Adjusting for genetic confounders in transcriptome-wide association studies improves discovery of risk genes of complex traits

Many methods have been developed to leverage expression quantitative trait loci (eQTL) data to nominate candidate genes from genome-wide association studies. These methods, including colocalization, transcriptome-wide association studies (TWAS) and Mendelian randomization-based methods; however, all suffer from a key problem—when assessing the role of a gene in a trait using its eQTLs, nearby variants and genetic components of other genes’ expression may be correlated with these eQTLs and have direct effects on the trait, acting as potential confounders. Our extensive simulations showed that existing methods fail to account for these ‘genetic confounders’, resulting in severe inflation of false positives. Our new method, causal-TWAS (cTWAS), borrows ideas from statistical fine-mapping and allows us to adjust all genetic confounders. cTWAS showed calibrated false discovery rates in simulations, and its application on several common traits discovered new candidate genes. In conclusion, cTWAS provides a robust statistical framework for gene discovery

Preparation of Hypophosphorous Acid by Bipolar Membrane Electrodialysis: Process Optimization and Phosphorous Acid Minimization

Hypophosphorous acid (H3PO2) is an important chemical product with wide applications in pharmaceuticals and electroless plating. In this study, bipolar membrane electrodialysis (BMED) was used to produce H3PO2 from sodium hypophosphite salt (NaH2PO2) to replace the traditional preparation methods. The BMED process was optimized in terms of current density, NaH2PO2 salt concentration, and initial NaOH concentration of the base solution. The results indicated that low Na+ leakage occurred at lower salt concentrations. Under the optimum conditions, such a BMED system obtained a high concentration of H3PO2, a low Na+ content, and a low energy consumption, equaling to 1.03 mol/L, 670 ppm, and 1.18 kW h/kg, respectively. To minimize the amount of phosphorous acid (H3PO3) generated from H3PO2 oxidation during the BMED process, a nitrogen aeration operation was applied in both the acid and salt chambers, decreasing the HPO32- content to 251 ppm, which was 44.1% lower than that without a dissolved oxygen content control strategy. The newly produced H3PO3 during the BMED process was reduced by 96.5%. The obtained results indicated that the BMED process has great potential for application in the production of high-quality H3PO2 from NaH2PO2 in industry

Freckles pattern and microstructure feature of Nb-Ti alloy produced by vacuum arc remelting

Nb-Ti alloys are normally produced by vacuum arc remelting process. Due to inadequate processing parameters, freckles can be observed in macroetched ingots. In the present work, visual, chemical, metallographic, and X-ray are presented which establish the appearance, composition, microstructure differences between freckle regions and normal regions. It has been observed that in freckles parallel to the ingot axis, the Ti content is up to 53wt%, 7wt% higher than normal regions. It is also shown that a lot of precipitation phases appeared in freckle regions, because of the thermosolutal convection in the mushy zone. The Rayleigh number, which recommended as a criterion for freckle initiation, has been calculated that using a VAR melting software. Based on the experimental results and simulation results, it is concluded that freckles can be influenced by processing parameters, and freckles in Nb-Ti alloy can be eliminated by matching appropriate processing parameters

Reorganization of 3D genome structure may contribute to gene regulatory evolution in primates

A growing body of evidence supports the notion that variation in gene regulation plays a crucial role in both speciation and adaptation. However, a comprehensive functional understanding of the mechanisms underlying regulatory evolution remains elusive. In primates, one of the crucial missing pieces of information towards a better understanding of regulatory evolution is a comparative annotation of interactions between distal regulatory elements and promoters. Chromatin conformation capture technologies have enabled genome-wide quantifications of such distal 3D interactions. However, relatively little comparative research in primates has been done using such technologies. To address this gap, we used Hi-C to characterize 3D chromatin interactions in induced pluripotent stem cells (iPSCs) from humans and chimpanzees. We also used RNA-seq to collect gene expression data from the same lines. We generally observed that lower-order, pairwise 3D genomic interactions are conserved in humans and chimpanzees, but higher order genomic structures, such as topologically associating domains (TADs), are not as conserved. Inter-species differences in 3D genomic interactions are often associated with gene expression differences between the species. To provide additional functional context to our observations, we considered previously published chromatin data from human stem cells. We found that inter-species differences in 3D genomic interactions, which are also associated with gene expression differences between the species, are enriched for both active and repressive marks. Overall, our data demonstrate that, as expected, an understanding of 3D genome reorganization is key to explaining regulatory evolution