Advanced Science最新文献

Rapid caries progression occurs even when salivary flow and calcium phosphate availability are preserved, suggesting a knowledge gap in how available minerals are used for repair. Early-stage Sjögren's syndrome was examined as a clinical model of this condition. Salivary citrate was markedly lower in the disease cohort and was inversely associated with caries burden, whereas salivary flow and the major mineral ions did not differ from healthy controls. In mineralization systems with matched calcium and phosphate concentrations, the disease-associated citrate concentration reduced intrafibrillar mineral deposition, disrupted hydroxyapatite organization, and limited structural and mechanical recovery of demineralized dentin. Human salivary gland tissue, an immunization-induced rat model, and primary salivary gland epithelial cells showed a similar metabolic pattern: increased metallothionein 1/2 (MT1/2), reduced labile Zn²⁺, increased aconitase 2 (ACO2) activity, and citrate depletion. ZnSO₄ repletion increased intracellular Zn²⁺, reduced ACO2 activity, restored citrate toward control levels, and improved the mineralization activity of epithelial-cell supernatants. The data indicate that citrate availability influences dentin mineral utilization and associate citrate depletion with glandular MT1/2-Zn²⁺-ACO2 dysregulation. These findings support an association between glandular zinc-citrate dysregulation and impaired remineralization, suggesting that this mechanism may account for impaired endogenous remineralization despite preserved availability of the major mineral ions.

Anterior cruciate ligament (ACL) reconstruction and related soft-hard tissue repairs remain challenged by grafts that either lack the characteristic "J-shaped" stress-strain profile or sacrifice compliance for stiffness while also offering poor biological integration. Here, we report a silk-glass fiber (SF-GF) hybrid ligament fabricated by scalable three-dimensional braiding, combining industrially available glass fibers with biocompatible silk. By tuning the braiding angle ( ${15}^{\circ }$ - ${45}^{\circ }$ ), the grafts exhibit programmable nonlinear mechanics and viscoelasticity. This design closely replicates the strain-stiffening response and long-term creep resistance of native ligaments. Silk-rich domains promote osseoligamentous integration and osteogenic differentiation, while glass fibers provide high strength and bases for biomimetic mineralization. In rabbit ACL reconstruction, the angle-optimized SF-GFs facilitated prompt tendon-bone healing and restored functional jumping ability within 4 weeks. Finite element modeling rationalizes the strain-dependent load transfer from silk to glass fibers, underlying the characteristic "J-shaped" response. Importantly, this material-structure co-design leverages mass-producible components and a manufacturable braiding process, facilitating translational potentials beyond ACL reconstruction toward diverse soft-hard tissue repairs.

Gel-based wet electrodes remain the gold standard for electrophysiology, but gel dehydration limits recordings. Existing dry electrodes partially address this limitation but suffer from high interfacial impedance. Here, a carbon fiber-based porous electrode (CFPE) is reported, comprising a three-dimensional conductive network coated with poly(3,4-ethylenedioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). The CFPE establishes contact at hairy-scalp sites with an impedance of approximately 10 kΩ·cm². On the forearm, its impedance at 10 Hz without skin preparation is 11.09 ± 1.03 kΩ·cm², compared with 13.57 ± 2.07 kΩ·cm² for wet electrodes. After 6 h of wear, CFPE impedance reaches 1.3 times its initial value without skin preparation or gel, whereas wet-electrode impedance reaches 56 times its initial value when applied with skin preparation and conductive gel. High-fidelity electrocardiography, electromyography, and electroencephalography signals are captured with correlation coefficients exceeding 90% and signal-to-noise ratios comparable to wet electrodes. The CFPE further resolves microvolt-level speech-evoked frequency-following responses (FFR) and long-latency responses (LLR), with fidelity comparable to wet electrodes and significantly higher LLR SNR. These results demonstrate gel-free acquisition of weak neural biomarkers, opening a pathway toward prolonged, preparation-free neurophysiology.

Excess-proton transport in water arises from the coupling of proton transfer (PT), hydrogen-bond rearrangement, and solvent polarization. While equilibrium Grotthuss diffusion has been widely studied, its response under strong electric fields remains difficult to resolve because simulations must capture both chemical reactivity and induced polarization over long time scales. Here, we have developed a reactive and polarizable machine-learning interatomic potential for molecular dynamics simulations of the hydrated excess proton in water. A fine-tuned PiNet2 model provides an accurate zero-field reference for structure and diffusion, while an AD(OS)-based finite-field coupling enables non-equilibrium simulations under an applied electric field. In the linear-response regime, below 0.04 V/Å, the proton mobility obtained from drift velocity agrees closely with the equilibrium diffusion coefficient. The proton drift velocity remains nearly linear with field strength up to 0.15 V/Å, a field strength at which the ionic mobility of a constrained hydronium ion decreases. Our simulations revealed a distinct field-response of protonated water, whose hydrogen-bond network largely preserves its structural fluctuations and mobility without a comparable dielectric-saturation signature. Furthermore, free-energy analysis shows that strong fields stabilize the hydronium species with four-fold H-bond coordination.

Delayed union and pseudarthrosis remain complications of lumbar interbody fusion. We investigated Fuyuan Huoxue decoction (FY) in a rat extreme lateral interbody fusion model. FY improved bone mineral density and trabecular architecture. Reduced inflammatory macrophage infiltration and nuclear factor kappa B (NF-κB) activation at 4 weeks were accompanied by improved bony bridging at 8 weeks. Transcriptomic and network analyses nominated Toll-like receptor 9 (TLR9)/NF-κB signaling for functional investigation. FY-medicated serum reduced macrophage inflammatory markers and extracellular double-stranded DNA (dsDNA), promoted bone marrow mesenchymal stem cell (BMSC) osteogenesis, and attenuated impairment induced by inflammatory macrophage-conditioned medium. DNase treatment reduced this medium's inhibitory effects, whereas a separate exogenous dsDNA challenge impaired osteogenesis and was attenuated by a TLR9 antagonist. TLR9 agonist and antagonist experiments in BMSCs and a 2-week in vivo agonist intervention supported pathway involvement. Human nonunion single-cell data showed increased phospholipid scramblase 1 and interleukin-6 expression in myeloid cells. These findings support complementary pro-osteogenic and anti-inflammatory actions of FY and identify TLR9/NF-κB as a candidate pathway contributing to fusion repair.

To treat acute myocardial infarction (MI), we previously engineered an infusible decellularized extracellular matrix (iECM) biomaterial that reduces vascular permeability and exerts immunomodulatory and pro-reparative effects. To probe the heterogenous contents of iECM and its contribution to infarct localization and downstream biological function, we separated iECM into high and low molecular weight (MW) components. Though mass spectrometry showed similar compositions, biochemical analysis and transmission electron microscopy revealed higher sGAG content within the nanofibrillar high MW, while the globular low MW had more exposed functional groups. These differences translated to a higher binding efficiency of the high MW to ECM proteins and cell surface receptors under flow, while the low MW drove the reduction in vascular permeability. Neither component alone achieved the infarct retention levels of complete iECM, showing that the two components exhibit dependent infarct localization and both are necessary for iECM's overall function. Via single‑nucleus RNA sequencing, both components elicited comparable immunomodulatory and pro‑reparative transcriptional profiles, suggesting that the similarity in composition likely drives the transcriptional response. These findings elucidate the material properties of an intravascularly deliverable ECM biomaterial and how those properties relate to downstream biological behavior, enabling future work investigating nanomaterial mimicry and improvements in material processing and potency.

Continuous, in situ monitoring of sweat biomarkers offers a promising approach for non-invasive metabolic assessment, but its practical implementation remains limited by sensing stability and the insufficiently defined physiological relationship between sweat and systemic biofluids. Here, we develop an epidermal sweat patch that integrates a non-enzymatic electrochemical interface based on Au-Ni(OH)₂ dual aerogels for glucose monitoring. The complementary roles of Ni(OH)₂-mediated glucose adsorption and Au-assisted electrooxidation enable sensitive and stable sensing, with a calculated detection limit of 0.1 µM and >95% signal retention after 5 weeks. Combined with microfluidic sweat sampling, signal processing and wireless communication, the patch enables real-time on-body tracking of sweat glucose during daily activities. In human studies, sweat glucose shows positive associations with interstitial fluid and blood glucose, with Pearson correlation coefficients of up to 0.828, while subgroup analyses further reveal interindividual variability. These results support the physiological relevance of sweat glucose as a complementary signal for metabolic monitoring. Overall, this work integrates non-enzymatic sensing, wearable system design and cross-biofluid analysis within a single platform, providing a practical framework for physiologically interpretable sweat-based glucose monitoring.

Subcellular Spatial Transcriptomics (SST) offers unprecedented opportunities to decipher tissue architecture at subcellular resolution. Consequently, accurate cell segmentation is a fundamental prerequisite for analyzing SST data, as precise transcript assignment is essential for downstream single-cell interpretation. Existing methods often overlook the spatial organization of transcripts, rely on simplified geometric priors, or struggle to coordinate transcript-derived features with morphology-derived spatial guidance. This limitation restricts their adaptability to irregular cell shapes, often leading to transcript misassignment. To address this, we propose SpaCut, a unified deep learning framework designed to effectively integrate transcriptomic feature learning with dynamic morphological guidance. SpaCut comprises a Gene-Wise Attention (GWA) module and a Nuclei-Guided Attentive Fusion (NGAF) module. GWA encodes the high-dimensional transcript map and aggregates features across multiple depths. NGAF uses the encoded transcript features to modulate distance-based nuclear softmasks and refine nucleus-anchored cell boundaries through progressive training. Extensive evaluations across seven datasets from diverse platforms (including Xenium, CosMx, MERSCOPE, and Stereo-seq) demonstrate that SpaCut significantly outperforms state-of-the-art methods in both segmentation accuracy and consistency with single-cell reference data. The source code is available at https://github.com/wenwenmin/SpaCut.

Dopant site occupancy bridges chemical composition, local crystal structure, and macroscopic functional responses in M-type hexaferrites. However, reliable occupancy hypotheses are difficult to establish before structural refinement. Here, we develop a pre-refinement machine-learning framework using 494 dopant-level records extracted from refined structures. This workflow combines Ba/Sr-vs.-Fe sublattice classification, fractional occupancy prediction over five inequivalent Fe sites, and reliability-aware assessment. The CatBoost classifier achieves 96% accuracy on external validation for sublattice assignment. For Fe-sublattice dopants, homogeneous occupancy-model screening and heterogeneous cooperative occupancy-model screening yield a macro mean absolute error as low as 0.0584, while preserving dominant-site identification and occupancy ranking. The results show that dopant site occupancy is jointly controlled by dopant chemistry, target-dopant amount, and co-doping environment rather than a universal site-preference rule. By integrating TabPFN baseline comparison, training-experience assessment, and model-consistency analysis, the framework identifies boundary and extrapolative samples that require priority refinement. Our predictions for W-doped and Sc-doped M-type hexaferrites successfully reproduce key experimental occupancy trends. This work offers a practical data-driven strategy to generate physically plausible occupancy hypotheses and assign refinement priorities for partially occupied oxide systems.

Resistance to bortezomib (BTZ) represents a major obstacle that limits the therapeutic efficacy and worsens the prognosis of multiple myeloma (MM). Ferroptosis, a form of regulated cell death triggered by excessive lipid peroxidation, has garnered increasing attention for anticancer intervention, yet the mechanisms underlying ferroptosis in MM remain enigmatic. Here, we confirmed that ALDH2 is upregulated in MM patients and that its altered expression is closely associated with BTZ resistance and poor prognosis. Functionally, ALDH2 promoted the proliferation, BTZ resistance, and ferroptosis resistance of MM cells, suggesting its oncogenic role. Mechanistically, ALDH2 competitively bound to KEAP1 and stabilized NRF2 by preventing its ubiquitin-proteasome-mediated degradation, thereby promoting the nuclear translocation of NRF2 and subsequent upregulation of GPX4, and in turn regulating ferroptosis, proliferation, and BTZ resistance in MM. In parallel, NRF2 bound directly to the promoter region of ALDH2 and further enhanced ALDH2 transcription, thus forming a positive feedback loop. Collectively, our findings reveal that the ALDH2/KEAP1/NRF2-GPX4 axis may serve as a key regulator of ferroptosis in MM and a promising therapeutic target for overcoming BTZ resistance.