T-cell acute lymphoblastic leukemia (T-ALL) is a highly aggressive hematologic malignancy with a poor prognosis, despite advancements in treatment. Many patients struggle with relapse or refractory disease. Investigating the role of the super-enhancer (SE) regulated gene ubiquitin-specific protease 20 (USP20) in T-ALL could enhance targeted therapies and improve clinical outcomes. Analysis of histone H3 lysine 27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) data from six T-ALL cell lines and seven pediatric samples identified USP20 as an SE-regulated driver gene. Utilizing the Cancer Cell Line Encyclopedia (CCLE) and BloodSpot databases, it was found that USP20 is specifically highly expressed in T-ALL. Knocking down USP20 with short hairpin RNA (shRNA) increased apoptosis and inhibited proliferation in T-ALL cells. In vivo studies showed that USP20 knockdown reduced tumor growth and improved survival. The USP20 inhibitor GSK2643943A demonstrated similar anti-tumor effects. Mass spectrometry, RNA-Seq, and immunoprecipitation revealed that USP20 interacted with hypoxia-inducible factor 1 subunit alpha (HIF1A) and stabilized it by deubiquitination. Cleavage under targets and tagmentation (CUT&Tag) results indicated that USP20 co-localized with HIF1A, jointly modulating target genes in T-ALL. This study identifies USP20 as a therapeutic target in T-ALL and suggests GSK2643943A as a potential treatment strategy.

Objective:To explore the clinical characteristics and related socio-demographic factors of schizo-phrenia patients with different ages of onset.Methods:Totally 2 016 patients with schizophrenia aged 15 to 70 were selected according to the diagnostic criteria for schizophrenia in the Diagnostic and Statistical Manual of Mental Disorders,Fifth Edition.All of the patients were interviewed by psychiatrists using the Mini International Neuropsy-chiatric Interview to diagnose schizophrenia,Clinical-Rated Dimensions of Psychosis Symptom Severity(CRDPSS)and the Positive and Negative Syndrome Scale(PANSS)to assess symptoms.The cut-off points were 18 and 25 years old for three age groups,i.e.early onset(EOS),youth onset(YOS)and adult onset(AOS).Statistical analy-ses were performed by analysis of variance Pearson correlation analysis,and multivariate linear regression.Results:The early-onset patients had the highest total PANSS score(73.8±28.0)and CRDPSS score(11.7±5.4).Fe-male gender,high education level,Han ethnicity,early onset age,and slower onset of illness were negatively corre-lated with the total and dimension score of PANSS scale and CRDPSS scale(standardized regression coefficient:0.04-0.47),and income level and smoking were negatively correlated with those score(standardized regression coefficient:-0.04--0.14).Conclusion:Early-onset schizophrenia patients have more severe symptoms,and fe-male,high education level,early-onset disease,and chronic onset are the risk factors of symptom severity in patients with schizophrenia.

Objective To investigate the effect of Enterococcus faecalis(E.faecalis)lipoteichoic acid(LTA)on the expression of the macrophage immune checkpoint-programmed cell death protein ligand 1(PD-L1)and explore the possible regulatory mechanisms.Methods In vitro model was established by stimulating mouse monocyte macrophage cell line(RAW264.7)with different concentra-tions of E.faecalis LTA.PD-L1 expression and nuclear factor kappa-B(NF-κB)p65 phosphorylation level were detected using flow cy-tometry,quantitative real-time polymerase chain reaction(qRT-PCR),Western blot and cellular immunofluorescence.Macrophages were pretreated with the NF-κB signaling pathway inhibitor BAY 11-7082,then the expression of PD-L1 and p65 phosphorylation level were detected by the above methods.Results LTA induced PD-L1 expression in RAW264.7 cells,and p65 phosphorylation level in-creased(P＜0.05).Inhibition of the NF-κB signaling pathway could reduce p65 phosphorylation level,simultaneously reducing the ex-pression of PD-L1 on LTA-stimulated RAW264.7 cells(P＜0.05).Conclusion E.faecalis LTA can promote the PD-L1 expression of macrophages and this process is regulated by the NF-κB signaling pathway,which provides further insights into the occurrence and treatment of chronic periapical inflammation.

Objective To observe the effects of different surgical approaches on the complications and tumor markers of patients undergoing radical resection of esophageal cancer.Method A prospective study was conducted on 100 patients with esophageal cancer who underwent radical surgery in our hospital from October 2019 to October 2022.They were randomly divided into an observation group and a control group using a random number table method,with 50 patients in each group,he right thoracic approach was used in the observation group and the left thoracic approach was used in the control group.Perioperative indexes,inflammatory factors[Substance P(SP),hypersensitive C-reactive protein(hs-CRP),interleukin6(IL-6)],tumor markers[cytokeratin 19 fragment antigen(CYFRA21-1),squamous cell carcinoma antigen(SCC-Ag)and carbohydrate antigen 199(CA199)]and lung function of the two groups were compared before and after surgery Indicators[vital capacity(VC),forced vital capacity(FVC),and forced expiratory volume in the first second(FEV1)]and complication rate.Result The operating time,blood loss,indwelling time,hospitalization time,and number of lymph node dissection in the observation group were(247.65±27.33)minutes,(211.82±25.49)ml,(6.97±2.12)days,(16.11±3.81)days,and(19.67±5.21),respectively,which were higher than those in the control group[(217.63±23.69)minutes,(175.67±22.13)ml,(5.43±1.80)days,(12.68±3.24)days,(15.45±4.12)](P＜0.05).On average,there was a significant increase in SP,hs CRP,and IL-6 levels in both groups 3 days after surgery(P＜0.05).The levels of SP,hs CRP,and IL-6 in the observation group were(273.96±35.45)ng/L,(11.35±2.12)mg/L,and(8.19±1.67)p.g/ml,respectively,which were lower than the control group[(298.33±38.42)ng/L,(14.29±2.68)mg/L,(10.35±1.82)pg/ml](P＜0.05);One month after surgery,there was a significant decrease in CYFRA21-1,SCC-Ag,and CA199 in both groups(P＜0.05),and in the observation group,the data of CYFRA21-1,SCC-Ag,and CA199 were(2.59±0.37)μg/L,(45.62±6.18)pg/L and(59.37±6.12)U/ml,respectively,which were lower than those in the control group[(3.12±0.43)μg/L,(60.27±7.35)pig/L,(63.28±6.49)U/ml](P＜0.05);One month after surgery,there was a significant decrease in VC,FVC,and FEV1 in both groups(P＜0.05).However,the VC,FVC,and FEV1 in the observation group were(67.21±8.69)％,(70.33±9.41)％,and(72.88±10.12)％,respectively,which were higher than those in the control group[(54.35±8.27)％,(61.65±8.79)％,(65.37±9.24)％](P＜0.05).There was no significant difference in the incidence of complications between the two groups(P＞0.05).Conclusion Both approaches can effectively treat esophageal cancer.Among them,the right chest approach can significantly improve the effect of lymph node dissection,inhibit inflammatory reactions,reduce tumor marker levels,and have less impact on lung function,without significantly increasing the risk of complications.However,the surgical time,bleeding volume,and postoperative recovery time are relatively long.Therefore,a suitable approach should be selected in clinical practice based on the patient's actual situation.

Cell Nucleus ; Cellular Senescence/genetics* ; CRISPR-Cas Systems/genetics*

ObjectiveTo investigate the effect of Jingui Shenqiwan on diabetic osteoporosis （DOP） in mice by regulating the advanced glycation end products （AGEs）/receptor activator of nuclear factor-κB ligand （RANKL）/nuclear factor-κB （NF-κB） signaling pathway based on the theory of "kidneys governing bones". MethodForty 6-week-old male and female skeletal-muscle-specific， dominant negative insulin-like growth factor-1 receptor （MKR） mice were selected and fed on a high-fat diet for eight weeks to establish the DOP model. The model mice were randomly divided into a model group， low- and high-dose Jingui Shenqiwan group （1.3， 2.6 g·kg^-1）， and an alendronate sodium group （0.01 g·kg^-1）， with 10 mice in each group. Additionally， 10 FVB/N mice of the same age were assigned to the normal group. The corresponding drugs were administered orally to each group once a day for four weeks. After the administration period， fasting blood glucose （FBG） measurement and oral glucose tolerance test （OGTT） were conducted. Kidney function and kidney index were measured. Renal tissue pathological changes were observed through hematoxylin-eosin （HE） and Masson staining. Immunohistochemistry was performed to assess the protein expression levels of AGEs， phosphorylated NF-κB （p-NF-κB）， and RANKL in renal tissues. Western blot analysis was conducted to measure the expression of proteins related to the AGEs/RANKL/NF-κB signaling pathway， osteoprotegerin （OPG）， and Runt-related transcription factor 2 （RUNX2） proteins in femoral bone tissues. ResultCompared with the normal group， mice in the model group exhibited significantly increased FBG （P<0.01）， trabecular bone degeneration， abnormal bone morphological parameters， significantly increased area under the curve （AUC） of OGTT （P<0.01）， enlarged kidney volume， significantly increased kidney function indicators and kidney index （P<0.01）， disrupted renal glomeruli and renal tubule structures， significantly increased expression of AGEs， RANKL， and p-NF-κB/NF-κB in renal tissues （P<0.05）， and significantly decreased expression of OPG and RUNX2 in femoral bone tissues （P<0.01）. Compared with the model group， mice in the Jingui Shenqiwan groups showed a significant decrease in OGTT AUC （P<0.01）. Histopathological analysis revealed alleviated structural lesions in renal glomeruli and renal tubules. Furthermore， the expression of AGEs， RANKL， and p-NF-κB/NF-κB in renal tissues was significantly reduced （P<0.05， P<0.01）， and the expression of RUNX2 and OPG in femoral bone tissues was significantly increased （P<0.05， P<0.01）. ConclusionJingui Shenqiwan can improve kidney function and downregulate the AGEs/RANKL/NF-κB signaling pathway to inhibit inflammatory reactions， thereby alleviating the symptoms of DOP in mice， demonstrating a therapeutic effect on DOP from the perspective of the kidney.

Objective:To investigate the distribution of intraocular pressure (IOP) in high-altitude population aged 18 years and over in Xining, Qinghai and establish the reference interval (RI) of IOP.Methods:A cross-sectional study was conducted in Xining, Qinghai Province at 2.271 km above sea level from September 2019 to May 2020.Ophthalmic examinations and IOP measurement were conducted among subjects from Physical Examination Center of Qinghai Provincial People's Hospital.The subjects who had been living in Xining without leaving for three months were enrolled.Ophthalmic examinations included vision examination, IOP measurement, slit-lamp microscopy, fundus photography, anterior and posterior segment optical coherence tomography.IOP was measured using Goldmann applanation tonometry under local anesthesia.Subjects with factors that could cause significant changes in IOP and affect the accuracy of IOP measurement, and those who were unable to receive IOP measurement were excluded.Subjects were grouped according to sex, age and ethnicity, and the distribution and RI of IOP were compared among all groups.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of Beijing Tongren Hospital, Capital Medical University (No.TRECKY2017-024). Written informed consent was obtained from each subject.Results:A total of 6 120 subjects (6 120 eyes) aged 18-90 years old were enrolled, including 2 850 males and 3 270 females with average age of (45.54±13.85) years.The average IOP of high-altitude population in Xining, Qinghai Province was (14.32±1.93) mmHg (1 mmHg=0.133 kPa), with the RI of 10.54-18.10 mmHg.The average IOP was (14.42±1.98) mmHg in male with the RI of 10.54-18.30 mmHg, (14.23±1.88) mmHg in female with the RI of 10.55-17.91 mmHg.The IOP of male was higher than that of female ( t=3.71, P<0.001). The IOP of Han, Tibetan, Hui and other nationalities were (14.38±1.91), (13.93±2.06), (14.21±1.87), (13.94±1.95) mmHg, respectively, with a statistically significant overall difference ( F=6.73, P<0.001). The IOP of Han nationality was significantly higher than that of Tibetan, Hui and other nationalities, and the differences were statistically significant (all at P<0.05). Conclusions:RI of IOP in high-altitude population from Xining, Qinghai is lower compared with normal altitude area.

Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.
Aged ; Animals ; Humans ; Aging/genetics* ; Forkhead Transcription Factors/metabolism* ; Myocytes, Cardiac/metabolism* ; Primates/metabolism* ; Repressor Proteins/metabolism* ; Transcriptome ; Macaca fascicularis/metabolism*

Objective:To explore the effect of the evidence-based practice nursing program for severe patients with physical constraints based on the guideline in Intensive Care Unit (ICU) patients.Methods:From February 2019 to July 2020, 4 663 patients in the Surgical Intensive Care Unit (SICU), Medicine Intensive Care Unit (MICU), Coronary Care Unit (CCU), and Emergency Intensive Care Unit (EICU) of the China-Japan Friendship Hospital were selected as the research object by purposive sampling. The evidence-based practice nursing program for severe patients with physical constraints based on the guideline of Promoting Safety: Alternative Approaches to the Use of Restraints was applied in clinical practice. We recorded the constraint duration, constraint rate, and substitution constraint rate of severe patients after the implementation of the program, and compared the differences in ICU nurses' scores on physical constraint knowledge, attitude, and practice before and after the implementation of the program. Results:Out of 4 663 patients, 871 received restraint, with a restraint rate of 18.68% and a restraint duration of (102.35±82.67) hours. The number of substitution constraint cases was 421, and the substitution constraint rate was 9.03%. The constraint rates in SICU, MICU, CCU and EICU were 23.68% (475/2 006), 28.26% (219/775), 7.29% (97/1 331) and 14.52% (80/551), respectively, and the differences in constraint rates among different departments were statistically significant ( P<0.05). Before and after the implementation of the program, there were statistically significant differences in the scores of ICU nurses on physical constraint knowledge, attitude, and practice dimensions and total scores ( P<0.05) . Conclusions:The evidence-based practice nursing plan program for severe patients with physical constraints based the guideline effectively reduces the rate and duration of physical constraint of ICU patients, improves the substitution constraint rate, standardizes the practice of physical constraint of ICU patients, and ensures patient safety.

Objective: This study was devoted to identifying natural thrombin inhibitors from traditional Chinese medicine (TCM) and evaluating its biological activity in vitro and binding characteristics. Methods: A combination strategy containing molecular docking, thrombin inhibition assay, surface plasmon resonance (SPR) and molecular dynamics simulation were applied to verify the study result. Results: Gallic acid was confirmed as a direct thrombin inhibitor with IC