in the same nucleus both the open chromatin landscape and gene expression levels enable the study of correlations (links) between these two modalities. Current best practices to infer the regulatory effect of candidate cis-regulatory elements (cCREs) in multiomic data involve removing biases associated with GC content by generating null distributions of matched ATACseq peaks drawn from different chromosomes. This strategy has been broadly adopted by popular single-nucleus multiomic workflows such as Signac. Here, we uncovered limitations and confounders of this approach. We found a strong loss of power to detect a regulatory effect for cCREs with high read counts in the dominant cell-type. We showed that this is largely due to cell-type-specific trans-ATACseq peak correlations creating bimodal null distributions. We tested alternative models and concluded that physical distance and/or the raw Pearson correlation coefficients are the best predictors for peak-gene links when compared to predictions from Epimap (e.g. CD14 area under the curve [AUC] = 0.51 with the method implemented in Signac vs. 0.71 with the Pearson correlation coefficients) or validation by CRISPR perturbations (AUC = 0.63 vs. 0.73).

Transcriptomic Profiling of Canine Atrial Fibrillation Models After One Week of Sustained Arrhythmia.

[Figure: see text].

Phase-Field Simulation of Grain Boundary Evolution In Microstructures Containing Second-Phase Particles with Heterogeneous Thermal Properties.

Understanding the interaction between complex thermal fields and metallic structures at the meso-scale is crucial for the prediction of microstructural evolution during thermomechanical processing. The competitive growth of crystal grains, driven by thermodynamic forces at the grain boundaries, is one of the most fundamental phenomena in metallurgy and solid state physics. The presence of second phase particles, which act as pinning sites for boundaries, drastically alters the coarsening behaviour of the system; particularly when considering that these particles have different thermal properties to the primary phase. In this work a multi-phase field model, incorporating thermal gradient and curvature driving forces, is used to predict grain growth in a Ti6Al4V alloy system with second phase particle inclusions representative of oxide and carbide precipitates. The multi-phase field framework is fully coupled to the heat equation. The incorporation of the thermal gradient driving force enables the detailed behaviour of the grain boundaries around the particles to be predicted. It is shown that the inclusion of particles with a lower thermal conductivity has a significant influence on the coarsening behaviour of various systems of grains, due to the combined effects of thermal shielding and the generation of thermal gradient driving forces between the boundaries and pinning particles.

Evaluation of Errors Associated with Cutting-Induced Plasticity in Residual Stress Measurements Using the Contour Method.

Cutting-induced plasticity can lead to elevated uncertainties in residual stress measurements made by the contour method. In this study plasticity-induced stress errors are numerically evaluated for a benchmark edge-welded beam to understand the underlying mechanism. Welding and cutting are sequentially simulated by finite element models which have been validated by previous experimental results. It is found that a cutting direction normal to the symmetry plane of the residual stress distribution can lead to a substantially asymmetrical back-calculated stress distribution, owing to cutting-induced plasticity. In general, the stresses at sample edges are most susceptible to error, particularly when the sample is restrained during cutting. Inadequate clamping (far from the plane of cut) can lead to highly concentrated plastic deformation in local regions, and consequently the back-calculated stresses have exceptionally high values and gradients at these locations. Furthermore, the overall stress distribution is skewed towards the end-of-cut side. Adequate clamping (close to the plane of cut) minimises errors in back-calculated stress which becomes insensitive to the cutting direction. For minimal constraint (i.e. solely preventing rigid body motion), the plastic deformation is relatively smoothly distributed, and an optimal cutting direction (i.e. cutting from the base material towards the weld region in a direction that falls within the residual stress symmetry plane) is identified by evaluating the magnitude of stress errors. These findings suggest that cutting process information is important for the evaluation of potential plasticity-induced errors in contour method results, and that the cutting direction and clamping strategy can be optimised with an understanding of their effects on plasticity and hence the back-calculated stresses.

Fetal fibronectin detection as a predictor of preterm birth in actual clinical practice.

OBJECTIVE: This study was undertaken to determine whether fetal fibronectin determination is more useful for predicting preterm delivery in clinical practice than it has appeared to be in prospective blinded studies. STUDY DESIGN: Charts of 151 patients with fetal fibronectin tests performed during 2 years were reviewed. Patients were included if they had symptoms of preterm labor, a singleton pregnancy at 24 to 35 weeks' gestation, intact membranes, and cervical dilatation < or =3 cm. RESULTS: Complete data were available for 85 tests. For delivery within 7 days after specimen collection the sensitivity, specificity, positive predictive value, and negative predictive value were 89%, 84%, 40%, and 98%, respectively. The positive predictive value was greater (P <.002) than those reported in three prospective studies evaluating delivery within 7 days in patients with symptoms. Gestational age at delivery and birth weight were lower for patients with positive results (P <. 0001 and P <.006, respectively). Patients with positive results were also treated more with tocolysis, corticosteroid use, and hospitalization than were patients with negative results. For direct comparison with studies of patients with cervical dilatation <3 cm, only 4 patients with cervical dilatation of 3 cm were enrolled. All 4 had negative results of fetal fibronectin testing, and their outcomes therefore did not affect the positive predictive value. CONCLUSION: The positive predictive value of fetal fibronectin measured in actual clinical practice was significantly greater for delivery within 7 days than has been reported in blinded prospective studies.

Vitamin A effects on UMR 106 osteosarcoma cells are not mediated by specific cytosolic receptors.

Retinol and retinoic acid at 20 microM altered cell morphology and inhibited cell proliferation of UMR 106 osteosarcoma cells in culture. No specific cytosolic binding proteins for retinol could be detected.