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

Mitochondria are the main site of energy metabolism in cardiomyocytes， and at the same time mediate apoptosis and immune response， so mitochondrial dysfunction is closely related to the development of heart failure. Combined with the pathogenesis of mitochondrial dysfunction and heart failure， it is proposed that the mitochondrial function is similar to "sweat pore - collaterals - zang and fu organs"， according to which the treatment of heart failure is based on the theory of "sweat pore - collaterals - zang and fu organs". It is believed that the core mechanism of heart failure is qi deficiency， and qi deficiency leads to the weakness of the sweat pore opening and closing， or even the sweat pore closure， then resulting in qi deficiency and blood stasis， collaterals stagnation fail to flourish， and qi， blood， and body fluids can not infiltrate and nourish zang-fu organs， so that the heart fail to be nourished， and the disease will develop. The treatment should be based on the method of boosting qi and opening sweat pore， using acridity to unblock the collaterals， and invigorating blood and draining water， with medicinal of boosting qi， invigorating blood， and draining water as treatment.

Objective: To explore the moderating role of estradiol in the relationship between parenting styles and preschool children's behavioral problems, so as to provide a theoretical basis for improving the development of human s emotional health development in early life stage. Methods: During September to November in 2022, 354 children aged 3-6 years and their parents from two kindergartens in Bengbu City were chosen by using stratified cluster sampling method for the questionnaire survey. The Parenting Style Scale and the Child Behavior Checklist (CBCL) were used to collect information on parenting style and child behavioral problems. Salivary estradiol of children was collected and tested. Independent samples t test was applied to compare the scores of the scale for parental up bringing and children s behavioral problems, and Pearson correlation analysis was conducted to explore the relationship among parental upbringing, estradiol and children s behavioral problems. Results: Parents doting, laissez faire, autocratic, and inconsistent parenting styles were positive associated with child behavior problems( r =0.14-0.70); fathers democratic parenting style was negatively associated with child behavior problems( r =-0.14，-0.22，-0.21，-0.17，-0.27，-0.20); mothers democratic parenting styles was negatively correlated with scores on all five dimensions of child behavior problems except the withdrawal dimension ( r =-0.14，-0.12，-0.13，-0.21，-0.12)( P <0.05). Estradiol levels had significant moderating effects on maternal doting parenting style and children s withdrawal ( β =0.68) as well as social problems ( β =-1.00), also moderating laissez faire parenting styles and children s withdrawal problems ( β =0.75)( P <0.05). For children with low levels of estradiol, withdrawal problem scores were negatively associated with mother s doting parenting style and positively associated with laissez faire parenting style, and socialization problem scores were associated with mother s doting parenting style; for children with high levels of estradiol, withdrawal problem scores were positively associated with mother s doting parenting style, and socialization problem scores were associated with mother s doting parenting style ( t=2.84, 6.24, 3.16 , 2.37, 4.49, P <0.05). Conclusions Parenting styles are strongly associated with child behavioral problems; estradiol levels play a moderating role in mothers doting, laissez faire parenting styles and children s withdrawal problems and social problems.Parents should adopt more positive parenting styles and focus on the role of estradiol levels in maternal education to reduce the occurrence of behavioral problems in children.

Objective:To screen T-cell exhaustion-related signature genes as the prognostic marker for osteosarcoma and establish a prognostic model for osteosarcoma patients based on weighted gene co-expression network analysis(WGCNA)and Least absolute shrinkage and selection operator(LASSO)-COX regression analysis. Methods:GSE21257 dataset was downloaded from Gene Expression Omnibus(GEO)database for the establishment of the prognostic model for osteosarcoma.4 T-cell exhaustion-related gene sets were downloaded from The Molecular Signatures Database(MisgDB)and their enrichment scores in GSE21257 samples were calculated by single sample gene set enrichment analysis(ssGSEA).WGCNA was carried out to screen the gene module that is highly associated with T-cell exhaustion based on ssGSEA results followed by GO(Gene Ontology)and KEGG(Kyoto Encyclopedia of Genes and Genomes)analysis of the biological processes and signaling transduction pathways that those genes are involved in.The signature genes that are highly associated with the prognosis of osteosarcoma patients were obtained through LASSO-COX regression and a prognostic model was established based on these signature genes.Osteosarcoma-related expression profile data from the GSE21257 and TAEGET datasets on XENA were downloaded from the Gene Expression Omnibus.Clinical information for the training and validation sets was obtained.T-cell exhaustion-related genes were screened using a weighted correlation network analysis.Realtime fluorescence quantitative PCR,COX regression analysis,external dataset and nomogram were used to evaluate the reliability and accuracy of the prognostic model.A immunotherapy-related dataset was used to assess the efficacy of this prognostic model for the prediction of patients'responses to immunotherapy. Results:Analysis results based on the ssGSEA scores showed that T-cell exhaustion-related genes were related to the metastasis and age of osteosarcoma patients.Many T-cell exhaustion-related genes were found to be differentially expressed in metastatic and non-metastatic osteosarcoma patients.1 256 T-cell exhaustion-related genes were identified through WGCNA and these candidate markers were mainly distributed in structures like secretory granule membranes and endocytic vesicles and were involved in T-cell activation.COX regression analysis screened 68 significant prognostic markers out of the 1 256 genes,and 12 signature genes were further confirmed with LASSO-COX regression analysis.A prognostic model was established based on the 12 signature genes.Results of real-time fluorescence quantitative PCR showed a similar trend in the expression of most of the signature genes in different osteosarcoma cell lines.COX regression analysis of the internal and external datasets verified that the risk score calculated with the prognostic model was an independent prognostic factor for osteosarcoma patients,and high-risk score was associated with poor prognosis of the patients.Receiver operating characteristic(ROC)curves demonstrated excellent prognostic efficacy of the model.Nomogram analysis verified the prognostic model is highly accurate and reliable in predicting the prognosis of osteosarcoma patients.Analysis using the immunotherapy-related dataset indicated that this prognostic model could also be used to predict patients'responses to immunotherapy. Conclusion:The 12 signature gene(CD300LB,TRO,SNX3,VENTX,PPM1M,DOT1L,CDC37,NAT9,TRMT1,PPP1R3C,CHTF18 and NSUN5)-based prognostic model can effectively predict the prognosis and responses to immune check-point inhibitors for osteosarcoma patients,which may provide evidence for the prediction of prognosis as well as the selection of immunotherapy plans in clinical practice.

Objective:To analyze the changes in self-efficacy and its influencing factors in type 2 diabetic patients after community-based self-management group intervention.Methods:From August to November 2014, a 3-month community-based self-management intervention study of type 2 diabetes patients was implemented in Fangshan District, Beijing. 510 patients were recruited through posters, household inquiries and telephone notification and then were randomly divided into intervention group (260 patients) and control group (250 patients). Finally, 500 patients completed the study, including 259 in the intervention group and 241 in the control group. Self-efficacy score was measured through face-to-face interview at different time points, including pre-intervention, post-intervention, 2 years after the intervention and 5 years after the intervention, respectively. A two-level random coefficient model was fitted to analyze the long-term trend of self-efficacy and its relationship with group intervention.Results:Individual-level educational attainment, disease duration as well as their treatment plans had a positive correlation with self-efficacy of type 2 diabetic patients while gender and age did not affect their self-efficacy. Patients with junior middle school education, senior high school education and university and above education had 4.66 ( P<0.05), 6.40 ( P<0.05) and 11.02 ( P<0.05) points higher than those with primary education, respectively. The self-efficacy of diabetic patients increased by 0.23 ( P<0.05) for each additional course year. The effect of treatment plan on self-efficacy was mainly reflected in the self-efficacy of taking medication or insulin injection as prescribed and blood glucose monitoring. After controlling for the confounding factors, i.e., gender, age, disease duration, educational attainment, and treatment plan, self-efficacy scores at the post-intervention increased in both groups compared to those at the pre-intervention. The intervention group had 7.95 points higher than the control group ( P<0.05). After the intervention, the self-efficacy scores of both groups decreased year by year while the intervention group declined faster, with 5.41 points ( P<0.05) at 2 years after the intervention and 8.94 points ( P<0.05) at 5 years after the intervention. Conclusion:Community-based self-management group intervention could improve the self-efficacy of type 2 diabetic patients while the self-efficacy decreases year by year in the absence of follow-up intervention.

Objective:To analyze the changes in self-efficacy and its influencing factors in type 2 diabetic patients after community-based self-management group intervention.Methods:From August to November 2014, a 3-month community-based self-management intervention study of type 2 diabetes patients was implemented in Fangshan District, Beijing. 510 patients were recruited through posters, household inquiries and telephone notification and then were randomly divided into intervention group (260 patients) and control group (250 patients). Finally, 500 patients completed the study, including 259 in the intervention group and 241 in the control group. Self-efficacy score was measured through face-to-face interview at different time points, including pre-intervention, post-intervention, 2 years after the intervention and 5 years after the intervention, respectively. A two-level random coefficient model was fitted to analyze the long-term trend of self-efficacy and its relationship with group intervention.Results:Individual-level educational attainment, disease duration as well as their treatment plans had a positive correlation with self-efficacy of type 2 diabetic patients while gender and age did not affect their self-efficacy. Patients with junior middle school education, senior high school education and university and above education had 4.66 ( P<0.05), 6.40 ( P<0.05) and 11.02 ( P<0.05) points higher than those with primary education, respectively. The self-efficacy of diabetic patients increased by 0.23 ( P<0.05) for each additional course year. The effect of treatment plan on self-efficacy was mainly reflected in the self-efficacy of taking medication or insulin injection as prescribed and blood glucose monitoring. After controlling for the confounding factors, i.e., gender, age, disease duration, educational attainment, and treatment plan, self-efficacy scores at the post-intervention increased in both groups compared to those at the pre-intervention. The intervention group had 7.95 points higher than the control group ( P<0.05). After the intervention, the self-efficacy scores of both groups decreased year by year while the intervention group declined faster, with 5.41 points ( P<0.05) at 2 years after the intervention and 8.94 points ( P<0.05) at 5 years after the intervention. Conclusion:Community-based self-management group intervention could improve the self-efficacy of type 2 diabetic patients while the self-efficacy decreases year by year in the absence of follow-up intervention.

OBJECTIVE： To study the relationships of polymorphism of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus with drug concentration of methotrexate （MTX） and high-dose MTX （HD-MTX）-induced ADR in acute lymphoblastic leukemia （ALL） children. METHODS： From Oct. 2015 to Sept. 2018， 70 ALL hospitalized children of Han nationality in Sichuan area who received HD-MTX treatment and were in consolidation chemotherapy were selected retrospectively from Sichuan People’s Hospital. The blood concentration of MTX at 48 and 72 hours after administration was measured by EMIT. The genetic typing of MTRR gene rs1801394 locus and SLCO1B1 gene rs11045879 locus were detected with real-time PCR. The relationships of the polymorphism of MTRR gene and SLCO1B1 gene with MTX blood concentration [dose-corrected concentration （c48 h/D，48 h）， the proportion of children with different concentration of MTX （≤0.1， ＞0.1 μmol/L）] and ADR （such as myelosuppression， liver function damage， gastrointestinal response， mucosal damage， rash， etc.） were analyzed. Binary Logistic regression analysis for the correlation of ADR with different influencing factors （gene polymor- phism， blood concentration of MTX， immunophenotyping， body mass index， etc.） was carried out by Wald method. RESULTS： Totally 31， 32， 7 children with MTRR gene AA， AG and GG genotype， while 23， 37， 10 children with SLCO1B1 gene TT， TC and CC genotype were detected. The distribution of each genotype in 70 children conformed to Hardy-Weinberg equilibrium （P＞0.05）. There was no significant difference in c48 h/D（48 h） of children and the proportion of children with different concentration of MTX （72 h） among difterent genotypes of MTRR and SLCO1B1 gene （P＞0.05）. There was statistical significance in the incidence of liver function injury in children with different genotypes of MTRR gene （P＜0.05）， and the AA genotype was significantly higher than the AG+GG genotype （P＜0.05）. There was no correlation of MTRR gene polymorphism with the incidence of other ADR， neither SLCO1B1 gene polymorphism with the incidence of ADR （P＞0.05）. The results of Binary Logistic regression analysis showed that liver function damage in ALL children was related to the gene polymorphism of MTRR； gastrointestinal reaction was related to whether the plasma concentration was more than 0.1 μmol/L at 72 h； mucosal damage was related to the immune type and BMI of children； the occurrence of skin allergy was correlated with body weight of children（P＜0.05）. CONCLUSIONS： Gene polymorphism of MTRR rs1801394 locus may associated with the occurrence of HD-HTX-induced liver function injury in ALL children， but its polymorphism and gene polymorphism of SLCO1B1 rs11045879 locus are not related to MTX blood concentration in ALL children.

Objective To explore the clinical value of real-time shear wave elastography (SWE) in liver tissue stiffness of normal children.Methods Totally 243 normal children were examined by SWE.The data of liver stiffness measurement (LSM) were recorded and analyzed.The differences of LSM between different genders and hepatic segments were compared.According to the age,243 normal children were divided into pre-school group,school age group and adolescent group;and the differences of LSM between 3 groups were compared.The consistency was analyzed in different operators.Results The mean value of LSM in normal children was (4.21±0.70)kPa,and the 95％ confidence interval was (4.11,4.31)kPa.The success rate of segment S5 was higher than that of segment S4 (100％ [243/ 243] vs 79.83％ [194/243]),and the mean value of LSM in segment S5 was lower than that in segment S4 (P＜0.05).The mean value of LSM increased with age,and the boys' was a slightly higher than the girls',but there were no statistical differences between them (all P＞ 0.05).LSM had good consistency in different operators,the intraclass correlation coefficient was 0.92.Conclusion SWE could be an objective and quantitative assessment in liver stiffness of children.

Objective To investigate the diagnostic value of high frequency color Doppler ultrasound combined with gastrointestinal filling in infants with duodenal obstruction . Methods One hundred infants who were suspected with duodenal obstruction underwent both gastrointestinal ultrasound and upper gastrointestinal tract ,put the surgical results as the ?gold standard ,the values of ultrasonic and upper gastrointestinal tract in the diagnosis of pediatric congenital duodenal obstruction were compared . Results The diagnostic accuracy of ultrasound and upper gastrointestinal tract in duodenal obstruction was 100%and 94% respectively ,the difference was statistically significant ( P = 0 .041) . The accuracy rate of obstruction location was 98 .04% and 84 .31% respectively , also was considered to denote statistical significance ( P = 0 .023 ) . The total diagnostic accuracy of congenital disorders caused by duodenal obstruction was 89% and 49% respectively ,and P = 0 .001 implies statistically significant difference . Conclusions There is a high diagnostic accuracy in high frequency ultrasound combined with gastrointestinal filling in children with congenital duodenal obstruction ,and the diagnosis of some diseases is better than that of the upper gastroenterography .

This article was aimed to study the optimum technological conditions of roller compaction of FKⅣ gran-ules. This experimentation compared content of two granule preparation techniques which were the dry process gran-ulation and the wet process granulation, and adopted L9(34) orthogonal experiment to study the technological parame-ters of FKⅣ granules. The dry process granulation was selected. And factors such as roller pressure, roller speedand moisture content of power, which influence the result of granule yield were also studied in the dry process gran-ulation. The results showed that the optimum technological conditions were roller pressure at 5.0 Mpa, roller speed at 400 rpm, and moisture content of power at 3.0%. It was concluded that the roller compaction process of FKⅣ gran-ules was feasible in production which was able to meet the requirement of production.