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 investigate the possible mechanism of Ruyi Heibai Power （如意黑白散， RHP） in the treatment of vitiligo. MethodsTwenty-four C57BL/6 mice were randomly divided into blank group， model group， high-dose and low-dose RHP groups， with 6 mice in each group. Model group， high- and low-dose RHP groups were all applied hydroquinone to establish vitiligo animal model. After modeling， High- and low-dose RHP groups were given 7.02 g/kg and 2.34 g/kg of RHP by gavage， respectively， while the blank group and model group were intragastrically given 10ml/kg of normal saline， once a day for 36 days. After administration， the skin lesions were observed with naked eye， and HE staining was used to observe the melanin content of the skin lesions. Immunohistochemistry was used to determine the expression of CD3⁺ and CD8⁺ T cells in skin tissue. Immunofluorescence staining was used to measure the expression of programmed death receptor 1 （PD-1） in the skin lesion tissue. RT-PCR was used to detect programmed cell death ligand 1 （PD-L1） mRNA expression. ELISA was used to detect serum superoxide dismutase （SOD）， tumor necrosis factor （TNF-α）， and tyrosinase （TYR） levels. ResultsCompared to those in the blank group， the skin of the mice in the model group was pale， and the melanin content was significantly reduced under the microscope after HE staining； the rate of excellent and good skin lesions decreased， and the melanin granules in the cells around the epidermis and hair follicles decreased significantly； the expression of CD3⁺ and CD8⁺ T cells in skin tissue increased significantly， and the expressions of PD-L1 mRNA and PD-1 decreased； the content of TYR decreased， while the content of SOD and TNF-α increased （P＜0.05）. Compared to those in the model group， the skin color of high- and low-dose RHP groups were deepened， and the melanin content increased； the rate of excellent and good skin lesions increased， as well as the melanin granules in the spinous cell layer， basal cells and hair follicles； the expression of CD3⁺ and CD8⁺ T cells in the skin lesions decreased， while PD-L1 mRNA and PD-1 expression increased； the content of TYR increased， while the content of SOD and TNF-α decreased （P＜0.05）. Compared to the low-dose RHP group， the high-dose group had a larger pigment recovery area in the modeling area， an increased rate of excellent and good skin lesions， an increase in spinous cell layer， basal cells， and hair follicle melanin granules， a decrease in CD3⁺ and CD8⁺ T cells expression， an increase in the expression of PD-L1 mRNA and PD-1， an elevated TYR content， and decreased SOD and TNF-α contents （P＜0.05）. ConclusionRHP can increase skin melanin content of vitiligo mice.The mechanism of action may be related to activating the PD-1/PD-L1 signaling pathway， and then reducing the destruction of melanocytes by T cell-mediated autoimmunity.

ObjectiveTo analyze the trends in life expectancy and cause-eliminated life expectancy of the registered residents in Qingpu District, Shanghai from 2002 to 2021, and to identify the major diseases causing life expectancy loss in the area, so as to provide a theoretical basis for strengthening disease prevention and interventions and optimizing health resources allocation. MethodsUsing the International Classification of Diseases (ICD)-10 classification of death causes, average life expectancy and cause-eliminated life expectancy were calculated with the abbreviated life table and the cause-eliminated life expectancy table. A trend forecast of life expectancy from 2022 to 2029 was made. ResultsFrom 2002 to 2021, the life expectancy of Qingpu District residents showed an increasing trend, with an average annual growth of 0.32 years (AAPC=0.39%, P<0.001). Among the seven major causes of death, the cause-eliminated expected life expectancy for circulatory system diseases showed the most significant upward trend (AAPC=0.53%, P<0.001), rising from the third leading cause of death in 2002 to the first in 2021. The life expectancy loss rate due to circulatory system diseases increased from 3.79% to 7.97%. Respiratory system diseases showed the largest decline, decreasing from the first leading cause of death in 2002 to the fourth in 2021, with the life expectancy loss rate decreasing from 6.83% to 0.99%. ConclusionLife expectancy of the registered residents in Qingpu District has reached a leading level in China. Future efforts should focus on effectively increasing the life expectancy of male residents, strengthening the comprehensive prevention and treatment of chronic diseases such as cerebrovascular diseases, diabetes, and malignant tumors, and improving health promotion policies for residents to achieve a steady long-term increase in regional life expectancy.

Lipotoxicity is a pivotal factor that initiates and exacerbates liver injury and is involved in the development of metabolic-associated fatty liver disease (MAFLD). However, there are few reported lipotoxicity inhibitors. Here, we identified a natural anti-lipotoxicity candidate, HN-001, from the marine fungus Aspergillus sp. C1. HN-001 dose- and time- dependently reversed palmitic acid (PA)-induced hepatocyte death. This protection was associated with IRE-1α-mediated XBP-1 splicing inhibition, which resulted in suppression of XBP-1s nuclear translocation and transcriptional regulation. Knockdown of XBP-1s attenuated lipotoxicity, but no additional ameliorative effect of HN-001 on lipotoxicity was observed in XBP-1s knockdown hepatocytes. Notably, the ER stress and lipotoxicity amelioration was associated with PLA2. Both HN-001 and the PLA2 inhibitor MAFP inhibited PLA2 activity, reduced lysophosphatidylcholine (LPC) level, subsequently ameliorated lipotoxicity. In contrast, overexpression of PLA2 caused exacerbation of lipotoxicity and weakened the anti-lipotoxic effects of HN-001. Additionally, HN-001 treatment suppressed the downstream pro-apoptotic JNK pathway. In vivo, chronic administration of HN-001 (i.p.) in mice alleviated all manifestations of MAFLD, including hepatic steatosis, liver injury, inflammation, and fibrogenesis. These effects were correlated with PLA2/IRE-1α/XBP-1s axis and JNK signaling suppression. These data indicate that HN-001 has therapeutic potential for MAFLD because it suppresses lipotoxicity, and provide a natural structural basis for developing anti-MAFLD candidates.

ObjectiveTo analyze the characteristics and changing trend of injury cause of mortality of residents in Qingpu District from 2002 to 2020， and to provide scientific reference for formulating regional prevention and control measures. MethodsThe injury mortality data of the registered residents in Qingpu District from 2002 to 2020 were collected. The indicators such as crude mortality rate， standardized mortality rate， and the ranking of causes of death were calculated. ResultsFrom 2002 to 2020， the average annual crude mortality rate was 50.27/100 000， the age-standardized mortality rate based on the world standard population（ASRW） was 30.08/100 000， and the age-standardized mortality rate based on the 2010 Chinese census（ASMRC） was 35.58/100 000. The average annual crude mortality rate of males was higher than that of females ［Z=54.402， Mantel-Hanszel χ²=1 742.509， P<0.01）. The overall injury mortality rate showed a downward trend with an average annual percent change（AAPC）of -4.07% （95%CI： -5.23%‒-2.90%）， P<0.001］. The top four causes of injury death were transportation accident， indeliberate fall， drowning， and suicide. The leading causes of death in 0‒ years old， 15‒ years old and ≥65 years old were drowning， transportation accident and indeliberate fall， respectively. The ASRW of transportation accident， drowning and suicide all showed a decreasing trend， and the AAPC were -8.22% （95%CI： -10.16%‒-6.24%）， -6.99% （95%CI： -9.68%‒-4.22%） and -6.21% （95%CI： -9.38%‒-2.94%）， respectively. ConclusionThe injury death rate of residents in Qingpu District shows a decreasing trend， and the distribution characteristics of injury death are different among different genders and age groups. Corresponding prevention and control strategies should be adopted for different populations.

Background::Hypothermia therapy has been suggested to attenuate myocardial necrosis; however, the clinical implementation as a valid therapeutic strategy has failed, and new approaches are needed to translate into clinical applications. This study aimed to assess the feasibility, safety, and efficacy of a novel selective intracoronary hypothermia (SICH) device in mitigating myocardial reperfusion injury.Methods::This study comprised two phases. The first phase of the SICH was performed in a normal porcine model for 30 minutes ( n = 5) to evaluate its feasibility. The second phase was conducted in a porcine myocardial infarction (MI) model of myocardial ischemia/reperfusion which was performed by balloon occlusion of the left anterior descending coronary artery for 60 minutes and maintained for 42 days. Pigs in the hypothermia group ( n = 8) received hypothermia intervention onset reperfusion for 30 minutes and controls ( n = 8) received no intervention. All animals were followed for 42 days. Cardiac magnetic resonance analysis (five and 42 days post-MI) and a series of biomarkers/histological studies were performed. Results::The average time to lower temperatures to a steady state was 4.8 ± 0.8 s. SICH had no impact on blood pressure or heart rate and was safely performed without complications by using a 3.9 F catheter. Interleukin-6 (IL-6), tumor necrosis factor-α, C-reactive protein (CRP), and brain natriuretic peptide (BNP) were lower at 60 min post perfusion in pigs that underwent SICH as compared with the control group. On day 5 post MI/R, edema, intramyocardial hemorrhage, and microvascular obstruction were reduced in the hypothermia group. On day 42 post MI/R, the infarct size, IL-6, CRP, BNP, and matrix metalloproteinase-9 were reduced, and the ejection fraction was improved in pigs that underwent SICH.Conclusions::The SICH device safely and effectively reduced the infarct size and improved heart function in a pig model of MI/R. These beneficial effects indicate the clinical potential of SICH for treatment of myocardial reperfusion injury.

Objective:To study and screen the differential expression of inflammatory proteins in diabetes skin ulcers and common skin ulcers, so as to provide experimental basis for further research on anti-inflammatory and healing drug targets of diabetes skin ulcers.Methods:The tissues of 11 patients with diabetes skin ulcer, 12 patients with common skin ulcer and 11 patients with normal skin were collected from the First Hospital of Hunan University of Chinese Medicine. The levels of inflammatory protein Toll like receptor 4 (TLR4), nuclear factor κB (NF-κB), pro-inflammatory factor interferon -γ (IFN -γ), tumor necrosis factor - α (TNF -α), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-1β (IL-1β), macrophage chemotactic protein-1 (MCP-1), anti-inflammatory factors epidermal growth factor (EGF), interleukin-4 (IL-4), and interleukin-10 (IL-10) were detected in three groups of tissues using enzyme-linked immunosorbent assay (ELISA).Results:Compared with normal tissues, the concentrations of TLR4, NF-κB, IFN -γ, TNF -α, IL-1β, IL-6, IL-8, MCP-1 and EGF in common ulcer skin tissues and diabetes ulcer tissues were higher, and the concentrations of IL-10 were lower, with statistically significant differences (all P<0.05); Compared with the normal tissue, the concentration of IL-4 in diabetes ulcer tissue was lower, the difference was statistically significant ( P<0.05); Compared with ordinary ulcer skin tissue, the concentrations of TLR4, NF-κB and MCP-1 in diabetes ulcer tissue were higher, and the concentrations of IL-4 were lower, with statistically significant differences (all P<0.05). Conclusions:The skin ulcer in diabetes patients will have inflammatory reaction, and high glucose promotes the inflammatory reaction of skin ulcer, which may be related to the abnormal expression of TLR4, NF-κB, MCP-1 and IL-4. TLR4/NF-κB signal pathway and inflammatory factors MCP-1 and IL-4 may be the target of the inflammation regulation of diabetes skin ulcer.

Objective To describe the distribution characteristics of knee and ankle joint range of motion and muscle atrophy related indexes in patients with Kashin-Beck disease(KBD)in Shaanxi Province so as to explore the correlation of knee and ankle joint range of motion(ROM)with muscle atrophy indexes and provide reference for clinical characteristics analysis of KBD patients.Methods To investigate the registered KBD patients from KBD areas in Shaanxi Province,we measured the general demographic data of the patients were collected and the ROM of the knee joint(flexion and extension),the ankle joint(dorsiflexion and plantar flexion),and the muscle atrophy related indexes such as the upper arm circumference,thigh circumference,calf circumference and grip strength.According to the population characteristics,i.e.,gender,age,body mass index(BMI)and KBD grade,the median and quartile of joint ROM and muscle atrophy of KBD patients were reported,and then the differences in each index among different groups were analyzed.Partial correlation analysis was used to explore the correlation between indicators after controlling for variables such as gender,age and BMI.Results A total of 480 patients with KBD were investigated in this study,who consisted of 249(51.9％)males and 231(48.1％)females,with an average age of(63.10±7.32)years and an average BMI of(23.49±8.90)kg/m2.The knee flexion ROM,knee extension ROM,ankle dorsiflexion ROM and ankle plantar flexion ROM were[105.0(95.0,120.0)]°,[0.0(-15.0,0.0)]°,[5.0(0.0,15.0)]° and[20.0(15.0,30.0)]°,respectively,in KBD patients in Shaanxi Province.The left thigh circumference,right thigh circumference,left calf circumference,right calf circumference,and upper arm circumference were[43.0(40.0,47.0)]cm,[43.0(39.0,47.0)]cm,[29.0(27.0,32.0)]cm,[29.5(27.0,32.0)]cm,[27.0(25.0,30.0)]cm,respectively.The left hand grip strength and right hand grip strength were[13.4(9.5,18.4)]kg and[13.9(9.8,18.2)]kg,respectively.With the increase of age,the extension range of the left and right knee joints of KBD patients showed a decreasing trend(H=31.499,31.847;all P＜0.001).The range of motion of bilateral knee flexion was higher in the normal BMI group than in the overweight or obese group,with statistically significant differences(H=7.753,12.333;P=0.021,0.002).The knee flexion,thigh circumference,and calf circumference of the left and right sides showed a decreasing trend under different KBD grades(H=14.345,17.256,8.000,8.462,8.558,9.633;all P＜0.05).Correlation analysis showed that knee flexion ROM was positively correlated with thigh circumference,calf circumference,and grip strength in patients with KBD(all P＜0.05).There was a positive correlation between knee extension ROM and thigh circumference in patients with KBD(P＜0.01).Conclusion The impaired joint ROM and muscle atrophy are serious in KBD patients in Shaanxi Province,and there is a correlation between joint motion and muscle atrophy.

Objective:To describe the prevalence of food allergy among children aged 0-5 years in China and to explore related influencing factors.Methods:Multistage stratified random sampling method was used to collect data from 275 surveillance sites of the China National Nutrition and Health Survey of Chinese children and lactating mothers programs in 31 provinces (autonomous regions and municipalities) of China in 2016-2017. A total of 70 107 participants aged 0-5 years were included in this study. The study collected information of participants' demographic characteristics and food allergies by face-to-face questionnaire. The prevalence of food allergy was analyzed, using the complex data weighting method. The logistic regression models were used to analyze the influencing factors related to food allergy.Results:The overall prevalence of self-reported food allergy among children aged 0-5 years was 4.81%. Prevalence rates in infants aged 0-5 months, and 6-23 months and preschool children aged 2-5 years were 0.81%, 4.68% and 5.26%, respectively. The results of logistic analysis showed that there was a significantly positive correlation between factors including children from 6 months to 5 years old, urban area, southwest area, first-born, mothers with college education or above, and the prevalence of food allergy in children. Shrimp, poultry eggs, crab shellfish, fruit, milk and fish appeared the common allergic foods in children aged 0-5 years, with prevalence rates of self-reported food allergy as 1.55%, 1.25%, 0.99%, 0.97%, 0.87% and 0.86%, respectively. The proportion of single food allergy in children with allergies was 69.85%.Conclusions:Among children aged 0-5 years, the prevalence of self-reported food allergy increases with age, in China. Foods that is prone to allergies include fish, shrimp, crab, shellfish, poultry eggs, milk and fruits, etc. Most allergies were only caused by single food in children, under observation.

Objective:To observe the therapeutic effect of compound Duzhong Jiangu granule on Kashin-Beck disease (KBD), and to provide a new alternative for the treatment of patients with KBD.Methods:According to the principle of random distribution, patients with KBD diagnosed clinically in Linyou County and Yongshou County of Shaanxi Province who meet the inclusion criteria were divided into a traditional Chinese medicine group and a Western medicine group, and they were treated with compound Duzhong Jiangu granule (Chinese medicine group) and ibuprofen sustained release capsule + 21 jinvita + chondroitin sulfate (Western medicine group), respectively, for a duration of one month. Questionnaire survey was conducted to collect the clinical data of all survey respondents before and after medication by using the Joint Dysfunction Index Scale and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) scales, for evaluation and analysis. The incidence of adverse reactions of the two groups were recorded.Results:A total of 218 KBD patients that met the inclusion criteria were selected, including 167 patients in the Chinese medicine group and 51 patients in the Western medicine group. There were 94 males and 73 females in the Chinese medicine group, aged (62.93 ± 6.72) years. In the Western medicine group, there were 18 males and 33 females, aged (63.29 ± 7.02) years. There was no statistically significant difference in age between the two groups ( Z = - 0.24, P = 0.813). After taking the compound Duzhong Jiangu granules for treatment of KBD patients in the traditional Chinese medicine group, there were significant changes in the number of patients with joint rest pain, joint movement pain, morning stiffness, maximum walking distance and lower limb mobility in the Joint Dysfunction Scale compared to before treatment. The difference between before and after medication was statistically significant (χ 2 = 37.93, 29.64, 50.40, 13.57, 25.25, P < 0.001). After 1 month of medication, there were 13 cases of significant effect, 64 cases of effectiveness, and 90 cases of ineffectiveness in the traditional Chinese medicine group, with a total effective rate of 46.11%. There were 0 cases of significant improvement, 13 cases of effectiveness, and 38 cases of ineffectiveness in the Western medicine group, with a total effective rate of 25.49%. The difference in total effective rates between the two groups was statistically significant (χ 2 = 8.62, P = 0.013). In addition, there was a statistically significant difference in the improvement of lower limb mobility (difficulty of daily activities) between the Chinese medicine group and the Western medicine group (χ 2 = 8.21, P = 0.017). After taking medication, the joint pain, stiffness, and difficulty of daily activities scores in the WOMAC scale of KBD patients in the Chinese medicine group and the Western medicine group were significantly reduced. The differences in scores before and after medication were statistically significant (Chinese medicine group, Z = - 7.60, - 7.74, - 9.75, P < 0.001; Western medicine group, Z = - 5.20, - 3.81, - 3.93, P < 0.001). There was a significant differences in the improvement degree of daily activity difficulty and total score between the Chinese medicine group and the Western medicine group ( Z = - 3.75, - 3.34, P < 0.01). During the medication period, the incidence of adverse reactions in the traditional Chinese medicine group was lower than that in the western medicine group (Chinese medicine group, 29.34%; Western medicine group, 45.09%, χ 2 = 4.38, P = 0.036). Conclusions:Compound Duzhong Jiangu granule has a good therapeutic effects on KBD, significantly improving joint dysfunction of patients. It has advantages in improving the activity ability of KBD patients and reducing the difficulty of daily activities, and has less adverse reactions else.