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

Purpose To assess the right atrial and right ventricular strain and right ventricular-pulmonary artery(RV-PA)coupling in rheumatoid arthritis(RA)via two-dimensional speckle tracking.Materials and Methods Sixty patients with RA in the General Hospital of Ningxia Medical University from June 2020 to June 2022 were prospectively selected,and all RA patients were divided into three groups according to pulmonary artery systolic pressure(PASP),including group A(n=20 cases)with PASP<33 mmHg,group B(n=20 cases)with PASP 33-39 mmHg as mild ePH,and group C(n=20 cases)PASP≥40 mmHg,twenty healthy individuals were selected as the control group.All subjects underwent transthoracic echocardiography,and right atrial and right ventricular systolic function was assessed by two-dimensional speckle tracking technique,and RV-PA coupling was assessed noninvasively by right ventricular free wall strain/pulmonary artery systolic pressure(RV FWS/PASP),pulmonary function was analyzed by pulmonary function instruments.Spearman's analysis was used to analyze the correlation between right heart function and RV-PA coupling to pulmonary diffusion function.Results There were statistical differences in right ventricular base diameter,right atrium diameter,tricuspid annular plane systolic excursion,inferior vena cava diameter,PASP,right ventricular global strain,RV FWS,right atrium strain-reservoi,right atrium strain-conduit(S-CD),RV FWS/PASP among the four groups(F/H=2.369-74.880,all P<0.05).Right atrium strain-reservoi[(36.0±7.9)%vs.(30.9±7.8)%],right atrium S-CD[(19.9±6.9)%vs.(15.3±4.7)%]and RV FWS/PASP(0.96±0.19 vs.0.56±0.13)in group B were significantly lower than those of group A(t=2.040,2.262,7.704,all P<0.05).There was a good correlation between diffusing capacity of the lung for carbon monoxide single-breathmethod and right ventricular global strain,RV FWS,right atrium S-CD and RV FWS/PASP in RA patients(r=0.392,0.472,0.431,0.572,all P<0.05).Conclusion The more increases of pulmonary artery pressures,the more decreases of right heart function in RA patients,and the more uncoupling in RV-PA.Right heart dysfunction and right ventricle-pulmonary artery uncoupling have developed in RA patients with PASP 33-39 mmHg,with association of pulmonary diffusion dysfunction.

Objective Chlorination is often used to disinfect recreational water in large amusement parks;however,the health hazards of chlorination disinfection by-products(DBPs)to occupational populations are unknown.This study aimed to assess the exposure status of chlorinated DBPs in recreational water and the health risks to employees of large amusement parks. Methods Exposure parameters of employees of three large amusement parks in Shanghai were investigated using a questionnaire.Seven typical chlorinated DBPs in recreational water and spray samples were quantified by gas chromatography,and the health risks to amusement park employees exposed to chlorinated DBPs were evaluated according to the WHO's risk assessment framework. Results Trichloroacetic acid,dibromochloromethane,bromodichloromethane,and dichloroacetic acid were detected predominantly in recreational water.The carcinogenic and non-carcinogenic risks of the five DBPs did not exceed the risk thresholds.In addition,the carcinogenic and non-carcinogenic risks of mixed exposure to DBPs were within the acceptable risk limits. Conclusion Typical DBPs were widely detected in recreational water collected from three large amusement parks in Shanghai;however,the health risks of DBPs and their mixtures were within acceptable limits.

Objective:The study aimed to assess the scientific rigor, transparency, and practicality of Chinese geriatric medicine guidelines and consensus published in academic journals.Methods:A systematic search was conducted across 8 major Chinese and English databases to identify guidelines and consensus documents from Chinese scholars in 2022.Results:The selected documents were evaluated using the STAR rating tool, resulting in the inclusion of 2 guidelines and 19 expert consensuses.The total scores ranged from 9.0 to 50.6 points, with an average score of 29.6±13.1 points.The highest score rate in the'Consensus Methods’category of expert consensuses was 47.4%, while the lowest score rate in the'Registration’category was 0.For guidelines, the highest score rate in the'Consensus Methods’category was 42.9%, while the lowest score rates were observed in the'Registration’, 'Plan’, and'Others’categories at 0.Conclusions:The overall quality of geriatric medicine guidelines and consensus in China requires enhancement.There is a need to improve training in guideline consensus development, involve methodologists, elevate the standards for journal publication, and strive to enhance the scientific rigor, transparency, and practicality of guidelines and consensus documents.

Purpose: Patients with advanced biliary tract cancer (BTC) have a poor survival. We aim to evaluate the efficacy and safety of nab-paclitaxel plus gemcitabine and cisplatin regimen in Chinese advanced BTC patients. Materials and Methods: Eligible patients with locally advanced or metastatic BTC administrated intravenous 100 mg/m2 nab-paclitaxel, 800 mg/m2 gemcitabine, and 25 mg/m2 cisplatin every 3 weeks. The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS) and adverse events, while exploratory endpoint was the association of biomarkers with efficacy. Results: After the median follow-up of 25.0 months, the median PFS and OS of 34 enrolled patients were 7.1 months (95% confidence interval [CI], 5.4 to 13.7) and 16.4 months (95% CI, 10.9 to 23.6), respectively. The most common treatment-related adverse events at ≥ 3 grade were neutropenia (26.5%) and leukopenia (26.5%). Survival analyses demonstrated that carcinoembryonic antigen (CEA) levels could monitor patients’ survival outcomes. A significant increase in the number of infiltrating CD4+ cells (p=0.008) and a decrease in programmed death-1–positive (PD-1+) cells (p=0.032) were observed in the response patients. Conclusion In advanced BTC patients, nab-paclitaxel plus gemcitabine and cisplatin regimen showed therapeutic potential. Potential prognostic factors of CEA levels, number of CD4+ cells and PD-1+ cells may help us maximize the efficacy benefit.

Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macro-phages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative acti-vation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

Objective:To investigate the correlation between serum vitamin D and the risk of pre-eclampsia at the early, middle and late stages of pregnancy.Methods:Pregnant women who registered and delivered in Electric Power Teaching Hospital of Capital Medical University from August 2020 to July 2021 were included. Pregnant women with pre-eclampsia during pregnancy were selected as the case group (150 cases), while pregnant women without any complications after delivery were selected as the control group (600 cases) according to the 1∶4 matching principle (age, pre-pregnancy body mass index and last menstruation). The levels of serum vitamin D in differences stages of pregnancy between the two groups were compared. Logistic regression model was used to analyze the association between serum vitamin D levels and the risk of pre-eclampsia.Results:The levels of serum vitamin D at the early, middle and late stages of pregnancy in the case group were lower than those in the control group: (14.32 ± 3.61) μg/L vs. (18.78 ± 4.73) μg/L, (15.06 ± 3.12) μg/L vs. (19.88 ± 4.25) μg/L, (16.04 ± 3.51) μg/L vs. (22.04 ± 5.63) μg/L, there were statistical differences ( P<0.05). Taking pregnant women with adequate serum Vitamin D as a reference, and adjusting for confounding factors such as gain weight and primipara, the risk of pre-eclampsia in early stages pregnant women with serum Vitamin D serious deficiency, middle deficiency and deficiency was increased and the OR and 95% CI were 4.84(1.25 -31.42), 3.09(1.12 - 8.96), 1.48(1.12 - 13.05); the risk of pre-eclampsia in middle stages pregnant women with serum vitamin D serious deficiency, middle deficiency and deficiency was increased and the OR(95% CI) were 4.43(1.23 - 13.55), 2.22(1.05 - 6.78), 1.12(0.45 - 7.73); the risk of pre-eclampsia in late stages pregnant women with serum vitamin D serious deficiency, middle deficiency and deficiency was increased and the OR(95% CI) were 2.13(1.12 - 8.64), 1.76(1.02 - 4.98), 1.22(0.72 - 3.94). Conclusions:The level of serum vitamin D is associated with the risk of pre-eclampsia in pregnant women in the early, middle and late stages of pregnancy, and the risk of pre-eclampsia is significantly increase when the level of serum vitamin D is severely deficient or deficient during pregnancy.

Objective:To explore the application value of non-invasive myocardial work imaging in evaluating the cardiac function of ST-segment elevation myocardial infarction (STEMI) patients with left ventricular remodeling (LVR) after percutaneous coronary intervention (PCI).Methods:One hundred and twenty-six patients with STEMI undergoing PCI in General Hospital of Ningxia Medical University from December 2021 to September 2022 were prospectively collected and divided into left ventricular remodeling group (LVR group, 34 cases) and non left ventricular remodeling group (NLVR group, 92 cases) according to whether there was left ventricular remodeling 3 months after surgery. General data were collected. Routine echocardiography and noninvasive myocardial work imaging were performed before, 1 week, 1 month, and 3 months after surgery, the differences in the above parameters between the two groups were compared. Pearson correlation analysis was used to analyze the correlation between the indicators.Logistic regression analysis was used to determine the independent risk factors of left ventricular remodeling after STEMI, and a predictive model was obtained. The diagnostic value of the model was judged by ROC curve.Results:①General information comparison: There were statistically significant differences between the two groups in BMI, systolic blood pressure, diastolic blood pressure, average number of stents implanted, and history of hyperlipidemia (all P<0.05), but there was no significant difference in other data (all P>0.05). There was no statistically significant difference in two-dimensional transthoracic echocardiography (2D-TTE) parameters and non-invasive myocardial work (MW) parameters between the two groups before and 1 week after operation (both P>0.05). ②2D-TTE parameter comparison: LVESV and LVEDV at 3 months after PCI in the LVR group were significantly higher than those in the NLVR group, and LVEF and E/A were significantly lower than those in the NLVR group (all P<0.05); There were no significant differences in other indexes between the two groups by conventional echocardiography at 3 months after PCI(all P>0.05). ③Comparisons of noninvasive myocardial work parameters: GLS, GWE, GWI, GCW at 1 month and 3 months after PCI in the LVR group were significantly lower than those in the NLVR group, and GWW were significantly higher than those in the NLVR group ( P<0.001). ④Correlation analysis: GLS, GWE, GCW, GWI and LVEDV were negatively correlated at 1 month after operation ( r=-0.42, -0.38, -0.50, -0.53, all P<0.001), GWW was positively correlated with LVEDV ( r=0.45, P<0.001). ⑤Logistic regression analysis: GLS<17%, GCW<1 900 mmHg%, GWW>105 mmHg%, and GWE<90 mmHg% at 1 month after PCI were independent predictors for LVR in STEMI patients after PCI (all P<0.05). The predictive model was Logit (P)=0.692GLS+ 0.804GCW+ 0.972GWW+ 0.880GWE. The AUC of this model was 0.886, 95% CI=0.845-0.926, which was significantly higher than single index, the sensitivity was 0.86, and the specificity was 0.79. Conclusions:GLS, GWE, GWI, GCW are positively correlated with LVR, while GWW is negatively correlated with left ventricular remodeling. Noninvasive myocardial work parameters are independent risk factors for left ventricular remodeling in patients with STEMI after PCI surgery. This technique can be used to evaluate LVR and has great clinical application value.

Objective:To analyze the differences of the clinical characteristics and laboratory indexes in children with positive dense fine spot (DFS) type anti-nuclear antibody, and thereby to explore the value of positive DFS in the diagnosis of immunological diseases.Methods:Among 9 613 cases who were routinely tested for antinuclear antibody (ANA) from August 2017 to February 2020, there were 197 cases with DFS positive, who were subjected to a retrospective analysis.These patients were divided into the autoimmune diseases (AID) group (39 cases) and the non-AID group (158 cases) according to clinical diagnosis.Healthy children in the same physical examination were used as healthy control group (40 cases). T test was applied to analyze the differences of humoral immunity markers between AID and non-AID groups.What′s more, DFS positive patients in different clinical departments, initial symptom and the part of body were further compared. Results:Among 9 613 children tested for autoantibodies, 2 654 (27.61%) were ANA positive, with the highest detection rate of the spotted type and 197 DFS positive cases, accoun-ting for 7.42% of ANA positive children; 97 DFS positive male patients accounted for 8.20% (97/1 183 case) of ANA positive male patients, 100 DFS positive female patients accounted for 6.80% (100/1 471 cases) of ANA positive female patients, and there was no significant difference in the positive rate.The departments with high positive ANA detection included the nephrology department (27.88%) and the rheumatology department (24.83%). The departments with a higher ANA positive rate in DFS positive children included the gastroenterology department (13.25%) and the infectious department (11.76%). Among the children with DFS antibody positive, 39 cases had AID, among which 38 cases had organ-specific AID, and juvenile idiopathic arthritis (JIA) had the highest detection rate in 13 cases.The diseases with a high DFS positive rate in 158 non-AID cases included allergic purpura (46 cases). Serum immunoglobulin (IgG) level in the AID group was significantly lower than this in the non-AID group, serum IgM and C 4 levels in AID children were significantly lower than those in the non-AID group and healthy control group, and the serum IgA level of DFS positive group was significantly higher than that of children in the healthy control group.All children with DFS antibody positive had no specific autoantibodies. Conclusions:DFS antibody positive is important for the diagnosis of systemic AID in children.The combined detection with the DFS, other autoimmunity antibody index, humoral immune function index contributes to the early differential diagnosis of autoimmune diseases in children.

Sterols, a class of cyclopentane poly-hydrophenanthrene derivatives, are the predominant membrane constituent of eukaryotes. These substances have a variety of biological activities and have been widely used in food and pharmaceutical industries. The presence of endogenous ergosterol biosynthetic pathway in Saccharomyces cerevisiae cells make it an ideal chassis for the de novo synthesis of sterol and its derivatives. Most recently, the rational modification of organelles provides a novel strategy for the directed transportation and storage of target products and the ultimate enhanced product synthesis. This review summarizes the phenotypic responses of S. cerevisiae cells upon different physiological stimulations and the underlying molecular mechanisms. Reinforcement of sterol production through directed storage, transportation, and excretion of sterols offers a novel strategy for breaking the limitation of de novo biosynthesis of sterols in yeast.
Ergosterol ; Phytosterols ; Saccharomyces cerevisiae ; Sterols