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 compare the clinical efficacies between arthroscopic anatomic single bundle reconstruction of posterior cruciate ligament (PCL) assisted by internal tension relieving technique combined with rapid rehabilitation and anatomic single bundle reconstruction combined with conventional rehabilitation in the treatment of PCL rupture.Methods:A retrospective cohort study was used to analyze the clinical data of 88 patients with PCL rupture admitted to First Affiliated Hospital of Kunming Medical University from September 2016 to September 2020. The patients included 65 males and 23 females, aged 18-55 years [(39.3±10.8)years]. Forty-four patients underwent arthroscopic anatomic single bundle reconstruction of PCL assisted by internal tension relieving technique combined with rapid rehabilitation therapy (tension-relieving group), and 44 patients underwent arthroscopic routine anatomic single bundle reconstruction of PCL combined with conventional rehabilitation (traditional group). The two groups were compared before and at 3, 12, and 24 months after surgery regarding the following items: International Knee Literature Committee (IKDC) score, Hospital for Special Surgery (HSS) score, Lysholm score, knee motion cycle (maximum stride length, minimum stride length, and stride frequency) and 6 kinematic indicators (angle of forward and back extension, angle of internal and external rotation, angle of internal and external rotation, up and down displacement, internal and external displacement, and forward and back displacement). The Marburger arthroscopy score (MAS) and Professor Ao Yingfang′s improved score by secondary arthroscopy were compared between the two groups at 12 months after surgery. The perioperative complications were observed.Results:All patients were followed for 24-36 months [(25.5±6.3)months]. In tension-relieving group and the traditional group, the values of IKDC score were (71.8±9.8)points and (68.5±6.5)points at 3 months after surgery, (87.6±6.0)points and (87.6±5.5)points at 12 months after surgery, and (95.5±3.1)points and (92.8±11.6)points at 24 months after surgery, respectively. The values were gradually increased, significantly higher than those before surgery [(48.1±16.9)points and (47.1±15.0)points] (all P<0.05). There were no significant differences between the two groups at each time point (all P>0.05). In tension-relieving group and the traditional group, the values of HSS score were (74.2±6.2)points and (68.4±9.5)points at 3 months after surgery, (91.9±5.4)points and (88.4±4.7)points at 12 months after surgery, and (97.1±2.0)points and (96.2±2.8)points at 24 months after surgery, respectively. The values of HSS score gradually increased, significantly higher than those before surgery [(57.5±17.7)points and (56.8±14.3)points] (all P<0.05). At 3 and 12 months after surgery, the values of HSS score in the tension-relieving group were significantly higher than those in the traditional group (all P<0.05), but others were not significantly different between the two groups (all P>0.05). In tension-relieving group and the traditional group, the values of Lysholm score were (74.2±14.9)points and (70.3±7.5)points at 3 months after surgery, (90.9±6.1)points and (88.7±4.7)points at 12 months after surgery, and (96.9±3.0)points and (96.3±2.8)points at 24 months after surgery, respectively. The values of Lysholm score were gradually increased, significantly higher than those before operation [(48.7±20.7)points and (48.2±19.9)points] (all P<0.05). There were no significant differences between the two groups at any time points (all P>0.05). At 3, 12, and 24 months after surgery, the motion cycle (maximum stride length, minimum stride length and stride frequency) and 6 kinematic indicators (angle of forward bending and backward extension, angle of internal and external rotation, angle of internal and external rotation, internal and external displacement, up and down displacement, and forward and backward displacement) of knee joint were significantly improved in both groups compared with those before surgery (all P<0.05). At 3, 12, and 24 months after surgery, the forward and backward displacement in the tension-relieving group was significantly decreased than that in the traditional group (all P<0.05), but others were not significantly different between the two groups (all P>0.05). The MAS was rated as excellent to good in 14 patients and fair to poor in 2, with the excellent and good rate of 87.5% (14/16) in the tension-relieving group, while the score was rated as excellent to good in 11 patients and fair to poor in 3, with the excellent and good rate of 78.6% (11/14) in the traditional group ( P>0.05). The Professor Ao Yingfang′s improved score was (10.6±1.5)points in the tension-relieving group, markedly higher than that in the traditional group [(9.6±2.3)points] ( P<0.05). No perioperative complications were observed. Conclusion:Compared with anatomic single bundle reconstruction combined with conventional rehabilitation, arthroscopic anatomic single bundle reconstruction of PCL assisted by internal tension relieving technique combined with rapid rehabilitation have higher subjective function score, better anteroposteric stability during knee movement, and better results of secondary microscopy.

Objective:To observe the effect of clinical pharmacists on the pain education in the patients with fracture. Methods:A total of 122 fracture patients with ASAⅠ/Ⅱaged 18-80 years were randomly divided into the intervention group (n=61) and the control group(n=61). The control group received the conventional orthopedic treatment..Flurbiprofen was injected for the postopera-tive analgesia,and if the pain VAS score was above 6,pethidine solution was given at the dose of 50 mg immediately. Based on the conventional treatment,the patients in the intervention group were educated by clinical pharmacist one day before the surgery,and then strengthened education was given after the surgery.The pain VAS score,and sleeping quality at 6h,24h,48h and 72h and satisfaction of pain management were compared between the groups.Results:The VAS score of the intervention group was significantly lower than that of the control group at 6 h,24 h,48 h and 72 h after the operation (P<0.05). The scores of sleeping quality in the intervention group at 6 h and 24 h after the operation were higher than those in the control group (P<0.05). The scores of patients' satisfaction were significantly higher in the intervention group than those of the control group (P<0.05). Conclusion: The clinical pharmacist's pain education can improve the degree of pain control and sleeping quality,increase the patients' satisfaction with pain control to a cer-tain extent.

Objective To observe the clinical efficacy of noninvasive ventilation (NIV) on the treatment of acute respiratory distress syndrome (ARDS) caused by severe pneumonia after kidney transplantation. Methods The clinical data of 17 patients who were diagnosed as ARDS caused by severe pneumonia after kidney transplantation and treated with NIV in Sichuan Provincial People's Hospital from January 1st, 2014 to June 1st, 2016 were collected and retrospectively analyzed. According to the result of NIV treatment, the patients were divided into NIV success group (n = 9) and NIV failure group (n = 8). The differences in gender, age, underlying diseases, acute physiology and chronic health evaluation Ⅱ (APACHEⅡ) score, laboratory parameters on the day when ARDS was diagnosed, daily immunosuppressive dosage, NIV support condition and duration, arterial blood gas analysis and adverse reactions between the two groups were compared. Receiver operating characteristic curve (ROC) was plotted, and the predictive value of each parameters for NIV results was evaluated. Results The two groups were similar in gender, age, and underlying diseases. The APACHEⅡ score, serum levels of procalcitonin (PCT) and brain natriuretic peptide (BNP), serum creatinine (SCr), daily tacrolimus dose, and NIV support condition in NIV failure group were significantly higher than those in NIV success group [APACHEⅡscore: 16.7±5.7 vs. 10.3±2.1, PCT (μg/L): 32.8 (1.2, 187.7) vs. 0.3 (0.1, 2.9), BNP (ng/L): 832.4 (263.7, 1 180.2) vs. 157.0 (33.9, 218.5), SCr (μmol/L): 284.8 (90.5, 474.2) vs. 186.6 (76.7, 206.3), daily tacrolimus dose (mg): 3.6 (3.1, 4.0) vs. 2.6 (2.0, 3.5), inspiratory positive airway pressure (IPAP,cmH2O, 1 cmH2O = 0.098 kPa): 14.8±4.1 vs. 9.0±1.1, expiratory positive airway pressure (EPAP, cmH2O): 7.6±1.8 vs. 4.7±0.8, fraction of inspired oxygen (FiO2): 0.75±0.25 vs. 0.43±0.06, all P < 0.05], and the oxygenation index (PaO2/FiO2) after treatment was significantly lower than that of NIV success group [mmHg (1 mmHg = 0.133 kPa):107.4±65.2 vs. 268.7±98.8, P < 0.05]. There was no significant difference in albumin (Alb), white blood cell count (WBC), daily mycophenolate mofetil dose, use of glucocorticold, NIV duration, pH value, arterial partial pressure of carbon dioxide (PaCO2), or the incidence of sputum drainage disorder or pneumothorax between the two groups. ROC curve analysis showed that the predictive value of APACHEⅡ score, serum PCT and BNP levels, tacrolimus daily dosage and PaO2/FiO2changes after NIV treatment for the efficacy of NIV was high, the area under the ROC curve (AUC) was 0.813, 0.778, 0.903, 0.778, 0.764, respectively; when the cut-off value of APACHEⅡ score was 16.0, PCT was 4.1 μg/L, BNP was 180.5 ng/L, tacrolimus daily dosage was 2.5 mg, PaO2/FiO2increased 49.5 mmHg, the sensitivity was 87.5%, 75.2%, 87.5%, 87.5% and 75.0%, respectively, and the specificity was 77.8%, 66.7%, 88.9%, 74.4%, 88.9%, respectively. However, SCr was not sensitive to the NIV effect prediction. Conclusions NIV in the treatment of ARDS caused by severe pneumonia after kidney transplantation has a certain value. The fewer tacrolimus daily dosage, the lower APACHE Ⅱ score and levels of PCT and BNP, the more effective promotion of PaO2/FiO2after NIV treatment, and the better curative effect is suggested.

Objective To analyze the laboratory index characteristics of pulmonary hypertention (PH ) patients with different function states and pressure stages .Methods 2 752 patients diagnosed with PH in the outpatient department ,emergency depart-ment and inpatient department of this hospital from January 2006 to December 2011 were retrospectively analyzed .The clinical as-sessment of the disease condition was done according to the function state and pressure stage of PH recommended by WHO .The characteristics of hematological indexes ,inflammatory indicators and blood gas analysis were observed as well .Results The most common hematological abnormal indexes were the serum brain natriuretic peptide (BNP) elevation(89 .12% ) ,abnormal liver func-tion(58 .32% ) and abnormal hemoglobin(58 .32% ) .The proportion of the PH patients with the elevation of erythrocyte sedimenta-tion rate(ESR) and high-sensitivity C-reactive protein (hs-CRP) were 78 .52% and 73 .59% respectively .The constituent ratio of the BNP increase ,liver function abnormality ,abnormal hemoglobin ,elevation of UA and ESR had statistical differences among the PH patients with different function states and pressure stages (P<0 .05) .The most commonly blood gas analysis abnormality was hypoxemia(83 .08% ) .Respiratory alkalosis had the highest incidence rate in the acid-base imbalance(24 .58% ) .Conclusion The most common hematological abnormal indexes among PH patients are the elevation of serum BNP ,abnormal liver function and he-moglobin abnormality .The laboratory abnormal indexes of above 3 items and the increase of UA and ESR are always related with the severity of disease ,which should to be followed-up .