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.

ObjectiveTo investigate the protective effect of Xielitang on dextran sulfate sodium （DSS）-induced ulcerative colitis （UC） mice and its possible mechanism. MethodsDSS was used to establish UC model. Sixty mice were randomly divided into a normal group， a model group， a sulfasalazine group （0.6 g·kg^-1）， and low-， medium-， and high-dose Xielitang groups （1.67， 3.34， 6.68 g·kg^-1）. After treatment for 42 d， the colon length was recorded， and the disease activity index （DAI） score was calculated. Enzyme-linked immunosorbent assay （ELISA） was used to detect the serum levels of tumor necrosis factor-α （TNF-α）， interleukin-6 （IL-6）， and interleukin-10 （IL-10）. Hematoxylin-eosin （HE） staining was used to observe the pathomorphological changes of colon. Western blot was used to detect the protein expression of farnesoid X receptor （FXR）， small heterodimer partner （SHP）， liver receptor homolog-1 （LRH-1）， cholesterol 7α-hydroxylase （CYP7A1）， and fibroblast growth factor receptor 4 （FGFR4） in liver and FXR， sodium-dependent bile acid transporter （ASBT）， and fibroblast growth factor 15 （FGF15） in ileum. 16S rRNA sequencing was used to analyze the intestinal flora. Moreover， ultra-high performance liquid chromatography–tandem mass spectrometry was used to detect the bile acid content. ResultsCompared with the normal group， the model group showed significantly decreased colon length， IL-10 content， α-diversity index， abundance of Firmicutes and Lactobacillus， and content of deoxycholic acid （DCA） and lithocholic acid （LCA） （P<0.01）， significantly increased DAI score， IL-6 and TNF-α content， abundance of Bacteroidetes， and the content of cholic acid （CA）， chenodeoxycholic acid （CDCA）， and taurocholic acid （TCA） （P<0.05， P<0.01）， significantly down-regulated protein expression of FXR， SHP， and FGFR4 in liver and FXR， ASBT， and FGF15 in ileum （P<0.01）， and significantly up-regulated protein expression of LRH-1 and CYP7A1 in liver （P<0.01）. In addition， the structure of colonic mucosa was destroyed， and inflammatory cells infiltrated in the model group. Compared with the model group， Xielitang could significantly increase the colon length， IL-10 content， α-diversity index， the abundance of Firmicutes and Lactobacillus， and DCA and LCA content （P<0.05， P<0.01）， decrease DAI score， abundance of Bacteroidetes， and the content of IL-6， TNF-α， CA， CDCA， and TCA （P<0.01）， up-regulate the protein expression of FXR， SHP， and FGFR4 in liver and FXR， ASBT， and FGF15 in ileum （P<0.01）， and down-regulate the protein expression of LRH-1 and CYP7A1 in liver （P<0.01）. The pathological damage of colonic mucosa was obviously alleviated. ConclusionXielitang protects against UC probably by regulating the "intestinal microbiota-bile acid" axis， regulating intestinal flora imbalance， and maintaining bile acid homeostasis.

ObjectiveTo study the regulatory effect of the partial sequence within the 3’ untranslated region （3’UTR） of slit guidance ligand 1 （Slit1） （Slit1-3’UTR） on the fibrotic phenotypes of cardiac fibroblasts （CFs） and its potential mechanism. MethodsThe adenovirus vector was used to overexpress the 1526nt sequence of Slit1-3’UTR in ICR neonatal mouse CFs （mCFs）. The expression of fibrosis-related genes in mCFs， such as collagen type 1 alpha1（COL1A1）， collagen type 3 alpha3 （COL3A1） and alpha smooth muscle actin （α-SMA） were detected by Western blot assay. The effect of Slit1-3’UTR 1526nt on the proliferation and migration of mCFs was assessed by EdU staining and Trans-well assays. Angiotensin Ⅱ （Ang Ⅱ） was used to treat mCFs， and the impact of Slit1-3’UTR 1526nt on the fibrotic phenotypes of Ang Ⅱ-induced mCFs was evaluated. After overexpression of Slit1-3’UTR 1526nt， miR-34a-5p mimic was transfected into mCFs， followed by actinomycin D treatment to detect the mRNA stability of Slit1-3’UTR 1526nt， and the levels of miR-34a-5p and its target gene SIRT1（si-SIRT1） in mCFs were determined. The effects of miR-34a-5p and small interfering RNA targeting SIRT1 on the Slit1-3’UTR 1526nt-mediated regulation of fibrotic phenotypes were also determined. ResultsAdenovirus-mediated overexpression of Slit 1-3’UTR 1526nt was achieved in mCFs. Overexpression of Slit 1-3’UTR 1526nt markedly inhibited the expression of the fibrosis-related genes， proliferation and migration of mCFs and fibrotic phenotypes of Ang Ⅱ. The results of actinomycin D assay showed that miR-34a-5p inhibited the stability of Slit1-3’UTR 1526nt in mCFs， while the level of miR-34a-5p was reduced in mCFs with overexpression of Slit1-3’UTR 1526nt. Transfection of miR-34a-5p promoted the fibrotic phenotypes， and reversed the inhibitory effect of Slit1-3’UTR 1526nt on the fibrotic phenotypes of mCFs. Overexpression of Slit1-3’UTR 1526nt significantly increased the level of miR-34a-5p target gene SIRT1 in mCFs. Transfection of miR-34a-5p and si-SIRT1 consistently reversed the inhibitory effects of Slit1-3’UTR 1526nt on the fibrotic phenotypes of mCFs. ConclusionSlit1-3’UTR1526nt inhibits the fibrotic phenotypes of mCFs by binding to miR-34a-5p and increasing the expression of its target gene of SIRT1.

ObjectiveBola-like short peptides exhibit novel self-assembly properties due to the formation of peptide dimers via hydrogen bonding interactions between their C-terminals. In this configuration, hydrophilic amino acids are distributed at both terminals, making these peptides behave similarly to Bola peptides. The electrostatic repulsive interactions arising from the hydrophilic amino acids at each terminal can be neutralized, thereby greatly promoting the lateral association of β-sheets. Consequently, assemblies with significantly larger widths are typically the dominant nanostructures for Bola-like peptides. To investigate the effect of hydrophilic amino acids on the self-assembly behavior of Bola-like peptides, the peptides Ac-RI₃-CONH₂ and Ac-HI₃-CONH₂ were designed and synthesized using the Bola-like peptide Ac-KI₃-CONH₂ as a template. Their self-assembly behavior was systematically examined. MethodsAtomic force microscopy (AFM) and transmission electron microscopy (TEM) were employed to characterize the morphology and size of the assemblies. The secondary structures of the assemblies were analyzed using circular dichroism (CD) and Fourier transform infrared (FTIR) spectroscopy. Small-angle neutron scattering (SANS) was used to obtain detailed structural information at a short-length scale. Based on these experimental results, the effects of hydrophilic amino acids on the self-assembly behavior of Bola-like short peptides were systematically analyzed, and the underlying formation mechanism was explored. ResultsThe aggregation process primarily involved three steps. First, peptide dimers were formed through hydrogen bonding interactions between their C-terminals. Within these dimers, the hydrophilic amino acids K, R, and H were positioned at both terminals, enabling the peptides to self-assemble in a manner similar to Bola peptides. Next, β-sheets were formed via hydrogen bonding interactions along the peptide backbone. Finally, self-assemblies were generated through the lateral association of β-sheets. The results demonstrated that both Ac-KI₃-CONH₂ and Ac-RI₃-CONH₂ could self-assemble into double-layer nanotubes with diameters of approximately 200 nm. These nanotubes were formed by the edge fusion of helical ribbons, which initially emerged from twisted ribbons. Notably, the primary assemblies of these peptides exhibited opposite chirality: nanofibers formed by Ac-KI₃-CONH₂ displayed left-handed chirality, whereas those formed by Ac-RI₃-CONH₂ exhibited right-handed chirality. This reversal in torsional direction was primarily attributed to the different abilities of K and R to form hydrogen bonds with water. In contrast, Ac-HI₃-CONH₂ formed narrower twisted ribbons with a significantly reduced width of approximately 30 nm, which was attributed to the strong steric hindrance caused by the imidazole rings. The multilayer height of these ribbons was mainly due to the unique structure of the imidazole rings, which can function as both hydrogen bond donors and acceptors, thereby promoting aggregate growth in the vertical direction. ConclusionThe final morphology of the self-assemblies resulted from a delicate balance of various non-covalent interactions. By altering the types of hydrophilic amino acid residues in Bola-like short peptides, the relative strength of non-covalent interactions that drive assembly formation can be effectively regulated, allowing precise control over the morphology and chirality of the assemblies. This study provides a simple and effective approach for constructing diverse self-assemblies and lays a theoretical foundation for the development of functional biomaterials.

Objective To investigate the regulation of synaptic plasticity by cannabinoid receptor 1(CB1R)and its effects on autism spectrum disorder(ASD)-like behavior.Methods CB1R-knockout(KO)mice and valproic acid(VPA)-induced ASD model mice(VPA mice)were used as study subjects.Behavioral experiments were used to assess the effects of CB1R on ASD-like behavior in mice,neuronal structural integrity and dendritic density were detected by microtubule-associated protein 2(MAP2)staining experiments,and the expression of synapse-associated proteins was detected by Western blot,to assess the effects of CB1R on synaptic plasticity.Results Behavioral result showed that VPA mice demonstrated significant ASD-like behavior,while CB1R-/-mice spent a significantly smaller proportion of residence time in the central region of the open field(P＜0.0001),showed significant increases in the number of marbles buried and self-grooming time(P＜0.01),significantly less time spent socializing with unfamiliar mice 2 and exploring unfamiliar objects(P＜0.001),and significantly more time exploring old objects(P＜0.05).The relative dwelling time was significantly reduced in CB1R+/-mice(P＜0.001),and the number of marbles buried and self-grooming time were significantly increased(P＜0.05).Synaptic plasticity assays revealed significant synaptic plasticity impairment in VPA mice.Hippocampal MAP2-positive neuron densities were significantly reduced in CB1R-/-and CB1R+/-mice,and expression levels of synapsin-1 were significantly increased(P＜0.05).Conclusions CB1R KO leads to ASD-like behavior such as anxiety and repetitive stereotyped behavior,social and cognitive impairments,as well as neuronal damage,dendritic dysplasia and disrupted synaptic protein expression in mice,suggesting that CB1R is involved in regulating synaptic plasticity as a pathological mechanism for the development of ASD-like behavior.

Objective:To explore the correlation between palm temperature,disease activity,and traditional chinese medicine syndrome types in patients with rheumatoid arthritis(RA).Methods:80 RA patients(RA group)who were admitted to our hospital from April 2022 to June 2024 were selected,they were divided into high group(DAS28 score＞5.1 score)and low to moderate group(2.6 score ≤ DAS28 score≤5.1 score)according to the 28 joint disease activity scores(DAS28).70 healthy volunteers who underwent physical examinations during the same period(control group)were selected.The palm temperature,erythrocyte sedimentation rate(ESR),C-reactive protein(CRP),and DAS28 scores between the control group and RA group were compared.The palm temperature,ESR,and CRP levels between low to moderate group and high group were compared.The correlation between palm temperature and disease activity,ESR,and CRP levels in RA patients was analyzed by Pearson correlation.The distribution of traditional chinese medicine syndrome types in RA patients was observed,the palm temperature,ESR,and CRP levels of RA patients with different traditional chinese medicine syndrome types were compared.Results:The palm temperature,ESR,CRP levels,and DAS28 score in the RA group were higher than those in the control group(P＜0.05).The palm temperature,ESR,and CRP levels in the high group were higher than those in the low to moderate group(P＜0.05).Pearson correlation analysis results showed that,the palm temperature of RA patients was positively correlated with DAS28 score,ESR,and CRP levels(P＜0.05).Among 80 RA patients,there were 17 cases(21.25％)of liver and kidney deficiency syndrome,23 cases(29.02％)of cold and dampness obstruction syndrome,14 cases(17.86％)of qi and blood deficiency syndrome,17 cases(21.47％)of damp heat obstruction syndrome,and 9 cases(11.52％)of phlegm and blood stasis obstruction syndrome.The palm temperature,ESR,and CRP levels of patients with Qi and blood deficiency syndrome,liver and kidney deficiency syndrome,and phlegm and blood stasis obstruction syndrome increased in sequence and were higher than those of patients with damp heat obstruction syndrome and cold and dampness obstruction syndrome(P＜0.05).There was no statistical difference in palm temperature,ESR,and CRP levels between the groups of damp heat obstruction syndrome and cold and dampness obstruction syndrome(P＞0.05).Conclusion:There is a certain correlation between the palm temperature and disease activity and traditional chinese medicine syndrome types of RA patients.Regular observation of palm temperature,ESR,CRP levels,and DAS28 score is helpful for assessing the condition of RA patients.

OBJECTIVE: To analyze the efficacy and safety of decitabine-based myeloablative preconditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML). METHODS: The clinical characteristics and efficacy of 115 AML patients who underwent allo-HSCT at the First Medical Center of Chinese PLA General Hospital from August 2018 to August 2022 were retrospectively analyzed, including 37 patients treated with decitabine conditioning regimen (decitabine group) and 78 patients without decitabine conditioning regimen (non-decitabine group). The cumulative incidence of relapse (CIR), overall survival (OS), leukemia-free survival (LFS), non-relapse mortality (NRM) and graft versus host disease (GVHD) were analyzed. RESULTS: For the patients in first complete remission (CR1) state before allo-HSCT, the 1-year relapse rates of decitabine group(22 cases) and non-decitabine group(69 cases) were 9.1% and 29.6%, respectively, the difference was statistically significant(P =0.042). The 1-year cumulative incidence of acute graft-versus-host disease (aGVHD) in decitabine group and non-decitabine group was 62.2% and 70.5%, respectively, and the 1-year cumulative incidence of chronic inhibitor-versus-host disease (cGVHD) was 18.9% and 14.1%, respectively, there were no significant differences in the incidence of aGVHD and cGVHD between the two groups (P >0.05). Of the 115 patients, there were no significantly differences in the 1-year CIR(21.7% vs 28.8%, P =0.866), NRM(10.9% vs 3.9%, P =0.203), OS(75.2% vs 83.8%, P =0.131) and LFS(74.6% vs 69.1%, P =0.912) between the decitabine group(37 cases) and the non-decitabine group(78 cases). CONCLUSION Decitabine-based conditioning regimen could reduce the relapse rate of AML CR1 patients with good safety.
Humans ; Leukemia, Myeloid, Acute/therapy* ; Hematopoietic Stem Cell Transplantation/methods* ; Decitabine/therapeutic use* ; Transplantation Conditioning/methods* ; Retrospective Studies ; Graft vs Host Disease ; Transplantation, Homologous ; Male ; Female ; Adult ; Middle Aged ; Adolescent ; Young Adult