High-dimensional quantile mediation analysis with application to a birth cohort study of mother-newborn pairs

MOTIVATION: There has been substantial recent interest in developing methodology for high-dimensional mediation analysis. Yet, the majority of mediation statistical methods lean heavily on mean regression, which limits their ability to fully capture the complex mediating effects across the outcome distribution. To bridge this gap, we propose a novel approach for selecting and testing mediators throughout the full range of the outcome distribution spectrum. RESULTS: The proposed high-dimensional quantile mediation model provides a comprehensive insight into how potential mediators impact outcomes via their mediation pathways. This method\u27s efficacy is demonstrated through extensive simulations. The study presents a real-world data application examining the mediating effects of DNA methylation on the relationship between maternal smoking and offspring birthweight. AVAILABILITY AND IMPLEMENTATION: Our method offers a publicly available and user-friendly function qHIMA(), which can be accessed through the R package HIMA at https://CRAN.R-project.org/package=HIMA

The Inhibitory Effect of Regulatory T Cells on the Intimal Hyperplasia of Tissue-Engineered Blood Vessels in Diabetic Pigs

Severe inflammatory response and functional impairment of endothelial progenitor cells (EPCs) often lead to the implantation failure of EPC-captured tissue-engineered blood vessels (TEBVs) in diabetes. Regulatory T cells (Treg cells) are the most important inhibitory immune cells, but their effects in angiogenesis remain undefined, and the differences in the microenvironment may be an important reason. Here, we constructed a TEBV coated with an anti-CD34 antibody-functionalized heparin-collagen multilayer (anti-CD34 antibody-modified TEBV) using layer-by-layer self-assembly. Then, TEBVs were implanted into diabetic pigs. All TEBVs remained unobstructed 60 days after implantation, although varying degrees of intimal hyperplasia were detectable. Severe intimal hyperplasia was observed in the control group and peripheral injection of Treg cells group. Intravenous injection of Treg cells significantly inhibited intimal hyperplasia, inflammation, and cell apoptosis. Moreover, intravenous injection increased the proportion of circulating EPCs, while peripheral injection did not have these effects and reduced microvessel density around the TEBV. Interestingly, many Nestin+ cells could be detected in TEBVs, most of which were fusiform, showing the characteristics of smooth-muscle cells. Treg cell intravenous transplantation markedly reduced the number of Nestin+ cells in the TEBV. In conclusion, Treg cells inhibited the intimal hyperplasia of TEBVs in diabetic pigs by promoting EPC mobilization, anti-inflammatory action, and cellular protection

Conjugation of soy protein isolate (SPI) with pectin by ultrasound treatment

peer-reviewedThe Maillard reaction in the aqueous system with and without ultrasound treatment was used to prepare conjugates between soy protein isolate (SPI) and citrus pectin (CP)/apple pectin (AP). Ultrasound treatment at a power of 450 W and a temperature of 70 °C significantly accelerated the conjugation processes between SPI and pectin samples and led to much greater grafting extents compared to the traditional wet heating. A higher degree of graft of the SPI-CP conjugates was achieved at a shorter ultrasound duration compared to the SPI-AP conjugates, possibly attributed to the larger molecular weight and the more flexible structure of AP. SDS-PAGE analysis confirmed the formation of SPI-pectin conjugates. Analysis of the protein secondary and tertiary structures suggested that the attachment of CP or AP changed the spatial conformation of SPI and led to a looser protein structure. In addition to the grafting process, ultrasound was also observed to play a marked role in unfolding the SPI resulting in more favorable structures for the Maillard reaction. Furthermore, the application of ultrasound to the conjugation process significantly increased the surface hydrophobicity and emulsifying properties of both conjugates, indicating that ultrasound can be a desirable method for protein-polysaccharide conjugation.National Natural Science Foundation of Chin

Identification of hub genes significantly linked to tuberous sclerosis related-epilepsy and lipid metabolism via bioinformatics analysis

BackgroundTuberous sclerosis complex (TSC) is one of the most common genetic causes of epilepsy. Identifying differentially expressed lipid metabolism related genes (DELMRGs) is crucial for guiding treatment decisions.MethodsWe acquired tuberous sclerosis related epilepsy (TSE) datasets, GSE16969 and GSE62019. Differential expression analysis identified 1,421 differentially expressed genes (DEGs). Intersecting these with lipid metabolism related genes (LMRGs) yielded 103 DELMRGs. DELMRGs underwent enrichment analyses, biomarker selection, disease classification modeling, immune infiltration analysis, weighted gene co-expression network analysis (WGCNA) and AUCell analysis.ResultsIn TSE datasets, 103 DELMRGs were identified. Four diagnostic biomarkers (ALOX12B, CBS, CPT1C, and DAGLB) showed high accuracy for epilepsy diagnosis, with an AUC value of 0.9592. Significant differences (p < 0.05) in Plasma cells, T cells regulatory (Tregs), and Macrophages M2 were observed between diagnostic groups. Microglia cells were highly correlated with lipid metabolism functions.ConclusionsOur research unveiled potential DELMRGs (ALOX12B, CBS, CPT1C and DAGLB) in TSE, which may provide new ideas for studying the psathogenesis of epilepsy

Correlation between systemic immune inflammatory index and prognosis of patients with hepatic alveolar hydatid disease and establishment of a nomogram prediction model

BackgroundTo explore the evaluation value of systemic immune inflammation index (SII) in the prognosis of patients with alveolar hydatid disease, and establish a nomogram prediction model.MethodsCollect the clinical data of 351 patients undergoing hepatic alveolar hydatid surgery admitted to the Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Qinghai University from January 2015 to December 2020, calculate the SII value, and use the receiver operating characteristic curve (ROC curve) to determine According to the optimal clinical cut-off value of SII, patients were divided into two groups with high SII and low SII, and the relationship between SII and clinicopathological factors and prognosis of patients with alveolar echinococcosis was analyzed. Establish a nomogram prediction model based on independent risk factors for patient prognosis, and evaluate the prediction accuracy and discrimination ability of the nomogram through the consistency index (C-index) and calibration curve. The result is through the use of bootstrapping validation with 1,000 re-sampling Method for internal verification.ResultsThe ROC curve was used to determine the optimal cut-off value of SII before operation 761.192, and patients were divided into low SII group (n = 184) cases and high SII group (n = 167) cases. The 1, 3, and 5-year survival rates of patients with hepatic alveolar hydatid in the low SII group and the high SII group were 98.90%, 96.90%, 86.50% and 98.20%, 72.50%, 40.30%, respectively. The survival rate of worm disease patients was significantly better than that of the high SII group, and the overall survival rate difference between the two groups was statistically significant (P < 0.001). Multivariate Cox regression model analysis results showed that intraoperative blood loss (HR = 1.810, 95%CI: 1.227–2.668, P = 0.003), SII (HR = 5.011, 95%CI: 3.052–8.228, P < 0.001), Complications (HR = 1.720, 95%CI: 1.162–2.545, P = 0.007) are independent risk factors for the prognosis of patients with alveolar hydatid disease. Draw a nomogram and include statistically significant factors in the multivariate Cox regression model to predict the overall survival rate of patients with alveolar hydatid disease at 1, 3, and 5 years. The survival probability calibration curve is displayed. The nomogram is compared with The actual results have a high degree of agreement. The concordance index (C-index) of the nomogram model in the modeling sample is 0.777, and the C-index in the verification sample is 0.797, indicating that the nomogram model of this study has good accuracy and discrimination.ConclusionsSII has a clear correlation to the prognosis of patients with alveolar echinococcosis. The nomogram prediction model constructed on this basis is beneficial to the clinically individualized analysis of the patient's prognosis

The deubiquitinating enzyme MINDY2 promotes pancreatic cancer proliferation and metastasis by stabilizing ACTN4 expression and activating the PI3K/AKT/mTOR signaling pathway

The pathogenic mechanisms of pancreatic cancer (PC) are still not fully understood. Ubiquitination modifications have a crucial role in tumorigenesis and progression. Yet, the role of MINDY2, a member of the motif interacting with Ub-containing novel DUB family (MINDY), as a newly identified deubiquitinating enzyme, in PC is still unclear. In this study, we found that MINDY2 expression is elevated in PC tissue (clinical samples) and was associated with poor prognosis. We also found that MINDY2 is associated with pro-carcinogenic factors such as epithelial-mesenchymal transition (EMT), inflammatory response, and angiogenesis; the ROC curve suggested that MINDY2 has a high diagnostic value in PC. Immunological correlation analysis suggested that MINDY2 is deeply involved in immune cell infiltration in PC and is associated with immune checkpoint-related genes. In vivo and in vitro experiments further suggested that elevated MINDY2 promotes PC proliferation, invasive metastasis, and EMT. Meanwhile, actinin alpha 4 (ACTN4) was identified as a MINDY2-interacting protein by mass spectrometry and other experiments, and ACTN4 protein levels were significantly correlated with MINDY2 expression. The ubiquitination assay confirmed that MINDY2 stabilizes the ACTN4 protein level by deubiquitination. The pro-oncogenic effect of MINDY2 was significantly inhibited by silencing ACTN4. Bioinformatics Analysis and Western blot experiments further confirmed that MINDY2 stabilizes ACTN4 through deubiquitination and thus activates the PI3K/AKT/mTOR signaling pathway. In conclusion, we identified the oncogenic role and mechanism of MINDY2 in PC, suggesting that MINDY2 is a viable candidate gene for PC and may be a therapeutic target and critical prognostic indicator

Folic acid therapy reduces the first stroke risk associated with hypercholesterolemia among hypertensive patients

Background and Purpose - We sought to determine whether folic acid supplementation can independently reduce the risk of first stroke associated with elevated total cholesterol levels in a subanalysis using data from the CSPPT (China Stroke Primary Prevention Trial), a double-blind, randomized controlled trial. Methods - A total of 20 702 hypertensive adults without a history of major cardiovascular disease were randomly assigned to a double-blind daily treatment of an enalapril 10-mg and a folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. The primary outcome was first stroke. Results - The median treatment duration was 4.5 years. For participants not receiving folic acid treatment (enalapril-only group), high total cholesterol (≥ 200 mg/dL) was an independent predictor of first stroke when compared with low total cholesterol (\u3c200 mg/dL; 4.0% versus 2.6%; hazard ratio, 1.52; 95% confidence interval, 1.18-1.97; P=0.001). Folic acid supplementation significantly reduced the risk of first s roke among participants with high total cholesterol (4.0% in the enalapril-only group versus 2.7% in the enalapril-folic acid group; hazard ratio, 0.69; 95% confidence interval, 0.56-0.84 P\u3c0.001; number needed to treat, 78; 95% confidence interval, 52-158), independent of baseline folate levels and other important covariates. By contrast, among participants with low total cholesterol, the risk of stroke was 2.6% in the enalapril-only group versus 2.5% in the enalapril-folic acid group (hazard ratio, 1.00; 95% confidence interval, 0.75-1.30; P=0.982). The effect was greater among participants with elevated total cholesterol (P for interaction=0.024). Conclusions - Elevated total cholesterol levels may modify the benefits of folic acid therapy on first stroke. Folic acid supplementation reduced the risk of first stroke associated with elevated total cholesterol by 31% among hypertensive adults without a history of major cardiovascular diseases