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Objectives: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with an unsatisfactory state of treatment. We aim to explore novel targets for SLE from a genetic standpoint. Methods: Cis-expression quantitative trait loci (eQTLs) for whole blood from 31,684 samples provided by the eQTLGen Consortium as well as two large SLE cohorts were utilized for screening and validating genes causally associated with SLE. Colocalization analysis was employed to further investigate whether changes in the expression of risk genes, as indicated by GWAS signals, influence the occurrence and development of SLE. Targets identified for drug development were evaluated for potential side effects using a phenome-wide association study (PheWAS). Based on the multiple databases, we explored the interactions between drugs and genes for drug prediction and the assessment of current medications. Results: The analysis comprised 5427 druggable genes in total. The two-sample Mendelian randomization (MR) in the discovery phase identified 20 genes causally associated with SLE and validated 8 genes in the replication phase. Colocalization analysis ultimately identified five genes (BLK, HIST1H3H, HSPA1A, IL12A, NEU1) with PPH4 > 0.8. PheWAS further indicated that drugs acting on BLK and IL12A are less likely to have potential side effects, while HSPA1A and NEU1 were associated with other traits. Four genes (BLK, HSPA1A, IL12A, NEU1) have been targeted for drug development in autoimmune diseases and other conditions. Conclusions:.This study identified five genes as therapeutic targets for SLE. Repurposing and developing drugs targeting these genes is anticipated to improve the existing treatment state for SLE. Key Points • We identified five gene targets of priority for the treatment of SLE, with BLK and IL12A indicating fewer side effects. • Among the existing drugs that target these candidate genes, Ustekinumab, Ebdarokimab, and Briakinumab (targeting the IL12 gene) and CD24FC (targeting HSPA1A) may potentially be repurposed for the treatment of SLE. [ABSTRACT FROM AUTHOR]

Dianthus superbus L. has been extensively studied for its potential medicinal properties in traditional Chinese medicine and is often consumed as a tea by traditional folk. It has the potential to be exploited in the treatment of inflammation, immunological disorders, and diabetic nephropathy. Based on previous studies, this study continued the separation of another subfraction of Dianthus superbus and established reversed-phase/reversed-phase and reversed-phase/hydrophilic (RPLC) two-dimensional (2D) high-performance liquid chromatography (HPLC) modes, quickly separating two C-glycosylflavones, among which 2″-O-rhamnosyllutonarin was a new compound and isomer with 6‴-O-rhamnosyllutonarin. This is the first study to investigate the effects of 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin on cellular glucose metabolism in vitro. First, molecular docking was used to examine the effects of 2″-O-rhamnosyllutonarin and 6″-O-rhamnosyllutonarin on AKT and AMPK; these two compounds exhibited relatively high activity. Following this, based on the HepG2 cell model of insulin resistance, it was proved that both of the 2″-O-rhamnosyllutonarin and 6‴-O-rhamnosyllutonarin demonstrated substantial efficacy in ameliorating insulin resistance and were found to be non-toxic. Simultaneously, it is expected that the methods developed in this study will provide a basis for future studies concerning the separation and pharmacological effects of C-glycosyl flavonoids. [ABSTRACT FROM AUTHOR]

In addition to measuring the strain, stress, and Young's modulus of materials through tension and compression, in-plane shear modulus measurement is also an important part of parameter testing of composites. Tensile testing of ±45° composite laminates is an economical and effective method for measuring in-plane shear strength. In this paper, the in-plane shear modulus of T800 carbon fiber/epoxy composites were measured through tensile tests of ±45° composite laminates, and acoustic emission (AE) was used to characterize the damage of laminates under in-plane shear loading. Factor analysis (FA) on acoustic emission parameters was performed and the reconstructed factor scores were clustered to obtain three damage patterns. Finally, the development and evolution of the three damage patterns were characterized based on the cumulative hits of acoustic emission. The maximum bearing capacity of the laminated plate is about 17.54 kN, and the average in-plane shear modulus is 5.42 GPa. The damage modes of laminates under in-plane shear behavior were divided into three types: matrix cracking, delamination and fiber/matrix interface debonding, and fiber fracture. The characteristic parameter analysis of AE showed that the damage energy under in-plane shear is relatively low, mostly below 2000 mV × ms, and the frequency is dispersed between 150–350 kHz. [ABSTRACT FROM AUTHOR]

Background: Chronic obstructive pulmonary disease (COPD) patients often exhibit gastrointestinal symptoms, A potential association between COPD and Colorectal Cancer (CRC) has been indicated, warranting further examination. Methods: In this study, we collected COPD and CRC data from the National Health and Nutrition Examination Survey, genome-wide association studies, and RNA sequence for a comprehensive analysis. We used weighted logistic regression to explore the association between COPD and CRC incidence risk. Mendelian randomization analysis was performed to assess the causal relationship between COPD and CRC, and cross-phenotype meta-analysis was conducted to pinpoint crucial loci. Multivariable mendelian randomization was used to uncover mediating factors connecting the two diseases. Our results were validated using both NHANES and GEO databases. Results: In our analysis of the NHANES dataset, we identified COPD as a significant contributing factor to CRC development. MR analysis revealed that COPD increased the risk of CRC onset and progression (OR: 1.16, 95% CI 1.01–1.36). Cross-phenotype meta-analysis identified four critical genes associated with both CRC and COPD. Multivariable Mendelian randomization suggested body fat percentage, omega-3, omega-6, and the omega-3 to omega-6 ratio as potential mediating factors for both diseases, a finding consistent with the NHANES dataset. Further, the interrelation between fatty acid-related modules in COPD and CRC was demonstrated via weighted gene co-expression network analysis and Kyoto Encyclopedia of Genes and Genomes enrichment results using RNA expression data. Conclusions: This study provides novel insights into the interplay between COPD and CRC, highlighting the potential impact of COPD on the development of CRC. The identification of shared genes and mediating factors related to fatty acid metabolism deepens our understanding of the underlying mechanisms connecting these two diseases. [ABSTRACT FROM AUTHOR]

Background: Asthma is a common respiratory disease caused by genetic and environmental factors, but the contribution of insulin use to the risk of asthma remains unclear. This study aimed to investigate the association between insulin use and asthma in a large population-based cohort, and further explore their causal relationship by Mendelian randomization (MR) analysis. Methods: An epidemiological study including 85,887 participants from the National Health and Nutrition Examination Survey (NHANES) 2001–2018 was performed to evaluate the association between insulin use and asthma. Based on the inverse-variance weighted approach, MR analysis were conducted to estimate the causal effect of insulin use on asthma from the UKB and FinnGen datasets, respectively. Results: In the NHANES cohort, we found that insulin use was associated with an increased risk of asthma [odd ratio (OR) 1.38; 95% CI 1.16–1.64; p < 0.001]. For the MR analysis, we found a causal relationship between insulin use and a higher risk of asthma in both Finn (OR 1.10; p < 0.001) and UK Biobank cohorts (OR 1.18; p < 0.001). Meanwhile, there was no causal association between diabetes and asthma. After multivariable adjustment for diabetes in UKB cohort, the insulin use remained significantly associated with an increased risk of asthma (OR 1.17, p < 0.001). Conclusions: An association between insulin use and an increased risk of asthma was found via the real-world data from the NHANES. In addition, the current study identified a causal effect and provided a genetic evidence of insulin use and asthma. More studies are needed to elucidate the mechanisms underlying the association between insulin use and asthma. [ABSTRACT FROM AUTHOR]

In this study, the two-phase flow coordination characteristics between α and β phases of H62 brass made by up-drawing continuous casting are investigated based on the upsetting process. An in situ and new research method for two-phase flow is put forward, and the two-phase flow and grain refinement characteristics are observed under different deformation conditions. The results show that α phase flows fast under 400 °C, β phase is pulled and overridden by α phase under this temperature. When the temperature increases to 500 °C, which is higher than β phase transition temperature, the flow velocity of β phase increases, and the deformation of β phase is found to bulge. The flow of β phase is more sensitive to low deformation rates than α phase. The deformation amount has a more significant impact on β phase than α phase, and the deformation of β phase promotes the grain fragmentation and refinement of α phase accompanied by huge β phase bulging obviously. Under the conditions of high temperature, low deformation rate, and large deformation amount, both phase α and β of up-drawing continuous casting brass alloy are broken and the grains are refined. Based on the two-phase flow characteristic, numerical simulation is used to obtain the optimal continuous extrusion parameters of the H-shaped wire of up-drawing continuous casting H62 brass. Then, the optimized complex cross-section wire is prepared by continuous extrusion experiment. This research aims to provide guidance for the complex processing of two-phase alloys. [ABSTRACT FROM AUTHOR]

Background: The anterior insular cortex (AIC), a prominent salience network node, integrates interoceptive information and emotional states into decision making. While AIC activation during delay discounting (DD) in alcohol use disorder (AUD) has been previously reported, the associations between AIC activation, impulsive choice, alcohol consumption, and connectivity remain unknown. We therefore tested AIC brain responses during DD in heavy drinkers and their association with DD performance, alcohol drinking, and task‐based connectivity. Methods: Twenty‐nine heavy drinkers (12 females; mean (SD) age=31.5 ± 6.1 years; mean (SD)=40.8 ± 23.4 drinks/week) completed a DD task during functional MRI. Regions activated during DD decision making were tested for correlation with DD behavior and alcohol drinking. Psychophysiological interaction (PPI) models assessed the task‐dependent functional connectivity (FC) of activation during choice. Results: Delay discounting choice activated bilateral anterior insular cortex, anterior cingulate cortex, and left precentral gyrus. Right dorsal (d) AIC activation during choice negatively correlated withdiscounting of delayed rewards and alcohol consumption. PPI analysis revealed FC of the right dAIC to both the anterior and posterior cingulate cortices—key nodes in the midline default mode network. Conclusions: Greater dAIC involvement in intertemporal choice may confer more adaptive behavior (lower impulsivity and alcohol consumption). Moreover, salience network processes governing discounting may require midline default mode (precuneus/posterior cingulate cortex) recruitment. These findings supporta key adaptive role for right dAIC in decision making involving future rewards and risky drinking. [ABSTRACT FROM AUTHOR]

Dynamic functional connectivity (dFC) estimates time-dependent associations between pairs of brain region time series as typically acquired during functional MRI. dFC changes are most commonly quantified by pairwise correlation coefficients between the time series within a sliding window. Here, we applied a recently developed bootstrap-based technique (Kudela et al., 2017) to robustly estimate subject-level dFC and its confidence intervals in a task-based fMRI study (24 subjects who tasted their most frequently consumed beer and Gatorade as an appetitive control). We then combined information across subjects and scans utilizing semiparametric mixed models to obtain a group-level dFC estimate for each pair of brain regions, flavor, and the difference between flavors. The proposed approach relies on the estimated group-level dFC accounting for complex correlation structures of the fMRI data, multiple repeated observations per subject, experimental design, and subject-specific variability. It also provides condition-specific dFC and confidence intervals for the whole brain at the group level. As a summary dFC metric, we used the proportion of time when the estimated associations were either significantly positive or negative. For both flavors, our fully-data driven approach yielded regional associations that reflected known, biologically meaningful brain organization as shown in prior work, as well as closely resembled resting state networks (RSNs). Specifically, beer flavor-potentiated associations were detected between several reward-related regions, including the right ventral striatum (VST), lateral orbitofrontal cortex, and ventral anterior insular cortex (vAIC). The enhancement of right VST-vAIC association by a taste of beer independently validated the main activation-based finding (Oberlin et al., 2016). Most notably, our novel dFC methodology uncovered numerous associations undetected by the traditional static FC analysis. The data-driven, novel dFC methodology presented here can be used for a wide range of task-based fMRI designs to estimate the dFC at multiple levels—group-, individual-, and task-specific, utilizing a combination of well-established statistical methods. [ABSTRACT FROM AUTHOR]