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

Healthy lifestyles and good living habits are effective strategies and important approaches to prevent chronic non-communicable diseases. With the development of evidence-based medicine, the evidence translation system has made some achievements in clinical practice. There is, however, no comprehensive, professional and efficient system for translating lifestyle evidence globally. Therefore, the Health Lifestyle Evidence (HLSE) Group of Lanzhou University constructed the HLSE Evidence Translation System (https://hlse.cn/), with the aim of synthesizing, evaluating, translating, and applying lifestyle-related evidence resources. This paper aims to introduce the functional module design of the evidence translation system, the system development process and testing, introduce the interface design and function demonstration, and explain the significance of constructing the HLSE.

Healthy lifestyles and good living habits are effective strategies and important approaches to prevent chronic non-communicable diseases. With the development of evidence-based medicine, the evidence translation system has made some achievements in clinical practice. There is, however, no comprehensive, professional and efficient system for translating lifestyle evidence globally. Therefore, the Health Lifestyle Evidence (HLSE) Group of Lanzhou University constructed the HLSE Evidence Translation System (https://hlse.cn/), with the aim of synthesizing, evaluating, translating, and applying lifestyle-related evidence resources. This paper aims to introduce the functional module design of the evidence translation system, the system development process and testing, introduce the interface design and function demonstration, and explain the significance of constructing the HLSE.

ObjectiveTo observe the mechanism of Jiawei Guizhi Fuling decoction （JGFD） in alleviating sciatic nerve injury in painful diabetic peripheral neuropathy （PDPN） rats by regulating mitophagy through the PTEN-induced putative kinase 1 （PINK1）/Parkin signaling pathway. MethodThe PDPN model was established by intraperitoneal injection of streptozotocin （STZ）. After modeling， the rats were randomly divided into JGFD high， medium， and low dose groups （JGFD-H， JGFD-M， JGFD-L； 39.6， 19.8， 9.9 g·kg^-1·d^-1， respectively）， a positive drug group （lipoic acid capsules， LA； 50 mg·kg^-1·d^-1）， and a model group （PDPN）. A blank control group （CON） was established. Drug intervention was administered continuously for 8 weeks after modeling. Measurements included body weight and fasting blood glucose of PDPN rats at weeks 0， 2， 4， and 8， mechanical pain threshold and thermal pain threshold at weeks 0 and 8， and motor nerve conduction velocity at week 8. Hematoxylin-eosin （HE） staining was used to observe the morphology of sciatic nerve tissue. The ultrastructure of mitochondria and autophagosomes was observed by transmission electron microscopy. Western blot was performed to detect the protein expression levels of PINK1， Parkin， p62， Beclin-1， and LC3 in sciatic nerve tissue. Additionally， real-time quantitative PCR （Real-time PCR） was performed to detect the mRNA expression levels of PINK1， Parkin， p62， Beclin-1， and LC3 in sciatic nerve tissue. ResultCompared with the CON group， the PDPN group showed a significant decrease in body weight at all time points， a significant increase in fasting blood glucose， significantly shortened mechanical pain and thermal pain thresholds， and significantly reduced motor nerve conduction velocity. The protein and mRNA expression of PINK1， Parkin， Beclin-1， and microtubule-associated protein light chain 3（LC3） in sciatic nerve tissue was significantly reduced， while p62 protein and mRNA expression was significantly increased （P<0.01）. Pathological changes included edema of sciatic nerve fibers， segmental demyelination， loose and disordered arrangement of the myelin sheath layers， significant swelling of mitochondria， reduced electron density， disappearance of cristae， and absence of typical autophagosome and autolysosome structures. Compared with the PDPN group， each JGFD dose group showed a significant increase in body weight and a significant reduction in fasting blood glucose （P<0.05， P<0.01）. The mechanical pain threshold and thermal pain threshold were significantly prolonged， and motor nerve conduction velocity was significantly increased across all JGFD and LA groups. The expression levels of PINK1， Parkin， Beclin-1， and LC3 proteins and mRNA in sciatic nerve tissue were significantly increased， while p62 protein and mRNA expression levels were significantly decreased （P<0.05， P<0.01）. Pathological damage to the sciatic nerve was alleviated to varying degrees， with a relatively intact myelin sheath morphology and intact or slightly edematous outer mitochondrial membrane. Autophagolysosome structures were observed in the JGFD-M and JGFD-H groups. Compared with the LA group， the JGFD-H group showed a significant increase in body weight， a significant reduction in fasting blood glucose， a significant increase in motor nerve conduction velocity， a significant increase in PINK1 protein expression and PINK1， Parkin， and Beclin-1 mRNA expression in sciatic nerve tissue， and a significant decrease in p62 mRNA expression （P<0.05， P<0.01）. ConclusionJGFD may alleviate sciatic nerve injury in PDPN rats by activating mitophagy through the regulation of the PINK1/Parkin signaling pathway.

Objective:To explore the medication law and core Traditional Chinese Medicine (TCM) compounds in the treatment of blood stasis vascular dementia (VD) based on data mining.Methods:The literature about TCM treatment for blood stasis VD was retrieved from the databases of CNKI, Wanfang, VIP, and CBM from January 2000 to November 2021. Microsoft Office Excel 2019, SPSS Modeler 18.0, SPSS Statistics 25.0, R X64 4.1.2, and Origin 2021 were used to perform medication frequency analysis, frequency analysis of four properties and five tastes of TCM, association rules, clustering analysis, factor analysis and data visualization.Results:A total of 196 articles were included, with 196 TCM prescriptions, involving 200 kinds of Chinese materia medica. High-frequency drugs were for Acori Tatarinowii Rhizoma, Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix et Rhizoma, Polygalae Radix, Carthami Flos. The medicinal properties were mainly warm, mild and cold, the tastes were mainly sweet, bitter and pungent, and the meridians were mainly liver meridian, spleen meridian and heart meridian. A total of 19 association rules were obtained from the analysis of association rules for 2 kinds of Chinese materia medica, and the rules of the representative were Acori Tatarinowii Rhizoma- Polygalae Radix, Chuanxiong Rhizoma- Carthami Flos, Acori Tatarinowii Rhizoma- Curcumae Radix. A total of 4 categories were extracted through clustering analysis. Factor analysis extracted a total of 8 common factors. Conclusion:The core pathogenesis of blood stasis VD is blood stasis blocking brain collaterals, and there were also pathological factors such as qi deficiency, yin deficiency, phlegm turbidity and so on. The basic treatment is promoting blood circulation and removing stasis, and different methods of promoting blood circulation and drugs are selected. The methods of strengthening spleen and reducing phlegm, nourishing yin and blood, inducing resuscitation, tonifying the kidney and spleen, regulating qi, promoting collaterals and so on can also be used based on syndromes and symptoms of the patients.

【Objective】 To explore a new treatment of primary bilateral macronodular adrenal hyperplasia (PBMAH) and its efficacy. 【Methods】 Clinical data of 20 PBMAH patients treated in our hospital during Mar.2010 and Apr.2021 were retrospectively analyzed. All patients underwent laparoscopic subcutaneous displacement of vascularized adrenal. The clinical symptoms, plasma free cortisol, adrenocorticotrophic hormone (ACTH), and 24 h urinary free cortisol were regularly monitored after surgery. 【Results】 Of all 20 patients, 19 were followed up for 18 to 120 months (median 60 months). Three months after surgery, reexamination showed 1 patient had decreased plasma free cortisol and increased ACTH, but had no symptoms of low corticosteroids. After another 3 months, the plasma free cortisol and ACTH returned to normal. After 4 to 48 months, the parameters recovered in all patients and the clinical symptoms disappeared. 【Conclusion】 Laparoscopic vascularized adrenal displacement is a new and effective method for the treatment of PBMAH. It can alleviate the Cushing syndrome with no obvious adverse reactions.

Objective:To compare the clinical effects of platelet-rich plasma (PRP) and sodium hyaluronate on rotator cuff injury.Methods:From February 2022 to December 2022, 226 patients with rotator cuff injury caused by military training were treated at Department of Orthopaedics, Jinling Hospital, School of Medicine, Nanjing University. They were all male, aged (24.5±3.7) years, and their time from injury to treatment was (4.6±2.2) months. They were divided into 2 even groups according to different treatments: an observation group of 113 cases into whose subacromial space PRP was injected, and a control group of 113 cases into whose subacromial space sodium hyaluronate was injected. In both groups, the injection was performed once a week for consecutive 3 weeks. The 2 groups were compared in terms of visual analogue scale (VAS) and Constant-Murley shoulder function scale (CMS) before treatment and 4 and 8 weeks after treatment, and the levels of TNF- α and IL-6 in the shoulder synovial fluid before treatment and 8 weeks after treatment. Results:There was no statistical difference between the 2 groups in general clinical data before treatment, indicating comparability ( P>0.05). At 4 and 8 weeks after treatment, compared with the pre-treatment values, the VAS scores were significantly decreased and the Constant-Murley scores significantly increased in both groups ( P<0.001). At 4 and 8 weeks after treatment, the VAS scores in the observation group (3.1±0.9 and 1.5±0.5) were significantly lower than those in the control group (3.7±0.8 and 2.3±0.6) while the Constant-Murley scores in the observation group (58.6±4.5 and 72.2±4.1) significantly higher than those in the control group (55.2±5.3 and 67.8±5.0) ( P<0.001). At 8 weeks after treatment, the levels of TNF- α and IL-6 in the 2 groups were significantly lower than the levels before treatment ( P<0.001). At 8 weeks after treatment, the levels of TNF- α and IL-6 in the observation group [(2.9±0.9) μg/L and (0.8±0.2) μg/L] were significantly lower than those in the control group [(4.0±0.4) μg/L and (1.1±0.4) μg/L] ( P<0.001). Conclusion:Injection of PRP or sodium hyaluronate can relieve pain and improve shoulder function obviously in patients with rotator cuff injury, but PRP is superior to sodium hyaluronate in the treatment of rotator cuff injury.

Osteoarthritis (OA), in which M1 macrophage polarization in the synovium exacerbates disease progression, is a major cause of cartilage degeneration and functional disabilities. Therapeutic strategies of OA designed to interfere with the polarization of macrophages have rarely been reported. Here, we report that SHP099, as an allosteric inhibitor of src-homology 2-containing protein tyrosine phosphatase 2 (SHP2), attenuated osteoarthritis progression by inhibiting M1 macrophage polarization. We demonstrated that M1 macrophage polarization was accompanied by the overexpression of SHP2 in the synovial tissues of OA patients and OA model mice. Compared to wild-type (WT) mice, myeloid lineage conditional Shp2 knockout (cKO) mice showed decreased M1 macrophage polarization and attenuated severity of synovitis, an elevated expression of cartilage phenotype protein collagen II (COL2), and a decreased expression of cartilage degradation markers collagen X (COL10) and matrix metalloproteinase 3 (MMP3) in OA cartilage. Further mechanistic analysis showed thatSHP099 inhibited lipopolysaccharide (LPS)-induced Toll-like receptor (TLR) signaling mediated by nuclear factor kappa B (NF-κB) and PI3K-AKT signaling. Moreover, intra-articular injection of SHP099 also significantly attenuated OA progression, including joint synovitis and cartilage damage. These results indicated that allosteric inhibition of SHP2 might be a promising therapeutic strategy for the treatment of OA.

Objective To find out if there is any difference in intercondylar fossa width and notch width index (NWI) between tibial intercondylar eminence avulsion fracture and anterior cruciate ligament (ACL) injury.Methods A retrospective study was conducted of the patients who had sought medical attention at Department of Sports Medicine and Adult Reconstructive Surgery,Drum Tower Hospital from June 2014 to May 2018.There were 10 patients with tibial intercondylar eminence avulsion fracture (4 males and 6 females with an average age of 32.7 ± 9.2 years),13 patients with ACL injury (8 males and 5 females with an average age of 31.8 ± 10.9 years) and 22 patients with simple meniscus injury as controls (13 males and 9 females with an average age of 30.9 ± 10.6 years).They all had MRI examination of the knee before surgery.The width of intercondylar fossa and the width and height of bilateral femoral condyles were measured on high resolution images of MRI axial view.NWI was calculated.The 3 groups were compared in intercondylar fossa width and NWI.Results The 3 groups of patients were comparable because there were no significant differences in gender,age,height,weight or BMI between them (P ＞ 0.05).The intercondylar fossa width in the ACL injury group (17.4 ± 3.5 mm) was significantly smaller than that in the avulsion fracture group (20.8 ± 1.1 mm) or in the control group (20.2 ±2.6 mm) (P ＜ 0.05),but no significant difference was detected between the avulsion fracture group and the control group (P ＞ 0.05).NWI in the avulsion fracture group (0.301 ±0.011) was similar to that in the control group (0.280 ±0.039) (P ＞ 0.05) but significantly higher than that in the ACL injury group (0.25 ± 0.05) (P ＜ 0.05).NWI in the ACL injury group was significantly lower than that in the control group (P ＜ 0.05).Conclusions Intercondylar notch stenosis may be a risk factor for ACL injury but may not be associated with tibial intercondylar eminence avulsion fracture.The difference in pathogenesis between tibial intercondylar eminence avulsion fracture and ACL injury may be associated with their difference in NWI.

Objective:To investigate the application of lateral upper arm free flap in the repair of postoperative soft tissue defects after operation in the patients with tongue cancer, and to evaluate its survival rate and repair effect. Methods:Ten patients with tongue cancer, having a desire to repair soft tissue defect after tongue cancer operation, and their systemic state could tolerate the long time operation, were selected to repair tongue cancer postoperative defects with lateral upper arm flaps. Among them, 7 cases were male, 3 cases were female;aged 45-67 years old, average 52.1 years old.Radical resection of tongue cancer was primarily finished, then the flaps were designed and prepared to repair the defects of tongue according to the location and size of defects.After the operation, the survival rate of the flap was observed, and the effect of repair was evaluated according to the shape, size, volume and movement of the tongue.Results:The lateral upper arm flaps were stable and simple to prepare, the donor sites were concealed, and the upper limbs were not abnormal.All of flaps survived, and all of wounds healed primarily.The shape, size, and texture of tongues were satisfied, and the movements of tongue were not significantly restricted.After repair, the voice, mastication and swallowing function of the patients were good without obvious influence.Conclusion:The survival rate of lateral flap of upper arm is high, and the tongue shape and function were good after tongue defect repair.It is an ideal free flap for repairing the tongue tissue defect of tongue cancer after operation.