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

ObjectiveTo explore the prevalence and influencing factors of multimorbidity among the HIV-infected individuals receiving anti-viral therapy (ART) in Dehong Prefecture of Yunnan Province, so as to provide a reference for the long-term follow-up management of HIV-infected patients and the comprehensive prevention and treatment of chronic diseases. MethodsA cross-sectional study was conducted to investigate the multimorbidity burden among the HIV-infected adults receiving ART in Dehong Prefecture from January to July 2021 and a self-designed questionnaire was used to analyze relevant disease indicators. Multivariate logistic regression analysis was used to investigate the influencing factors of multimorbidity among the HIV-infected individuals. ResultsA total of 3 946 HIV-infected individuals receiving ART were enrolled in this study, of which 63.7% aged ≤50 years, with a male to female ratio of 1.1∶1. Among the 3 946 cases, 825 of them had ≥2 comorbidities, with a co-prevalence rate of 20.9% (95%CI:19.6%‒22.2%), and the main comorbidities were dyslipidemia, diabetes, and hypertension. Multivariate logistic regression analysis showed that 40≤ aged <50 years (aOR=1.86, 95%CI: 1.45‒2.40, P<0.001), 50≤ aged ≤85 years (aOR=3.75, 95%CI: 2.93‒4.80, P<0.001), Dai nationality (aOR=1.21, 95%CI: 1.01‒1.47, P=0.043), BMI≥24.0 kg∙m^-2 (aOR=1.79, 95%CI: 1.49‒2.14, P<0.001), 10.0≤ with ART duration for <12.5 years (aOR=1.49, 95%CI: 1.05‒2.12, P=0.024), with ART duration for ≥12.5 years (aOR=1.50, 95%CI: 1.05‒2.15, P=0.026), use of second-line HIV therapy (aOR=1.43, 95%CI: 1.19‒1.70, P<0.001) and other therapy options (aOR=3.16, 95%CI: 2.17‒4.61, P<0.001) were positively correlated with multimorbidity. ConclusionThe prevalence of multimorbidity among the HIV-infected individuals receiving ART in Dehong Prefecture is high, which is associated with the advancing age and prolonged treatment time, particularly with a significant burden of dyslipidemia, diabetes, and hypertension. Comprehensive surveillance and targeted management of comorbidities, along with ART follow-up, need to be strengthened in the future.

Objective:To analyze factors associated with timely vaccination of pertussis-containing vaccines in children born in Shanghai from 2019 to 2023.Methods:Children born in Shanghai between 2019 and 2023 were selected using a stratified random sampling method, and their vaccination data were obtained from the Shanghai Vaccine Management and Vaccination Service Information System. The vaccination rates, timely vaccination rates, and the proportions of diphtheria-tetanus-acellular pertussis-haemophilus influenzae type b combination vaccine (DTaP-Hib) and diphtheria-tetanus-acellular pertussis-inactivated poliovirus-haemophilus influenzae type b combination vaccine (DTaP-IPV-Hib) for the substitution of diphtheria- tetanus-acellular pertussis vaccine (DTaP) were calculated. Also, the factors associated with timely vaccination rate was analyzed with multivariate logistic regression analysis.Results:The average vaccination coverage rate of pertussis-containing vaccines in children born in Shanghai from 2019 to 2023 ranged from 94.71% to 99.53%. There were significant differences in the vaccination coverage of the 1 st-4 th doses of pertussis-containing vaccines among children born in different years (all P<0.05), but no gender and area specific significant differences were observed (all P>0.05). Non-national immunization program (non-NIP) vaccines were used to substitute DTaP vaccines in some children, with the proportion of DTaP-IPV-Hib vaccine accounting for 50.11%-52.69% and the proportion of DTaP-Hib vaccine accounting for 27.22%-28.43%. The proportions of DTaP-Hib and DTaP-IPV-Hib for the substitution of DTaP had increasing trends over the years. The overall timely vaccination rate of pertussis-containing vaccine vaccination was 84.09%. Analysis on the factors affecting the timely vaccination rate showed that the rate gradually decreased with the increase of the doses. Children who received the self-paid quadrivalent or pentavalent vaccines were less likely to have vaccination delays. Birth year had a significant impact on the timely vaccination rate, while the area had less impact. Additionally, the timely vaccination rate was also influenced by the degree of non-pharmaceutical intervention measures. Conclusions:The substitution of pertussis- containing vaccines with non-NIP vaccines was common in Shanghai. The coverage and timeliness of pertussis-containing vaccine vaccination were relatively high. The timely vaccination rate was significantly associated with gender, dose, vaccine type, and the degree of non-pharmaceutical interventions. There was a certain proportions of delayed and missed vaccinations, and it is necessary to pay attention to children who are not vaccinated timely and conduct high-quality catch-up vaccination to ensure timely and complete vaccination of pertussis-containing vaccines.

Objective To define the effect of hypothyroidism on oxidative stress,p38 and c-Jun N-terminal kinases (JNK) mRNA expression in testicular mitochondria of male rats,and to explore the mechanism of hypothyroidism on reproduction.Methods According to body weight (240-270 g),30 male Wistar rats were divided into control group (C group,1 ml/kg normal saline by intragastric administration),low-dose group (L group,0.1 mg/kg propylthiouracil 1 ml/kg by intragastric administration) and high-dose group (H group,10.0 mg/kg propylthiouracil 1 ml/kg by intragastric administration),10 rats in each group,body mass was weighed once every 3 days.After 60 days,all rats were killed.The levels of thyroid hormones [total triiodothyronine (TT3),total thyroxine (TT4),and thyroid stimulating hormone (TSH)] were measured by radioimmunoassay.The activities of superoxide dismutase (SOD) and catalase (CAT) in the testicular mitochondria were determined with spectrophotometric assay.The mRNA expression levels of p38 and JNK in testicular mitochondria were detected by real-time quantitative PCR.Results The weights of H group in 30 and 60 days [(265.73 ± 5.10),(253.72 ± 5.09) g] were significantly decreased in comparison with those of C group [(344.62 ± 4.69),(395.33 ± 8.36) g] and L group [(333.66 ± 3.53),(386.08 ± 7.70) g,P ＜0.05].While,testis organ coefficient of H group [(1.20 ± 0.05) g/100 g] were significantly increased compared with those of L group [(0.93 ± 0.03) g/100 g] and C group [(0.88 ± 0.03) g/100 g,P ＜ 0.05].The serum levels of TT3 [(0.39 ± 0.01) nmol/L] and TT4 [(15.47 ± 1.21) nmol/L] in H group were found to be significantly decreased compared with those of C group [(0.86 ± 0.07),(45.56 ± 1.52) nmol/L] and L group [(0.79 ± 0.06),(39.02 ± 1.33) nmol/L,P ＜ 0.05];whereas the level of TSH [(0.65 ± 0.09) mU/L)] was increased in comparison with those of the C group [(0.18 ± 0.06) mU/L] and L group [(0.27 ± 0.05) mU/L,P ＜ 0.05].In addition,the level of SOD in H group [(60.37 ± 3.14) U/mg prot] was decreased compared with that of C group [(75.18 ± 6.13) U/mg prot,P ＜ 0.05];the level of CAT in H group [(1.46 ± 0.25) U/mg prot] and L group [(1.67 ± 0.39) U/mg prot] decreased significantly compared with that of C group [(3.79 ± 0.44) U/mg prot,P ＜ 0.05].And compared with C (1.000 0 ± 0.000 0) and L (1.114 2 ± 0.124 1) groups,p38 mRNA expression in H group (1.387 4 ± 0.122 0) was significantly increased (P ＜ 0.05).However,there was no significant change in JNK mRNA expression between groups (F =0.95,P ＞ 0.05).Conclusion Hypothyroidism may induce oxidative stress of testicular mitochondria leading to the change of p38 cell signal path and then damage the reproductive system in male rats.

Objective This study aims to define the effects of hypothyroidism on c-fos and c-jun mRNA expression in rat testes to provide a theoretical basis for prevention and control of iodine deficiency disorders (IDD). Methods According to body weight (200 - 240 g), 20 Wistar male rats were divided into control group and hypothyroidism group (1 ml/100 g, 0.1% propylthiouracil by intragastric administration) by digital table. There were 10 male rats in each group and body weight was observed every 3 days. After 60 days, all rats were killed. The levels of thyroid hormones [total triiodothyronine (TT3), total thyroxine (TT4), and thyroid stimulating hormone (TSH)] were measured by radioimmunoassay. The mRNA expression levels of c-fos and c-jun in testes were detected by real-time quantitative PCR. Results Compared with control groups [(298.20 ± 12.15), (344.00 ± 13.73) g], the weights of hypothyroidism groups in 30 days [(239.00 ± 15.02) g] and in 60 days [(232.67 ± 17.86) g] were significant decreased (t=7.704, 11.380, all P<0.05). The levels of TT3 [(373.32 ± 101.31) ng/L] and TT4 [(4.00 ± 0.89) × 103 ng/L] in serum of hypothyroidism group were found to be significantly decreased, whereas the level of TSH [(5.77 ± 0.89) × 103 U/L] was increased in comparison with those of the control groups [(1 000.01 ± 273.53) ng/L, (44.33 ±7.84) × 103 ng/L, (1.87 ± 0.70) × 103 U/L, t = 5.262, 12.520, 8.413, all P< 0.05]. Compared with control group (1.00 ± 0.08, 1.01 ± 0.04), the c-fos and c-jun mRNA expression (0.67 ± 0.03, 0.75 ± 0.02) of hypothyroidism group was significant decreased (t = 12.382, 13.784, all P < 0.05). Conclusion Hypothyroidism may reduce mRNA expression levels of testicular c-fos and c-jun, and then damage the reproductive system in male rats.

OBJECTIVETo study the frequency of rare blood group Lu(a-b-) phenotype in a population from Shanghai region, and to explore the molecular basis of Lu(a-b-) by detecting the Lu and Lu relative mediator gene EKLF/KLF1.

METHODSDonors from Shanghai region were screened for Lutheran blood group by monoclonal anti-Lub using serological methods. Individuals with Lu(b-) were determined Lua, P1 and i antigens. Fifteen exons of the LU gene and 3 exons of the EKLF/KLF1 gene for the identified Lu(a-b-) samples were amplified and sequenced.

RESULTSTen Lu(a-b-) donors were obtained from 44 331 donors from Shanghai region. No homozygous or heterozygous mutations were found in the LU gene, whilst 7 mutations in EKLF/KLF1 gene were identified in the 10 samples.

CONCLUSIONThe frequency of rare Lu(a-b-) blood group in Shanghai was approximately 0.02%, and all the individuals had an In(Lu) phenotype. The molecular basis of such samples may be related to mutations in the EKLF/KLF1 gene.

China ; ethnology ; Humans ; Kruppel-Like Transcription Factors ; genetics ; Lutheran Blood-Group System ; genetics ; Mutation ; Phenotype