Objective: To analyze the burden of bipolar disorder among adolescents aged 10-24 in China from 1990 to 2021 and its trend of change, so as to provide theoretical basis for the prevention and treatment of bipolar disorder. Methods: The latest data from the Global Burden of Disease (GBD) database in 2021 were selected. The Joinpoint regression model, age-period-cohort (APC) model, and bayesian age-period-cohort (BAPC) model were used to analyze and predict indicators such as the age standardized incidence rate and age standardized disability adjusted life year (DALY) rate of bipolar disorder among Chinese adolescents, and the average annual percent change (AAPC) was calculated. Results: From 1990 to 2021, the overall age standardized incidence rate (1990:22.92/100 000, 2021:23.17/100 000) showed an upward trend ( AAPC=0.03, t=8.20, P <0.01) and change trend of age standardized DALY rate (1990:33.61/100 000, 2021:33.76/100 000) was relatively flat ( AAPC=0.01, t= 0.99 , P =0.32). From 1990 to 2021, age standardized incidence rate and age standardized DALY rate of girls were higher than boys ( χ 2=16.38, P <0.01). The net drift values for the incidence rate and DALY rate of bipolar disorder among Chinese adolescents aged 10-24 years were -0.23% and -0.22%, respectively. The highest incidence rate of bipolar disorder among Chinese adolescents aged 10-24 years was observed in the 15-19 age group, with a rate of 33.14/100 000; the highest DALY risk was in the 20- 24 age group, with a rate of 57.26/100 000. The lowest incidence risk and DALY risk RR values for bipolar disorder among Chinese adolescents aged 10-24 years were observed in 2017-2021, with RR values of 0.99 (95% CI =0.97-1.00) and 0.98 (95% CI = 0.97- 0.99), respectively ( P <0.05). Similarly, the lowest incidence risk and DALY risk RR values for this age group were observed in the 2000-2004 birth cohort, both of which were 0.86 (95% CI =0.84-0.87) ( P <0.05). It was projected that the overall age standardized incidence rate and age standardized DALY rate of bipolar disorder among Chinese adolescents aged 10-24 years will continue to increase from 2022 to 2031, reaching 24.10/100 000 and 34.90/100 000, respectively, by 2031. Conclusions From 1990 to 2021, both the age standardized incidence rate and age standardized DALY rate of bipolar disorder among Chinese adolescents shows an upward trend. Special attention should be given to female adolescents, with a focus on controlling the age standardized incidence rate of bipolar disorder among 15-19 year-old adolescents and the age standardized DALY rate among 20-24 year-old ones. Efforts should be enhanced to increase awareness and screening for bipolar disorder among adolescents.

SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat. The SARS-CoV-2 main protease (M^pro) is a critical target for the development of antiviral agents that can inhibit viral replication and transcription. In this study, we identified chebulagic acid (CHLA), isolated from Terminalia chebula Retz., as a potent non-peptidomimetic and non-covalent M^pro inhibitor. CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants, including the wild-type, Delta, Omicron BA.1.1, BA.2.3, BA.4, and BA.5, with EC₅₀ values below 2 μmol/L. Moreover, in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice. Notably, CHLA bound to a unique groove at the interface between M^pro domains I and II, which was revealed by the high-resolution crystal structure (1.4 Å) of the M^pro-CHLA complex, shrinking the substrate binding pocket of M^pro and inducing M^pro aggregation. CHLA was proposed to act as an allosteric inhibitor. Pharmacokinetic profiling and safety assessments underscore CHLA's potential as a promising broad-spectrum antiviral candidate. These findings report a novel binding site on M^pro and identify antiviral activity of CHLA, providing a robust framework for lead compounds discovery and elucidating the underlying molecular mechanisms of inhibition.

OBJECTIVE To set up normal ranges for indexes in embryo-fetal development toxicity studies in Sprague-Dawley(SD)rats and to establish a background database to provide reference for the embryo-fetal development toxicity evaluation of drugs.METHODS The data on embryonic develop-ment and fetal growth from embryo-fetal development toxicity studies(11 items)conducted by our center between 2013 and 2022 was statistically analyzed,involving 205 pregnant rats and 3037 fetuses in total,with the mean and standard deviation,coefficient of variation and 95%confidence interval calculated.The indexes included body mass,body mass gain and food consumption during pregnancy,pregnancy outcomes(pregnancy rate,average corpora lutea,average Implant sites,average live conceptuses,live conceptuse rate,resorption rate and dead conceptuse rate),fetal growth and development(fetal mass,placental mass and sex ratio),appearance abnormality rate,visceral abnormality rate,and skeletal abnormality rate.RESULTS The mass of pregnant rats trended up during gestation,with significant increases in the late period.Food consumption increased along with gestation.Caesarean section was conducted on gestation day 20,and the pregnancy rate was 93.2%.The average corpora lutea,Implant sites and live conceptuses were 18.0±3.2,15.9±2.8 and 14.8±3.0,respectively.The live conceptuse rate was 93.4%while the total dead embryo rate was 6.6%.The average mass of fetuses and placenta were respectively 3.6±0.3 and(0.6±0.3)g,and the fetal sex ratio(male/female)was 0.94.The incidence of fetal appearance abnormalities was about 0.2%,and that of soft tissue abnormalities was approximately 0.8%.The rate of skeletal abnormalities was about 1.2%,with higher incidence of non-ossification and incomplete ossification mostly identified on sternum and hyoid bone.The numbers of ossifications of metacarpal bones,metatarsal bones and sacrococcygeal vertebrae were 7.0±0.7,8.0±0.1 and 7.4±0.5,respectively.The rate of ossification of sternumⅠtoⅣwas higher,with an average of about 98.6%-99.9%.The ossification rates of sternum Ⅴ and Ⅵ were(68.0±28.4)%and(82.8±23.9)%.CONCLUSION The background database of indexes in the embryo-fetal development toxicity study on SD rats is established for our GLP laboratory,which provides reference for reproductive toxicity studies.

Tongxie Yaofang， also known as Baizhu Shaoyaosan， was first recorded in Danxi's Experiential Therapy （《丹溪心法》） by ZHU Danxi in the Yuan dynasty. It is composed of Atractylodis Macrocephalae Rhizoma， Paeoniae Radix Alba， Citri Reticulatae Pericarpium， and Saposhnikoviae Radix， and serves as the representative prescription for the treatment of painful diarrhea. It has the functions of tonifying the spleen， emolliating the liver， relieving pain， and checking diarrhea， and is mainly used in the treatment of gastrointestinal diseases such as irritable bowel syndrome （IBS） and ulcerative colitis （UC）. In addition， it is effective in treating gastrointestinal disorders with mental and psychological abnormalities， as well as obstinate anorexia in children， depression syndrome， and respiratory diseases. Experimental research and clinical practice have shown that Tongxie Yaofang has multi-component， multi-pathway， and multi-target characteristics in the treatment of diseases. The mechanism of Tongxie Yaofang in treating diseases is mainly attributed to anti-inflammation， immune function regulation， intestinal hypersensitivity improvement， emotion regulation， etc. Monoterpene glycosides， flavonoids， chromones， lactones， and other components contained play an important therapeutic role. The research on the systems biology of Tongxie Yaofang， such as metabolomics， proteomics， and network pharmacology， provides a scientific basis for clarifying its mechanism of action and expanding its clinical application. However， there are still some problems to be solved， such as difficulty in combining diseases and syndromes and lack of in-depth systematic research. Through the retrieval and collation of relevant literature， this paper systematically reviewed the material basis， pharmacological effects， and systems biology research of Tongxie Yaofang， aiming to lay a foundation for in-depth research on its mechanism in treating diseases and rational application in clinical practice.

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

【Objective】 To construct an easy-to-use individual survival prognostic tool based on competing risk analyses to predict the risk of 1-, 2- and 3- year recurrence for patients with non-muscle invasive bladder cancer (NMIBC). 【Methods】 The follow-up data of 419 NMIBC patients were obtained. The patients were randomly divided into training cohort (n=293) and validation cohort (n=126). The variables included age at diagnosis, sex, history of smoking, tumor number, tumor size, histolo-gic grade, pathological stage, and bladder perfusion drug. The cumulative incidence function (CIF) of recurrence was estimated using all variables in the training cohort and potential prognostic variables were determined with Gray’s test. The Fine-Gray subdistribution proportional hazard approach was used as a multivariate competitive risk analysis to identify independent pro-gnostic variables. A competing risk nomogram was developed to predict the recurrence. The performance of the competing risk model was evaluated with the area under the receiver operating characteristic curve (AUC), calibration curve, and Brier score. 【Results】 Five independent prognostic factors including age, number of tumors, tumor size, histologic grade and pathological stage were used to construct the competing risk model. In the validation cohort, the AUC of 1-, 2- and 3- year recurrence were 0.895 (95%CI: 0.831-0.959), 0.861(95%CI: 0.774-0.948) and 0.827(95%CI: 0.721-0.934), respectively, indicating that the model had a high predictive performance. 【Conclusion】 We successfully constructed a competing risk model to predict the risk of 1-, 2- and 3-year recurrence for NMIBC patients. It may help clinicians to improve the postoperative management of patients.

Heme/metabolism* ; Cryoelectron Microscopy ; Membrane Transport Proteins ; Escherichia coli Proteins/metabolism*

Antiviral Agents/pharmacology* ; COVID-19 ; Coronavirus 3C Proteases ; Humans ; Lactams ; Leucine ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Nitriles ; Proline ; Protease Inhibitors/pharmacology* ; SARS-CoV-2

A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Antiviral Agents/therapeutic use* ; Binding Sites ; COVID-19/virology* ; Coronavirus Papain-Like Proteases/metabolism* ; Crystallography, X-Ray ; Drug Evaluation, Preclinical ; Drug Repositioning ; High-Throughput Screening Assays/methods* ; Humans ; Imidazoles/therapeutic use* ; Inhibitory Concentration 50 ; Molecular Dynamics Simulation ; Mutagenesis, Site-Directed ; Naphthoquinones/therapeutic use* ; Protease Inhibitors/therapeutic use* ; Protein Structure, Tertiary ; Recombinant Proteins/isolation & purification* ; SARS-CoV-2/isolation & purification*