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 evaluate the development of fetal cerebral sulci and gyrus and the blood perfusion in pregnant women with gestational diabetes mellitus(GDM) by ultrasound.Methods:A total of 1 540 pregnant women with 28-34 weeks of pregnancy who underwent systematic screening in Henan Provincial People′s Hospital from January 2022 to October 2022 were prospectively selected, 100 pregnant women with GDM were selected as the GDM group. According to the effect of blood glucose control, the GDM group was divided into 2 groups: the satisfied control group (GDM group 1), and the dissatisfied control group (GDM group 2), with 50 cases in each group. At the same period, 50 healthy pregnant women at 28-34 weeks of gestation were enrolled as the control group. The differences of the sylvian fissure, parietooccipital sulci, calcarine sulci and cinguli sulci among the 3 groups were statistically analyzed. And the correlations between the deep of the brain cerebral sulci and gyrus and controlled blood glucose levels were evaluated. The umbilical artery pulsation index(UAPI), middle cerebral artery pulsation index(MCAPI) and ductus venosus pulsation index(DVPI) among the 3 groups were compared, and the differences in fetal blood perfusion among the 3 groups were evaluated.Results:There were no significant differences in the depths of the sylvian fissure, parietooccipital sulci, calcarine sulci and cinguli sulci between the control group and the GDM group 1 (all P>0.05), and they were larger than those of the GDM group 2 (all P<0.05). The depths of lateral fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus were negatively correlated with fasting blood glucose, 1 h and 2 h postprandial blood glucose (all P<0.05). There were no significant differences in MCAPI, UAPI and DVPI between the control group and GDM1 group (all P>0.05). The MCAPI in GDM 2 group was lower than that in the control group and GDM 1 group, and the UAPI and DVPI values were higher than those in the control group and GDM1 group(all P<0.05). Conclusions:The maturity of fetal cerebral sulci and gyrus in GDM pregnant women is related to the blood glucose control of pregnant women. The change of blood perfusion caused by persistent hyperglycemia in pregnant women and intrauterine hypoxia may cause the development retardation of cerebral sulci and gyrus.

Objective:To analyze immune reconstitution and influencing factors in HIV infected men who have sex with men (MSM) with access to antiviral therapy (ART) in Guangxi Zhuang Autonomous Region (Guangxi) during 2005-2021.Methods:The data were collected from Chinese Disease Prevention and Control Information System. The study subjects were HIV infected MSM with access to the initial ART for ≥24 weeks in Guangxi from 2005 to 2021 and HIV RNA lower than the detection limit within 24 months. The proportion of infected MSM who had immune reconstitution after ART was calculated. Cox proportional hazard regression model was used to analyze the influencing factors of immune reconstitution. Software SPSS 24.0 was used for statistical analysis.Results:A total of 3 200 HIV infected MSM were enrolled, in whom 15.56 % (498/3 200) had no immune reconstitution, 14.78% (473/3 200) had moderate immune reconstitution, and the rate of complete immune reconstitution was 69.66% (2 229/3 200). The M ( Q1, Q3) of ART time for immune reconstitution was 12 (5, 27) months. Multivariate Cox proportional risk regression model analysis results showed that compared with those with initial ART at age ≥30 years, WHO clinical stage Ⅲ/Ⅳ illness, baseline BMI <18.50 kg/m 2 and baseline CD4 +T lymphocyte (CD4) counts <200 cells/μl, HIV infected MSM with initial ART at age <30 years, WHO clinical stageⅠ/Ⅱ illness, baseline BMI≥24.00 kg/m 2 and baseline CD4 counts ≥200 cells/μl were more likely to have complete immune reconstitution. Conclusions:In the HIV infected MSM in Guangxi, failures to achieve moderate and complete immune reconstitution were observed. Surveillance and ART regimen should be improved for key populations, such as those with older age and low baseline CD4 counts.

Ferroptosis is a new programmed cell death dependent on iron ions.Ferroptosis can be induced by endogenous or exogenous pathways,and cells exhibit specific cell morphological signs and are regulated by a variety of molecular mechanisms.In recent years,more and more studies have shown that ferroptosis plays an important role in the treatment of cancer.This article summarizes the mechanism of ferroptosis in bladder cancer and the regulation of cancer cells,as well as the role of ferroptosis-related factors,non-coding RNA regulation,N6-methyladenosine(m6A),amino acid metabolism and autophagy dependent ferroptosis in the growth and proliferation of bladder cancer,with a view to provide new strategies for the treatment of bladder cancer.

Objective To explore the value of one-stop spectral CT scanning of computer tomography pulmonary angiography(CTPA)combined with abdominal-pelvic enhancement in preoperative evaluation for patients with gynecological tumors.Methods Ninety-six patients with gynecological tumors who received both spectral CTPA and abdominal-pelvic enhanced CT examination at Zhongshan Hospital(Xiamen Branch),Fudan University,between January 2022 and December 2023 were collected.The conventional scanning group(n=48)received two independent spectral CT scans with twice contrast injections,while the one-stop scanning group(n=48)received one-stop spectral CTPA and abdominal-pelvic enhancement with once contrast injection.Virtual monochromatic images(VMIs)at 65 keV for CTPA,50 keV VMIs for abdominal-pelvic enhancement,contrast-enhanced iodine maps and effective atomic number images for the two parts were generated for all patients.The scanning parameters such as contrast agent dose,scanning duration,objective parameters of the images(CT values,iodine concentration,effective atomic number,etc.),as well as overall image quality score,the confidence score in diagnosing pulmonary embolization(PE),and the conspicuity of gynecological tumors were compared between the two groups.Results A total of 24 cases(25% )of PE were found in 96 patients.Compared with the conventional scanning group,the one-stop scanning group showed a significant reduction in contrast agent dosage([62.88±3.59]mL vs[98.52±2.63]mL,P＜0.001)and scan duration([95.94±0.38]s vs[108.91±0.35]s,P＜0.001).There was no statistically significant difference in dose length product(DLP),volume CT dose index,and effective dose(ED)between the two groups.There was no statistically significant difference in objective parameters and subjective image scores between the two groups of patients'CTPA images,abdominal and pelvic CT plain scans,and enhanced images.All image scores were≥3 points,meeting the diagnostic requirements.There was no statistically significant difference of confidence score in diagnosing PE and the ability to display tumor lesions between the two groups.Conclusions In comparison to conventional scanning,one-stop spectral scanning provides comparable image quality,confidence in diagnosing PE,and the conspicuity of gynecological tumors under a lower contrast agent dosage,a shorter scanning time,and a less patient waiting time in the preoperative evaluation for patients with gynecologic tumors,which is highly valuable.

Objective To compare the image quality of carotid contrast-enhanced magnetic resonance angiography(ceMRA)under different flow rates using high relaxation rate contrast agent named Gadobutrol,and to find the best flow rate for carotid ceMRA.Methods Total of 117 patients,who were scheduled to perform carotid ceMRA examination using Gadobutrol with a dosage of 0.1 mL/kg body weight on a 1.5T MR platform,were enrolled in the study.They were divided into four groups according to four kinds of flow rates,which were 1.0 mL/s(n=29),1.5 mL/s(n=30),2.0 mL/s(n=30)and 3.0 mL/s(n=28).The signal-to-noise ratio(SNR)of bilateral carotid initiation and bilateral carotid bifurcation were calculated.The SNR of carotid initiation or carotid bifurca-tion between different flow rates were compared.And the scores of image quality among different flow rates were also compared.Results For bilateral carotid bifurcations and carotid initiations,the SNR under 1.5 mL/s were highest,which were significantly higher than those under 1.0 mL/s,while there were no significant differences between each two other flow rates.For the bilateral carotid bifurca-tions,the SNR under 1.0 mL/s were lower than those under other flow rates,and were significantly lower than those under 1.5 mL/s and 3.0 mL/s.The score of the image quality at 1.0 mL/s was significantly lower than that under other flow rates.The score of the image quality at 1.5 mL/s was the highest,but no significant difference was found compared to that at 2.0 mL/s or 3.0 mL/s.Conclusion The rate of 1.5 mL/s is recommended as the best flow rate for carotid ceMRA with Gadobutrol based on 1.5T MR.

Objectives:To identify the risk factors associated with delirium in intensive care unit (ICU) hospitalization of sepsis patients and construct a clinical prediction model to to provide a reference for the prevention and control of delirium in sepsis patients.Methods:Data were collected of sepsis patients admitted in the Intensive Care Unit in the Second Affiliated Hospital of Soochow University from September 2020 to August 2022.The patients were divided into delirium group and non-delirium group according to whether delirium occurred or not. Comparing of the differences in general and clinical data between the two groups, the independent risk factors for delirium were screened by backward stepwise regression method, and the delirium risk prediction model was constructed and evaluated. An independent risk factor analysis for delirium was conducted using a backward stepwise regression approach to identify significant predictors. A delirium risk prediction model was constructed based on the identified risk factors, followed by a comprehensive evaluation of the model's performance.Results:A total of 381 sepsis patients were included in the study, 114 patients (29.9%) developed delirium during the ICU hospitalization. Univariate analysis revealed statistically significant differences ( P< 0.05) between the delirium and non-delirium groups for several factors including age ≥ 65 years, blood transfusion, use of midazolam, use of adrenaline, APACHEⅡ score>15, SOFA score>4, metabolic acidosis, urea>7.1 mmol/L, coagulation disorders, lactate levels, and platelet count. Multivariate analysis identified age ≥ 65 years, use of midazolam, APACHEⅡ score>15, metabolic acidosis, urea>7.1 mmol/L, and coagulation disorders as independent risk factors for delirium in sepsis patients during ICU hospitalization.The predictive model was evaluated with an area under the ROC curve of 0.813, a non-significant Hosmer-Lemeshow goodness-of-fit test ( P=0.957>0.05), and a Brier score of 0.149 (<0.25), indicating good predictive performance and calibration. Clinical decision and impact curves demonstrated the model's favorable clinical applicability. Conclusions:The occurrence of delirium in ICU sepsis patients closely associate with six factors: age ≥ 65 years, use of midazolam, APACHEⅡ score>15, metabolic acidosis, urea>7.1 mmol/L, and coagulation disorders. This sepsis delirium prediction model has good clinical predictive ability and clinical applicability.

The gut microbiota plays a pivotal role in the immunomodulatory and protumorigenic microenviron-ment of colorectal cancer(CRC).However,the effect of ginsenoside Rk3(Rk3)on CRC and gut microbiota remains unclear.Therefore,the purpose of this study is to explore the potential effect of Rk3 on CRC from the perspective of gut microbiota and immune regulation.Our results reveal that treatment with Rk3 significantly suppresses the formation of colon tumors,repairs intestinal barrier damage,and regulates the gut microbiota imbalance caused by CRC,including enrichment of probiotics such as Akkermansia muciniphila and Barnesiella intestinihominis,and clearance of pathogenic Desulfovibrio.Subsequent metabolomics data demonstrate that Rk3 can modulate the metabolism of amino acids and bile acids,particularly by upregulating glutamine,which has the potential to regulate the immune response.Furthermore,we elucidate the regulatory effects of Rk3 on chemokines and inflammatory factors associated with group 3 innate lymphoid cells(ILC3s)and T helper 17(Th17)signaling pathways,which inhibits the hyperactivation of the Janus kinase-signal transducer and activator of transcription 3(JAK-STAT3)signaling pathway.These results indicate that Rk3 modulates gut microbiota,regulates ILC3s immune response,and inhibits the JAK-STAT3 signaling pathway to suppress the development of colon tumors.More importantly,the results of fecal microbiota transplantation suggest that the inhibitory effect of Rk3 on colon tumors and its regulation of ILC3 immune responses are mediated by the gut microbiota.In summary,these findings emphasize that Rk3 can be utilized as a regulator of the gut microbiota for the prevention and treatment of CRC.

Objective To investigate the efficacy of transcranial direct current stimulation(tDCS)on sleep disorder in patients with Parkinson's disease(PD).Methods From July 2021 to July 2023,patients with PD and sleep disorders in the Department of Neurosurgery of the Second People's Hospital of Guangdong Province were selected.The enrolled patients were divided into sham stimulation group(n=28)and true stimulation group(tDCS)(n=29)according to the inclusion and exclusion criteria.MDS-UPDRS,PDSS and other rating scales were used to evaluate the patients.Before and after tDCS treatment,MS-11 was used for intelligent sleep monitor-ing.The baseline and improvement of sleep disorders in the two groups before and after treatment were analyzed.Results Before tDCS treatment,there was no significant difference in general conditions and scale scores between the two groups(P＞0.05).There was no significant difference in polysomnographic monitoring results between the two groups before treatment(P＞0.05).Compared with pre-treatment,there was no significant difference in sleep monitoring results in the sham stimulation group(P＞0.05),while the sleep duration and sleep efficiency signifi-cantly increased,the nighttime awakening duration,nighttime awakening frequency,MDS-UPDRS-Ⅲ score,and LEDD dose significantly decreased in the true stimulation group,with statistical significance(P＜0.05).Conclusion Pharmacological treatment combined with tDCS treatment is effective for sleep disorders and motor function in patients with PD,which could increase the sleep duration and sleep efficiency of PD patients with sleep disorders to a certain extent,reduce the nighttime awakening duration and frequency,thereby improving the fatigue symp-toms during the daytime,and improving the efficacy of conventional pharmacological treatment for PD.