As a severe clinical manifestation of nonalcoholic fatty liver disease， nonalcoholic steatohepatitis （NASH） is characterized by lipid deposition and inflammatory damage in the liver. At present， clinical medications for NASH are still in the exploratory phase， and it is urgent to make progress. Recent studies have shown that the pathogenesis of NASH is associated with circadian rhythm disorders in the liver， with the specific manifestation of dysregulated expression of liver clock genes such as BMAL1， which increases hepatic lipogenesis， reduces fatty acid oxidation， and activates pro-inflammatory factors. Therefore， improving circadian rhythm of the liver and regulating the expression of liver clock genes are feasible strategies for the prevention and treatment of NASH. Currently， some medications for NASH via activating the proteins encoded by clock genes have been applied in animal experiments， for example， the REVERB full-agonist SR9009 can inhibit the development of liver inflammation， which confirms the possibility of NASH treatment by targeting the proteins encoded by clock genes. This article summarizes the role of hepatic clock genes in regulating lipid metabolism and the development and progression of inflammation in the liver and elaborates on the recent advances in medications targeting clock genes and the proteins encoded by clock genes， in order to provide new targets for the treatment of NASH.

Objective To analyze the clinical outcomes of early invasive fungal disease(IFD)in patients after allogenetic hematopoietic stem cell transplantation(allo-HCST)with metagenomic next-generation sequencing(mNGS).Methods A retrospective analysis was conducted on patients undergoing allo-HCST in our Bone Marrow Transplantation Center between July 2021 and October 2022.These patients experienced one of the following conditions within 100 d after transplantation:① Patients with persistent fever and negative blood culture after empiric antimicrobial therapy for 72 h or longer;② Hyperpyrexia of unknown origin occurred again after effective anti-infection in the past;③ Symptoms in lower respiratory tract associated with lung lesions on CT scan,and empiric anti-infective therapy was ineffective.Peripheral blood or bronchoscopic alveolar lavage fluid were tested with mNGS,and overall survival(OS)and non-relapse mortality(NRM)were analyzed.Results There were 60 patients enrolled in this study.For the peripheral blood samples of 47 cases and bronchoalveolar lavage fluid samples of 13 cases,mNGS found that 19 cases were negative to pathogens,30 cases were non-fungal positive,and 11 case were fungal positive,including 3 cases of aspergillus,5 cases of mucor,2 cases of Candida tropicalis,and 1 case of Trichosporon asahii.Of the 11 patients with fungal positive,8 achieved complete remission after antifungal therapy according to the mNGS results.The 1-year OS and NRM of the 60 patients were 70.0％(95％CI:64.1％～75.9％)and 20.0％(95％CI:11.9％～32.5％),respectively,while those of the fungal infection patients were 54.5％(95％CI:49.5％～69.5％)and 36.4％(95％ CI:15.5％～70.3％),respectively.No significant differences were seen in 1-year OS(P=0.487)and 1-year NRM(P=0.358)among the negative,fungal infection and non-fungal infection patients,neither OS(P=0.238)and NRM(P=0.154)between the fungal infection and the non-fungal infection patients.Conclusion mNGS can rapidly diagnose the early IFD after allo-HSCT,which is helpful for timely and effective treatment and improves the prognosis of patients.

The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (M^pro) and papain like protease (PL^pro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851M^pro inhibitors and 205 PL^pro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both M^pro and PL^pro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of M^pro inhibitors and over 20% of PL^pro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 M^pro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Humans ; Antiviral Agents/chemistry* ; COVID-19 ; COVID-19 Drug Treatment ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Protease Inhibitors/chemistry* ; SARS-CoV-2/enzymology* ; Viral Nonstructural Proteins

Aldolase B (ALDOB), a glycolytic enzyme, is uniformly depleted in clear cell renal cell carcinoma (ccRCC) tissues. We previously showed that ALDOB inhibited proliferation through a mechanism independent of its enzymatic activity in ccRCC, but the mechanism was not unequivocally identified. We showed that the corepressor C-terminal-binding protein 2 (CtBP2) is a novel ALDOB-interacting protein in ccRCC. The CtBP2-to-ALDOB expression ratio in clinical samples was correlated with the expression of CtBP2 target genes and was associated with shorter survival. ALDOB inhibited CtBP2-mediated repression of multiple cell cycle inhibitor, proapoptotic, and epithelial marker genes. Furthermore, ALDOB overexpression decreased the proliferation and migration of ccRCC cells in an ALDOB-CtBP2 interaction-dependent manner. Mechanistically, our findings showed that ALDOB recruited acireductone dioxygenase 1, which catalyzes the synthesis of an endogenous inhibitor of CtBP2, 4-methylthio 2-oxobutyric acid. ALDOB functions as a scaffold to bring acireductone dioxygenase and CtBP2 in close proximity to potentiate acireductone dioxygenase-mediated inhibition of CtBP2, and this scaffolding effect was independent of ALDOB enzymatic activity. Moreover, increased ALDOB expression inhibited tumor growth in a xenograft model and decreased lung metastasis in vivo. Our findings reveal that ALDOB is a negative regulator of CtBP2 and inhibits tumor growth and metastasis in ccRCC.
Humans ; Carcinoma, Renal Cell/genetics* ; Fructose-Bisphosphate Aldolase/metabolism* ; Co-Repressor Proteins/metabolism* ; Transcription Factors/genetics* ; Kidney Neoplasms/genetics* ; Cell Line, Tumor ; Cell Proliferation/genetics* ; Gene Expression Regulation, Neoplastic

Cardiovascular diseases (CVDs) and metabolic disorders are major components of noncommunicable diseases, causing an enormous health and economic burden worldwide. There are common risk factors and developmental mechanisms among them, indicating the far-reaching significance in exploring the corresponding therapeutic targets. MST1/2 kinases are well-established proapoptotic effectors that also bidirectionally regulate autophagic activity. Recent studies have demonstrated that MST1/2 influence the outcome of cardiovascular and metabolic diseases by regulating immune inflammation. In addition, drug development against them is in full swing. In this review, we mainly describe the roles and mechanisms of MST1/2 in apoptosis and autophagy in cardiovascular and metabolic events as well as emphasis on the existing evidence for their involvement in immune inflammation. Moreover, we summarize the latest progress of pharmacotherapy targeting MST1/2 and propose a new mode of drug combination therapy, which may be beneficial to seek more effective strategies to prevent and treat CVDs and metabolic disorders.

Objective:To evaluate the rehabilitation efficacy of early mobilization based on collaboration care model for patients with laparoscopic colorectal surgery.Methods:Cluster sampling method was used in the department to recruit colorectal cancer patients with laparoscopic surgery. The control group (49 cases) received routine perioperative care and exercise, and the intervention group (47 cases) received the coordinated early mobilization combined with routine perioperative care and exercise, from January to March 2019. Primary outcome were health status and the proportion of patients returning to preoperative functional walking capacity (6-min walk test) at 4 weeks after surgery. The in-hospital mobilization (time out-of-bed), time to achieve discharge criteria, time to recover gastrointestinal function and complication rate were explored.Results:In intervention group,89.4%(42/47) of patients achieved mobilization target on 4 days after surgery compared with 42.6%(20/47) on the day of surgery. Time out of bed were greater in the intervention group compared with the control group, and there were differences between the two groups( Z values were -8.437--7.381, P<0.01). Time to recover gastrointestinal function and the recovery of energy on 3 days after surgery were (58.74±17.41) h, (59.02±9.46) points in the observation group, and (71.82±21.53) h, (62.61±7.68) points in the control group, and there were significant differences between the two groups ( t values were -3.263, -2.046, P<0.05). But other outcome measures were not different between the two groups ( P>0.05). Conclusions:For colorectal laparoscopic surgery patients, the coordinated early mobilization improved the adherence to ambulation, in-hospital mobilization, time to recover gastrointestinal function and recovery of energy to promote rehabilitation.

Objective: To evaluate the clinical performance of HPV genotyping with cytology for detecting cervical precancer among women attending co-testing. Methods: A total of 2 883 females who participated in cervical cancer screening program were recruited from Erdos in 2016. All the participants were tested by cytology and HPV genotyping. In 2017, women with abnormal cytology results or HPV positive were followed up. Pathological cervical intraepithelial neoplasia (CIN) 2+ was the study end-point. Clinical performance indexes were calculated, including sensitivity, specificity, positive predictive value, negative predictive value, referral rate and missed cases. Results: INNO-LiPA resulted in a detection rate of 18.87%(544/2 883) for the 14-type high risk HPV. HPV16 was the most common infectious genotype (4.06%), followed by HPV52 (3.61%), HPV51 (2.50%), HPV58 (1.98%), and HPV18 (1.56%). With more HPV genotypes added into the group, sensitivity increased and the specificity decreased. Addition of HPV16, 58, 33, 39, 52, 18, 31 for detection lead to the maximun value of area under the curve (AUC)=0.913 (95%CI: 0.882-0.944). Compared with traditional screening method by cytology, cotesting decreased the number of missed diagnosis. Meanwhile, the fifth method (co-testing: triage of women with HPV16/18+ , cytological minor abnormalities and HPV58, 33, 39, 52, 31+ or cytological high grade abnormalities) did not increase referral rate (8.99% vs. 8.71%, P=0.525), with five cases of missed diagnosis (sensitivity of 92.1% and specificity of 93.2%). Conclusions Co-testing with triage of women with HPV16/18+ , cytological minor abnormalities and HPV58, 33, 39, 52, 31+ or cytological high grade abnormalities would provide better clinical performance. In co-testing, triage of HPV16/18 was used in women with normal cytology; triage of HPV58, 33, 39, 52 and 31 was used in women with low-grade abnormal cytology; referral colposcopy was used in women with high-grade abnormal cytology, which would provide better clinical performance.

Objective To study plasmid-mediated transfer,plasmid replicon typing,and genetic environment of blaNDM-1 gene in Enterobacteraerogenes(E.aerogenes).Methods E.aerogenes HN-NDM0711 was used as the subject of this research,the transferable properties of plasmid were analyzed by conjugation testing,conjugant was performed stability testing,plasmid type was determined by PCR-based replicon typing (PBRT),downstream and upstream of blaNDM-1 were sequenced using chromosome walking method,genetic context was analyzed by BLASTN and BALSTP,as well as annotated using Vector NTI 11.5.1 software,sequence pipeline graph was made,the sequence was submitted to Genbank through software Banklt.Results The conjugation testing of E.aerogenes pHN-NDM0711 was positive,after positive conjugant was conducted 4-day passage,minimal inhibitory concentrations (MICs) of imipenem and meropenem to all the cloned strains didn't change,blaNDM-1 were all positive.The replicon type was IncA/C;blaNDM-1 gene was localized between ISAba14 and IS91,at upstream of the blaNDM-1,class 1 integron and Tn3 transposon were identified,class 1 integron contained a new mosaic structure of a drug-resistant resistance gene cassette.Conclusion E.aerogenes pHN-NDM071 1,bearing blaNDM-1 gene in IncA/C plasmid,derived from gene recombination under different antimicrobial selection pressure.Antimicrobial use in clinical,industrial and agricultural area should be strictly controlled,so as to reduce the emergence of such bacteria.

Neurology is one of the most difficult subjects in clinical medical education.How to improve the teaching model of neurology is a crucial problem.The systematic instructional design and problem-based learning (PBL) emerge as mature teaching techniques,and having a broad application prospect.However,simple PBL teaching model has not achieved the desired results,because PBL teaching method pays excessive attention to the subjective initiative of students,but ignores the supervision and assessment mechanisms,such as assessment,feedback,adjustment,which are the major concerns of systematic instructional design.This research tries to combine systematic instructional design with PBL teaching model,and explore the position in neurology teaching.By determining the teaching target,analysis of PBL teaching,writing teaching plans,organization of PBL teaching,feedback to adjust teaching design method,the final summative evaluation is done and the teaching,was completed.After practice tips may bring progress on neurology teaching mode.

Ginsenoside Rb3 (GRb3) is one of the main components in plasma of Panax quinquefolius Saponin of stem and leaf (PQS), which can be into human plasma. Previous studies have found PQS has estrogen-like vascular protective effects. In the present study, we investigated the estrogen-like protective effect of GRb3 on oxidative stress and dysfunction of endothelial cells induced by oxidized low-density lipoprotein. The activities of SOD, NOS and the contents of MDA in the cell lysate were examined by enzyme method or spectrophotometry. The NO and ET-1 concentrations in the cell culture supernatant were measured by ELISA method. The iNOS and eNOS mRNA expression were measured by real time RT-PCR, while the phosphorylation levels of Akt was measured by Western blotting. The results showed that GRb3 could enhance the activity of SOD, reduce the content of MDA, increase the level of NOS, NO, ET-1 and iNOS mRNA expression while decrease the eNOS mRNA expression and the phosphorylation level of Akt. These effects were blocked by estrogen receptor antagonist ICI182780. GRb3 can play a role in protecting vascular endothelial cells by estrogen receptors, the protective mechanism is similar to 17-β estrodiol.