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

Aim To evaluate the bioequivalence of two oral preparations of rivaroxaban tablets(test preparation T and refe-rence preparation R)in fasting/postprandibular state in healthy Chinese subjects.Methods A randomized,open,single-dose,four-cycle,completely repeated crossover experiment was used in this study.A total of 70 healthy male and female subjects were enrolled,including 38 subjects in the fasting group and 32 sub-jects in the postprandial group.Rivaroxaban tablets(2.5 mg/tablet)were taken orally once per cycle and their reference preparations were tested.The plasma rivaroxaban concentration was determined by LC-MS/MS method.The pharmacokinetic parameters of rivaroxaban tablets were calculated by WinNonlin software,and the parameters were analyzed and processed.Re-sults The PK parameters of rivaroxaban tablets and reference preparations in fasting group were as follows:Cmax was(72.48±17.08)and(66.36±15.64)μg·L-1,respectively.AUC0-t were(383.49±101.06)and(370.43±102.16)h·ng·mL-1,and AUC0-inr were(389.58±102.28)and(375.84±103.01)h·μg·L-,respectively.Main PK parameters of subjects taking rivaroxaban tablets orally after meals:Cmax were(66.48±15.64 and 60.87±13.44)μg·L-1,AUC0-t were(404.44±72.58)and(381.80±79.93)h·μg·L-1,re-spectively.AUC0_inf was(410.88±73.55)and(393.64±69.71)h·μg·L-1,respectively.Under fasting and postmeal conditions,subjects took rivaroxaban test and reference prepara-tion orally,one tablet(2.5 mg/tablet)each time.The geometric mean of the main pharmacokinetic parameters of rivaroxaban in plasma(Cmax,AUC0-t,AUC0-inf)and their corresponding values had a 90％confidence interval ranging from 80.00％to 125.00％.No serious adverse events or unexpected adverse e-vents occurred in both groups.Conclusion Rivaroxaban tablets are bioequivalent and safe in vivo under fasting and postprandial conditions.

Aim To evaluate the bioequivalence of two oral preparations of rivaroxaban tablets(test preparation T and refe-rence preparation R)in fasting/postprandibular state in healthy Chinese subjects.Methods A randomized,open,single-dose,four-cycle,completely repeated crossover experiment was used in this study.A total of 70 healthy male and female subjects were enrolled,including 38 subjects in the fasting group and 32 sub-jects in the postprandial group.Rivaroxaban tablets(2.5 mg/tablet)were taken orally once per cycle and their reference preparations were tested.The plasma rivaroxaban concentration was determined by LC-MS/MS method.The pharmacokinetic parameters of rivaroxaban tablets were calculated by WinNonlin software,and the parameters were analyzed and processed.Re-sults The PK parameters of rivaroxaban tablets and reference preparations in fasting group were as follows:Cmax was(72.48±17.08)and(66.36±15.64)μg·L-1,respectively.AUC0-t were(383.49±101.06)and(370.43±102.16)h·ng·mL-1,and AUC0-inr were(389.58±102.28)and(375.84±103.01)h·μg·L-,respectively.Main PK parameters of subjects taking rivaroxaban tablets orally after meals:Cmax were(66.48±15.64 and 60.87±13.44)μg·L-1,AUC0-t were(404.44±72.58)and(381.80±79.93)h·μg·L-1,re-spectively.AUC0_inf was(410.88±73.55)and(393.64±69.71)h·μg·L-1,respectively.Under fasting and postmeal conditions,subjects took rivaroxaban test and reference prepara-tion orally,one tablet(2.5 mg/tablet)each time.The geometric mean of the main pharmacokinetic parameters of rivaroxaban in plasma(Cmax,AUC0-t,AUC0-inf)and their corresponding values had a 90％confidence interval ranging from 80.00％to 125.00％.No serious adverse events or unexpected adverse e-vents occurred in both groups.Conclusion Rivaroxaban tablets are bioequivalent and safe in vivo under fasting and postprandial conditions.

OBJECTIVE To study the improvement effects of Shangke xiaoyan hydrogel plaster on osteoarthritis （OA） model rats. METHODS Rats were randomly divided into blank group， model group， voltaren group （200 mg/rat）， Shangke xiaoyan ointment group （500 mg/rat， containing Shangke xiaoyan fluid extract 50 mg） and Shangke xiaoyan hydrogel plaster group （200 mg/rat， containing Shangke xiaoyan fluid extract 50 mg）， with 8 rats in each group. Except for blank group， OA model was established in the other groups by injecting papain and L-cysteine into the right knee joint cavity of the rats； they applied the corresponding drugs， and changed the dressing once a day， for 14 consecutive days. The degree of knee joint swelling in rats was detected， and the magnetic resonance imaging characteristics of the knee joint in rats were observed； the levels of interleukin 1β （IL-1β）， IL-6， IL-18 and tumor necrosis factor （TNF- α） in rat serum were detected； the pathological and morphological characteristics of knee joint tissue were observed， and the histopathological and cartilage Mankin scores were performed； the protein expressions of IL-1β， IL-6 and TNF-α in knee joint tissue were all detected. RESULTS Compared with blank group， severe joint swelling， obvious joint effusion and patchy wear of the anterior horn of the lateral meniscus were observed in model group； the serum levels of IL-1β， IL-6， IL-18 and TNF- α and histopathological score and Mankin score were significantly increased （P＜0.05）； protein expressions of IL-1β， IL-6 and TNF-α in knee joint tissue were increased. Compared with model group， the knee swelling degree of the rats in Shangke xiaoyan hydrogel plaster group was reduced， a small amount 　　 of joint cavity effusion could be seen， and the shape of the meniscus was completely normal； the histopathological score E-mail：frankyan@cpu.edu.cn and Mankin score were significantly reduced （P＜0.05）levels of inflammatory factors in serum were reduced （P＜0.05） and those of knee tissue were decreased. CONCLUSIONS Shangke xiaoyan hydrogel plaster can improve OA of rats， the mechanism of which may be associated with reducing the levels of inflammatory factors in joint and serum.

Genetic risk factors have been shown to contribute to the development of sexual dysfunction. However, the role of methylenetetrahydrofolate reductase (MTHFR) gene variants in the risk of erectile dysfunction (ED) remains unclear. In this study, we recruited 1254 participants who underwent ED assessed by the International Index of Erectile Function-5. The MTHFR c.677C>T variant was also measured by fluorescence polymerase chain reaction (PCR). No significant difference in the genotypic frequency of the MTHFR C677T polymorphism (CC, CT, and TT) was observed between men from the ED and non-ED groups. In addition, on binary logistic regression analysis, both crude and adjusted models showed that the risk of ED was not significantly associated with the C677T polymorphism. Interestingly, a significantly higher frequency of the 677TT polymorphism was found in severe and moderate ED (P = 0.02). The positive correlation between the MTHFR 677TT polymorphism and severe ED was confirmed by logistic regression analysis, even after adjusting for potential confounders (odds ratio [OR] = 2.46, 95% confidence interval [CI]: 1.15-5.50, P = 0.02). These findings suggest a positive correlation between the MTHFR 677TT polymorphism and the risk of severe ED. Identification of MTHFR gene polymorphisms may provide complementary information for ED patients during routine clinical diagnosis.

As an important intracellular genetic and regulatory center, the nucleus is not only a terminal effector of intracellular biochemical signals, but also has a significant impact on cell function and phenotype through direct or indirect regulation of nuclear mechanistic cues after the cell senses and responds to mechanical stimuli. The nucleus relies on chromatin-nuclear membrane-cytoskeleton infrastructure to couple signal transduction, and responds to these mechanical stimuli in the intracellular and extracellular physical microenvironments. Changes in the morphological structure of the nucleus are the most intuitive manifestation of this mechanical response cascades and are the basis for the direct response of the nucleus to mechanical stimuli. Based on such relationships of the nucleus with cell behavior and phenotype, abnormal nuclear morphological changes are widely used in clinical practice as disease diagnostic tools. This review article highlights the latest advances in how nuclear morphology responds and adapts to mechanical stimuli. Additionally, this article will shed light on the factors that mechanically regulate nuclear morphology as well as the tumor physio-pathological processes involved in nuclear morphology and the underlying mechanobiological mechanisms. It provides new insights into the mechanisms that nuclear mechanics regulates disease development and its use as a potential target for diagnosis and treatment.
Cell Nucleus ; Biophysics ; Cytoskeleton ; Phenotype ; Signal Transduction

The current development situation and the hotspot of the relevant research on refractory facial paralysis are explored. The articles on refractory facial paralysis are retrieved from CNKI database. The bibliographic items co-occurrence matrix builder (BICOMB) 2.0 is adopted to extract and analyze statistically literature characteristics and generate the high-frequency keywords matrix. The graphical clustering toolkit (gCLUTO) 1.0 is used to cluster the high-frequency keywords. A total of 750 articles are included, mostly published in
Acupuncture Points ; Acupuncture Therapy ; Bibliometrics ; China ; Facial Paralysis/therapy* ; Humans ; Moxibustion

BACKGROUND: Coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread throughout the world. In this study, we aimed to identify the risk factors for severe COVID-19 to improve treatment guidelines. METHODS: A multicenter, cross-sectional study was conducted on 313 patients hospitalized with COVID-19. Patients were classified into two groups based on disease severity (nonsevere and severe) according to initial clinical presentation. Laboratory test results and epidemiological and clinical characteristics were analyzed using descriptive statistics. Univariate and multivariate logistic regression models were used to detect potential risk factors associated with severe COVID-19. RESULTS: A total of 289 patients (197 nonsevere and 92 severe cases) with a median age of 45.0 (33.0, 61.0) years were included in this study, and 53.3% (154/289) were male. Fever (192/286, 67.1%) and cough (170/289, 58.8%) were commonly observed, followed by sore throat (49/289, 17.0%). Multivariate logistic regression analysis suggested that patients who were aged ≥ 65 years (OR: 2.725, 95% confidence interval [CI]: 1.317-5.636; P = 0.007), were male (OR: 1.878, 95% CI: 1.002-3.520, P = 0.049), had comorbid diabetes (OR: 3.314, 95% CI: 1.126-9.758, P = 0.030), cough (OR: 3.427, 95% CI: 1.752-6.706, P < 0.001), and/or diarrhea (OR: 2.629, 95% CI: 1.109-6.231, P = 0.028) on admission had a higher risk of severe disease. Moreover, stratification analysis indicated that male patients with diabetes were more likely to have severe COVID-19 (71.4% vs. 28.6%, χ2 = 8.183, P = 0.004). CONCLUSIONS The clinical characteristics of those with severe and nonsevere COVID-19 were significantly different. The elderly, male patients with COVID-19, diabetes, and presenting with cough and/or diarrhea on admission may require close monitoring to prevent deterioration.
Adult ; COVID-19/pathology* ; China/epidemiology* ; Comorbidity ; Cough ; Cross-Sectional Studies ; Diarrhea ; Female ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Risk Factors

Urea transporters (UT) play a vital role in the mechanism of urine concentration and are recognized as novel targets for the development of salt-sparing diuretics. Thus, UT inhibitors are promising for development as novel diuretics. In the present study, a novel UT inhibitor with a diarylamide scaffold was discovered by high-throughput screening. Optimization of the inhibitor led to the identification of a promising preclinical candidate,