Cyclin-dependent kinase 9 (CDK9) is a member of the transcription CDK subfamily and plays a role in transcriptional regulation. Selective CDK9 degraders possess potent clinical advantages over reversible CDK9 inhibitors. Herein, we report the first ATG101-recruiting selective CDK9 degrader, AZ-9, based on the hydrophobic tag kinesin degradation technology. AZ-9 showed significant degradation effects and selectivity toward other homologous cell cycle CDKs in vitro and in vivo, which could also affect downstream related phenotypes. Mechanism research revealed that AZ-9 recruits ATG101 to initiate the autophagy-lysosome pathway, and forms autophagosomes through the recruitment of LC3, which then fuses with lysosomes to degrade CDK9 and the partner protein Cyclin T1. These dates validated the existence of non-proteasomal degradation pathway of hydrophobic driven protein degradation strategy for the first time, which might provide research ideas for chemical induction intervention on other types of pathogenic proteins.

[This corrects the article DOI: 10.1016/j.apsb.2021.08.008.].

Oleanolic acid (OA), a pentacyclic triterpenoid, exhibits a broad spectrum of biological activities, including antitumor, antiviral, antibacterial, anti-inflammatory, hepatoprotective, hypoglycemic, and hypolipidemic effects. Since its initial isolation and identification, numerous studies have reported on the structural modifications and pharmacological activities of OA and its derivatives. Despite this, there has been a dearth of comprehensive reviews in the past two decades, leading to challenges in subsequent research on OA. Based on the main biological activities of OA, this paper comprehensively summarized the modification strategies and structure-activity relationships (SARs) of OA and its derivatives to provide valuable reference for future investigations into OA.
Oleanolic Acid ; Structure-Activity Relationship ; Anti-Inflammatory Agents/pharmacology* ; Triterpenes ; Anti-Bacterial Agents/pharmacology*

Critical care medicine-related treatment is an interdisciplinary and multi-professional process,often leading to secondary or concomitant mental disorders in clinical practice.Currently,there is no consensus on the pharmacological treatment of related mental illnesses in China.The Chinese Society of Psychosomatic Medicine collaborated with the Critical Care Medicine expert group to form a consensus writing expert group.After a systematic review of relevant literature,summarizing published domestic and foreign literature,and extensive discussions,the consensus was developed.The consensus elaborates on the principles and processes of the standardized use of psychotropic drugs in critical care medicine,as well as the clinical indications,precautions,and specific drug selection of various psychiatric medications,providing feasible suggestions and guidance for the clinical application of psychiatric medications in the intensive care unit.

Intestinal dysbiosis and disrupted bile acid(BA)homeostasis are associated with obesity,but the precise mechanisms remain insufficiently explored.Hepatic protein phosphatase 1 regulatory subunit 3G(PPP1R3G)plays a pivotal role in regulating glycolipid metabolism;nevertheless,its obesity-combatting potency remains unclear.In this study,a substantial reduction was observed in serum PPP1R3G levels in high-body mass index(BMI)and high-fat diet(HFD)-exposed mice,establishing a positive correlation between PPP1R3G and non-12α-hydroxylated(non-12-OH)BA content.Additionally,hepatocyte-specific overexpression of Ppp1r3g(PPP1R3G HOE)mitigated HFD-induced obesity as evidenced by reduced weight,fat mass,and an improved serum lipid profile;hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology.PPP1R3G HOE considerably impacted systemic BA homeostasis,which notably increased the non-12-OH BAs ratio,particularly lithocholic acid(LCA).16S ribosomal DNA(16S rDNA)sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population,and elevating the relative abundance of Blautia,which exhibited a positive correlation with serum LCA levels.A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent.Mechanistically,PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase(CYP7A1)and sterol-12α-hydroxylase(CYP8B1),and concurrently upregulated oxysterol 7-α hydroxylase and Takeda G protein-coupled BA receptor 5(TGR5)expression under HFD conditions.Furthermore,LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels.These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis,which may serve as potential ther-apeutic targets for obesity-related disorders.

Objective: To analyze the status of noise hazard in workplace of key industries in Guangdong Province. Methods: A total of 1 061 enterprises from 14 key industries in 21 prefecture-level cities in Guangdong Province were selected as the research subjects using stratified sampling method. The occupational health survey was carried out, and the noise intensity in the workplace was detected. Results: There were 12 606 workplaces and 5 570 work sites involved among 1 061 enterprises. The median and the 0-100th percentile value ［M (P₀-P₁₀₀)］ of noise intensity in workplace were 82.6 (46.5-112.6) dB(A), and 35.03% of the workplace exceeded the national noise intensity standard. The regions and industry with the highest rate of noise exceeded the national noise intensity standard in workplace were in the northern part of Guangdong and the stone processing industry respectively. The M (P₀-P₁₀₀) of noise intensity in the work sites was 83.7 (47.5-106.2) dB(A), and 36.00% of the work sites exceeded the national noise intensity standard. The regions and industry with the highest rate of noise exceeded the national noise intensity standard in work sites were in the Pearl River Delta region and the ferrous metal mining and dressing industry respectively. The rate of noise protection facilities setting was 66.45%, and the validity of personal protection was 61.73%. The occupational medical examination was performed in 73.24% of the research subjects, and 3.25% of the result was abnormal. The industry with the highest occupational medical examination rate was nonferrous metal smelting and rolling processing, and the industry with the highest abnormal rate of occupational medical examination was stone processing industry. Conclusion: Noise hazards in workplaces of key industries in Guangdong Province are relatively severe, necessitating strengthened supervision and management, noise control measures, and efforts to reduce noise exposure levels in workplaces and work sites.

Objective To investigate the level of finger systolic blood pressure (FSBP) in healthy young adults. Methods A total of 28 healthy young adults were selected as the study subjects by convenient sampling method. The FSBP of the study subjects was detected at 30 and 10 ℃, and the FSBP index (F_i) was calculated. Results The FSBP of the study subjects at 30 and 10 ℃ were (102.0±16.5) and (104.4±15.2) mmHg, respectively. The FSBP in male group at 30 and 10 ℃ was (99.6±18.6) and (107.2±17.0) mmHg, respectively. The FSBP in female group at 30 and 10 ℃ was (104.4±13.9) and (101.5±2.8) mmHg, respectively. The results of factorial analysis showed that the interaction between gender and temperature on FSBP was statistically significant (P<0.05). FSBP in male group was higher at 10 than 30 ℃ (P<0.05) and higher than female group at 10 ℃ (P<0.05). There was no statistical significance for the main effect of gender, temperature, finger, or the interaction effect of gender and finger, temperature and finger for FSBP (all P>0.05). The average F_i of the study subjects was (98.0±16.6)%, with males and females having the average F_i of (100.7±20.7) % and (95.2±10.6) % respectively. The results of factorial analysis of variance showed that there was no significant difference on F_i in the main effect gender and fingers or the interaction effect between them(all P>0.05). Conclusion The FSBP test could be used as a detection method for assessing peripheral microcirculation function in Chinese population. However, further research is needed to establish reference ranges and influencing factors.

Humans ; Aripiprazole/therapeutic use* ; Schizophrenia/drug therapy* ; Antipsychotic Agents/therapeutic use* ; Risperidone ; China ; Treatment Outcome

Objective:To explore the clinical diagnosis and treatment methods and curative effect of retroperitoneal ganglioneuromaMethods:The clinical data of 32 cases of retroperitoneal ganglioneuroma admitted to Peking University International Hospital from Apr 2015 to May 2022 were retrospectively analyzed, and their clinical characteristics, surgical efficacy and prognosis were discussed.Results:Of the 32 patients with retroperitoneal ganglioneuroma, 17 had no obvious clinical symptoms, 7 complained abdominal distension and pain, 6 had lower back pain, and 2 had abdominal mass. Tumors were located near the adrenal and renal regions in 18 cases, on both sides of the spine below the kidneys in 11 cases, and in the pelvis in 3 cases. tumors were single in 28 cases, multiple in 4 cases.Tumors were surrounded by major blood vessels in 12 cases. R 0 or R 1 resection was carried out in 27 cases, and palliative R 2 resection in 5 cases, combined organ resection in 6 cases, and piecemed resection in 8 cases. The maximum tumor diameter was (13.2±4.9)cm, the intraoperative blood loss was 500 (50-6 000 ml), and 6 cases suffered from major postoperative complications. Between patients with tumors encircling and encroaching major blood vessels or not, there were significant differences in age, intraoperative blood loss, R 2 resection rate, and pieceneal resection rate between the two groups ( t=2.44, P=0.021; Z=2.37, P=0.018; χ2=4.57, P=0.033; χ2=11.38, P=0.001). There was no recurrence in patients with R 0 or R 1 resection. Conclusions:The prognosis of complete resection of retroperitoneal ganglioneuroma is good .Major blood vessels encroachment of the tumor often leads to incomplente (R 2) resection.

Objective:To identify the risk factors for functional delayed gastric emptying(FDGE)after retroperitoneal tumor resection.Meth-ods:Sixty-seven patients with postoperative FDGE after retroperitoneal tumor resection from September 2017 to December 2022 admited in Peking University International Hospital were included in the observation group,and 836 normal patients who underwent ret-roperitoneal tumor resection during the same period were included in the control group.Medical histories and clinical treatment data were obtained for each group and compared to identify the risk factors for FDGE after retroperitoneal tumor resection.Results:The overall incid-ence of postoperative FDGE was 7.42%.Factors that were significantly elevated(P<0.05)in the observation group relative to the control group included adverse mental factors(37.31%),preoperative digestive tract obstruction(41.79%),postoperative abdominal cavity complic-ations(79.10%),diabetes(29.86%),average age of(61.85±6.11)years,and blood loss(1 011.94±507.30)mL.Pre-and post-surgery albumin levels[(38.22±3.75)g/L and(30.22±3.36)g/L,respectively]were significantly reduced(P<0.05)in the observation group compared to the control group.Risk factor analyses revealed that advanced age,diabetes,preoperative digestive tract obstruction,intraoperative blood loss,perioperative albumin level,postoperative abdominal cavity complications,and adverse mental factors were correlated with postoperative FDGE.Conclusions:Diverse factors could impact the risk of FDGE after retroperitoneal tumor resection.Patients should be accurately evalu-ated;reasonable and detailed prevention and treatment plans should be developed.