Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3), represents the most common autosomal dominant cerebellar ataxia worldwide. Despite its progressive and debilitating nature, disease-modifying therapies remain elusive. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a promising non-invasive intervention; however, its clinical application has been hindered by inconsistent protocols and a lack of mechanistic understanding. A recent landmark study published in Brain Stimulation by Chen et al. addressed these challenges by combining a high-dose intermittent theta-burst stimulation (iTBS) protocol with concurrent transcranial magnetic stimulation-electroencephalography (TMS-EEG). This commentary provides an in-depth analysis of their findings, highlighting the restoration of cerebello-cortical inhibition (CBI) as a key therapeutic mechanism. Furthermore, we discuss the broader implications of this work, proposing that future translational research should integrate accelerated iTBS (aiTBS) paradigms, cortical response measurements (CRM), and individualized neuro-navigation to establish a new era of precision neuromodulation for ataxia.

ObjectiveTo investigate the T lymphocyte subset levels and viral loads in newly human immunodeficiency virus (HIV) antibody-confirmed positive cases in Suzhou (2021‒2024), and to analyze potential influencing factors by integrating their demographic characteristics, immune status, and viral replication patterns, thereby providing evidence for HIV/acquired immune deficiency syndrome (AIDS) prevention and control. MethodsPeripheral whole blood samples were collected from newly confirmed HIV-positive cases in Suzhou from 2021 to 2024. T lymphocyte subset analysis and viral load testing were performed, and influencing factors were identified in combination with demographic characteristics. Logistic regression models were employed to identify factors associated with CD4⁺T lymphocyte counts ≤350 cells·μL^-1, and Spearman’s rank correlation test was used to analyze the correlation between logarithmic value of viral load and CD4⁺/CD8⁺ ratio. ResultsAmong the 3 022 confirmed HIV-positive samples, the median CD4⁺T lymphocyte count was 298.00 cells·μL^-1, with 882 cases (29.19%) showing CD4⁺ T lymphocyte counts <200 cells·μL^-1. The median CD8⁺T lymphocyte count was 1 011.00 cells·μL^-1. The median CD4⁺/CD8⁺ ratio was 0.28, with 32.46% of cases exhibiting CD4⁺/CD8⁺ ratios <0.20, and there were statistically significant differences in CD4⁺/CD8⁺ ratio among different genders, age groups, marital status, and sample sources (all P<0.05). Multivariate logistic regression analyses indicated that individuals aged ≥20 years, those who were divorced or widowed, and cases identified through medical institutions had a significantly higher proportion of CD4⁺T lymphocyte counts ≤350 cells·µL⁻¹ compared to those aged <20 years, unmarried individuals, and cases sourced from voluntary counseling and testing (VCT) clinics, respectively. The mean logarithmic value of viral load was (4.29±1.15) copies·mL^-1. The logarithmic value of viral load demonstrated a significantly negative correlation with both CD4⁺/CD8⁺ ratio (r=-0.43, P<0.001) and CD4⁺T lymphocyte count (r=-0.37, P<0.001). ConclusionA substantial proportion of newly diagnosed HIV/AIDS cases in Suzhou are late presenters with high viral load levels. Targeted interventions should prioritize high-risk populations through enhanced active surveillance and the implementation of combined T lymphocyte subsets analysis and viral load testing, which can enable earlier case-finding and timely antiretroviral therapy initiation.

3CL protease (3CLpro) of SARS-CoV-2 is a pivotal enzyme required in coronavirus replication and transcription. Its highly conserved structure and the absence of homologous proteins in the host make it an ideal target for broad-spectrum anti-coronavirus drug development. In this work, we systematically investigated and compared the binding modes and dynamic properties of the four stereoisomers of a pyridyl-urea diyne ester (PyDU) molecule with two chiral centers within the 3CLpro active site. Through molecular docking, MD simulations, MM/GBSA binding free-energy calculations, and DCCM analysis, all four stereoisomers were stabilized primarily by hydrophobic packing. Among them, the (R,S) isomer exhibited the best overall performance, including docking score, binding free-energy components, and key residue interactions. The (R,S) and (S,R) isomers also enhanced the cooperative motions around the binding pocket, while the (R,S) isomer further modulated the flexibility of domain III, which may influence 3CLpro dimerization. Conversely, the (S,S) isomer exhibited the weakest affinity due to insufficient hydrophobic contact. By innovatively integrating chirality, binding energy and protein dynamical features, we revealed the dual role of chirality in modulating affinity and dynamic responses, which provides a theoretical basis for the chiral-guided design of coronavirus inhibitors.

OBJECTIVE To identify the active components of Desmodium styracifolium （Osb.） Merr. extract （DME） against cholestatic liver injury （CLI）， and to verify its target and molecular mechanism， so as to provide scientific evidence for the clinical application of D.styracifolium （Osb.） Merr. and the development of new hepatoprotective agents.METHODS High-performance liquid chromatography was applied to establish fingerprints of 19 batches of DME， followed by similarity evaluation and identification of common peaks. An in vitro CLI model was constructed by lithocholic acid （LCA）-induced injury in HepG2 cells to evaluate the in vitro protective effect of DME against CLI. Spearman correlation analysis， grey relational analysis and partial least-squares regression analysis were adopted to investigate the spectrum-effect relationship of DME against CLI and preliminarily screen the core active components. Molecular docking and surface plasmon resonance technology were used to predict and verify the binding capacity between core active components and farnesoid X receptor （FXR）. qRT-PCR， Western blot and immunofluorescence staining tests were performed to validate the influences of core active components on the expression of molecules related to FXR/bile salt export pump （BSEP） pathway in CLI model cells.RESULTS A total of 12 common peaks were calibrated in the fingerprints of 19 batches of DME， and the similarity values were all above 0.990. Four common peaks were identified， namely peak 6 （schaftoside）， peak 7 （isoorientin）， peak 11 （isoschaftoside） and peak 12 （isovitexin）. DME at 80 μg/mL exerted the optimal protective effect on CLI-model cells， and the cell viability reached （75.66±4.60）% after 24 h of treatment. Spectrum-effect analysis revealed that schaftoside possessed the strongest correlation with the anti-CLI activity of DME and served as the core active component. Target prediction and validation results showed that the binding energy between schaftoside and FXR was －8.1 kcal/mol， and the equilibrium dissociation constant was 27.3 μmol/L. Mechanistic experiments demonstrated that 100 μmol/L schaftoside significantly elevated the expression levels of FXR and BSEP， and mRNA of their encoded genes Nr1h4 ， Abcb11 in CLI-model cells （ P ＜0.05）.CONCLUSIONS Schaftoside may be the core active component of DME against CLI， and its mechanism may be related to the activation of FXR/BSEP pathway.

Objective:To explore the mediating role of dietary health beliefs in the relationship between family functioning and the frequency of sugar-containing food intake among adolescents with dental caries, in order to clarify the underlying mechanism through which dietary health beliefs influence caries-related dietary behaviors via family factors.Methods:Using convenience sampling method, we selected adolescents patients diagnosed with dental caries and their parents who visited the Affiliated Stomatological Hospital of Nanjing Medical University from July to September 2023 as the research subjects. Conducted a cross-sectional survey using a general information questionnaire, Family Functioning Scale, Adolescent Dietary Health Belief Scale, and Sugar-Sweetened Diet Intake Frequency Scale. Mediation analysis was conducted.Results:A total of 475 questionnaires were distributed, and 460 valid responses were obtained, yielding a valid response rate of 96.84%. Among the 460 adolescent patients, 306 were female and 154 were male, with a mean age of (13.42 ± 1.17) years old. The mother's age was (40.28 ± 4.24) years old, and the father's age was (42.12 ± 4.48) years old. The score for the frequency of sugar-containing food intake was 15.95 ± 5.34, the dietary health belief score was 75.57 ± 18.62, and the family functioning score was 174.24 ± 25.39. Family functioning was positively correlated with dietary health beliefs ( r = 0.428, P<0.05), and negatively correlated with the frequency of sugar-containing food intake ( r = -0.225, P<0.05). Dietary health beliefs were negatively correlated with the frequency of sugar-containing food intake ( r = -0.332, P<0.05). The mediating effect of dietary health beliefs on the relationship between family functioning and sugar-containing food intake frequency was -0.332, accounting for 43.92% of the total effect. Conclusions:Dietary health beliefs play a partial mediating role between family function and the frequency of sugary diet intake. It is suggested that family function construction should be strengthened to improve adolescents' health beliefs and reduce the incidence of dental caries.

Hyperlipidemia refers to abnormal transport of lipids and metabolic disorders in the blood,which can easily cause cardiovascular diseases.At present,there are many adverse reactions and poor tolerance of chemical drugs.Traditional Chinese medicine and minority medicine have a long history and rich clinical experience,which have the advantages of low cost,convenience,high efficiency and little side effects.To provide reference for clinicians and researchers,the clinical research of traditional Chinese medicine and ethnic medicine in the prevention and treatment of hyperlipidemia was summarized.

A mounting body of research suggests that circRNAs significantly contribute to the develop-ment of myocardial fibrosis.The microarray results of human circular RNA expression profile indicated that circHERC4_041 expression increased in the myocardium of patients with heart failure,RT-qPCR a-nalysis confirmed that the myocardial expression level of circHERC4_041 in individuals with heart failure were considerably elevated compared to that in healthy organ donors.Fluorescence in situ hybridization(FISH)confirmed that circHERC4_041 was abundant in the cytoplasm of human cardiomyocyte AC16.Overexpression of circHERC4_041 in mouse myocardial fibroblasts(mCFs)mediated by adenovirus in-hibited the expression of fibrosis-related proteins in mCFs.Experiments involving cell proliferation,wound healing,and Transwell assays demonstrated that overexpression of circHERC4_041 suppressed the growth and mobility of mCFs(P＜0.001).Sequence analysis results suggested that circHERC4_041 con-tains potential ribosome entry sequence(IRES)and open reading frame(ORF).Western blot confirmed that circHERC4_041 could translate the 516 amino acid HERC4-516aa protein,which was mainly located in the cytoplasm of the cell.Cell functional experiments confirmed that circHERC4_041 inhibited the fi-brotic phenotype of mCFs by specifically translating HERC4-516aa(P＜0.05).The specific interaction between HERC4-516aa and transglutaminase 2(TGM2)was confirmed by IP-MS screening and Co-IP i-dentification.Further results found that the degradation of TGM2 was promoted through proteasome path-way.The overexpression of TGM2 in mCFs facilitated by adenoviral vectors could counteract the suppres-sive effects of HERC4-516aa on the fibrotic phenotype of mCFs.Therefore,this study confirmed that the HERC4-516aa protein translated by circHERC4_041 can specifically bind to TGM2 to inhibit the fibrotic phenotype of myocardial fibroblasts.

Objective:To investigate the effect of microRNA-204-5p (miR-204-5P) on silica (SiO 2) -induced inflammatory response in macrophages and its mechanism. Methods:In September 2023, SiO 2-induced mouse macrophage (RAW264.7) model in vitro was constructed. The experiment was divided into blank control group, SiO 2 treatment group, SiO 2+ mimic transfection control group and SiO 2+ mimic transfection group. RAW264.7 cells were evenly seeded into 6-well plates and cultured for 24 hours prior to transfection. The SiO 2+mimic control group and SiO 2+mimic group were transfected with miR-204-5P mimic control and miR-204-5P mimic, respectively. After 6 hours of transfection, except for the blank control group, the other three groups were treated with SiO 2 suspension, while the blank control group received an equal volume of PBS for 24 hours of stimulation.Cell viability was detected by CCK-8 assay. RT-qPCR was used to detect the mRNA expression levels of miR-204-5P and dishevelled 3 (DVL-3) in cells. Western blot was used to detect Wnt/β-catenin pathway related proteins DVL-3, β-catenin, T cell factor 4 (TCF4) and matrix metalloproteinase 9 (MMP-9) . JAK2/STAT3 pathway related proteins Janus kinase 2 (JAK2) , signal transducer and activator of transcription 3 (STAT3) , phosphorylated JAK2 (p-JAK2) , phosphorylated STAT3 (p-STAT3) ; Inducible nitric oxide synthase (iNOS) expression level. ELISA was used to detect the expression levels of inflammatory factors interleukin-6 (IL-6) , tumor necrosis factor-α (TNF-α) and transforming growth factor-β1 (TGF-β1) in cell supernatant. The t test was used to compare the differences between the two groups, and the one-way analysis of variance was used to compare the differences among multiple groups. Results:Compared with SiO 2+ mimic transfection control group, the cell viability of SiO 2+ mimic transfection group had no significant change. The mRNA and protein levels of DVL-3 were significantly decreased ( P<0.05) . The protein expression levels of β-catenin, TCF4 and MMP-9 were significantly decreased ( P<0.05) . The protein expression levels of p-JAK2 and p-STAT3 decreased. The levels of inflammatory factors IL-6, TNF-α, and TGF-β 1 and the expression level of protein iNOS were significantly decreased ( P<0.05) . Conclusion:miR-204-5P alleviates SiO 2- induced macrophage inflammation by regulating the wnt/β-catenin pathway and JAK2/STAT3 pathway.

[Objective]To investigate the regulatory effect and potential mechanisms of isocitrate dehydrogenase 3A(IDH3A)on cardiomyocyte hypertrophy.[Methods]The expression of IDH3A in the myocardium of healthy volunteers(n=10)and patients with heart failure(HF)(n=10),and in the myocardium of mice subjected to transverse aortic constriction(TAC)surgery and sham operation,as well as in phenylephrine(PE)-induced neonatal rat ventricular cardiomyocytes(NRVCs),was assessed by real-time quantitative polymerase chain reaction(RT-qPCR)and Western blot assay.The effect of adenovirus-mediated overexpression of IDH3A on the expression of hypertrophy-related genes in PE-induced NRVCs was also evaluated.The effect of IDH3A on NRVCs area was examined by phalloidin staining assay.A mutant of IDH3A with abolished enzymatic activity,IDH3A_D208A,was generated through site-directed mutagenesis.The impact of this IDH3A mutant on the hypertrophic phenotype,ATP and ROS levels in NRVCs was evaluated to investigate whether the regulatory role of IDH3A in cardiomyocyte hypertrophy was dependent on its enzymatic activity.The effect of exogenous α-ketoglutaric acid(AKG)on cardiomyocyte hypertrophy was also detected by Western blot and phalloidin staining assay,respectively.[Results]IDH3A was significantly decreased in the myocardium of HF patients,in the myocardium of TAC-operated mice,and in PE-induced NRVCs(P=0.005 2,P=0.026 6,P=0.041 3 and P=0.006 6,respectively).Overexpression of IDH3A markedly suppressed the expression of hypertrophy-related genes and the increase of cell size of PE-induced NRVCs(P<0.000 1,P=0.000 1 and P=0.000 2,respectively).The ATP and ROS analysis indicated that IDH3A inhibited the increases of ATP and ROS levels in PE-induced NRVCs(P=0.001 2 and P<0.000 1,respectively),whereas the enzymatically inactive IDH3A mutant lacked this effect.Exogenous AKG provision could,but overexpression of IDH3A mutant failed to suppress PE-induced NRVCs hypertrophy.[Conclusion]IDH3A inhibits cardiomyocyte hypertrophy via elevating AKG level,providing scientific evidence for study on IDH3A-based treatment of cardiac hypertrophy.