Objective: To characterize perioperative dynamic changes in immune-cell phenotypes and inflammatory cytokines in patients undergoing CPB (cardiopulmonary bypass) cardiac surgery, and to explore their associations with postoperative outcomes. Methods: In this prospective cohort study, 120 adult patients who underwent elective cardiac surgery under CPB at West China Hospital from May 2022 to March 2023 were enrolled. Perioperative immune-cell phenotypes and concentrations of 40 inflammation-related cytokines were measured. The primary outcomes were the sequential organ failure assessment (SOFA) score at 24 h after surgery and ΔSOFA (the peak SOFA score within 48 h after surgery minus the preoperative SOFA score). Secondary outcomes included major adverse cardiovascular events (MACE), acute kidney injury (AKI), respiratory failure, severe liver injury, and infection. Results: The mean age of enrolled patients was 57±10 years. Of these, 52% (62/120) were male and 90% (108/120) underwent valve surgery. During the rewarming to the end of CPB, neutrophil counts rapidly increased (7.39×10 /L vs preoperative 3.07×10 /L, P<0.001), with significant upregulation of CD11b (7.30×10 /L vs preoperative 3.05×10 /L, P<0.001) and CD54 (7.15×10 /L vs preoperative 2.99×10 /L, P<0.001). Lymphocyte counts increased at the end of CPB (1.75×10 /L vs preoperative 1.12×10 /L, P<0.001) but decreased significantly at 24 h after surgery (0.59×10 /L vs preoperative 1.12×10 /L, P<0.001). Plasma analysis showed that multiple pro-inflammatory cytokines increased during CPB and remained elevated up to 24 h after surgery; five chemokines and the anti-inflammatory cytokine IL-10 peaked at the end of CPB. The SOFA score increased from 1 (1, 2) preoperatively to 7 (5, 10) at 24 h after surgery, with a ΔSOFA of 6 (4, 8). Within 30 days after surgery, 48 patients (40.0%) developed AKI, 17 (14.2%) developed infection, 4 (3.3%) developed severe liver injury, 3 (2.5%) developed respiratory failure, and 3 (2.5%) experienced MACE. During the 2-year follow-up, 8 patients (6.7%) experienced MACE and 5 (4.2%) died. Conclusion: Multi-organ dysfunction is common after cardiac surgery under CPB (median ΔSOFA, 6), accompanied by perioperative activation of multiple immune-cell subsets and upregulation of pro-inflammatory, anti-inflammatory, and chemotactic mediators. This study provides data-driven evidence and research clues for further investigation of the associations between CPB-related immune perturbations and postoperative organ dysfunction and clinical outcomes.

ObjectiveAs a common lifestyle habit, alcohol consumption has a controversial association with the onset of Parkinson’s disease (PD). To demonstrate the correlation between alcohol consumption and PD and to identify associated genes, we integrated findings from clinical surveys, genomics, transcriptomics, and animal experiments. MethodsWe investigated the alcohol consumption rates (including both before and after disease onset) among 244 PD patients in China and 177 PD patients from the U.S. NHANES database. Mendelian randomization (MR) analysis was performed using genome-wide association study (GWAS) data for three alcohol-related traits and seven PD-related datasets from the MRC IEU OpenGWAS database. Transcriptomic data from the substantia nigra of PD patients were obtained from three GEO datasets (GSE7621, GSE20141, and GSE49036) to analyze RIT2 gene transcription. Finally, three groups of animal experiments (water/20% ethanol/20% liquor, with 4 C57BL/6J mice per group) were conducted to examine changes in brain RIT2 gene expression and transcriptomic profiles following alcohol consumption. ResultsThe alcohol consumption rates among PD patients in China and the U.S. (9%-18.87%) were significantly lower than the general population rates of 15%-45% in their respective regions (P<0.001), suggesting a possible negative association between alcohol consumption and PD. Subsequently, in 21 bidirectional MR analyses using 3 alcohol-related GWAS datasets and 7 PD-related GWAS datasets, the forward MR analyses (alcohol intake as exposure, PD as outcome) yielded 12 negative associations (OR_IVW<1) and 9 positive associations (OR_IVW>1). Among these, only two negative associations reached statistical significance: alcohol intake frequency (OR_IVW=0.75, 95% CI: 0.60-0.93, P=0.010) and alcohol consumption (OR_IVW=0.20, 95% CI: 0.05-0.83, P=0.026). The forward MR analysis (alcohol intake→PD) identified 235 SNPs, annotated to 316 genes, while the reverse MR analyses (PD→alcohol intake) identified 37 SNPs, annotated to 53 genes. Notably, only the RIT2 gene appeared in both the forward and reverse MR analyses (alcohol intake→PD: rs28597806, rs8083110; PD→alcohol intake: rs4588066). RIT2 is selectively expressed in the human brain (FPKM: 5.259±2.103), with low or no expression in peripheral tissues (FPKM: <1). Analysis of three human substantia nigra transcriptomic datasets revealed a decreasing trend in RIT2 gene expression in PD patients (GSE20141 array signal: 3.49±1.23 vs. 2.33±0.87, P=0.044). Animal experiments demonstrated that administration of 20% ethanol or 20% liquor (approximately 8% ethanol) stimulated a >2-fold upregulation of RIT2 gene expression in the mouse brain. Furthermore, transcriptomic sequencing revealed that the two alcohol-treated groups exhibited 96 (20% ethanol vs. water control) and 4 (20% liquor vs. water control) differentially expressed genes, respectively, indicating that low-dose alcohol consumption can achieve RIT2 upregulation while minimizing impact on other brain genes. In addition to its anti-infective effects, low-dose alcohol consumption primarily influences signaling pathways related to neurodegenerative diseases such as PD and Prion diseases. ConclusionAlcohol consumption is generally considered as a harmful lifestyle habit. However, some studies have also shown a lower risk of mortality among individuals who consume low doses of alcohol (100 g/week of ethanol) or drink occasionally. Currently, one of the research focuses on alcohol consumption is whether the human body can benefit from low-dose alcohol intake. This study provides new evidence supporting a negative association between alcohol consumption and PD, and for the first time, through MR analysis, identifies the RIT2 gene as a potential mediator of the effect of alcohol consumption on PD. RIT2 is selectively expressed in the human brain. Building upon existing evidence indicating downregulated RIT2 gene expression in PD pathogenesis, our experiments confirm that low-dose alcohol consumption can upregulate RIT2 expression in the brain. In brief, alcohol consumption may suppress the pathogenesis of PD by upregulating RIT2 expression in the substantia nigra. China is facing a serious problem of population aging. This study offers important insights for long-term PD prevention and treatment strategies, with the aim of benefiting more potential PD patients through lifestyle modifications, thereby improving the quality of life of the aging population and reducing the economic burden on healthcare.

Objective To analyze the infection status and epidemic trends of soil-borne nematode infections in Yubei, Chongqing City, in 2010,2021, and 2022. Methods The local populations from four survey sites of four towns in 2010 and five sites of five towns in 2021 and 2022 were surveyed regarding their basic information using a unified form. Fecal samples of the participants were collected and tested for soil-borne nematode infections using the modified Kato-Katz thick smear method. Results In 2010, 2 049 participants were surveyed, followed by 1 000 participants in 2021 and 2022. The overall prevalence of parasitic infections declined significantly from 3.86% to 0.20%. In 2010, soil-transmitted nematode included hookworms(3.81%) and roundworms(0.29%). In 2021, the infection rates of roundworms and hookworms were 1.70% and 0.10% respectively. Notably, only Ascaris was identified in 2022(0.20%). The≥60 age group consistently exhibited the highest infection rates across all surveys, followed by the 40-59 age group. The infection rates of males in the three surveys were 3.31%,1.92%, and 0.20% respectively, and those of females were 4.37%, 1.46%, and 0.20% respectively. There was no statistically significant difference in the infection rates between males and females. Educational attainment was inversely associated with infection; in 2010, the highest prevalence was observed among those with primary education or below, whereas in 2021, illiterate or semi-literate individuals showed the highest susceptibility. The occupational distribution of infections in 2010 indicated that retirees (8.33%), farmers(4.86%), and homemakers or unemployed individuals(3.45%)were the most affected. However, in 2021 and 2022, farmers emerged as the predominant occupational group with soil-transmitted nematode infections. Conclusions The infection rate of soil-borne nematodes showed a decreasing trend in Yubei, and the infection species changed from hookworms in 2010 to Ascaris in 2022. Farmers, the elderly, and people with low education levels should continue to be the focus of preventive and control efforts.

Objective To investigate the association between school bullying and comorbidity of overweight/obesity and depressive symptoms in middle school students, and to provide a basis for formulating intervention strategies for the prevention and control of common diseases and comorbidities among students. Methods In September 2023, a stratified cluster random sampling method was employed to select junior high school, high school, and vocational high school students in 103 districts and counties across 17 cities (prefectures) in Hubei Province. A questionnaire survey was conducted on these students regarding school bullying and depressive symptoms, and physical measurements of height and weight were taken. The association between school bullying and comorbidity of overweight/obesity and depressive symptoms was analyzed using a logistic regression model. Results A total of 99 921 middle school students aged 11-19 years old were included in the study. The detection rate of overweight/obesity was 29.39%, the detection rate of depressive symptoms was 31.15%, and the detection rate of comorbidity of overweight/obesity and depressive symptoms was 9.15%. Among all students, 24.12% reported experiencing school bullying. Multivariate logistic regression analysis showed that experiencing school bullying was positively associated with the comorbidity of overweight/obesity and depressive symptoms among middle school students (OR = 2.692, 95% CI: 2.571-2.817, P < 0.001). Stratified analysis results showed that both male and female students who experienced school bullying were more likely to have comorbidity of overweight/obesity and depressive symptoms (OR values were 2.756 for males and 2.594 for females; P values were both < 0.001). Students in all educational stages who experienced school bullying had an increased risk of comorbidity of overweight/obesity and depressive symptoms (OR values were 2.739 for junior high, 2.676 for senior high, and 2.378 for vocational high; P values were all < 0.001). Conclusion The comorbidity of overweight/obesity and depressive symptoms among middle school students is widespread, and there is a significant association between school bullying and comorbidity of overweight/obesity and depressive symptoms. It is necessary to strengthen the prevention and control of school bullying to promote the healthy physical and mental development of adolescents.

Colorectal tumorigenesis generally progresses from adenoma to adenocarcinoma, accompanied by dynamic changes in the tumor microenvironment (TME). A randomized controlled trial has confirmed the efficacy and safety of Shen-Bai-Jie-Du decoction (SBJDD) in preventing colorectal tumorigenesis. However, the mechanism remains unclear. In this study, we employed single-cell RNA sequencing (scRNA-seq) to investigate the dynamic evolution of the TME and validated cell infiltration with multiplex immunohistochemistry and flow cytometry. Bulk RNA sequencing was utilized to assess the underlying mechanisms. Our results constructed the mutually verifiable single-cell transcriptomic atlases in Apc ^Min/+ mice and clinical patients. There was a marked accumulation of CCL22⁺ dendritic cells (DCs) and an enhanced immunosuppressive action, which SBJDD and berberine reversed. Combined treatment with cholesterol and lipopolysaccharide induced characteristic gene expression of CCL22⁺ DCs, which may represent "exhausted DCs". Intraperitoneal injection of these DCs after SBJDD treatment eliminated its therapeutic effects. TMEM131 derived CCL22⁺ DCs generation by TNF signaling pathway and may be a potential target of berberine in retarding colorectal tumorigenesis. These findings emphasize the role of exhausted DCs and the regulatory mechanisms of SBJDD and berberine in colorectal cancer (CRC), suggesting that the multi-component properties of SBJDD may help restore TME homeostasis and offer novel cancer therapy.

T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Extensive epigenetic reprogramming involves in memory CD8+ T-cell differentiation. The elaborate epigenetic rewiring underlying the heterogeneous functional states of CD8+ T cells remains hidden. Here, we profile single-cell chromatin accessibility and map enhancer-promoter interactomes to characterize the differentiation trajectory of memory CD8+ T cells. We reveal that under distinct epigenetic regulations, the early activated CD8+ T cells divergently originated for short-lived effector and memory precursor effector cells. We also uncover a defined epigenetic rewiring leading to the conversion from effector memory to central memory cells during memory formation. Additionally, we illustrate chromatin regulatory mechanisms underlying long-lasting versus transient transcription regulation during memory differentiation. Finally, we confirm the essential roles of Sox4 and Nrf2 in developing memory precursor effector and effector memory cells, respectively, and validate cell state-specific enhancers in regulating Il7r using CRISPR-Cas9. Our data pave the way for understanding the mechanism underlying epigenetic memory formation in CD8+ T-cell differentiation.
CD8-Positive T-Lymphocytes/metabolism* ; Cell Differentiation ; Chromatin/immunology* ; Animals ; Mice ; Immunologic Memory ; Epigenesis, Genetic ; SOXC Transcription Factors/immunology* ; NF-E2-Related Factor 2/immunology* ; Mice, Inbred C57BL ; Gene Regulatory Networks ; Enhancer Elements, Genetic

Objective: To investigate the risk factors affecting the early diagnosis of ABO-hemolytic disease of the fetus and newborn (ABO-HDFN) in neonates with maternal-fetal blood group incompatibility, and to develop a risk prediction model and validate its predictive performance, so as to provide a reference for the early diagnosis of neonates with ABO-HDFN in primary hospitals. Methods: A total of 1 229 neonates with maternal-fetal blood group incompatibility suspected of ABO-HDFN, admitted to our hospital between between June 2021 and September 2024, were enrolled. The sample size was calculated by using the events per variable (EPV) method. The cohort was divided into a modeling group (n=860) and a validation group (n=369), and the results and clinical information of laboratory examination indicators were collected. Univariate and multivariate logistic regression analysis were used to explore the risk factors affecting the early diagnosis of ABO-HDFN in neonates with maternal-fetal blood group incompatibility. The risk prediction model was developed and internally validated by the Bootstrap method. The goodness-of-fit of the model was evaluated by the Hosmer-Lemeshow (H-L) test, and the receiver operating characteristic (ROC) curve was used to analyze the predictive performance of the model. The prediction model was validated by using the validation group data, and the predictive performance of the model was evaluated. Results: Among the 860 neonates with maternal-fetal incompatibility in the modeling group, 346 (346/860, 40.23%) were diagnosed with ABO-HDFN. Univariate and multivariate logistic regression analyses identified the following as significant risk factors for early diagnosis: the number of postnatal days at specimen collection, maternal type O blood group, parity >1, time of onset for pathologic jaundice, maternal-fetal blood group incompatibility due to A antigen, the level of total bilirubin, and the immature reticulocyte fraction (IRF). A risk prediction model was established, and the calibration degree of the model was validated by the Bootstrap internal validation method, Brier=0.143. The results of H-L test showed that χ =3.464, P=0.902. The area under the ROC curve (AUC) was 0.885. The maximum value of the Youden index was 0.611, the sensitivity was 0.832, and the specificity was 0.778. The results of the validation group showed that the area under the ROC curve was 0.863, with a sensitivity of 0.875 and specificity of 0.735. Conclusion: The risk prediction model developed based on these risk factors has good predictive performance for ABO-HDFN, facilitating early diagnosis of suspected ABO-HDFN cases by clinicians in primary hospitals.

Objective: To investigate the risk factors affecting the early diagnosis of ABO-hemolytic disease of the fetus and newborn (ABO-HDFN) in neonates with maternal-fetal blood group incompatibility, and to develop a risk prediction model and validate its predictive performance, so as to provide a reference for the early diagnosis of neonates with ABO-HDFN in primary hospitals. Methods: A total of 1 229 neonates with maternal-fetal blood group incompatibility suspected of ABO-HDFN, admitted to our hospital between between June 2021 and September 2024, were enrolled. The sample size was calculated by using the events per variable (EPV) method. The cohort was divided into a modeling group (n=860) and a validation group (n=369), and the results and clinical information of laboratory examination indicators were collected. Univariate and multivariate logistic regression analysis were used to explore the risk factors affecting the early diagnosis of ABO-HDFN in neonates with maternal-fetal blood group incompatibility. The risk prediction model was developed and internally validated by the Bootstrap method. The goodness-of-fit of the model was evaluated by the Hosmer-Lemeshow (H-L) test, and the receiver operating characteristic (ROC) curve was used to analyze the predictive performance of the model. The prediction model was validated by using the validation group data, and the predictive performance of the model was evaluated. Results: Among the 860 neonates with maternal-fetal incompatibility in the modeling group, 346 (346/860, 40.23%) were diagnosed with ABO-HDFN. Univariate and multivariate logistic regression analyses identified the following as significant risk factors for early diagnosis: the number of postnatal days at specimen collection, maternal type O blood group, parity >1, time of onset for pathologic jaundice, maternal-fetal blood group incompatibility due to A antigen, the level of total bilirubin, and the immature reticulocyte fraction (IRF). A risk prediction model was established, and the calibration degree of the model was validated by the Bootstrap internal validation method, Brier=0.143. The results of H-L test showed that χ =3.464, P=0.902. The area under the ROC curve (AUC) was 0.885. The maximum value of the Youden index was 0.611, the sensitivity was 0.832, and the specificity was 0.778. The results of the validation group showed that the area under the ROC curve was 0.863, with a sensitivity of 0.875 and specificity of 0.735. Conclusion: The risk prediction model developed based on these risk factors has good predictive performance for ABO-HDFN, facilitating early diagnosis of suspected ABO-HDFN cases by clinicians in primary hospitals.