Rheumatoid arthritis (RA) is characterized by persistent synovial inflammation and progressive bone destruction. Transcriptomic profiling identified hyperactivated B cells as key contributors to osteoimmune dysregulation, supporting localized B cell intervention as a therapeutic strategy. Here, an injectable thermosensitive hydroxypropyl chitin hydrogel incorporating Cu/Zn-doped bioactive glass particles, termed BG@HPCH, was developed for localized metalloimmunotherapy. BG incorporation improved the shear-thinning behavior, thermosensitive gelation, storage modulus, and stability of the hydrogel. In vitro, ionic release from BG@HPCH selectively reduced pathogenic B cell survival while preserving mesenchymal stem cell (MSC) viability. The optimized M-BG@HPCH increased the B cell dead-cell area from 1.93 ± 0.48% to 91.12 ± 0.90% at 24 h, while maintaining MSC viability at 98.59 ± 0.26% after 3 days. In TNF-transgenic mice, a single intra-articular injection of BG@HPCH reduced arthritis index scores from 2.88 ± 0.18 to 1.81 ± 0.13 at day 28, limited bone erosion, and showed no detectable systemic toxicity. Micro-CT analysis showed improved bone preservation, with BV/TV increasing from 30.00 ± 6.74% to 55.66 ± 1.07%. OCN staining further confirmed enhanced osteogenic activity, with the OCN+ area increasing by 2.16 times. Flow cytometry confirmed reduced B220+CD45.2+ B cell accumulation in treated joints. Single-cell RNA sequencing of 23,921 joint cells showed that BG@HPCH reduced inflammatory B cell, macrophage, and fibroblast subsets while expanding osteoblast-associated regenerative populations, accompanied by suppression of CD23− and CD74-associated B cell signaling axes. These findings establish BG@HPCH as a localized immunoregenerative biomaterial for coordinating pathogenic B cell depletion and bone repair in RA.
Coronary artery disease (CAD), primarily caused by arterial stenosis or occlusion, remains a leading cause of mortality worldwide. Invasive coronary angiography (ICA) is the clinical gold standard for CAD diagnosis and treatment planning, yet its effectiveness critically depends on accurate coronary artery segmentation and stenosis assessment. However, ICA images are often affected by low contrast, severe noise, and complex multi-scale vascular morphology, substantially challenges existing segmentation methods. This study aims to improve the robustness and reliability of ICA-based coronary artery segmentation and stenosis detection by learning structure-consistent representations that jointly capture geometric priors, cross-dataset variability, long-range spatial dependencies, and frequency-aware vascular features. We propose SFD-Mamba2Net, an end-to-end framework for coronary artery segmentation and stenosis detection. A Curvature-Aware Structural Enhancement (CASE) module is introduced in the encoder to highlight elongated vascular structures while suppressing background interference. To alleviate performance degradation induced by inter-dataset discrepancies, a Supervised Domain Adaptation (SDA) strategy is incorporated at the bottleneck to encourage domain-invariant feature learning. Long-range spatial dependencies and complex vessel topology are modeled via an Axial-Alternating Dual-Stream Mamba2 (AA-DS Mamba2) module. In the decoder, a Progressive High-Frequency Perception (PHFP) module integrates multi-level wavelet decomposition with deep convolution to refine high-frequency vascular details while preserving global structural. Experiments on three large-scale ICA datasets show that SFD-Mamba2Net achieves superior segmentation accuracy and strong cross-domain generalization, obtaining Dice scores of 89.31%, 77.01%, and 74.14% on JSPH-ICA, DCA1, and ARCADE, respectively. It also achieves high true positive and positive predictive values in stenosis detection, demonstrating robustness and clinical potential.
Nitric oxide (NO)-based therapy represents a promising noninvasive treatment strategy for peripheral artery disease (PAD) by enhancing microvascular and endothelial function. However, the efficacy of NO is severely limited by vascular sparsity and dysfunction in PAD patients, which hinder efficient targeted delivery of highly unstable NO and reduce the conversion efficiency of NO donors at the lesion site, even with the assistance of NO carriers. To address this, we developed novel ultrasound-responsive dual-drug-loaded nanodroplets (A&C-NDs) using a modified ultrasonic emulsification method for co-loading and targeted delivery of L-arginine (L-Arg) and cilostazol (CLZ). The A&C-NDs exhibited uniform size, high drug-loading efficiency, and favorable ultrasound imaging capability and ultrasound-responsive drug-release properties, enabling effective drug accumulation and penetration in ischemic limbs. Importantly, ultrasound-triggered vaporization and CLZ release synergistically activated endothelial nitric oxide synthase (eNOS), significantly enhancing local NO production. Through targeted modulation of the eNOS/NO pathway, this system successfully achieved limb preservation in mouse models of hindlimb ischemia. Non-invasive super-resolution ultrasound (SRUS) imaging and immunofluorescence staining further demonstrated that the combination of ultrasound and A&C-NDs promoted vasodilation and microvascular angiogenesis, while attenuating muscle injury in the ischemic limbs, resulting in comprehensive therapeutic improvement. Collectively, this study presents a novel ultrasound-activated nanoplatform that combines synergistic L-Arg/CLZ delivery with localized ultrasound stimulation to precisely activate the eNOS/NO pathway, promoting angiogenesis and tissue repair, thereby offering a new strategy for the noninvasive treatment of limb ischemia.
Abstract Background The simplified risk stratification tool from the 2018 WSPH has become widely accepted for evaluating the severity of conditions in patients with pulmonary arterial hypertension (PAH) and plays a crucial role in guiding treatment. In this study, we aimed to explore the value of soluble suppression of tumorigenicity 2 (sST2) in assessing the prognosis of connective tissue disease-associated PAH (CTD-PAH) patients based on simplified risk stratification. Methods Based on the inclusion and exclusion criteria, a total of 84 patients with CTD-PAH diagnosed by right heart catheterization were enrolled in this study. A retrospective chart review was completed to assess the clinical presentation and laboratory test results of the patients. The baseline risk stratification of all patients was assessed using the simplified risk stratification model proposed by the 2018 WSPH. The endpoint of the study was clinical worsening. Survival rates were evaluated using Kaplan‒Meier analysis, and differences between the groups were compared using the log-rank test. Results (1) Patients classified as intermediate or low risk demonstrated no difference in the event-free survival rate. (2) A sST2 concentration ≥ 35 ng/mL can predict the occurrence of clinical worsening events in low- and intermediate-risk patients. (3) The event-free survival rate was significantly lower in patients whose sST2 levels were maintained or increased to > 35 ng/mL within 1 year. Conclusion sST2 enhances the prognostic value of simplified risk stratification in patients with CTD-PAH, most notably in the intermediate-risk group. Furthermore, variations in sST2 levels may predict the clinical prognosis of this disease.
Transcutaneous auricular vagus nerve stimulation (taVNS) has emerged as a promising neuromodulation technique for enhancing cognitive functions such as working memory (WM), yet its neural mechanisms remain unclear. In this study, fifty healthy young adults were randomly assigned to an active taVNS group or a sham group in a single-blind, sham-controlled design. Participants performed semantic and spatial 2-back WM tasks before and after stimulation. Hemodynamic activity was measured by functional near-infrared spectroscopy (fNIRS), autonomic activity was assessed by heart rate variability (HRV), and cortical excitability was indexed by central motor conduction time (CMCT) derived from single-pulse transcranial magnetic stimulation (TMS). Compared to sham, taVNS significantly accelerated reaction times across tasks and increased HRV metrics (HF, SDNN, RMSSD), indicating enhanced parasympathetic regulation. In addition, CMCT was shortened, reflecting improved corticospinal transmission efficiency. fNIRS revealed lateralized activation patterns, with greater hemodynamic engagement in regions corresponding to the left supramarginal gyrus (SMG.L) in semantic tasks and the putative right SMG (SMG.R) in spatial tasks. Mediation analyses suggested that HRV modulated semantic WM performance via SMG.L activation, while spatial WM performance was mediated by CMCT reduction. These findings support a neural resource allocation model in which taVNS facilitates WM through both domain-specific cortical modulation and enhanced efficiency in descending motor pathways, highlighting its potential as a non-invasive intervention to modulate brain–body interactions and enhance cognition.
