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 analyze the relationship between Cardiovascular Health(CVH)and Pelvic Inflamma-tory Disease(PID)using data from the National Health and Nutrition Examination Surveys(NHANES).Meth-ods:Participants from the NHANES database were extracted based on the inclusion of PID,LE8 scores,and mul-tiple potential confounding factors,excluding those with missing variables.Multivariate Logistic regression analysis was conducted using R to assess the relationship between the CVH and the risk of PID.Additionally,subgroup a-nalysis and interaction tests were performed for age,race,poverty,marital status,education,BMI,menstrual regu-larity,and pregnancy history.Results:A total of 3934 female participants were included,with an average age of 39.95±11.42 years.Multivariable Logistic regression analysis showed that after adjusting for age,race,BMI,edu-cation level,marital status,household income,menstrual cycle,and pregnancy history,the risk of PID gradually decreased with an increase in CVH assessment metric LE8 scores(OR 0.98,95％CI 0.97-0.99,P＜0.001).Stratified analysis indicated significant interactions between age,race,and marital status in the association be-tween CVH and PID(interaction P＜0.05 for all),while household income level,education level,BMI,menstrual regularity,and pregnancy history showed no significant interactions with the CVH and PID association(P＞0.05).Conclusions:There is a significant negative relationship between CVH and PID in adult women in the United states,suggesting that better cardiovascular health may help reduce the risk of PID.

[Purpose]To analyze the incidence and mortality of liver cancer in cancer registration areas of Zhejiang Province in 2021 and the epidemiological trends of liver cancer from 2000 to 2021.[Methods]Using liver cancer data from 2000 to 2021 reported by Zhejiang Provincial Can-cer Registries,stratified by sex,age,and urban-rural areas,indicators including crude incidence rate,crude mortality rate,age-standardized incidence rate by Chinese standard population(ASIRC),age-standardized mortality rate by Chinese standard population(ASMRC),age-standardi-zed incidence rate by world standard population(ASIRW),age-standardized mortality rate by world standard population(ASMRW)were calculated.Joinpoint Regression Program(Version 5.3.0)was used to fit the log-linear relationship between rates and years,and calculate the annual percentage change(APC)and average annual percentage change(AAPC)with 95％confidence interval(CI).[Results]In 2021,the crude incidence rate of liver cancer in Zhejiang cancer registration areas was 26.93/105(ASIRC:13.35/105),and the crude mortality rate was 20.87/105(ASMRC:9.52/105).The number of new cases and deaths of liver cancer accounted for 5.07％and 11.33％of all malig-nant tumor cases and deaths,respectively.The incidence and mortality rates of liver cancer in male were significantly higher than those in female(crude incidence rate:40.17/105 vs 13.85/105;ASIRC:20.60/105 vs 6.34/105;crude mortality rate:30.78/105 vs 11.07/105;ASMRC:14.67/105 vs 4.57/105),and those in rural areas were higher than those in urban areas(crude incidence rate:30.39/105 vs 24.79/105;ASIRC:15.35/105 vs 12.10/105;crude mortality rate:24.32/105 vs 18.72/105;ASMRC:11.30/105 vs 8.40/105).In 2021,the incidence rate of liver cancer was low before the age of 30 years old,and increased significantly with age after 30 years old,reaching the peak in male aged 85 years old and above(170.04/105)and in female aged 80～84 years old(84.74/105).The mortality rate showed a similar trend to the incidence rate,which was low before the age of 30 years old and increased significantly with age after 30 years old,peaking in male aged 85 years old and above(211.64/105)and in female aged 80～84 years old(98.31/105).From 2000 to 2021,the crude incidence rate of liver cancer in Zhejiang Province showed an overall upward trend(AAPC=1.01％,95％CI:0.44％～1.58％),while the ASIRC remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％)with a significant remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％),after 2010,the ASIRC remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％)with a significant decreased significantly.Both the crude mortality rate(AAPC=-0.84％,95％CI:-1.23％～-0.36％)and ASMRC(AAPC=-2.78％,95％CI:-3.28％～-2.20％)showed sig-nificant downward trends,and the decline of ASMRC was more obvious.[Conclusion]From 2000 to 2021,the incidence of liver cancer in cancer registration areas of Zhejiang Province showed a fluctuating downward trend,and the mortality showed a steady downward trend,but the disease burden remains heavy.Rural areas,the elderly,and males are high-risk populations,which should be the key targets of liver cancer prevention and control.

Objective:To analyze the relationship between Cardiovascular Health(CVH)and Pelvic Inflamma-tory Disease(PID)using data from the National Health and Nutrition Examination Surveys(NHANES).Meth-ods:Participants from the NHANES database were extracted based on the inclusion of PID,LE8 scores,and mul-tiple potential confounding factors,excluding those with missing variables.Multivariate Logistic regression analysis was conducted using R to assess the relationship between the CVH and the risk of PID.Additionally,subgroup a-nalysis and interaction tests were performed for age,race,poverty,marital status,education,BMI,menstrual regu-larity,and pregnancy history.Results:A total of 3934 female participants were included,with an average age of 39.95±11.42 years.Multivariable Logistic regression analysis showed that after adjusting for age,race,BMI,edu-cation level,marital status,household income,menstrual cycle,and pregnancy history,the risk of PID gradually decreased with an increase in CVH assessment metric LE8 scores(OR 0.98,95％CI 0.97-0.99,P＜0.001).Stratified analysis indicated significant interactions between age,race,and marital status in the association be-tween CVH and PID(interaction P＜0.05 for all),while household income level,education level,BMI,menstrual regularity,and pregnancy history showed no significant interactions with the CVH and PID association(P＞0.05).Conclusions:There is a significant negative relationship between CVH and PID in adult women in the United states,suggesting that better cardiovascular health may help reduce the risk of PID.

[Purpose]To analyze the incidence and mortality of liver cancer in cancer registration areas of Zhejiang Province in 2021 and the epidemiological trends of liver cancer from 2000 to 2021.[Methods]Using liver cancer data from 2000 to 2021 reported by Zhejiang Provincial Can-cer Registries,stratified by sex,age,and urban-rural areas,indicators including crude incidence rate,crude mortality rate,age-standardized incidence rate by Chinese standard population(ASIRC),age-standardized mortality rate by Chinese standard population(ASMRC),age-standardi-zed incidence rate by world standard population(ASIRW),age-standardized mortality rate by world standard population(ASMRW)were calculated.Joinpoint Regression Program(Version 5.3.0)was used to fit the log-linear relationship between rates and years,and calculate the annual percentage change(APC)and average annual percentage change(AAPC)with 95％confidence interval(CI).[Results]In 2021,the crude incidence rate of liver cancer in Zhejiang cancer registration areas was 26.93/105(ASIRC:13.35/105),and the crude mortality rate was 20.87/105(ASMRC:9.52/105).The number of new cases and deaths of liver cancer accounted for 5.07％and 11.33％of all malig-nant tumor cases and deaths,respectively.The incidence and mortality rates of liver cancer in male were significantly higher than those in female(crude incidence rate:40.17/105 vs 13.85/105;ASIRC:20.60/105 vs 6.34/105;crude mortality rate:30.78/105 vs 11.07/105;ASMRC:14.67/105 vs 4.57/105),and those in rural areas were higher than those in urban areas(crude incidence rate:30.39/105 vs 24.79/105;ASIRC:15.35/105 vs 12.10/105;crude mortality rate:24.32/105 vs 18.72/105;ASMRC:11.30/105 vs 8.40/105).In 2021,the incidence rate of liver cancer was low before the age of 30 years old,and increased significantly with age after 30 years old,reaching the peak in male aged 85 years old and above(170.04/105)and in female aged 80～84 years old(84.74/105).The mortality rate showed a similar trend to the incidence rate,which was low before the age of 30 years old and increased significantly with age after 30 years old,peaking in male aged 85 years old and above(211.64/105)and in female aged 80～84 years old(98.31/105).From 2000 to 2021,the crude incidence rate of liver cancer in Zhejiang Province showed an overall upward trend(AAPC=1.01％,95％CI:0.44％～1.58％),while the ASIRC remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％)with a significant remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％),after 2010,the ASIRC remained relatively stable(AAPC=-0.81％,95％CI:-1.48％～0.02％)with a significant decreased significantly.Both the crude mortality rate(AAPC=-0.84％,95％CI:-1.23％～-0.36％)and ASMRC(AAPC=-2.78％,95％CI:-3.28％～-2.20％)showed sig-nificant downward trends,and the decline of ASMRC was more obvious.[Conclusion]From 2000 to 2021,the incidence of liver cancer in cancer registration areas of Zhejiang Province showed a fluctuating downward trend,and the mortality showed a steady downward trend,but the disease burden remains heavy.Rural areas,the elderly,and males are high-risk populations,which should be the key targets of liver cancer prevention and control.

Objective:To investigate the genetic causal relationship of leukocyte telomere length(LTL)with prostatitis,orchi-tis and epididymitis by two-sample Mendelian randomization(MR).Methods:Using LTL as the exposure factor and prostatitis,or-chitis and epididymitis as outcome factors,we mined the Database of Genome-Wide Association Studies(GWAS).Then,we analyzed the causal relationship of LTL with prostatitis,orchitis and epididymitis by Mendelian randomization using inverse variance weighting(IVW)as the main method and weighted median and MR-Egger regression as auxiliary methods,determined the horizontal multiplicity by MR-Egger intercept test,and conducted sensitivity analysis using the leaving-one-out method.Results:A total of 121 related sin-gle nucleotide polymorphisms(SNPs)were identified in this study.IVW showed LTL to be a risk factor for prostatitis(OR=1.383,95％CI:1.044-1.832,P=0.024),and for orchitis and epididymitis as well(OR=1.770,95％CI:1.275-2.456,P=0.000 6).Conclusion:Genetic evidence from Mendelian randomized analysis indicates that shortening of LTL reduces the risk of prostatitis,orchitis and epididymitis.

Gambogic acid, a caged xanthone compound derived from Garcinia, has been proven to be an important substance basis for the pharmacological effects of the plant. In recent years, it has received continuous attention due to its broad and significant pharmacological activities. Modern pharmacological investigations have demonstrated that gambogic acid endows various therapeutic effects such as anti-inflammatory, antioxidant, and anti-tumor activities, as well as benefits in retinopathy, organ protection, anti-microbial infection, bone protection, and neuropathic pain relief. Nevertheless, there is currently a lack of systematic summary and integration of the pharmacological effects and mechanisms of gambogic acid, which is critical for advancing the clinical application of this natural product. In addition, current research has raised concerns about potential safety risks associated with gambogic acid, such as organ toxicity, developmental toxicity, and hemolysis. Given this, this paper systematically reviewed and summarized the pharmacological effects, mechanisms, and toxicological profiles of gambogic acid, aiming to provide reference and data support for its clinical translation.
Xanthones/toxicity* ; Humans ; Animals ; Drugs, Chinese Herbal/toxicity* ; Garcinia/chemistry*

OBJECTIVE: To evaluate the clinical efficacy and safety of Wuziyuye Decoction in the treatment of type-II diabetes mellitus (DM) with qi-yin deficiency complicated by asthenospermia. METHODS: We selected 100 cases of type-II DM with qi-yin deficiency complicated by asthenospermia treated in the First Hospital Affiliated to Ningbo University from January 2023 to March 2024, and randomly assigned them to receive Wuziyuye Decoction (the trial group, n = 50) and oral L-carnitine solution (the control group, n = 50) in addition to Western medicine to reduce fasting blood glucose to normal in both groups. After 12 weeks of medication, we followed up the patients for 24 weeks, obtained their semen parameters, traditional Chinese medicine (TCM) syndrome scores and levels of reproductive hormones, and the clinical pregnancy outcomes of their partners, followed by comparison of the data collected between the two groups before and after treatment. RESULTS: After 12 weeks of treatment, the trial group showed significant improvement over the baseline in the percentage of progressive motility (PR%) (［35.5±6.1］% vs ［18.0±4.2］%, P<0.05), sperm concentration (［54.0±33.4］ vs ［40.0±36.1］ × 10⁶/ml, P<0.05), and TCM syndrome score (4.5±2.3 vs 18.5±5.2, P<0.05), but no statistically significant difference in the semen volume (［2.85±0.36］ vs ［2.84±0.59］ ml, P>0.05), while the controls exhibited markedly improved percentage of PR% (［29.5±6.2］% vs ［18.5±4.5］%, P<0.05) and sperm concentration (［45.0±34.1］ vs ［42.0±38.3］ × 10⁶/ml, P<0.05), but no statistically significant difference in the semen volume (［3.04±0.89］ vs ［2.90±0.78］ ml, P>0.05) and TCM syndrome score (17.2±4.5 vs 17.8±4.8, P>0.05). The patients treated with Wuziyuye Decoction achieved even more significant improvement than the controls in the percentage of PR%, sperm concentration and TCM syndrome score (P<0.05), but there were no statistically significant differences in the reproductive hormone levels and clinical pregnancy outcomes between the two groups of patients after treatment (P>0.05). And no severe adverse reactions were observed in either group. CONCLUSION Wuziyuye Decoction is safe and effective for the treatment of type-II DM with qi-yin deficiency complicated by asthenospermia by improving the sperm motility and concentration of the patient.
Humans ; Drugs, Chinese Herbal/therapeutic use* ; Male ; Asthenozoospermia/complications* ; Diabetes Mellitus, Type 2/drug therapy* ; Yin Deficiency/complications* ; Adult ; Medicine, Chinese Traditional ; Sperm Motility ; Qi ; Female ; Pregnancy

The comparison between traditional Chinese medicine Jinzhen oral liquid (JZOL) and Western medicine in treating children with acute bronchitis (AB) showed encouraging outcomes. This trial evaluated the efficacy and safety of the JZOL for improving cough and expectoration in children with AB. 480 children were randomly assigned to take JZOL or ambroxol hydrochloride and clenbuterol hydrochloride oral solution for 7 days. The primary outcome was time-to-cough resolution. The median time-to-cough resolution in both groups was 5.0 days and the antitussive onset median time was only 1 day. This randomized controlled trial showed that JZOL was not inferior to cough suppressant and phlegm resolving western medicine in treating cough and sputum and could comprehensively treat respiratory and systemic discomfort symptoms. Combined with clinical trials, the mechanism of JZOL against AB was uncovered by network target analysis, it was found that the pathways in TRP channels like IL-1β/IL1R/TRPV1/TRPA1, NGF/TrkA/TRPV1/TRPA1, and PGE2/EP/PKA/TRPV1/TRPA1 might play important roles. Animal experiments further confirmed that inflammation and the immune regulatory effect of JZOL in the treatment of AB were of vital importance and TRP channels were the key mechanism of action.

Objective:To investigate the association between the Doppler variables of the ophthalmic artery with the severity of preeclampsia(PE).Methods:Systematic literature was searched between January 1995 and March 2023 in PubMed,Web of Science,Embase,and the Cochrane Library.Studies comparing ophthalmic artery Doppler variables,including peak systolic velocity(PSV),end-diastolic velocity(EDV),resistive index(Rl),pulsa-tility index(PI),and peak ratio(PR,the ratio of the flow velocity of the second peak to that of the initial peak)in patients with PE,severe preeclampsia(sPE),and healthy pregnant women were included.The random-effects model was adopted as the method of pooled analysis,and the I2value was used to assess heterogeneity.The pooled standardized mean difference(SMD)with 95％confidence interval(CI)was used to estimate the associa-tion between ophthalmic artery Doppler variables and PE patient's characteristics.Results:Eight retrospective studies were eventually included in this Meta-analysis.Our pooled results suggested that compared with PE ca-ses,sPE patients had lower PI levels(SMD-0.56,95％CI-0.92～-0.20,P=0.000),higher EDV levels(SMD 0.47,95％CI 0.12～0.83,P=0.028)and higher PR levels(SMD0.96,95％CI 0.13～1.78,P=0.023).Howev-er,there was no significant difference between PE and sPE patients about the PSV and RI(P=0.361,P=0.626).Conclusions:This review demonstrates that ophthalmic artery Doppler variables(PI,EDV and PR)could be useful for predicting PE and PE development(especially in identifying sPE),which in turn may help the practitioner in the management of these complicated cases and in taking early necessary precautions.