Objective:This study aims to analyze the disease burden trends of schizophrenia and bipolar disorder from 1990 to 2021 in China, and to predict the trends of these two disorders over the next 20 years.Methods:This study was conducted between September and October 2024. The data on incidence, prevalence, and disease burden of schizophrenia and bipolar disorder in China were retrieved from the database of the Global Burden of Disease Study 2021 (GBD2021). Temporal trends were quantified via the annual percentage change, average annual percentage change (AAPC), and their corresponding P-values, which were calculated using the empirical quantile method with the Joinpoint software. The autoregressive integrated moving average (ARIMA) model was constructed using data on the incidence, prevalence, and disease burden of schizophrenia and bipolar disorder from 1990 to 2021 to predict the trends in prevalence and disease burden of these two diseases from 2022 to 2041. Results:In China, during the period from 1990 to 2021, the age-standardized incidence rate (ASIR), age-standardized prevalence rates (ASPR), and age-standardized disability-adjusted life year (DALY) rate (ASDR) of schizophrenia all showed a fluctuating upward trend. By 2021, the AAPC of these rates was 3.83% ( P<0.001), 12.99% ( P<0.001), and 14.11% ( P<0.001), respectively, indicating a significant increase. Regarding bipolar disorder, the annual average ASIR in China significantly increased (AAPC=1.25%, P<0.001), while the annual average ASPR significantly decreased (AAPC=-1.03%, P<0.001), and the annual average ASDR showed no significant change (AAPC=-0.08%, P=0.342). The incidence of schizophrenia was mainly concentrated in the 15-34 age group. The prevalence and DALY rates of schizophrenia were on the rise across all age groups. For bipolar disorder, the peak incidence occurred between the ages of 10 and 19, with higher incidence, prevalence, and DALY rates in females compared to males. Looking ahead from 2022 to 2041, the overall ASIR, ASIR for both females and males, and ASPR for males with schizophrenia are projected to gradually increase, while the ASPR and ASDR of bipolar disorder are expected to remain stable, with females continuing to bear a higher disease burden than males. Conclusion:In China, the disease burden of schizophrenia and bipolar disorder substantially changed from 1990 to 2021, with distinct differences across gender and age-groups. The disease burden of schizophrenia is projected to keep rising in the next 20 years. It is imperative to develop targeted and precise prevention and control strategies for different populations.

Objective:This study aims to analyze the disease burden trends of schizophrenia and bipolar disorder from 1990 to 2021 in China, and to predict the trends of these two disorders over the next 20 years.Methods:This study was conducted between September and October 2024. The data on incidence, prevalence, and disease burden of schizophrenia and bipolar disorder in China were retrieved from the database of the Global Burden of Disease Study 2021 (GBD2021). Temporal trends were quantified via the annual percentage change, average annual percentage change (AAPC), and their corresponding P-values, which were calculated using the empirical quantile method with the Joinpoint software. The autoregressive integrated moving average (ARIMA) model was constructed using data on the incidence, prevalence, and disease burden of schizophrenia and bipolar disorder from 1990 to 2021 to predict the trends in prevalence and disease burden of these two diseases from 2022 to 2041. Results:In China, during the period from 1990 to 2021, the age-standardized incidence rate (ASIR), age-standardized prevalence rates (ASPR), and age-standardized disability-adjusted life year (DALY) rate (ASDR) of schizophrenia all showed a fluctuating upward trend. By 2021, the AAPC of these rates was 3.83% ( P<0.001), 12.99% ( P<0.001), and 14.11% ( P<0.001), respectively, indicating a significant increase. Regarding bipolar disorder, the annual average ASIR in China significantly increased (AAPC=1.25%, P<0.001), while the annual average ASPR significantly decreased (AAPC=-1.03%, P<0.001), and the annual average ASDR showed no significant change (AAPC=-0.08%, P=0.342). The incidence of schizophrenia was mainly concentrated in the 15-34 age group. The prevalence and DALY rates of schizophrenia were on the rise across all age groups. For bipolar disorder, the peak incidence occurred between the ages of 10 and 19, with higher incidence, prevalence, and DALY rates in females compared to males. Looking ahead from 2022 to 2041, the overall ASIR, ASIR for both females and males, and ASPR for males with schizophrenia are projected to gradually increase, while the ASPR and ASDR of bipolar disorder are expected to remain stable, with females continuing to bear a higher disease burden than males. Conclusion:In China, the disease burden of schizophrenia and bipolar disorder substantially changed from 1990 to 2021, with distinct differences across gender and age-groups. The disease burden of schizophrenia is projected to keep rising in the next 20 years. It is imperative to develop targeted and precise prevention and control strategies for different populations.

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*

Objective:To investigate the relationship between the expression of serum exsomal miRNA-155-5p (miR-155-5p) and prognosis in patients with esophageal squamous cell carcinoma (ESCC).Methods:A total of 336 samples from ESCC patients in Fujian Provincial Cancer Hospital from October 2014 to December 2015 were collected. The relative expression levels of serum exsomal miR-155-5p were detected by using real-time fluorescent quantitative polymerase chain reaction (qRT-PCR). Cut-off value of the expression levels of serum exsomal miR-155-5p was determined by using X-tile software. Based on the optimal cut-off value, patients were divided into miR-155-5p low expression group and miR-155-5p high expression group. The survival curve was drawn by using Kaplan-Meier method and Cox proportional hazards regression model was used to make survival analysis.Results:The cut-off value of serum exsomal miR-155-5p expression level was 2.340. According to the cut-off value, patients were divided into miR-155-5p low expression group (<2.340) of 51 cases and miR-155-5p high expression group (≥2.340) of 285 cases. There were no statistical differences in age ( χ2 = 0.020, P = 0.887), gender ( χ2 = 0.283, P = 0.595), tumor location ( χ2 = 0.063, P = 0.977), differentiation grade ( P = 0.474), clinical staging ( χ2 = 3.996, P = 0.136) and surgery treatment ( χ2 = 0.941, P = 0.332) of patients in both groups. ESCC patients in serum exsomal miR-155-5p high expression had a higher risk of death compared with patients in miR-155-5p low expression group ( HR = 1.763, 95% CI 1.049-2.961, P = 0.032). Conclusion:The high expression level of serum exsomal miR-155-5p is associated with poor prognosis in ESCC patients and it could be used as a prognostic new marker in ESCC patients.

Inhibition of Mycobacterium tuberculosis (Mtb) cell wall assembly is an established strategy for anti-TB chemotherapy. Arabinosyltransferase EmbB, which catalyzes the transfer of arabinose from the donor decaprenyl-phosphate-arabinose (DPA) to its arabinosyl acceptor is an essential enzyme for Mtb cell wall synthesis. Analysis of drug resistance mutations suggests that EmbB is the main target of the front-line anti-TB drug, ethambutol. Herein, we report the cryo-EM structures of Mycobacterium smegmatis EmbB in its "resting state" and DPA-bound "active state". EmbB is a fifteen-transmembrane-spanning protein, assembled as a dimer. Each protomer has an associated acyl-carrier-protein (AcpM) on their cytoplasmic surface. Conformational changes upon DPA binding indicate an asymmetric movement within the EmbB dimer during catalysis. Functional studies have identified critical residues in substrate recognition and catalysis, and demonstrated that ethambutol inhibits transferase activity of EmbB by competing with DPA. The structures represent the first step directed towards a rational approach for anti-TB drug discovery.

Protein phosphatase 2A (PP2A) accounts for the majority of total Ser/Thr phosphatase activities in most cell types and regulates many biological processes. PP2A holoenzymes contain a scaffold A subunit, a catalytic C subunit, and one of the regulatory/targeting B subunits. How the B subunit controls PP2A localization and substrate specificity, which is a crucial aspect of PP2A regulation, remains poorly understood. The kinetochore is a critical site for PP2A functioning, where PP2A orchestrates chromosome segregation through its interactions with BubR1. The PP2A-BubR1 interaction plays important roles in both spindle checkpoint silencing and stable microtubule-kinetochore attachment. Here we present the crystal structure of a PP2A B56-BubR1 complex, which demonstrates that a conserved BubR1 LxxIxE motif binds to the concave side of the B56 pseudo-HEAT repeats. The BubR1 motif binds to a groove formed between B56 HEAT repeats 3 and 4, which is quite distant from the B56 binding surface for PP2A catalytic C subunit and thus is unlikely to affect PP2A activity. In addition, the BubR1 binding site on B56 is far from the B56 binding site of shugoshin, another kinetochore PP2A-binding protein, and thus BubR1 and shugoshin can potentially interact with PP2A-B56 simultaneously. Our structural and biochemical analysis indicates that other proteins with the LxxIxE motif may also bind to the same PP2A B56 surface. Thus, our structure of the PP2A B56-BubR1 complex provides important insights into how the B56 subunit directs the recruitment of PP2A to specific targets.
Amino Acid Motifs ; Binding Sites ; Cell Cycle Proteins ; chemistry ; Crystallography, X-Ray ; Humans ; Multienzyme Complexes ; chemistry ; Protein Phosphatase 2 ; chemistry ; Protein Structure, Quaternary ; Protein-Serine-Threonine Kinases ; chemistry

Gram-negative Enterobacteriaceae with resistance to carbapenem conferred by New Delhi metallo-β-lactamase 1 (NDM-1) are a type of newly discovered antibioticresistant bacteria. The rapid pandemic spread of NDM-1 bacteria worldwide (spreading to India, Pakistan, Europe, America, and Chinese Taiwan) in less than 2 months characterizes these microbes as a potentially major global health problem. The drug resistance of NDM-1 bacteria is largely due to plasmids containing the blaNDM-1 gene shuttling through bacterial populations. The NDM-1 enzyme encoded by the blaNDM-1 gene hydrolyzes β-lactam antibiotics, allowing the bacteria to escape the action of antibiotics. Although the biological functions and structural features of NDM-1 have been proposed according to results from functional and structural investigation of its homologues, the precise molecular characteristics and mechanism of action of NDM-1 have not been clarified. Here, we report the three-dimensional structure of NDM-1 with two catalytic zinc ions in its active site. Biological and mass spectroscopy results revealed that D-captopril can effectively inhibit the enzymatic activity of NDM-1 by binding to its active site with high binding affinity. The unique features concerning the primary sequence and structural conformation of the active site distinguish NDM-1 from other reported metallo-β-lactamases (MBLs) and implicate its role in wide spectrum drug resistance. We also discuss the molecular mechanism of NDM-1 action and its essential role in the pandemic of drug-resistant NDM-1 bacteria. Our results will provide helpful information for future drug discovery targeting drug resistance caused by NDM-1 and related metallo-β-lactamases.
Amino Acid Sequence ; Anti-Bacterial Agents ; metabolism ; Binding Sites ; Captopril ; chemistry ; pharmacology ; Catalytic Domain ; Crystallography, X-Ray ; Drug Resistance, Bacterial ; Enterobacteriaceae ; enzymology ; Molecular Sequence Data ; Sequence Alignment ; Sequence Homology, Amino Acid ; beta-Lactamases ; chemistry ; metabolism