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

Alzheimer's disease(AD)is the most common neurodegenerative disease,typically affecting individuals aged 65 and older.Mild cognitive impairment is generally regarded as a precursor stage of AD.The underlying molecular and cellular processes of AD can be visualized in vivo using PET/CT technology.Multi-modal imaging based on Aβ PET,tau PET,and FDG PET within the ATN framework can effectively characterize the core neuropathological features of AD.Many novel PET tracers have recently been developed and applied to deeply probe the pathophysiological dysfunction and internal environmental alterations in AD.Therefore,this review will summarize the recent advances of amyloid,tau protein,FDG,and neuroinflammatory PET probes in AD research within the ATN framework.

[This corrects the article DOI: 10.1016/j.apsb.2022.10.016.].

Objective:To analyze 12 antithrombins (AT) gene mutations that cause AT deficiency and discuss the relationship between the SERPINC1 gene. mutations and venous thrombotic events.Methods:This study belongs to case series of observational studies. Collected the clinical data of 12 AT deficiency cases in the First Affiliated Hospital of Wenzhou Medical University from April 2014 to April 2021 and collected the blood samples before treatment. The AT activity (AT: A) and AT antigen (AT: Ag) was detected by chromogenic substrate and immunoturbidimetry, respectively. The 7 exons and flanking sequences of the SERPINC1 gene were sequenced directly by PCR, the suspected mutations were validated by reverse sequencing. Analyzed the correlation between the SERPINC1 gene. mutations and venous thrombotic events and figured out the proportion.Results:The AT: A of the 12 patients all decreased significantly, ranging from 30% to 66%, and the AT: Ag of the 7 patients decreased accordingly, showing type Ⅰ AT deficiency, and the AT: Ag of the other 5 patients were normal, presented type Ⅱ AT deficiency. 12 mutations were found including 6 heterozygous mutations which were discovered for the first time: c.456_458delCTT(p.phe121del), c.318_319insT(p.Asn75stop), c.922G>T(p.Gly276Cys), c.938T>C (p.Met281Thr), c.1346T>A(p.Leu417Gln)and c.851T>C(p.Met252Thr). All 12 patients had venous thrombosis, and 3 cases including 2 compound heterozygotes and 1 single heterozygote all suffered from deep venous thrombosis (DVT) when they were younger without obvious triggers. The other 9 patients all combined with the other thrombotic factors including old age, hypertensive, smoking, pregnancy, and prolonged immobilization.Conclusion:Patients with AT deficiency caused by SERPINC1 gene defects are prone to venous thrombosis, especially combined with other thrombotic factors.

Sepsis-induced liver injury (SILI) is an important cause of septicemia deaths. BaWeiBaiDuSan (BWBDS) was extracted from a formula of Panax ginseng C. A. Meyer, Lilium brownie F. E. Brown ex Miellez var. viridulum Baker, Polygonatum sibiricum Delar. ex Redoute, Lonicera japonica Thunb., Hippophae rhamnoides Linn., Amygdalus Communis Vas, Platycodon grandiflorus (Jacq.) A. DC., and Cortex Phelloderdri. Herein, we investigated whether the BWBDS treatment could reverse SILI by the mechanism of modulating gut microbiota. BWBDS protected mice against SILI, which was associated with promoting macrophage anti-inflammatory activity and enhancing intestinal integrity. BWBDS selectively promoted the growth of Lactobacillus johnsonii (L. johnsonii) in cecal ligation and puncture treated mice. Fecal microbiota transplantation treatment indicated that gut bacteria correlated with sepsis and was required for BWBDS anti-sepsis effects. Notably, L. johnsonii significantly reduced SILI by promoting macrophage anti-inflammatory activity, increasing interleukin-10⁺ M2 macrophage production and enhancing intestinal integrity. Furthermore, heat inactivation L. johnsonii (HI-L. johnsonii) treatment promoted macrophage anti-inflammatory activity and alleviated SILI. Our findings revealed BWBDS and gut microbiota L. johnsonii as novel prebiotic and probiotic that may be used to treat SILI. The potential underlying mechanism was at least in part, via L. johnsonii-dependent immune regulation and interleukin-10⁺ M2 macrophage production.

OBJECTIVE To systematically evaluate the efficacy and safety of fondaparinux versus low molecular weight heparin（nadroparin，enoxaparin）in the treatment of non-ST-elevation acute coronary syndrome （NSTE-ACS）. METHODS The computer searched PubMed ，Medline，Embase，EBSCO，CNKI，Wanfang medical network ，VIP Chinese Journal Full-text Database and relevant clinical trial registration network for the clinical retrospective cohort study （RCS）of fondaparinux （as trial group）and low molecular weight heparin （natroparin，enoxaparin）（as control group ）in the treatment of NSTE-ACS. The retrieval time limit was from the establishment of the database to August 2021. Newcastle Ottawa scale （NOS）was used to evaluate the quality of literature. Outcome indicators included primary efficacy indicators （incidence of acute myocardial infarction and recurrent angina pectoris during hospitalization ），secondary efficacy indicators [revascularization of target vessels during 话：0835-2862024。E-mail：xiexingxing07@163.com hospitalization， prothrombin time （PT）， activated partial thromboplastin time （APTT）]，safety indicators （incidence of serious cardiovascular events ，severe bleeding ，slight bleeding and severe puncture site co mplications during hospitalization ），combined endpoint indicators （30 and 180 days combined endpoint）. RevMan 5.3 software was used for Meta-analysis of each effect index. RESULTS Finally，17 RCS articles were included，involving 4 946 patients with NSTE-ACS ，including 2 507 in the trial group and 2 439 in the control group.The results of NOS literature quality evaluation showed that there were 8 high-quality studies ，accounting for 47.06％ . The results of Meta-analysis showed that there was no significant difference in the incidence of acute myocardial infarction ，recurrent angina pectoris，revascularization of target vessels ，PT and serious cardiovascular events between 2 groups （P＞0.05）；there was significant difference in the APTT （MD＝1.34，95％CI of 0.22-2.45，P＜0.05），the incidence of severe bleeding （RR＝0.47， 95％CI of 0.30-0.74，P＜0.05），the incidence of slight bleeding （RR＝0.48，95％CI of 0.32-0.71，P＜0.05），the incidence of severe puncture site complications （RR＝0.48，95％CI of 0.25-0.95，P＜0.05），30 day combined endpoint （RR＝0.57，95％CI of 0.46-0.72，P＜0.05），180 days combined endpoint （RR＝0.73，95％CI of 0.54-0.98，P＜0.05）. CONCLUSIONS Fondaparinux in the treatment of NSTE-ACS in China has the same efficacy as low molecular weight heparin （nadroparin，enoxaparin），and has more obvious advantages in drug safety such as bleeding ，severe puncture site complications.

Objective:To study the clinical characteristics and gene mutations in a family with combined inherited antithrombin (AT) and factor Ⅶ (FⅦ) deficiency, and explore the relationship between AT gene, F7 gene mutations and diseases. Methods:Pedigree investigation. Blood samplesand clinical dataswere collected fromthe proband and her family members (a total of 16 people in 3 generations) who admitted to the First Affiliated Hospital of Wenzhou Medical University in November 2018. The prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), antithrombin activity (AT: A), antithrombin antigen (AT: Ag), protein C activity (PC: A), protein S activity (PS: A), FⅦ activity (FⅦ: C), FⅦ antigen (FⅦ: Ag) and other indicators were detectedto confirm the diagnosis. DNA direct sequencing analysis of all exons, flanking sequences, 5′ and 3′ untranslated regions of AT genes and F7 genes, and the mutation sites were confirmed by clone sequencingor reverse sequencing. Results:The AT: A and AT: Ag of the proband were 46% and 135 mg/L, respectively (reference range: 250-360 mg/L), some of her family members′ s (father, aunt, two cousins, younger brother and nephew) AT: A and AT: Ag were reduced to 50% of normal range. Her father (Ⅰ 2), aunt (Ⅰ 4), elder brother (Ⅱ 7), younger brother (Ⅱ 8), and nephew (Ⅲ 3)′s FⅦ: C were 45%, 50%, 48%, 47% and 48%, respectively; and their FⅦ:Ag was within the normal range. Genetic analysis revealed that the proband(Ⅱ 6) and some of her family members (father, aunt, two cousins, younger brother and nephew) took rs3138521 polymorphism in the 5′ untranslated region of AT gene. Her father (Ⅰ 2), aunt (Ⅰ 4), elder brother (Ⅱ 7), younger brother (Ⅱ 8), nephew (Ⅲ 3) took c.1091G>A heterozygous missense mutationin exon 8 of F7 gene, resulting in p.Arg304Gln. Conclusion:The rs3138521 in AT gene and c.1091G>A in F7 gene, which may be the molecular mechanism leading to combined inherited AT and FⅦ deficiency in this family.

β-defensin is a primary protein immune factor in channel catfish's (Ietalurus punetaus) resistance to pathogenic microorganisms. Its primary structure contains a signal peptide composed of 24 amino acid residues at the N-terminal and a mature peptide composed of 43 amino acid residues at the C-terminal. The mature peptide region is responsible for the biological activity of β-defensin. In the present study, a recombinant strain of Pichia pastoris that produces channel catfish β-defensin, was constructed to realize the biosynthesis of channel catfish β-defensin based on eukaryotic expression. First, the β-defensin gene "IPBD" was isolated from the skin of channel catfish by RT-PCR. After linking it with the expression vector pPICZA, pPICZA-IPBD was transferred into competent P. pastoris X-33 cells to obtain recombinant P. pastoris strains. The yeast transformants with multi-copy gene inserts were obtained by using the culture medium containing 1 000 μg/mL zeocin. Using BMM culture medium (without amino nitrogen culture medium) instead of BMMY culture medium (with amino nitrogen culture medium), the fermentation and culture conditions of the recombinant strain were optimized, and the optimal conditions for producing channel catfish β-defensin were determined as follows: the expression was induced for 96 h with 1.0% methanol at 28 °C , 250 r/min. Purified protein with molecular weight of 5.98 kDa was obtained by nickel affinity chromatography, and MALDI-TOF/TOF mass spectrometry proved that it was the expected recombinant IPBD. The antibacterial test results showed that the inhibitory rates of recombinant IPBD on Gram-positive Staphylococcus aureus and Listeria monocytogenes and Gram-negative Pseudomonas aeruginosa were 69.6%, 71.6% and 65.8%, respectively. This study provides a recombinant DNA technique for the development of small molecule natural antibacterial peptide from fish.

Objective:To explore the influencing factors of uterine myometrial and parauterine venous plexus reflux during transvaginal four-dimensional contrast-enhanced hysterosalpingography, which will help reduce and avoid the occurrence of reflux and improve the accuracy of diagnosis.Methods:A total of 306 infertile patients who underwent transvaginal four-dimensional contrast-enhanced hysterosalpingograph from June 2016 to June 2017 in the Third Affiliated Hospital of Guangzhou Medical University were retrospectively enrolled. The ultrasonographic characteristics were reviewed and the correlations between reflux and endometrial thickness, days after menstruation, intrauterine operation history and patency of fallopian tube were analyzed.Results:The incidence of countercurrent during four-dimensional contrast-enhanced hysterosalpingography was 14.71%. The chi-square test showed that the endometrial thickness and the days after menstruation had statistically significant effects on the incidence of reflux ( P=0.031 and <0.001, respectively). There were no statistically significant effects of intrauterine operation history and patency of the fallopian tube on the incidence of reflux ( P=0.610, 0.137). Logistic regression analysis showed that the incidence of reflux was associated with endometrial thickness ( B=-1.171, P<0.001) and the days after menstruation ( B=0.439, P=0.015). Conclusions:Transvaginal ultrasound measurement of endometrial thickness before angiography and selection of appropriate examination time according to the menstrual cycle can effectively reduce the incidence of reflux, and adverse reactions, and improve the accuracy of four-dimensional contrast-enhanced hysterosalpingography.

Objective: To understand hepatitis B virus(HBV) infection in high school students in Guangxi, and to provide scientific foundation for hepatitis B prevention and control strategies. Methods: A selfdesigned epidemiological questionnaire was used among 2 632 participants. Information regarding general demographic characteristics, lifestyle habits, HBV infection history, knowledge of viral hepatitis prevention and control, as well as hepatitis B vaccination. Univariate and multivariate logistics regression analysis was used to analyze associated factors for hepatitis B infection. Results: A total of 192 out of 2 632 participants were found HBsAg positive and 2 440 were HBsAg negative. Multivariate analysis showed that family liver disease history and hairdressing injury positively associated with hepatitis B virus infection risk (OR=3.62, 95% CI=2.28-5.73;OR=3.06, 95%CI=1.94-4.83), and hepatitis B vaccination was negatively associated with hepatitis B virus infection risk (OR=0.08, 95%CI=0.05-0.11). Conclusion Family history of liver disease, hairdressing injury experiences, as well as low rate of hepatitis B vaccination may associate with relatively high prevalence of hepatitis B virus infection among high school students in Guangxi.