ObjectiveTo evaluate the antitumor activity of Periplaneta americana extract（PAE） against human-derived lung adenocarcinoma organoids（LUAD-PDOs） and to elucidate its potential mechanism based on transcriptomics. MethodsFresh tumor and adjacent normal tissues from patients with LUAD were collected to construct LUAD-PDOs and normal lung organoid（Nor-PDOs） models using 3D organoid culture technology. The effective intervention concentration of PAE was determined using the cell counting kit-8（CCK-8） assay. Experimental groups included the model group（LUAD-PDOs）， normal group， model administration group（LUAD-PDOs+PAE）， and normal administration group（Nor-PDOs+PAE）. Hematoxylin-eosin（HE） staining was used to observe the pathological structures of PDOs， immunohistochemistry（IHC） was performed to detect the expressions of the proliferation marker Ki-67 and lung adenocarcinoma differentiation markers cytokeratin-7（CK-7） and Napsin A， TUNEL staining was applied to detect cell apoptosis. RNA sequencing（RNA-Seq） was conducted to identify differentially expressed genes（DEGs）， followed by Gene Ontology（GO）， Kyoto Encyclopedia of Genes and Genomes（KEGG）， and Gene Set Enrichment Analysis（GSEA）， alongside protein-protein interaction（PPI） network analysis to screen core mechanisms. Finally， key targets were validated by integrating external database analysis with immunofluorescence（IF）. ResultsNor-PDOs and LUAD-PDOs that highly recapitulated the pathological characteristics of the primary tissues were successfully established. The CCK-8 assay determined that the effective intervention concentration of PAE was 16 g·L^-1. Morphological observation showed that Nor-PDOs exhibited lumen-forming structures， whereas LUAD-PDOs displayed dense， solid structures. CCK-8 and TUNEL assays revealed that， compared with the model group， PAE intervention inhibited the proliferation of LUAD-PDOs and promoted apoptosis in LUAD cells， while showing no significant effect on the viability of Nor-PDOs. Transcriptomic analysis identified 719 DEGs that were significantly reversed after PAE intervention（347 up-regulated and 372 down-regulated）（P<0.05）. GO enrichment analysis indicated that DEGs in the model administration group were significantly enriched in biological processes related to cell cycle regulation compared to the model group. KEGG pathway analysis revealed that PAE affected pathways related to proliferation and metabolism， including pathways in cancer and the p53 signaling pathway. GSEA further confirmed that PAE significantly enhanced the activity of the p53 signaling pathway（P<0.05）. PPI network analysis indicated that breast cancer type 1 susceptibility protein（BRCA1） and checkpoint kinase 1（CHEK1） were the core down-regulated targets in the p53 pathway. IF verified the high expression of BRCA1 and CHEK1 in LUAD-PDOs and their significant downregulation after PAE intervention（P<0.05）. Furthermore， survival analysis based on The Cancer Genome Atlas（TCGA） database indicated that low expression of BRCA1 and CHEK1 was significantly associated with prolonged overall survival in patients with LUAD（P<0.05）. ConclusionPAE effectively inhibits proliferation of LUAD-PDOs and promotes their apoptosis， its anti-tumor mechanism is potentially associated with the activation of the p53 signaling pathway， with BRCA1 and CHEK1 genes likely serving as key downstream targets for the effects of PAE.

ObjectiveTo identify and validate the optimal compatibility dosage of astragaloside Ⅰ （ASⅠ） and calycosin （CY） in the treatment of cholestatic liver fibrosis. MethodsA 3，5-diethoxycarbonyl-1，4-dihydrocollidine （DDC） diet was used to establish a mouse model of liver fibrosis， and the uniform design method was used to identify the optimal combination ratio of the saponin component ASⅠ and the flavonoid component CY in Astragalus membranaceus. In the uniform design experiment， 80 male C57/BL6J mice were divided into normal group， model group， total astragalosides （TAS） group， groups A — F with a uniform design， and obeticholic acid （OCA） group using a random number table， with 8 mice in each group. The multiple regression analysis was used to establish the optimal regression equation and obtain the potential optimal combination ratio. The in vivo efficacy of the empirically optimal combination identified in the uniform design and the optimal dose combination predicted by the regression equation were compared for validation. A one-way analysis of variance was used for comparison of continuous data between multiple groups； the Levene test was used to determine the homogeneity of variance， and the least significant difference t-test was used for comparison of data with homogeneity of variance between two groups， while the Dunnett T3 test was used for comparison of data with heterogeneity of variance. ResultsIn the uniform design regimen， the JYB combination （3.125 mg/kg ASI+50 mg/kg CY） significantly reduced the serum levels of alanine aminotransferase （ALT）， aspartate transaminase （AST）， alkaline phosphatase （ALP）， total bile acid （TBA）， total bilirubin （TBil）， and indirect bilirubin （IBil） in mice with DDC-induced cholestatic liver fibrosis （all P<0.05）， and it also reduced hepatic Hyp content （P<0.01）， semi-quantified collagen deposition area （P<0.001）， and the mRNA expression levels of Acta2， Col1a1， Ck7， Ck19， Adgre1， TLR4， TNF-α， and CCL5 in liver tissue （all P<0.05）. The regression equation showed that 50 mg/kg ASⅠ+50 mg/kg CY was the potential optimal combination， which was named as P1 combination. However， subsequent validation experiments showed that P1 combination only significantly improved the serum levels of AST and IBil and hepatic Hyp content in DDC mice （all P<0.05）， with no significant impact on hepatic collagen deposition and the mRNA expression levels of Acta2， Ck7， Ck19， Adgre1， and CCL5 （all P>0.05）. In contrast， the JYB combination significantly improved the serum levels of ALP， ALT， AST， TBA， TBil， and IBil， hepatic collagen deposition， hepatic Hyp content， and the mRNA expression levels of Acta2， Col1a1， Ck7， Ck19， Adgre1， TLR4， TNF-α， and CCL5 （all P<0.05）. ConclusionThis study shows that the JYB combination （3.125 mg/kg ASⅠ+50 mg/kg CY） can significantly alleviate DDC-induced liver fibrosis， with comparable efficacy to total saponins from Astragalus membranaceus， and compared with ASⅠ or CY administered alone， the JYB combination has a significantly better regulatory effect on the serum levels of ALP and TBA.

Brain’s neural activities encompass both periodic rhythmic oscillations and aperiodic neural fluctuations. Rhythmic oscillations manifest as spectral peaks of neural signals, directly reflecting the synchronized activities of neural populations and closely tied to cognitive and behavioral states. In contrast, aperiodic fluctuations exhibit a power-law decaying spectral trend, revealing the multiscale dynamics of brain neural activity. In recent years, researchers have made notable progress in studying brain aperiodic dynamics. These studies demonstrate that aperiodic activity holds significant physiological relevance, correlating with various physiological states such as external stimuli, drug induction, sleep states, and aging. Aperiodic activity serves as a reflection of the brain’s sensory capacity, consciousness level, and cognitive ability. In clinical research, the aperiodic exponent has emerged as a significant potential biomarker, capable of reflecting the progression and trends of brain diseases while being intricately intertwined with the excitation-inhibition balance of neural system. The physiological mechanisms underlying aperiodic dynamics span multiple neural scales, with activities at the levels of individual neurons, neuronal ensembles, and neural networks collectively influencing the frequency, oscillatory patterns, and spatiotemporal characteristics of aperiodic signals. Aperiodic dynamics currently boasts broad application prospects. It not only provides a novel perspective for investigating brain neural dynamics but also holds immense potential as a neural marker in neuromodulation or brain-computer interface technologies. This paper summarizes methods for extracting characteristic parameters of aperiodic activity, analyzes its physiological relevance and potential as a biomarker in brain diseases, summarizes its physiological mechanisms, and based on these findings, elaborates on the research prospects of aperiodic dynamics.

Objective To investigate the clinical effect of autologous bone combined with allogeneic bone in repairing bone defect after microwave in situ inactivation for bone giant cell tumor around the knee.Methods A retrospective analysis was conducted on the clinical data of 39 patients with bone giant cell tumor around the knee treated in our hospital from January 2015 to December 2022.The tumor tissues of all patients were performed microwave in situ inactivation first,then followed by curettage;the subchondral bone defect adjacent to the articular surface was reconstructed with autologous bone graft,and the remaining tumor cavity was filled with a composite of autologous and allogeneic bone;then a locking plate was applied for protective fixation.The early outcomes including operative time,intraoperative blood loss,hospital stay,wound healing,and surgery-related complications were recorded.The regular follow-up was conducted after surgery,then the tumor recurrence or metastasis was observed and the status of internal fixation and bone graft fusion along with its fusion time were recorded.The knee functions before operation and at the end of follow-up were evaluated with the Musculoskeletal Tumor Society(MSTS)scoring system.The radiographic joint degeneration was evaluated by the Aboulafia classification system at the end of follow-up.Results The patients showed a mean operative time of(134.7±14.2)minutes,an averaged intraoperative blood loss of(153.9±23.0)mL,and a mean hospital stay of(17.4±3.2)days.The patients obtained Ⅰ phase wound healing without any surgery-related complications such as neurovascular injury.All patients underwent the postoperative follow-up,without local recurrence or metastasis cases during the follow-up.At the end of follow-up,the MSTS score of patients was higher than that before operation(P<0.05),with an excellent and good rate of knee function recovery of 89.7%.At the end of follow-up,X-ray films showed good filling of the lesion and bone graft fusion,with a mean fusion time of(9.4±2.1)months.No collapse or fracture of the articular surface occurred.According to the Aboulafia classification,there were 20 cases of grade 0,11 cases of grade 1,and 8 cases of grade 2.Conclusion The autologous bone and allogeneic bone in repair of bone defect after microwave in situ inactivation for bone giant cell tumor around the knee has perfect knee function recovery,and can effectively prevent the collapse and degeneration of articular surfaces,which helps in the reconstruction of tumor cavity.

Objective To explore the application of goal-directed fluid therapy based on pulse pressure variation rate(PPV)combined with low central venous pressure(LCVP)technique in liver surgery.Methods A total of 86 patients who underwent liver lobe/segment resection in our hospital from January 2022 to December 2023 were included,and randomly divided into two groups by random sequence method.Patients in the conventional group were treated with LCVP technique,while patients in the test group were given PPV goal-directed intervention on the basis of the conventional group.The surgical indicators,hemodynamic indicators,cognitive function,adverse reactions and recovery of gastrointestinal function of patients in the two groups were compared.Results There was no statistically significant difference in the operation time,Pringle maneuver time,first postoperative exhausting time or first postoperative defecation time of patients between the two groups(P>0.05).However,the intraoperative blood loss,intraoperative fluid infusion volume and hospital stay of patients in the test group were all less/shorter than those in the conventional group(P<0.05).Compared with the time point of T0,patients in the two groups showed increased heart rate(HR)but decreased mean arterial pressure(MAP)and central venous pressure(CVP)at time points of T1 and T2(P<0.05).There was no statistically significant difference in the HR or MAP of patients between the two groups at time points of T0,T1,T2 and T3(P>0.05).At time points of T1 and T2,the CVP of patients in the test group was lower than that in the conventional group(P<0.05).One day after operation,the mini-mental state examination(MMSE)score of patients in the test group was higher than that in the conventional group(P<0.05).The MMSE scores 7 days after operation of patients in the two groups were higher than those 1 day after operation(P<0.05).Patients in the test group had a lower total incidence of adverse reactions and a shorter recovery time of gastrointestinal function than those in the conventional group(P<0.05).Conclusion The goal-directed fluid therapy based on PPV combined with LCVP technique has a good application effect in liver surgery,which can reduce intraoperative blood loss and fluid infusion volume of patients,shorten hospital stay,increase hemodynamic stability,improve postoperative cognitive dysfunction,and promote the recovery of gastrointestinal function,with a relatively high treatment safety.

Aim To clarify the mechanism by which Qishen Yixin Granules improved microcirculation vas-cular endothelial dysfunction(VED)in mice,through activating the Nrf2/HO-1 signaling pathway to regulate oxidative stress.Methods C57 mice were randomly divided into six groups:blank group,model group,pos-itive drug group,and low-,medium-,and high-dose groups of Qishen Yixin Granules.The VED model was established by long-term infusion of Ang Ⅱ combined with a high-fat diet.Each treatment group received the corresponding drug intervention.After four weeks of drug intervention,cardiac function was assessed by echocardiography.Carstairs staining was used to ob-serve the formation of microthrombi in myocardial tis-sue.The micro vascular ischemia was evaluated by Hei-denhain staining.The ultrastructure of endothelial cells was observed by electron microscopy.The levels of EMPs,ROS,NO,ET-1,TF,TM,VWF,and TXA2 in serum were measured by ELISA.The expression levels of MDA,SOD,and GSH-Px in mouse heart tissue were determined by chemical methods.Cardiac microvascu-lar density and the expression of Nrf2,Keap1,and HO-1 proteins were detected by Immunohistochemical stai-ning.The protein expressions of Keap1,cytoplasmic Nrf2,nuclear Nrf2,and HO-1 in myocardial tissue were detected by Western blot.Results Qishen Yixin Granules could effectively improve the cardiac function of mice,alleviate the damage of endothelial cells and endothelial function.They could up-regulate serum NO levels and the activities of antioxidant enzymes SOD and GSH-Px,while down-regulating the expression of ROS and vascular inflammatory injury factors such as ET-1,VWF,TXA2,TF,TM,and EMPs.Qishen Yixin Granules also increased the positive counts of CD34,Nrf2,and HO-1,as well as microvessel density.Fur-thermore,they inhibited the expression of MDA,Keap1,and cytoplasmic Nrf2 protein in myocardial tis-sue,while increasing the expression of nuclear proteins HO-1 and Nrf2.Conclusions Qishen Yixin Granules may inhibit oxidative stress and inflammatory response by regulating the Nrf2/HO-1 signaling pathway,thereby improving vascular endothelial damage and cardiac function in VED mice.

Objective To analyze the association between lifestyle and the risk of type 2 diabetes(T2D)among adult residents.Methods The data was sourced from the Shanghai Suburban Adult Cohort and Biobank.A total of 42 096 adult residents who had not developed T2D were recruited from four districts of Shanghai(Songjiang,Jiading,Minhang,and Xuhui)between 2016 and 2019.The follow-up ended on Feb 28,2023.A structured questionnaire was used to collect information on six lifestyle-related items,including smoking,alcohol consumption,BMI,waist circumference(WC),physical activity,and diet.The unhealthy lifestyle scores(UHLS)were calculated by counting the number of all the unhealthy lifestyle items,with a range of 0-6.New-onset T2D events diagnosed by physicians were obtained through the medical information system.Cox proportional hazards regression model and restricted cubic spline model were utilized to evaluate the association between unhealthy lifestyles and the risk of T2D incidence.Results About 28.1%of the participants led 4-6 unhealthy lifestyles.A total of 1 752 new T2D cases were identified during 218 513.4 person-years of follow-up.Analysis of single unhealthy lifestyle showed that abnormal WC(HR=1.5,95%CI:1.4-1.7)and abnormal BMI(HR=1.3,95%CI:1.2-1.5)were associated with an increased risk of T2D.Compared with individuals with a UHLS of 0-1,those with a UHLS of 3 and 4-6 had 30%(95%CI:1.1-1.6)and 50%(95%CI:1.2-1.8)higher risks of T2D,respectively.Each additional unhealthy lifestyle was associated with a 10%increase in T2D incidence risk(HR=1.1,95%CI:1.1-1.2).Conclusion The risk of T2D in adult residents increases with the cumulative number of unhealthy lifestyles.Adult residents with abnormal WC or BMI,or have three or more unhealthy lifestyles accumulated,will increase the risk of new-onset T2D.

Objective To examine the changing prevalence and antimicrobial resistance profiles of Burkholderia cepacia in 52 hospitals across China from 2015 to 2021.Methods A total of 9 261 strains of B.cepacia were collected from 52 hospitals between January 1,2015 and December 31,2021.Antimicrobial susceptibility of the strains was tested using Kirby-Bauer method or automated antimicrobial susceptibility testing systems according to a unified protocol.The results were interpreted according to the breakpoints released in the Clinical & Laboratory Standards Institute(CLSI)guidelines(2023 edition).Results A total of 9 261 strains of B.cepacia were isolated from all age groups,especially elderly patients.The proportion was 11.1％(1 032 strains)in children,significantly lower than the proportion in adults.About half(46.5％,4 310/9 261)of the strains were isolated from patients at least 60 years old and 42.3％(3 919/9 261)of the strains were isolated from young adults.Most isolates(71.1％)were isolated from sputum and respiratory secretions,followed by urine(10.7％)and blood samples(8.1％).B.cepacia isolates were highly susceptible to the five antimicrobial agents recommended in the CLSI M100 document(33rd edition,2023).B.cepacia isolates showed relatively higher resistance rates to meropenem and levofloxacin.However,the resistance rates to ceftazidime,trimethoprim-sulfamethoxazole,and minocycline remained below 8.1％.The percentage of B.cepacia strains resistant to levofloxacin was the highest compared to other antibiotics in any of the three age groups(from 12.4％in the patients＜18 years old to 20.6％in the patients aged 60 years or older).Conclusions B.cepacia is one of the clinically important non-fermenting gram-negative bacteria.Accurate and timely reporting of antimicrobial susceptibility test results and ongoing antimicrobial resistance surveillance are helpful for rational prescription of antimicrobial agents and proper prevention and control of nosocomial infections.

Objective To compare five time series models and predict the monthly incidence of bacillary dysentery in Qinghai Province in 2024,and provide reference for the prevention and control.Methods The epidemic charac-teristics of bacterial dysentery in Qinghai Province from 2014 to 2023 were analyzed.R4.3.1 software was used for establishing seasonal autoregressive integrated moving average(SARIMA)model,Holt-Winters triple exponential smoothing(Holt Winters)model,exponential smoothing(ETS)model,neural network autoregression(NNAR)model,and trigonometric seasonality,Box-Cox transformation,ARMA errors,trend and seasonal components(TBATS)model.Fitting effect of the models was analyzed and accuracy was compared.Results From 2014 to 2023,a total of 5 833 cases of bacterial dysentery were reported in Qinghai Province,without deaths,male to fe-male ratio being 1.23∶1.The highest incidence was reported in 2016(15.45 per 100 000 people),and the lowest in-cidence was reported in 2023(3.68 per 100 000 people).Incidence increased from 2014 to 2016,then decreased,showing an obvious overall downward trend.Case number in＜5 years age group was the highest,accounting for 29.76％of the total cases(n=1 736).Regarding population distribution,the top three were children in childcare institutions and scattered children(35.56％),farmers(24.65％),and students(12.62％).Except the additive Holt-Winters model,the predicted trends of the other four models were consistent with actuality.The ETS model had the best fitting effect,with a relatively balanced overall performance(training set:MAE=0.13,RMSE=0.21,MAPE=19.55％;testing set:MAE=0.11,RMSE=0.16,MAPE=28.66％).It is recommended to pre-dict the incidence of bacillary dysentery in Qinghai Province based on ETS model.Conclusion From 2014 to 2023,bacterial dysentery in Qinghai Province showed a downward trend,with the peak of the epidemic from June to Au-gust.Preschool and scattered children were high-risk groups.Among the five prediction models,ETS model has the best fitting effect,and can be used to predict the incidence of bacillary dysentery.

Aim To explore the potential mechanisms underlying therapeutic effects of cordycepin in asthma by utilizing network pharmacology,molecular docking,and in vitro cellular validation.Methods The thera-peutic targets associated with asthma and the drug tar-gets of cordycepin were systematically identified through comprehensive database searches.An overlap analysis of the two gene sets was performed,followed by the construction of a protein-protein interaction(PPI)network and topological analysis to identify the core targets.The core targets were subjected to Kyoto Ency-clopedia of Genes and Genomes(KEGG)pathway a-nalysis and Gene Ontology(GO)enrichment analysis,and a drug-target-pathway network was constructed.To validate the interaction between cordycepin and core targets,molecular docking and molecular dynamics sim-ulations were conducted.Subsequently,the pharmaco-logical effects and underlying mechanisms of cordyce-pin were validated in vitro using Beas-2B cells,emplo-ying Cell Counting Kit-8(CCK-8)assay and quantita-tive real-time reverse transcription PCR(RT-qPCR).Results A total of 438 potential targets of cordycepin were identified,113 of which overlapped with asthma-related therapeutic targets.Topological analysis based on the PPI network revealed 22 core targets.Using KEGG enrichment analysis,165 significantly enriched pathways were identified,including the TNF and HIF-1 signaling pathways.Molecular docking analysis re-vealed high binding affinities between cordycepin and select core targets,which further corroborated by mo-lecular dynamics simulations.In vitro experiments showed that after cordycepin pretreatment,the upregu-lation of MAPK1,HIF1A,MTOR,MYC,IL10,and JUN mRNA was significantly rescued in HDM-stimulated Beas-2B cells.Conclusions Cordycepin exerts anti-asthmatic effects by targeting MAPK1 and other key molecules,thereby providing a scientific foundation for its further development and clinical application.