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Systemic lupus erythematosus (SLE) is a multi-organ autoimmune disorder with a prominent genetic component. Individuals of Asian-Ancestry (AsA) disproportionately experience more severe SLE compared to individuals of European-Ancestry (EA), including increased renal involvement and tissue damage. However, the mechanisms underlying elevated severity in the AsA population remain unclear. Here, we utilized available gene expression data and genotype data based on all non-HLA SNP associations in EA and AsA SLE patients detected using the Immunochip genotyping array. We identified 2778 ancestry-specific and 327 trans-ancestry SLE-risk polymorphisms. Genetic associations were examined using connectivity mapping and gene signatures based on predicted biological pathways and were used to interrogate gene expression datasets. SLE-associated pathways in AsA patients included elevated oxidative stress, altered metabolism and mitochondrial dysfunction, whereas SLE-associated pathways in EA patients included a robust interferon response (type I and II) related to enhanced cytosolic nucleic acid sensing and signaling. An independent dataset derived from summary genome-wide association data in an AsA cohort was interrogated and identified similar molecular pathways. Finally, gene expression data from AsA SLE patients corroborated the molecular pathways predicted by SNP associations. Identifying ancestry-related molecular pathways predicted by genetic SLE risk may help to disentangle the population differences in clinical severity that impact AsA and EA individuals with SLE.

IntroductionMushroom-forming fungi comprise diverse species that develop complex multicellular structures. In cultivated species, both ecological adaptation and artificial selection have driven genome evolution. However, little is known about the connections among genotype, phenotype and adaptation in mushroom-forming fungi.ObjectivesThis study aimed to (1) uncover the population structure and demographic history of Lentinula edodes, (2) dissect the genetic basis of adaptive evolution in L. edodes, and (3) determine if genes related to fruiting body development are involved in adaptive evolution.MethodsWe analyzed genomes and fruiting body-related traits (FBRTs) in 133 L. edodes strains and conducted RNA-seq analysis of fruiting body development in the YS69 strain. Combined methods of genomic scan for divergence, genome-wide association studies (GWAS), and RNA-seq were used to dissect the genetic basis of adaptive evolution.ResultsWe detected three distinct subgroups of L. edodes via single nucleotide polymorphisms, which showed robust phenotypic and temperature response differentiation and correlation with geographical distribution. Demographic history inference suggests that the subgroups diverged 36,871 generations ago. Moreover, L. edodes cultivars in China may have originated from the vicinity of Northeast China. A total of 942 genes were found to be related to genetic divergence by genomic scan, and 719 genes were identified to be candidates underlying FBRTs by GWAS. Integrating results of genomic scan and GWAS, 80 genes were detected to be related to phenotypic differentiation. A total of 364 genes related to fruiting body development were involved in genetic divergence and phenotypic differentiation.ConclusionAdaptation to the local environment, especially temperature, triggered genetic divergence and phenotypic differentiation of L. edodes. A general model for genetic divergence and phenotypic differentiation during adaptive evolution in L. edodes, which involves in signal perception and transduction, transcriptional regulation, and fruiting body morphogenesis, was also integrated here.

During the thermite welding of in-service oil pipelines, empirical values are often used for the dosage of aluminum powder welding flux, and the uncertainty of temperature and residual stress generated during the welding poses a serious threat to the construction of pipeline and its safe operation. In response to this problem, the thermite welding process of pipelines in different wall thickness and with different dosages of welding flux was analyzed with the numerical simulation software ANSYS.Specifically, a finite element model of thermite welding was established, and thus the change law of the temperature field and residual stress field with different dosages of aluminum powder welding flux and different pipeline wall thicknesses was obtained,which was also verified by test. As indicated by the results, the maximum temperature in the welding area of pipelines with same wall thickness rises with the increasing dosage of welding flux. The maximum temperature in the welding area decreases with the increasing of pipeline wall thickness in the case that equivalent welding flux is used. Besides, with the increasing of pipeline wall thickness, the maximum residue stress at the weld is up to 150 MPa, lower than the yield limit of material, so that no burn-through and crack will occur during thermite welding, and the simulation results are consistent with the test results. Moreover, it is safe and reliable to conduct thermite welding in 6 mm to 8 mm pipeline in service with 10 g to 20 g of aluminum powder. Generally, the numerical simulation method could provide reference for the safe operation of thermite welding of in-service pipelines, thus reducing the construction risks of pipelines in service.

Abstract Finely tuned mitogen-activated protein kinase (MAPK) signaling is important for cancer cell survival. Perturbations that push cells out of the MAPK fitness zone result in cell death. Previously, in a screen of the North China Pharmaceutical Group Corporation’s pure compound library of microbial origin, we identified elaiophylin as an autophagy inhibitor. Here, we demonstrated a new role for elaiophylin in inducing excessive endoplasmic reticulum (ER) stress, ER-derived cytoplasmic vacuolization, and consequent paraptosis by hyperactivating the MAPK pathway in multiple cancer cells. Genome-wide CRISPR/Cas9 knockout library screening identified SHP2, an upstream intermediary of the MAPK pathway, as a critical target in elaiophylin-induced paraptosis. The cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) assay further confirmed the direct binding between the SHP2 and elaiophylin. Inhibition of the SHP2/SOS1/MAPK pathway through SHP2 knockdown or pharmacological inhibitors distinctly attenuated elaiophylin-induced paraptosis and autophagy inhibition. Interestingly, elaiophylin markedly increased the already-elevated MAPK levels and preferentially killed drug-resistant cells with enhanced basal MAPK levels. Elaiophylin overcame drug resistance by triggering paraptosis in multiple tumor-bearing mouse models resistant to platinum, taxane, or PARPi, suggesting that elaiophylin might offer a reasonable therapeutic strategy for refractory ovarian cancer.

As a technology for water landscape performance that considers landscape, ecological, and social effects, nature-based solutions play a crucial role in enhancing the functionality of integrated ecosystem services on the micro-scale. This study conducted a systematic investigation into the landscape performance of the "Clear as a Drain" composite sponge facility at Handan Garden Expo Park. The following conclusions were drawn: (1) In terms of ecological restoration support services, the "Clear as a Drain" artificial wetland exhibited diverse habitat types, a rich variety of plant species specific to the site's region, and high plant diversity indices for shrubs (1.776) and herbaceous aquatic plants (3.352). Reclaimed water reused in the artificial terraced wetland promoted plant growth and diversity while contributing to site self-rehabilitation; plants also significantly contributed to carbon fixation, oxygen release, and carbon emission reduction. (2) Regarding ecological restoration regulation services, the artificial wetland effectively purified reclaimed water with substantial improvements observed in incoming water quality during spring, summer, and autumn—particularly notable purification effects were observed during the summer months. Pollutant reduction rates for COD, BOD5 ammonia nitrogen, TP, and TN reached 75.8%, 72.1%, 93.8%, 96.7%, and 90.3%, respectively; different independent subsystems within the wetland demonstrated distinct advantages in pollutant removal; park plants displayed strong air purification capabilities; annual energy savings from park plants could fully cover daily energy consumption for nearby residents. This case could serve as guidance for scientific management and design parameter optimization of other composite sponge facilities. [ABSTRACT FROM AUTHOR]