Background/Aims: Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell’s intrinsically fine-tuned regulatory framework is urgently needed. Methods: We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models. Results: ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1–SCAP–SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11–ERLIN1 interaction and restoring cholesterol homeostasis. Conclusions ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11–ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.

OBJECTIVE To explore the clinical characteristics of Tropheryma whipplei(TW)infection and observe the application of pathogenic metagenomic next-generation sequencing(mNGS)in diagnosis of TW infection.METHODS The clinical data were collected from 1 patient who was diagnosed by mNGS in the Affiliated Hospital of Jining Medical University on Apr.9,2022.The data including the results of laboratory tests and treatment out-comes were summarized,and a literature review was conducted.RESULTS A 50-year-old woman presented to the hospital with chest tightness and chest pain lasting for 3 days,accompanied by dyspnea,palpitations,and expec-toration.The chest plain CT scan and magnetic resonance imaging(MRI)scan suggested a high probability of pul-monary infection.Normal flora were isolated by culture of bronchoalveolar lavage fluid(BALF);TW and human βherpes virus type 7 were detected in BALF by mNGS,with the sequence numbers 327 000 and 9,respectively.The pulmonary symptoms of the patient were improved after joint treatment of the infection with etimicin,levo-floxacin and minocycline.The patient repeatedly sought for medical treatment due to the pain of shoulder joint and limitation of motion.CONCLUSIONS TW is one of major pathogens leading to the infections of systemic multiple systems,and it is necessary to attach great importance to the diagnosis and treatment.The traditional laboratory test method can not achieve ideal diagnosis effect and is more likely to make a missed diagnosis.mNGS is more ac-curate and more efficient than the traditional detection method in diagnosis of TW-induced diseases.Early use of mNGS can make a rapid identification of pathogens and facilitate the reasonable clinical use of antibiotics.It is of great significance for control of the disease progression,improvement of prognosis and prevention of recurrence.

Objective To develop a three-compartment kinetic fatigue model for the isometric muscle endurance of the hip,knee,and ankle joints at 50％IPT(isometric peak torque),so as to provide a theoretical basis for simulation-based assessments and load evaluations in biomechanics and sports science.Methods The IPT of the hip,knee,and ankle joints was measured in 40 male university students.Isometric endurance tests were then performed on all three joints at 50％IPT until exhaustion.Electromyography data and endurance time(ET)of major lower limb muscles were collected concurrently.The differences between ETs predicted by models based on previously recommended F and R parameters and actual ETs were analyzed.Subsequently,experimental ETs were used in a grid search to optimize Fand R parameters,allowing for the development of an accurate three-compartment kinetic model.Results The ET of the hip and ankle joints was significantly longer than that of the knee joint(P＜0.001).Models using previously recommended Fand R parameters overestimated ET,with significantly higher predicted values than experimentally measured ET(P＜0.001),as well as elevated root mean squared error(RMSE)and mean relatvie error(MRE)values.The grid search successfully identified Fand R parameters for the three-compartment model in isometric endurance tests of lower limb joints,with no statistical difference between model-predicted ET and experimental ET(P＞0.05).Conclusions The developed model in this study can serve as an indirect measurement tool for evaluating load in similar activities.

Objective:To achieve the conversion from dual-energy cone-beam CT (DECBCT) at the kilovolt (KV) level to projections at the megavolt (MV) level using an improved CycleGAN network, in order to provide a potential reference benchmark and real-time monitoring of in vivo doses delivered by exit beams for the safe implementation of advanced techniques such as online adaptive radiotherapy. Methods:Simulated patient data were generated using a 4D extended cardiac torso (XCAT) model, and projections were generated based on the geometric parameters of Varian′s onboard cone-beam CT. Furthermore, relative electron density (RED) images were derived from DECBCT images using an iterative dual-energy decomposition algorithm. The SE-CycleGAN and CycleGAN networks were trained to generate MV projection images using DECBCT projections and RED images, respectively. The performance of both methods was evaluated using metrics including structural similarity index (SSIM), peak signal-to-noise ratio (PSNR), and root mean square error (RMSE).Results:SE-CycleGAN significantly outperformed CycleGAN in all evaluation metrics ( Z = -23.92, -26.17, -25.54, -26.80, -11.54, -11.21, P<0.05), particularly in learning global information. Besides, although both methods generated satisfactory MV projections, training using DECBCT projections as input yielded better effects than training using RED images. For all the 3 636 sets of projections in the test set, the SE-CycleGAN and CycleGAN networks using DECBCT projections as input respectively yielded SSIMs of 0.997 7±0.000 7 and 0.997 1±0.001 6, PSNRs of 39.625 0±4.684 4 and 36.272 2±5.566 3, and RMSEs of 0.004 1±0.002 7 and 0.006 3±0.0043, respectively. In contrast, the SE-CycleGAN and CycleGAN networks using RED projections as input respectively yielded SSIMs of 0.996 8±0.001 0 and 0.996 2±0.001 5, PSNRs of 38.548 7±3.637 4 and 36.007 3±4.437 8, and RMSEs of 0.004 3±0.002 2 and 0.006 1±0.0037, respectively. Conclusions:This study proposed a new method to establish reference benchmarks for in vivo dose monitoring based on DECBCT and deep learning technologies. This method is accurate and effective according to the preliminary validation using virtual simulation experiments.

Objective To explore the correlation between the expression level of serum fibrinogen-like protein 1(FGL1)and the indexes of metabolism and renal function in patients with diabetic nephropathy(DN)and diabetes mellitus(DM),and provide reference for clinical diagnosis and treatment.Methods From January 2017 to April 2023,30 patients with DM and treated in Jiangsu Province Hospital of Chinese Medicine were selected as the DM group,68 patients with DN were selected as the DN group,and 36 healthy subjects were selected as the control group.The DN group was further divided into the early DN(DN-E)group(n=38)and the late DN(DN-A)group(n=30)according to whether there was a large amount of proteinuria and the severity.Clinical data such as serum albumin(ALB),estimated glomerular filtration rate(eGFR)and albumin-to-creatinine ratio(ACR)were collected.Serum FGL1 level was detected by enzyme-linked immunosorbent assay(ELISA).Pearson linear correlation was used for correlation,the diagnostic value was analyzed by ROC curve.Results Compared with the control group,the levels of ACR,FGL1 in patients with DM group increased,the levels of eGFR decreased,and the differences were statistically significant(t=5.686,4.336,-4.683,all P<0.05).Compated with the DM group,the levels of ACR,FGL1 in patients with DN-E group was increased,and the level of eGFR was decreased,and the differences were statistically significant(t=5.275,3.454,-4.969,all P<0.05).Compared with the DN-E group,the levels of ACR,FGL1 in the DN-A group were increased,the levels of eGFR were decreased,and the differences were statistically significant(t=7.881,7.051,-5.596,all P<0.05).Serum FGL1 level was negatively correlated with ALB and eGFR(r=-0.638,-0.547,all P<0.05),and positively correlated with ACR(r=0.691,P<0.05).The AUC(95%CI),specificity and sensitivity of serum FGL1 level in the diagnosis of DN were 0.947(0.908～0.987),100%and 82.4%,respectively.Conclusion The level of serum FGL1 in DN and DM patients is high,and the level of serum FGL1 is closely related to the common metabolic indexes such as ALB,eGFR and ACR in the diagnosis of DN,which may have certain clinical diagnostic value.

Objective To give references for future study,the current state of research and identify key areas of interest,and development trends in the field of Chinese Materia Medica interventions for PD were examined.Methods Literature on Chinese Materia Medica treatment of PD published between 2004 and 2024 was retrieved from the China National Knowledge Infrastructure(CNKI)and Web of Science(WOS)databases.After screening,689 articles were included(412 in Chinese,277 in English).CiteSpace software was used for bibliometric and knowledge graph analysis,generating author collaboration networks,institutional collaboration networks,keyword clustering,timeline maps,and keyword burst analysis.Results Over the past two decades,the number of publications has continued to grow globally.Chinese-language studies focused primarily on clinical research,with core authors such as Yi Liu,Jiancheng He,and Jianfen Liang,and institutions like Guangxi University of Chinese Medicine making significant contributions.English-language literature emphasized mechanistic studies,with Kyung Hee University and Beijing University of Chinese Medicine as leading research teams.High-frequency keywords included"Parkinson's disease"(346 occurrences),"traditional Chinese medicine(TCM)"(60 occurrences),and"oxidative stress"(11 occurrences).Keyword clustering revealed research hotspots in TCM formulas(e.g.,Zhichan decoction),mechanisms(e.g.,oxidative stress),and integrated TCM-Western medicine therapies(e.g.,Madopar).Burst analysis indicated emerging frontiers in the gut-brain axis,iron metabolism,molecular docking,gut microbiota,and signaling pathways.Conclusions Although there is a lot of potential for treating PD in TCM,there are also a lot of challenges.In order to realize the transformation of TCM from a supportive to a mainstream treatment for PD,and to bring better efficacy to patients in the future,it is necessary to strengthen evidence-based research,deepen the research of mechanisms,promote the construction of standards,explore the integration of Chinese and Western medicine,and improve the evaluation system.

BACKGROUND:Surface electromyography has been extensively utilized for monitoring muscle fatigue. However,traditional electromyographic metrics typically focus on individual muscles and fail to assess the variations in a muscle group during the fatigue process. OBJECTIVE:To establish a muscle functional network to extract complex network parameters and investigate the topological property changes of the muscle functional network under different levels of fatigue,aiming to provide theoretical and methodological foundations for fatigue monitoring and prevention. METHODS:Eleven participants performed single-leg leg press exercise at 50％ of one-repetition maximum until exhaustion. Simultaneously,electromyographic signals of seven muscles (rectus femoris,vastus lateralis,vastus medialis,biceps femoris,tibialis anterior,lateral gastrocnemius,and medial gastrocnemius),electrocardiographic signals,and Borg CR-10 scale scores were collected. The Borg CR-10 scale was used to categorize three fatigue stages:mild,moderate,and severe. Heart rate and heart rate variability were calculated to validate the effective division of fatigue stages. Using the coherence of muscle signals,a muscle functional network was constructed with the seven muscles as nodes,and four complex network parameters (clustering coefficient,average weighted degree,global efficiency,and eigenvector centrality) were extracted. Additionally,four electromyographic indices (root mean square,median frequency,instantaneous mean frequency,and co-activation ratio) were extracted and compared under the three levels of fatigue. RESULTS AND CONCLUSION:(1) Differences in heart rate and heart rate variability were observed across three fatigue stages,indicating the effectiveness of fatigue stage delineation. (2) Electromyographic indicators for different muscles under three levels of fatigue:root mean square and co-activation ratio showed no differences;however,median frequency exhibited robust fatigue trends in vastus lateralis,vastus medialis,and biceps femoris,while instantaneous mean frequency demonstrated robust fatigue trends in rectus femoris,vastus lateralis,vastus medialis,and biceps femoris. Instantaneous mean frequency outperformed median frequency and root mean square,yet all three indicators showed robust trends only for the major working muscle groups,unaffected by fatigue factors,unlike the co-activation ratio. (3) The connectivity strength between vastus lateralis and vastus medialis,vastus lateralis and biceps femoris,vastus lateralis and gastrocnemius medialis,and vastus medialis and biceps femoris gradually increased,showing significant differences in average weighted degree,clustering coefficient,and global efficiency post-fatigue,significantly correlated with fatigue levels. To conclude,changes in connectivity strength reflect the synergy and complementarity among muscles during fatigue. Clustering coefficient,average weighted degree,and global efficiency serve as fatigue markers reflecting overall muscle changes.

AIM:To investigate the role and underlying mechanisms of NADPH oxidase 4(NOX4)/transient receptor potential channel subfamily C member 6(TRPC6)in the context of podocyte damage in diabetic nephropathya comprehensive investigative study was warranted.METHODS:(1)Male Sprague-Dawley rats were randomly divided in-to four distinct groups:a control group,a diabetic nephropathy group,a NOX4 inhibitor GKT137831-treated group,and a combined diabetic nephropathy with NOX4 inhibitor GKT137831-treated group,each consisting of 8～10 rats.The type 1 diabetes mellitus model was constructed via a single intraperitoneal injection of streptozotocin(STZ)(70 mg/kg),subse-quent to the successful induction of the model,GKT137831(at the dose of 5 mg/kg)was administered intraperitoneally.Regular monitoring of blood glucose levels was conducted,and urinary albumin excretion was quantified after 24 hours.Moreover,blood and kidney tissues were harvested for further analysis.(2)Mouse glomerular podocytes were divided into four distinct groups:a normal control group,a high glucose group,a GKT137831-treated group and a high glucose GKT137831-treated group.These podocytes were subsequently cultivated in vitro under high glucose conditions for 2 weeks.Thereafter,transfection of podocytes was carried out using NOX4 inhibitors and short interfering RNA targeting(siRNA)TRPC6.To detect the expression levels of NOX4 and TRPC6,a battery of techniques including Western blot,Immunohistochemistry,and reverse transcription polymerase chain reaction(RT-qPCR)were employed.(3)The morpho-logical changes of podocyte mitochondria under the condition of high glucose were observed by fluorescence confocal mi-croscopy,and the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1α(PGC1α),mito-chondrial transcription factor A(TFAM),cytochromec oxidase subunit Ⅰ(COX Ⅰ)and cytochromec oxidase subunit Ⅳ(COX Ⅳ)in podocytes were assessed utilizing the Western blot technique.RESULTS:(1)Compared with normal con-trol group,mice with diabetic nephropathy manifested pronounced glomerular hypertrophy,thickening of basement mem-brane,expansion of the mesangial region,and an increased rate of urinary albumin excretion was observed.Analytical techniques such as Western blot and Immunohistochemistry showed a significant upsurge in the expression level of the NOX4 protein in kidney tissue,a diminished expression of glomerular podocyte protein(nephrin),an increased expression of interstitial cell markers(desmin),and an enhanced level of TRPC6 expression(P＜0.05).GKT137831 was assoiated with a reduction in desmin expression in renal tissue,preservation of glomerular nephrin expression,and a decrease in uri-nary albumin excretion(P＜0.05).(2)In vitro podocyte experiment,the expression of NOX4 and TRPC6 in podocyte was significantly increased in the context of high glucose(P＜0.05).Findings from Immunofluorescence and Western blot showed that GKT137831 effectively diminished the expression levels of TRPC6 and desmin while partially rescuing neph-rin expression in podocellular cells(P＜0.05).Western blot results showed that transfection of TRPC6 small interfering RNA could further promote the protective effect of GKT137831 on podiocytes.(3)Under high-glucose conditions,fluores-cence confocal microscopy revealed mitochondrial morphological damage in podocytes.However,therapeutic intervention with GKT137831 and transfection of TRPC6 siRNA partially rescued the mitochondrial structural integrity.Under high glucose conditions,immunoblot analysis demonstrated a marked decrement in the protein expression levels of PGC1α,TFAM,COX Ⅰ,and COX Ⅳ in podocytes.Importantly,GKT137831 and the transfection of TRPC6 siRNA significantly upregulated the levels of PGC1α,TFAM,COX Ⅰ,and COX Ⅳ(P＜0.05).CONCLUSION:In the context of the patho-genesis of diabetic nephropathy,the increased expression of NOX4 in the kidneys contributes to podocyte damage,with the effect being partially mediated via the TRPC6 channel.Inhibiting the NOX4-TRPC6 signaling pathway has the potential to ameliorate mitochondrial dysfunction in podocytes.This finding offers novel perspectives and strategies for the clinical di-agnosis and treatment of diabetic nephropathy.

Objective:To construct a debriefing and reflection training program for nursing undergraduate interns, and to provide a basis for implementing such a program and improve the practical clinical skills of the interns.Methods:Based on competency theory, the draft of the debriefing and reflection training program for undergraduate nursing interns was constructed through literature review and expert conference discussion. Delphi expert consultation was conducted from August to October 2024, and the final version of the program was established based on the experts' opinions. The weight of each indicator was determined using the analytic hierarchy process. Excel 2019 was used for data entry, and SPSS 19.0 was used for data analysis.Results:Two rounds of expert consultation were conducted, with a questionnaire recovery rate of 100.00% for both. The experts consulted in the second round had an authority coefficient of 0.861, a coefficient of variation for each index of 0.048 to 0.237, and a Kendall's concordance coefficient of 0.137 ( P<0.05). The final program included 5 primary indicators, 16 secondary indicators, and 73 tertiary indicators. Conclusions:The debriefing and reflection training program for undergraduate nursing interns proposed in this study has high scientifical validity and reliability. It can provide a reference for debriefing and reflection training of nursing undergraduate interns in China, thereby cultivating qualified clinical nursing talents.

Objective To develop a three-compartment kinetic fatigue model for the isometric muscle endurance of the hip,knee,and ankle joints at 50％IPT(isometric peak torque),so as to provide a theoretical basis for simulation-based assessments and load evaluations in biomechanics and sports science.Methods The IPT of the hip,knee,and ankle joints was measured in 40 male university students.Isometric endurance tests were then performed on all three joints at 50％IPT until exhaustion.Electromyography data and endurance time(ET)of major lower limb muscles were collected concurrently.The differences between ETs predicted by models based on previously recommended F and R parameters and actual ETs were analyzed.Subsequently,experimental ETs were used in a grid search to optimize Fand R parameters,allowing for the development of an accurate three-compartment kinetic model.Results The ET of the hip and ankle joints was significantly longer than that of the knee joint(P＜0.001).Models using previously recommended Fand R parameters overestimated ET,with significantly higher predicted values than experimentally measured ET(P＜0.001),as well as elevated root mean squared error(RMSE)and mean relatvie error(MRE)values.The grid search successfully identified Fand R parameters for the three-compartment model in isometric endurance tests of lower limb joints,with no statistical difference between model-predicted ET and experimental ET(P＞0.05).Conclusions The developed model in this study can serve as an indirect measurement tool for evaluating load in similar activities.