ObjectiveThe malaria parasites remodel the host erythrocyte structure by exporting parasite proteins that interact with the membrane skeleton proteins of red blood cells (RBCs), facilitating their intracellular survival and pathogenicity. Skeleton-binding protein 1 (SBP1) is a conserved exported protein across Plasmodium species. In Plasmodium falciparum, SBP1 has been reported to interact with erythrocyte membrane skeleton proteins 4.1R and spectrin, while its contribution to erythrocyte remodeling and parasite virulence in Plasmodium berghei (Pb) remains unclear. This study aims to determine whether PbSBP1 associates with the host cytoskeletal protein 4.1R and to investigate its role in the remodeling of host RBCs and the pathogenicity of Plasmodium berghei. MethodsIn Plasmodium berghei, the relationship between PbSBP1 and the erythrocyte cytoskeletal protein 4.1R was examined using co-immunoprecipitation. A Pbsbp1 gene knockout mutant of Plasmodium berghei (Pbsbp1∆) was generated based on the principle of double crossover homologous recombination. The deformability of erythrocytes infected with Pbsbp1∆ parasites was assessed using microfluidic methods. Microchannels with an array of cylindrical pillars were used to detect modifications in infected RBC deformability. The infected RBCs were squashed between the rows and recovered between the columns and the transit velocity (μm/s) of infected RBCs travelling through the microchannel was recorded. The component of the erythrocyte membrane skeleton junctional complex, tropomodulin (TMOD), was fluorescently labeled, and the cytoskeletal network of infected erythrocytes was imaged using super-resolution stochastic optical reconstruction microscopy (STORM) to analyze ultrastructural changes in the cytoskeleton of wild-type (WT) and Pbsbp1∆-infected erythrocytes. Actin-based junctional complexes were displayed as individual clusters by the labeled TMOD in the STORM images, and the cluster densities and distances between adjacent clusters of infected RBCs were calculated. Additionally, rodent malaria models (BALB/c mice) and experimental cerebral malaria models (C57BL/6 mice) were employed to monitor the growth of Pbsbp1∆ and WT parasites during the intraerythrocytic stage and their capacity to induce cerebral malaria in mice. ResultsPbSBP1 may participate in the remodeling of infected erythrocytes through direct or indirect interaction with the erythrocyte cytoskeletal protein 4.1R. Microfluidic assays revealed that the deformability of erythrocytes infected with Pbsbp1∆ parasites was significantly enhanced compared to those infected with WT parasites. STORM imaging further demonstrated that the ultrastructure of the erythrocyte cytoskeleton in Pbsbp1∆-infected cells was altered relative to that in WT-infected erythrocytes. The distances between nearest neighbors of clusters had a tendency to increase while the cluster densities were decreased in Pbsbp1∆-infected RBCs compared to WT-infected RBCs. Subsequent phenotypic analysis indicated that the growth rate of Pbsbp1∆ parasites during the intraerythrocytic stage was significantly slower than that of WT parasites, and their ability to induce cerebral malaria in mice was also attenuated. These findings suggest that PbSBP1 is involved in the remodeling of the erythrocyte membrane skeleton, likely through its direct or indirect interaction with protein 4.1R, thereby regulating the deformability of infected erythrocytes and influencing the pathogenicity of the blood-stage parasites. ConclusionThis study establishes a role for PbSBP1 in host erythrocyte remodeling and parasite virulence, providing new research strategies for the prevention and treatment of malaria.

Objective: To define the mechanism by which swine TRIM25 restricts vesicular stomatitis virus replication. Methods: Porcine 3D4/21 cells with TRIM25 overexpression or knockdown were infected with vesicular stomatitis virus. Viral replication was quantified by immunoblotting, quantitative reverse transcription polymerase chain reaction, and 50% tissue culture infectious dose assays. Type I interferon signaling was assessed by transcript quantification, interferon-beta and interferon-stimulated response element reporter assays, and co-immunoprecipitation.Viral RNA binding was tested by RNA immunoprecipitation. Results: TRIM25 overexpression reduced viral RNA and infectious titers, whereas TRIM25 knockdown increased replication (p < 0.01). TRIM25 increased interferon-beta and interferon-stimulated gene expression and enhanced interferon-beta and interferonstimulated response element promoter activity (p < 0.01). Mechanistically, TRIM25 promoted Lys63-linked ubiquitination of RIG-I and increased phosphorylation of TANK-binding kinase 1 and interferon regulatory factor 3. TRIM25 also bound vesicular stomatitis virus genomic RNA, and binding required the C-terminal region. Conclusions and Relevance: Porcine TRIM25 restricts vesicular stomatitis virus replication by amplifying type I interferon signaling and directly binding viral RNA.

Biosynthesized selenium nanoparticles (SeNPs) have attracted much attention because of their unique physical, chemical, and biological properties. The microbial reduction of selenium salts to SeNPs has great potential, while there is a lack of elite strains. In this study, we explored the reduction of Na₂SeO₃ by Streptomyces avermitilis into SeNPs. The colonies and hyphae of the strain and the synthesized SeNPs were characterized by optical microscopy, scanning electron microscopy (SEM), transmission electron microscope (TEM), energy dispersive spectrometry (EDS), X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). At the same time, the inhibitory activity of SeNPs on Fusarium oxysporum, the main pathogen causing root rot of Lycium barbarum, was studied. The results showed that S. avermitilis converted Na₂SeO₃ into SeNPs and tolerated 300 mmol/L Na₂SeO₃, demonstrating strong tolerance. S. avermitilis synthesized spherical SeNPs in the cytoplasm, and most of SeNPs had a diameter of about 100 nm and were released by hyphal fracture. The SeNPs synthesized by S. avermitilis were amorphous, and their surfaces were dominated by C and Se, with the existence of O, N and other elements. SeNPs had functional groups such as -OH, C=O, C-N, and C-H, which were closely related to the stability and biological activity of SeNPs. The SeNPs synthesized by S. avermitilis showcased significant inhibitory activity on F. oxysporum, and 25.0 μmol/mL SeNPs showcased the inhibition rate of 77.61% and EC₅₀ of 0.556 μmol/mL. In conclusion, S. avermitilis can tolerate high Na₂SeO₃ stress and mediate the synthesis of SeNPs. The synthesized SeNPs have good stability and strong inhibitory activity, demonstrating the potential application value in the preparation of SeNPs and the control of L. barbarum root rot.
Streptomyces/metabolism* ; Fusarium/drug effects* ; Lycium/microbiology* ; Selenium/metabolism* ; Nanoparticles/chemistry* ; Plant Diseases/microbiology* ; Metal Nanoparticles/chemistry* ; Antifungal Agents/pharmacology*

Objective To analyze the usage of pediatric drugs in 17 pediatric specialty hospitals from 2016 to 2020, and provide reference and guidance for the development of the essential medicine list （EML） for children and the improvement of the National Reimbursement Drug List （NRDL） in China. Methods Based on the pediatric medication monitoring data from 17 children's specialized hospitals reported to the Chinese Medical Economic Information Network (CMEI) of the Chinese Pharmaceutical Association between 2016 and 2020, this study analyzes the overall situation of the sample hospitals and the clinical use of pediatric drugs according to the major categories of the Anatomical Therapeutic Chemical Classification System （ATC）. Results In the various ATC categories, the trend of systemic use of anti-infective drugs decreasing was significant in the average hospital expenditure, while the trend of respiratory and digestive system and metabolic drugs decreasing was significant in the average hospital DDDS. In 2020, the average number of hospital grade standards for essential drugs （2018 version） accounted for 15.82% of the total number of drug use standards, while the average number of hospital grade standards for medical insurance （2019 version） accounted for 8.23% of the total number of drug use standards. Conclusion The use of pediatric medication in sample hospitals from 2016 to 2020 was generally reasonable, and there would still a certain gap between the actual clinical usage habits with the existing EML and NRDL，which still need to be adjusted.

ObjectiveTo investigate the association between cumulative atherogenic index of plasma （cumAIP） and the risk of new-onset nonalcoholic fatty liver disease （NAFLD） in young and middle-aged individuals. MethodsA prospective cohort study was conducted among the young and middle-aged individuals （aged 18 to <60 years） in the Kailuan study cohort who underwent physical examination in Kailuan General Hospital and its 10 affiliated hospitals in June 2006 to October 2010， and after screening based on the inclusion and exclusion criteria， 33 987 individuals were included in the observation cohort. The individuals were divided into Q1， Q2， Q3， and Q4 groups based on the quantiles of cumAIP. The Kaplan-Meier method was used to calculate the cumulative incidence rate of new-onset NAFLD in the four groups， while the log-rank test was used for comparison between groups. A multivariate Cox regression analysis was used to obtain the hazard ratio （HR） and 95% confidence interval （CI） of the risk of new-onset NAFLD in the four groups. A one-way analysis of variance was used for comparison of normally distributed continuous data between multiple groups， and the Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups； the chi-square test was used for comparison of categorical variables between groups. ResultsThe mean follow-up was 10.89±2.54 years， and there were 6 011 cases of new-onset NAFLD， including 995 cases in the Q1 group， 1 366 in the Q2 group， 1661 in the Q3 group， and 1 989 in the Q4 group， with an incidence density of 11.37， 16.02， 19.97， and 24.91 per thousand person-years. The log-rank test showed that there was a significant difference in cumulative incidence rate between the four groups （P<0.001）. With the presence or absence of NAFLD as the dependent variable and the quantiles of different exposure levels to cumAIP as the independent variable， the multivariate Cox regression model analysis showed that compared with the Q1 group， the Q2， Q3， and Q4 groups had an HR of 1.30 （95%CI： 1.20 — 1.41）， 1.52 （95%CI： 1.41 — 1.65）， and 1.79 （95%CI： 1.64 — 1.95）， respectively， for new-onset NAFLD， with a P_trend value of <0.001. With the presence or absence of new-onset NAFLD as the dependent variable and the cumulative exposure to AIP for 0， 2， 4， and 6 years as the independent variable， the Cox regression analysis showed that compared with cumulative exposure to AIP for 0 years， cumulative exposure to AIP for 2， 4， and 6 years had an HR of 1.24 （95%CI： 1.15 — 1.35）， 1.51 （95%CI： 1.40 — 1.64）， and 1.70 （95%CI： 1.56 — 1.84）， respectively， with a P_trend value of <0.001. A sensitivity analysis was performed after exclusion of the individuals with new-onset NAFLD within 2 years， the individuals who experienced atherosclerotic cardiovascular disease events during follow-up， and the individuals taking antihypertensive， hypoglycemic， and lipid-lowering drugs， and the results were similar to those of the main analysis. Considering the competitive relationship between all-cause death and outcome events， a competing risk analysis of death was performed， which showed that the results of risk analysis were similar to those of the main analysis. ConclusionA high level of cumAIP exposure can increase the risk of new-onset NAFLD in young and middle-aged individuals.

Objective:To investigate the effect of Simiao Yong'an Decoction on AMPK/ULK1 autophagy axis and inflammatory reaction in atherosclerotic(AS)mice.Methods:ApoE-/-mice were randomly divided into control group,model group,low,medium and high doses of Simiao Yong'an Decoction groups and simvastatin group,with 10 mice in each group.Mice model of AS was induced by high-fat diet.Simao Yong'an Decoction given low(10.13 g/kg),medium(20.25 g/kg),high dose(40.5 g/kg)and simvastatin tablets(3 mg/kg)by gavage for 6 weeks.After administration,serum and aortic tissue of mice were collected,and serum lipid level was detected by automatic biochemical analyzer;HE staining was used to observe the pathological changes of aorta;autophagy level of plaque tissue was observed by transmission electron microscope;levels of inflammatory factors IL-18,IFN-γ and CRP in serum were detected by ELISA;expression levels of AMPK,ULK1 and p62 mRNA were detected by qRT-PCR;expressions of LC3Ⅱ and p-ULK1 protein were detected by immunofluorescence labeling;expressions of p-AMPK and p62 were detected by immunohistochemis-try.Results:Compared with model group,aortic plaque in Simiao Yong'an Decoction and simvastatin groups were significantly reduced,and serum levels of TC,TG,LDL-C,IFN-γ,IL-18 and CRP were significantly decreased(P<0.05 or P<0.01),while the level of HDL-C was increased(P<0.05 or P<0.01);electron microscopy showed that autophagic bodies were increased;expressions of autophagy related factors LC3 Ⅱ,AMPK and ULK1 were induced,and expression of p62 was inhibited.Conclusion:Simiao Yong'an Decoction can induce AMPK/ULK1 autophagy axis and inhibit IFN-γ,IL-18 and CRP overexpressions in AS mice of may be one of the important mechanisms of Simiao Yong'an Decoction in anti-atherosclerosis.

Objective:To predict the monthly incidence of hemorrhagic fever with renal syndrome (HFRS) in Hebei Province by using the generalized additive model (GAM).Methods:The incidence data of HFRS in Hebei from 2006 to 2020 were collected, and the correlation coefficients between meteorological factors and the monthly incidence of HFRS in Hebei were analyzed by Spearman's correlation, and the meteorological factors were lagged by 0-6 orders, and those with the largest absolute values of the correlation coefficients were screened to be included in the multifactorial GAM to evaluate the effects of meteorological factors.Results:The monthly incidence of HFRS had the strongest correlation with monthly mean air temperature at lag order 2, monthly mean wind speed at lag order 0, monthly mean sunshine at lag order 4, monthly mean precipitation at lag order 2 and monthly mean humidity at lag order 1, which were diagnosed by the variance inflation factor and included in the multifactorial GAM, and the results showed significant differences among the factors (all P<0.001), and they showed non-linear relationships with the monthly incidence of HFRS. Mean monthly temperature was an important factor influencing HFRS incidence. Mean monthly air temperature, mean monthly sunshine and mean monthly wind speed were negatively associated with HFRS incidence, whereas mean monthly precipitation and mean monthly humidity were positively associated with HFRS incidence. Conclusions:There was a complex non-linear relationship between meteorological factors and the incidence of HFRS. GAM incorporated with lagged meteorological factors can be used to predict the incidence of HFRS in Hebei.

OBJECTIVE: To investigate the susceptibility of venetoclax-resistant acute myeloid leukemia (AML) cell lines to ferroptosis and to uncover the underlying molecular mechanisms using transcriptomic and metabolomic analysis methods. METHODS: Venetoclax-resistant AML cell lines were constructed using a low-dose concentration escalation method. The sensitivity of cells to chemotherapeutic drugs was detected by CCK-8 assay. The susceptibility of drug-resistant cell lines to ferroptosis was assessed using transcriptomic and metabolomic analysis methods. The expression of cellular GPX4 and SLC7A11 protein was detected by Western blot, and cell death and lipid peroxidation levels were measured by flow cytometry. Depmap database and TCGA cohort were applied to explore the effect of ferroptosis-related genes expression on prognosis. RESULTS: Venetoclax-resistant cell lines exhibited sensitivity to ferroptosis inducers RSL3, APR246, and sorafenib. The ferroptosis inhibitor Fer-1 partially inhibited cell death induced by these inducers. Compared with the parental cells, significant changes in metabolites and gene expression levels related to ferroptosis were observed in the resistant cell lines. In particular, deregulated expression of SLC7A11 and GPX4 may play critical role in ferroptosis susceptibility. Besides, GPX4 was identified as more important for AML cell survival and higher GPX4 expression may predict shortened overall survival, NPM1 mutant and IDH1 R132 mutation positive patients may prone to possess higher GPX4 expression. CONCLUSION Venetoclax-resistant AML cell lines remain susceptible to ferroptosis, higher GPX4 expression maybe a critical marker for poor prognosis. Regulating the expression of ferroptosis-related genes and metabolites may enhance the efficacy of venetoclax and provide new treatment options for AML patients.
Humans ; Ferroptosis ; Leukemia, Myeloid, Acute/metabolism* ; Sulfonamides/pharmacology* ; Bridged Bicyclo Compounds, Heterocyclic/pharmacology* ; Drug Resistance, Neoplasm ; Metabolomics ; Cell Line, Tumor ; Phospholipid Hydroperoxide Glutathione Peroxidase ; Amino Acid Transport System y+/metabolism* ; Transcriptome

OBJECTIVE: To study the efficacy and prognosis of patients with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) treated with hypomethylating agents (HMA), and to analyze the factors that may affect their efficacy and prognosis, in order to provide a clinical basis for the choice of treatment options for patients with MDS/MPN. METHODS: 35 patients with newly diagnosed MDS/MPN who received hypomethylating therapy from January 2018 to April 2024 in the Department of Hematology of Affiliated Hospital of Xuzhou Medical University were included. The patients were divided into decitabine group (15 cases) and azacitidine group (20 cases) according to the treatment regimen. The efficacy, median overall survival (OS), and median progression-free survival (PFS) of the patients after HMA treatment were evaluated. The differences in efficacy and survival between the two groups were compared, and factors affecting efficacy and prognosis of MDS/MPN patients were analyzed. RESULTS: The overall response rate (ORR) of the 35 MDS/MPN patients treated with HMA was 51.4%. The ORR was 73.3% in decitabine group and 35.0% in azacitidine group, with a statistically significant difference (P =0.041). Survival analysis showed that the median OS was 12 months and the median PFS was 10 months in the entire cohort of the patients. There was no difference in median OS between decitabine group and azacitidine group. The median PFS in decitabine group was 12 months, higher than that in azacitidine group (7 months), but the difference was not statistically significant (P =0.505). Multivariate analysis showed that the treatment regimen and platelet count were independent influencing factors for the efficacy of HAM treatment; The course and therapeutic efficacy of HMA treatment were independent influencing factors for OS in MDS/MPN patients. The main adverse reactions of HMA treatment were myelosuppression and pulmonary infection. Gastrointestinal reactions were more likely to occur in the azacitidine group than in the decitabine group, and the difference was statistically significant (P =0.027). CONCLUSION HMA treatment is effective and well-tolerated in some MDS/MPN patients. Decitabine shows superior efficacy compared with azacitidine and is less likely to cause gastrointestinal reactions. Patients who received ≥4 courses of HMAs and responded to hypomethylating therapy had longer OS.
Humans ; Prognosis ; Decitabine/therapeutic use* ; Azacitidine/therapeutic use* ; Male ; Female ; Myelodysplastic Syndromes/drug therapy* ; Middle Aged ; Myelodysplastic-Myeloproliferative Diseases/drug therapy* ; Antimetabolites, Antineoplastic/therapeutic use* ; Treatment Outcome ; Aged ; Myeloproliferative Disorders/drug therapy* ; Adult ; DNA Methylation

OBJECTIVE: To evaluate the safety and effectiveness of robot-assisted percutaneous coronary intervention (R-PCI) compared to traditional manual percutaneous coronary intervention (M-PCI). METHODS: This prospective, multicenter, randomized controlled, non-inferior clinical trial enrolled patients with coronary heart disease who met the inclusion criteria and had indications for elective percutaneous coronary intervention. Participants were randomly assigned to either the R-PCI group or the M-PCI group. Primary endpoints were clinical and technical success rates. Clinical success was defined as visually estimated residual post-percutaneous coronary intervention stenosis < 30% with no 30-day major adverse cardiac events. Technical success in the R-PCI group was defined as successful completion of percutaneous coronary intervention using the ETcath200 robot-assisted system, without conversion to M-PCI in the event of a guidewire or balloon/stent catheter that was unable to cross the vessel or was poorly supported by the catheter. Secondary endpoints included total procedure time, percutaneous coronary intervention procedure time, fluoroscopy time, contrast volume, operator radiation exposure, air kerma, and dose-area product. RESULTS: The trial enrolled 152 patients (R-PCI: 73 patients, M-PCI: 79 patients). Lesions were predominantly B2/C type (73.6%). Both groups achieved 100% clinical success rate. No major adverse cardiac events occurred during the 30-day follow-up. The R-PCI group had a technical success rate of 100%. The R-PCI group had longer total procedure and fluoroscopy times, but lower operator radiation exposure. The percutaneous coronary intervention procedure time, contrast volume, air kerma, and dose-area product were similar between the two groups. CONCLUSIONS For certain complex lesions, performing percutaneous coronary intervention using the ETcath200 robot-assisted system is safe and effective and does not result in conversion to M-PCI.