BACKGROUND: The protective effect of mesenchymal stem cells (MSCs) on cardiac ischemia-reperfusion (I/R) injury has been widely reported. Dental pulp-derived mesenchymal stem cells (DP-MSCs) have therapeutic effects on various diseases, including diabetes and cirrhosis. This study aimed to determine the therapeutic effects of DP-MSCs on I/R injury and elucidate the underlying mechanism. METHODS: Myocardial I/R injury model mice were treated with DP-MSCs or a miR-19a-3p mimic. The infarct volume, fibrotic area, pyroptosis, inflammation level, and cardiac function were measured. Cardiomyocytes exposed to hypoxia-reoxygenation were transfected with the miR-19a-3p mimic, miR-19a-3p inhibitor, or negative control. Pyroptosis and protein expression in the interferon regulatory factor 8/mitogen-activated protein kinase (IRF-8/MAPK) pathway were measured. RESULTS: DP-MSCs protected cardiac function in cardiac I/R-injured mice and inhibited cardiomyocyte pyroptosis. The upregulation of miR-19a-3p protected cardiac function, inhibited cardiomyocyte pyroptosis, and inhibited IRF-8/MAPK signaling in cardiac I/R-injured mice. DP-MSCs inhibited cardiomyocyte pyroptosis and the IRF-8/MAPK signaling by upregulating the miR-19a-3p levels in cardiomyocytes injured by I/R. CONCLUSION DP-MSCs protected cardiac function by inhibiting cardiomyocyte pyroptosis through miR-19a-3p under I/R conditions.
Animals ; MicroRNAs/metabolism* ; Pyroptosis/genetics* ; Mesenchymal Stem Cells/metabolism* ; Myocytes, Cardiac/cytology* ; Mice ; Male ; Mice, Inbred C57BL ; Dental Pulp/cytology* ; Myocardial Reperfusion Injury/therapy* ; MAP Kinase Signaling System/physiology*

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 explore the feasibility of using two-dimensional speckle tracking echocardiography for measuring right ventricular strain and function in healthy adults, and to analyze the impact of age and gender.Methods:This study is a cross-sectional study. Healthy adults who underwent physical examination in the Physical Examination Center of Beijing Hospital from January 1, 2020 to January 1, 2021 were included. Two researchers independently measured various right ventricular longitudinal strain indices using the Echopac software, including (global longitudinal strain (GLS), apical longitudinal strain (ALS), midventricle longitudinal strain (MLS), basal longitudinal strain (BLS), free wall GLS (FWGLS), free wall ALS (FWALS), free wall MLS (FWMLS) and free wall BLS (FWBLS)) as well as tricuspid annular plane systolic excursion (TAPSE) and right ventricle-fraction of area change (RVFAC). The above indicators were taken as the average of two physicians. The consistency of the measurements by two physicians was evaluated by the within-group correlation coefficient ( ICC). Results:A total of 233 subjects were included, including 137 males, aged (58.5±14.2) years. ICC values was all above 0.8 with excellent agreement. The values of FWGLS and GLS in healthy adults were -26.63% and -21.89%, respectively. There was no statistically significant difference in TAPSE ((2.06±0.41)cm vs. (2.10±0.39)cm, P=0.510) and RVFAC ((51.17±9.91)% vs. (50.89±8.65)%, P=0.826) between males and females. The values of various right ventricular long axis strain indicators (GLS, ALS, MLS, BLS, FWGLS, FWMLS, FWMLS, FWBLS) in females aged 18 to 40 and 41 to 65 years were higher than those in males of the same age (all P<0.05), while there was no statistically significant difference in the values of various right ventricular long axis strain indicators between the sexes in subjects aged 65 years and above (all P>0.05). In females, the right ventricular GLS, ALS, MLS, FWGLS, FWALS, FWMLS, and FWBLS values in the groups aged 18 to 40 and 41 to 65 years were significantly higher than those in the group aged 65 years and above (all P<0.05). In contrast, no significant differences were found in these indices among different age groups in males (all P>0.05). Conclusions:Using two-dimensional speckle tracking technology in echocardiography to measure right ventricular strain indicators is feasible and highly reproducible. Gender and age have an impact on right ventricular strain indicators.

Objective:This study aimed to assess left atrial function in adults across various age groups using 4-dimensional automated left atrial quantification(4D Auto LAQ)technology.The study also aimed to compare the differences in two-dimensional(2D)and four-dimensional(4D)strains of the left atrium among different age groups, with the goal of enhancing the clinical utility of 4D Auto LAQ.Methods:A total of 409 healthy volunteers were recruited for the research.Two-dimensional and four-dimensional images were obtained using a GE Vivid E95 ultrasound system with a 4Vc four-dimensional probe.The study examined variations in 2D and 4D ultrasound parameters across various age groups.Furthermore, the relationship between left atrial reservoir strain(LASr), Left atrial conduit strain(LAScd), left atrial contraction strain(LASct), and age was explored.Results:The study involved 409 volunteers, with 217 males and 192 females, who were categorized into three age groups: young(18-45 years, n=56), middle-aged(46-65 years, n=202), and elderly(>65 years, n=151).Conventional ultrasound measurements indicated changes in left atrial anterior-posterior diameter with age progression: (31.70±3.65)mm for the young group, (34.02±3.91)mm for the middle-aged group, and(35.2±4.37)mm for the elderly group( P<0.01).The 2D and 4D left atrial parameters across the age groups were as follows: LASr(2D)(%): 37.48±7.51, 30.95±8.23, 26.9±7.56( P<0.01); LA VImax(ml/m 2): 23.54±5.79, 26.33±7.6, 28.99±8.15( P<0.01); LASr(%): 31.2±17.07, 22.5±8.59, 19.49±7.47( P<0.01).Both 2D and 4D left atrial parameters exhibited significant associations with age.Specifically, the correlations between LASr(2D)(%), LAScd(2D)(%), LASr(%), LAScd(%), and age were -0.429, 0.580, -0.354, 0.298, respectively( P<0.01). Conclusions:The 4D Auto LAQ technology is efficient in assessing left atrial function across various age groups, with age playing a significant role in influencing left atrial parameters.When compared to other ultrasound parameters, both 2D and 4D left atrial strain parameters have the ability to detect differences at an early stage, making them suitable for the early screening, evaluation, and monitoring of age-related left atrial dysfunction, especially in the elderly population.

Objective To investigate the correlation between subclinical peripheral neuropathy(sDPN)and time in range(TIR)in type 2 diabetes mellitus(T2DM),and to explore the risk factors of sDPN.Methods A total of 485 T2DM patients without DPN symptoms and underwent EMG examination during hospitalization were divided into the sDPN group(n=209)and the non-sDPN group(n=276)according to nerve function conduction examination.The differences of age,course of the disease,blood pressure,complications,biochemical index and continuous glucose monitoring index were compared between the two groups of patients.The correlation between sDPN and TIR was analyzed.Logistic regression analysis was used to analyze influence factors of sDPN.Results Compared with the non-sDPN group,patients in the sDPN group were older and had longer diabetes course,higher systolic blood pressure(SBP),urinary albumin/urinary creatinine(UACR),blood glucose 1 h postprandial(1 h-PG),2 h-PG,TBR,mean blood glucose fluctuation range(MAGE),standard deviation of blood glucose level(SD)and glycemic coefficient of variation(CV)levels,higher proportion of hypertension(HT),diabetic nephropathy(DN),diabetic retinopathy(DR)and diabetic peripheral vascular disease(PAD),and lower levels of total cholesterol(TC),right limb ankle brachial index(R-ABI),L-ABI,hemoglobin A1c(HbA1c)and TIR.The differences in the above indexes were statistically significant(P＜0.05).The occurrence of sDPN was positively correlated with TBR(rs=0.104,P＜0.05),and negatively correlated with TIR(rs=-0.093,P＜0.05).Logistic regression analysis showed that increased TBR(OR=1.093,95%CI:1.009-1.183),combined with DN(OR=3.004,95%CI:1.020-8.849)and DR(OR=9.736,95%CI:3.499-27.087)were independent risk factors for sDPN,and increased R-ABI(OR=0.005,95%CI:0.000-0.424)was protective factor for sDPN.Conclusion sDPN was negatively correlated with TIR.For patients with T2DM complicated with DN,DR and decreased ABI,it is necessary to timely improve neuroelectrophysiological examination to identify sDPN as soon as possible and give early intervention.

ObjectiveTo explore the exposure-lag-response relationship between temperature and risk of varicella incidence，and to provide a scientific evidence for early warning and precise prevention and control of varicella epidemic. MethodsDaily varicella cases and daily meteorological data were collected in Minhang District， Shanghai from 2010 to 2022. A distributed lag nonlinear model was used to determine the exposure-lag-response relationship between temperature and risk of varicella incidence. Furthermore， effect of temperature on the incidence risk was determined across different age groups. ResultsIn 2010‒2022， the total number of notified varicella cases was 26 207 in Minhang District， with the highest incidence in the group aged 3‒14 years （50.35%）. The seasonal pattern of daily varicella cases showed a double peak. The large peak was found in November and December， followed by a smaller peak in May and June. Moreover， the distributed lag nonlinear model showed a unimodal curve in the relationship between temperature and varicella incidence. The RR value reached its maximum peak of 1.90 （95%CI： 1.25‒2.87） at 7 ℃. A reverse U-shape was found in the lag-response curves between temperature and varicella incidence. Furthermore， the effect of temperature on the varicella incidence showed a unimodal pattern in the varicella cases aged 3‒14 years. The RR value reached its peak at 11 ℃ （RR=2.89， 95%CI： 1.33‒6.24）. In contrast， the effect of temperature on the varicella incidence in the cases aged 15 years and above showed a unimodal pattern， with RR value reaching the peak at 5 ℃ （RR=2.14， 95%CI： 1.33‒3.44）. ConclusionThe unimodal curve is found in the relationship between temperature and varicella incidence. Low temperature is associated with increased risk of varicella incidence. Children aged 3‒14 years are more susceptible to the effect of temperature on the varicella incidence.

Hypertension has a high prevalence in China, and the predominant reliance on drug treatment consumes enormous medical resources.Physical exercise is the only widely-accepted nonpharmacologic therapy for hypertension and is potentially cost-effective.How to incorporate exercise into a prescription for rational treatment of hypertension is a topic that needs to be addressed.This review examines the research progress on the treatment of hypertension combining physical exercise with anti-hypertensive drugs in elderly people, aiming to provide some information and options to promote personalized treatment strategies for hypertension in elderly people.

Objective:To compare the differences in the prevalence of mild micro-hepatic encephalopathy (MHE) among patients with cirrhosis by using the psychometric hepatic encephalopathy score (PHES) and the Stroop smartphone application (Encephal App) test.Methods:This prospective, multi-center, real-world study was initiated by the National Clinical Medical Research Center for Infectious Diseases and the Portal Hypertension Alliance and registered with International ClinicalTrials.gov (NCT05140837). 354 cases of cirrhosis were enrolled in 19 hospitals across the country. PHES (including digital connection tests A and B, digital symbol tests, trajectory drawing tests, and serial management tests) and the Stroop test were conducted in all of them. PHES was differentiated using standard diagnostic criteria established by the two studies in China and South Korea. The Stroop test was evaluated based on the criteria of the research and development team. The impact of different diagnostic standards or methods on the incidence of MHE in patients with cirrhosis was analyzed. Data between groups were differentiated using the t-test, Mann-Whitney U test, and χ2 test. A kappa test was used to compare the consistency between groups. Results:After PHES, the prevalence of MHE among 354 cases of cirrhosis was 78.53% and 15.25%, respectively, based on Chinese research standards and Korean research normal value standards. However, the prevalence of MHE was 56.78% based on the Stroop test, and the differences in pairwise comparisons among the three groups were statistically significant (kappa = -0.064, P < 0.001). Stratified analysis revealed that the MHE prevalence in three groups of patients with Child-Pugh classes A, B, and C was 74.14%, 83.33%, and 88.24%, respectively, according to the normal value standards of Chinese researchers, while the MHE prevalence rates in three groups of patients with Child-Pugh classes A, B, and C were 8.29%, 23.53%, and 38.24%, respectively, according to the normal value standards of Korean researchers. Furthermore, the prevalence rates of MHE in the three groups of patients with Child-Pugh grades A, B, and C were 52.68%, 58.82%, and 73.53%, respectively, according to the Stroop test standard. However, among the results of each diagnostic standard, the prevalence of MHE showed an increasing trend with an increasing Child-Pugh grade. Further comparison demonstrated that the scores obtained by the number connection test A and the number symbol test were consistent according to the normal value standards of the two studies in China and South Korea ( Z = -0.982, -1.702; P = 0.326, 0.089), while the other three sub-tests had significant differences ( P < 0.001). Conclusion:The prevalence rate of MHE in the cirrhotic population is high, but the prevalence of MHE obtained by using different diagnostic criteria or methods varies greatly. Therefore, in line with the current changes in demographics and disease spectrum, it is necessary to enroll a larger sample size of a healthy population as a control. Moreover, the establishment of more reliable diagnostic scoring criteria will serve as a basis for obtaining accurate MHE incidence and formulating diagnosis and treatment strategies in cirrhotic populations.

Objective: To construct and identify an overexpression recombinant adenovirus vector carrying the mouse PTG gene(NM＿016854), and to lay a foundation for in-depth study of the function of PTG. Methods: The coding sequence of the mouse PTG gene was chemically synthesized, amplified by polymerase chain reaction(PCR), digested with restriction enzymes, and inserted into the GV314 vector(CMV-MCS-3 FLAG-SV40-EGFP) to obtain the recombinant shuttle plasmid pGV314-PTG. BamHⅠ/AgeⅠ double enzyme digestion was further carried out, and the product was transferred into linearized expression vector pDC315 to construct recombinant adenovirus Ad-PTG, which was transfected into HEK293 T cells and packaged into recombinant virus particles. After repeated amplification of several generations of HEK293 T cells, the recombinant adenovirus was purified and titer detected. Finally, PCR, Western blot and sequencing were used to verify the recombinant adenovirus. Results: After PCR, Western blot and sequencing, the results showed that the pGV314-CMV-MCS-3 FLAG-SV40-EGFP-PTG overexpression adenovirus vector(Ad-PTG) was successfully constructed, and the virus titer measured by end-point dilution method was 4×1010PFU/ml, Western blot and RT-qPCR showed that the protein and mRNA expression levels of PTG increased significantly. Conclusion The recombinant adenovirus vector carrying mouse PTG gene is successfully constructed, and the expression of PTG gene in hepatocytes is effectively up regulated.

Objective:To explore the risk factors for atrial fibrillation(AF)in elderly Chinese patients with severe valvular heart disease(VHD).Methods:This was a cross-sectional study and consecutively enrolled 978 elderly patients with severe VHD diagnosed in 18 Class A tertiary hospitals across the country from September 2021 to March 2022, including 322(32.9%)patients with concurrent AF.Clinical and echocardiographic data were collected to analyze the risk factors for AF.Results:Among VHD patients, compared with the non-AF group, the AF group was older, had a higher female ratio, higher diastolic blood pressure, higher proportions with cerebrovascular disease and chronic kidney disease, lower serum low density lipoprotein cholesterol and higher serum creatinine, amino-terminal A-type natriuretion peptide and glycosylated hemoglobin.As for echocardiographic parameters, the left atrial diameter was larger, the left ventricular end-diastolic diameter, interventricular septum thickness, and left ventricular posterior wall thickness were smaller in the AF group than in the non-AF group.All of the differences were statistically significant(all P<0.05). The results of multivariate Logistic regression analysis showed that the left atrial anteroposterior diameter increased( OR=1.166, P<0.01), the left ventricular end-diastolic diameter decreased( OR=0.929, P<0.01), and advanced age( OR=1.051, P<0.05)was an independent risk factor for elderly VHD patients with concurrent AF. Conclusions:In elderly patients with severe VHD, advanced age, an increased left atrial anteroposterior diameter, and a decreased left ventricular end-diastolic diameter were independently associated with AF.Therefore, evaluation of cardiac structure and regular follow-up should be performed in elderly patients with severe VHD for early intervention to reduce the incidence of AF.