Emotional disorders associated with multiple sclerosis (MS) are key drivers of disease progression. Recently, resting-state functional magnetic resonance imaging (rs-fMRI) and cerebrospinal fluid (CSF) metabolites have been found to play a crucial role in elucidating this process, but the causal relationship between them remains to be clarified. Exploring underlying mechanisms is critical for developing targeted therapies, especially combined multidimensional neuromodulation. This study employed bidirectional two-sample Mendelian randomization (MR) analysis to investigate the causal relationships between 191 rs-fMRI phenotypes and MS, while also exploring the mediating role of 338 CSF metabolites. Forward MR analysis revealed that enhanced functional connectivity in networks such as the saliency and visual networks (pheno56, pheno461, pheno624, pheno932, pheno1183) is related to an elevated risk of MS, whereas enhanced functional connectivity in the motor and attention networks (pheno2, pheno681, pheno705, pheno1322, pheno1696) is linked to a reduced risk of MS. Reverse MR analysis demonstrates that MS exhibits a positive correlation with four of these phenotypes (pheno74, pheno606, pheno767, and pheno1013), and a negative correlation with one phenotype (pheno286). Furthermore, five CSF metabolites-N-formylanthranilic acid, N6-methyllysine, succinimide, methyl glucopyranoside(alpha+beta), and hypoxanthine-were identified as key mediators in the MS process acting through resting-state brain functional networks. The study establishes causal rs-fMRI signatures affecting MS susceptibility and progression, and identifies critical CSF metabolites mediating MS effects via functional networks. These findings not only provide novel intervention targets for MS and related emotional disorders but also lay a theoretical foundation for the development of multidimensional therapeutic strategies leveraging neuromodulation techniques.
Biodegradable zinc (Zn) has limitations in the orthopedic conditions due to its low mechanical strength. Alloying with magnesium (Mg) and thermomechanical process are effective ways to overcome the limitations. This work demonstrates that the average grain size decreases from 10.4 mu m in the as-extruded Zn-0.2 Mg alloys to the lowest value of 3.2 mu m after multi-directional compression (MDC) for 18 passes. A notable increase in twin boundary density was observed in the MDC-treated samples, reaching a peak of 53.52%. During processing, dislocation density initially rose and subsequently declined. The refinement of grains and the proliferation of twin boundaries were key factors enhancing the alloy's strength. The as-extruded sample exhibited a tensile strength of 309 MPa and an elongation of 27.8%. Following MDC, strength increased to 408 MPa for both 12p and 18p samples, while peak elongation reached 30.6%. Regarding corrosion behavior, corrosion rates slightly decreased from 0.174 mm/year in the as-extruded condition to 0.139 mm/year after 12p-MDC, a result associated with the formation of stable corrosion films that suppressed localized attack. Furthermore, alloy extracts promoted high cell viability over extended culture durations or under one-fold dilution. Compared to bioinert titanium, the Zn alloy extracts also demonstrated enhanced in vitro osteogenic potential. The in-vivo experiments also demonstrate the formation of more new bone around biodegradable implants. Collectively, these findings suggest a promising route to boost mechanical strength in biodegradable Zn alloys, supporting their potential use in orthopedic implant applications.
2-diethylamino-N-2,5-dimethylphenyl acetamide (JM25-1), a novel anti-inflammatory agent with epithelial barrier protective function, requires comprehensive pharmacokinetic evaluation to support clinical translation. A quantitative analysis method was developed to characterize the pharmacokinetics of JM25-1 in Wistar rats after oral and intraperitoneal (i.p) administration. Plasma, obtained via centrifugation and methanol protein precipitation, was analyzed using HPLC-MS/MS. Chromatographic separation was achieved on a Kinetex column embedded with C-18 stationary phase, using a binary-gradient mobile phases consisting of water containing 0.1% formic acid (phase A) and methanol containing 0.1% formic acid (phase B). The flow rate was set at 0.6 mL min(-1) with a total run time of 4 min. Mass spectrometric detection was performed by monitoring the m/z transitions of 235.1/86.2 and 235.1/58.1 for JM25-1, 241.2/86.2 and 241.2/58.1 for Lidocaine-d6 (used as internal standard) in the electrospray ionization positive mode. The method exhibited excellent linearity over concentration ranges of 1-200 ng mL(-1) (r(2) = 0.9998). All validation parameters, including specificity, extraction recovery (89.65-98.44%), matrix effect (absolute: 97.22-99.82%; relative: <15%), accuracy (87.93-104.18%), and precision (intra- and inter-day RSD <= 7.26%), met bioanalytical acceptance criteria. Stability assessments confirmed that JM25-1 remained stable under all tested conditions. Pharmacokinetically, oral administration showed rapid absorption (t(max) = 10 min) but significantly lower systemic exposure compared to i.p, resulting in low bioavailability. This study developed a rapid, sensitive, and reproducible HPLC-MS/MS method for JM25-1 quantification in rat plasma, and the validated method was successfully applied to the pharmacokinetic study of JM25-1 following oral and i.p administration.
Photodynamic therapy (PDT) is an effective adjunct treatment for oral squamous cell carcinoma (OSCC). Enhancing photosensitizer targeting and inducing effective cytotoxic T-cell responses through photoimmunotherapy have become key strategies to improve PDT efficacy. Migrasomes, as vesicular structures assembled by TSPAN4 and cholesterol microdomains, are implicated in immune escape and are emerging as sensitization targets for PDT. Here, we report a biomimetic nanoplatform, MOF-919@CCM, that combines enhanced tumor-cell membrane adhesion with light-controlled cholesterol degradation. Cloaking with a homologous cancer-cell membrane (CCM) imparts specific adhesion to tumor cells and improves targeted delivery of the photosensitizer. Moreover, the transition-metal nodes of MOF-919 exhibit peroxidase- and catalase-like activities that alleviate tumor hypoxia and, under laser irradiation, effectively reduce cellular cholesterol levels. Experiments further revealed that PDT based on MOF-919@CCM markedly suppresses migrasome formation via effective degradation of cholesterol and promotes CD8⁺ T-cell infiltration and cytotoxic activity against tumor cells. This work develops a targeted PDT approach using MOF-919@CCM and provides a new strategy for the immunotherapy of OSCC.
Background:The complexity of coronary artery lesions and glucose metabolic disorders contributes to adverse long-term prognosis following percutaneous coronary intervention (PCI). This study aimed to evaluate the synergistic effect of coronary artery lesions-assessed by the SYNTAX score-and glucose metabolic disorders-quantified by the hemoglobin glycation index (HGI)-on predicting major adverse cardiac and cerebrovascular events (MACCEs) after PCI. Methods:A total of 609 coronary artery disease (CAD) patients undergoing PCI were enrolled in the final analysis. HGI was calculated by subtracting the predicted HbA1c (derived from fasting plasma glucose regression) from the observed HbA1c. Pearson's coefficients were used for correlation analyses. Kaplan-Meier and Cox regression analyses were used to assess associations with MACCEs. Mediation analysis evaluated whether the SYNTAX score mediated the HGI-MACCEs relationship. Results:Patients with higher HGI and SYNTAX scores (≥1.16764 and >22, respectively) exhibited a significantly increased mortality risk (p = 0.0052) and more complex coronary lesions. Multivariable analysis confirmed HGI and SYNTAX score as independent predictors of MACCEs. Additionally, the SYNTAX score partially mediated the association between HGI and adverse outcomes, with a mediation proportion of 13.05%. Conclusion:The HGI and SYNTAX score exert a synergistic effect in predicting the severity of CAD and the risk of adverse prognosis after PCI. It highlights the necessity of integrating both metabolic and anatomical assessment indices for comprehensive risk stratification of CAD patients undergoing PCI.
