Advanced Science最新文献

Burn wounds complicated by bacterial infection and fibrotic scarring remain a major clinical challenge, demanding therapeutics capable of coordinated infection control, inflammation modulation, and tissue regeneration. Here, we report a phase-programmed microneedle (MN) patch (QR/AB-MNs) that enables spatiotemporally controlled release of ammonia borane (AB) and quercetin (QR) to achieve synergistic antimicrobial and anti-fibrotic therapy. The MNs comprise a poly (lactic-co-glycolic acid) (PLGA) shell encapsulating QR and a sulfobutylether-β-cyclodextrin (SBECD) core loaded with the H₂-releasing prodrug AB. Upon exposure to the mildly acidic wound microenvironment, the system triggers sustained generation of hydrogen (H₂) and AB degradation products, effectively eliminating bacteria and biofilms while mitigating oxidative stress. Subsequently, gradual PLGA degradation ensures prolonged QR release, suppressing fibroblast hyperproliferation and TGF-β mediated collagen deposition, thereby preventing hypertrophic scarring. In murine and rabbit burn models, QR/AB-MNs markedly accelerated wound closure, reduced inflammation and bacterial burden, restored skin appendages, and yielded scar-reduced regeneration with native-like collagen architecture. Transcriptomic profiling further revealed that QR/AB-MNs orchestrate a broad anti-fibrotic transcriptional program, concurrently attenuating pro-fibrotic signaling, cell-extracellular matrix interactions, and collagen synthesis. Collectively, this programmable MN platform integrates redox modulation, anti-infective therapy, and matrix remodeling to achieve comprehensive, scarless-like healing of infected burn wounds.

High-throughput chromatin conformation capture technologies, such as Hi-C and its derivatives, have revolutionized the study of 3D genome organization. However, the robustness of contact-frequency-based analyses to sequencing depth remains a major challenge, particularly for sparse datasets such as single-cell Hi-C. To overcome this challenge, we present a novel computational framework that employs the mean first passage time (MFPT) from Markov chain theory to convert chromatin contact matrices into a graph-based effective distance representation. We demonstrate that the MFPT representation is empirically more robust to sequencing-depth reduction and supports reliable downstream 3D genomic analyses, including TAD and chromatin loop detection, differential chromatin contact analysis, as well as the imputation and representation of sparse single-cell Hi-C data. Building on this representation, we developed STRIDE (spatial topological representation of interaction distance evaluation), a library similarity metric that does not require dataset-specific parameter optimization. STRIDE is robust to sparse and noisy data and shows improved resilience to technical variation, thereby facilitating accurate identification of cellular states and developmental trajectories in the datasets analyzed. Together, the MFPT representation and STRIDE provide a robust computational framework for sequencing-depth-resilient analysis of 3D genome organization.

Bats are major reservoirs of emerging viruses, including severe acute respiratory syndrome-related coronaviruses, yet they exhibit remarkable tolerance to viral infections with limited clinical manifestations-a longstanding immunological paradox. Here, we generate a telomere-to-telomere (T2T) de novo genome assembly for Rhinolophus sinicus (R. sinicus), designated T2T-RSC1.0 (2.14 Gb), comprising 17 fully anchored autosomes and both sex chromosomes. This gapless assembly resolves 129.19 Mb of previously unresolved regions (PURs) and enables annotation of 848 previously unannotated genes, including 131 protein-coding genes and five pseudogenes on the 33.75 Mb Y chromosome. Using 2.12 × 10⁵ newly identified single-nucleotide polymorphisms within PURs, population genomic analyses resolve three major genetic groups and provide improved resolution of genome-wide population structure. Comparative analyses further reveal population-level associations between major histocompatibility complex polymorphism and viral diversity. Multi-omics and functional analyses reveal a coordinated evolutionary remodeling of antiviral defense, antigen presentation, cytokine signaling, and inflammatory regulation in horseshoe bats. This study provides an unparalleled genomic resource for R. sinicus and establishes an integrated framework for investigating immune evolution, long-term host-virus coexistence, and mammalian adaptive evolution.

Excessive free radical production and dysregulated immune responses contribute to myocardial ischemia-reperfusion (IR) injury. However, the mechanisms by which macrophages regulate reactive oxygen species (ROS) homeostasis and orchestrate immune responses during IR injury remain elusive. Here, we show that glutamate dehydrogenase 1 (GLUD1) expression is induced in monocytes from patients with acute myocardial infarction after interventional therapy and in cardiac-recruited macrophages from mice subjected to IR injury. GLUD1-deficient macrophages exacerbate IR injury by increasing mitochondrial ROS accumulation and amplifying pro-inflammatory responses. Mechanistically, GLUD1 deficiency leads to mitochondrial ROS accumulation due to reduced NADPH/NADP⁺ and GSH/GSSG ratios during IR injury. Elevated mitochondrial ROS inhibits PHD2 activity, stabilizing HIF-1α and enhancing NF-κB signaling, promoting the release of pro-inflammatory factors and exacerbating myocardial damage. Systemic activation of GLUD1 or adoptive transfer of monocytes pre-treated with a GLUD1 activator preserved cardiac function and mitigated IR injury. These findings highlight macrophage GLUD1 as a critical regulator of redox balance and immune homeostasis, presenting a promising therapeutic target for alleviating IR injury and preserving cardiac function.

Atypical sensory processing is commonly observed in autism, particularly when integration across sensory modalities is required. The neural mechanisms underlying multisensory differences remain unclear. We recorded EEG while autistic children aged 8-13 (AU;n = 40), siblings of autistic children (SIB;n = 26), and non-autistic controls (NA;n = 36) performed a simple reaction-time task to auditory (A), visual (V), and audiovisual (AV) stimuli. Analyses targeted event-related potentials (ERPs), alpha-band event-related desynchronization (α-ERD), and long-range theta-band functional connectivity. Groups did not differ across unisensory measures, indicating comparable unisensory processing. By contrast, multisensory integration (MSI;AV-(A+V)) differed across groups: NA children showed significant ERP MSI over parieto-central sites that was absent in AU and SIB; and α-ERD MSI was significantly reduced in AU, with SIB showing an intermediate profile. Connectivity analyses revealed reduced AV fronto-parieto-occipital coupling in autistic children relative to non-autistic children, suggesting weaker large-scale coordination during multisensory processing. These results point to a multisensory-specific deficit spanning early sensory encoding, posterior α-ERD, and fronto-posterior coupling and support disrupted multisensory influences on sensory processing due to reduced multisensory attentional orienting. SIB profiles suggest inherited liability for these neural phenotypes. These results help explain well-documented behavioral MSI differences in autism by linking impaired early enhancement with attenuated top-down control of sensory cortex.

Development of sustainable, high-performance structural materials capable of replacing traditional engineering plastics and lightweight alloys is critical to achieving carbon neutrality. However, engineering renewable wood into structural materials intrinsically relies on reconstitution and bonding, during which traditional polymer adhesives introduce compositionally and mechanically heterogeneous interfaces. These discontinuities produce stress concentrations under water-induced swelling and shrinkage, undermining long-term stability. Herein, we proposed a synergistic strategy integrating interfacial reconstruction and water-induced regeneration to reconstruct heterogeneous interfaces into homogeneous ones with compositional and structural continuity. This approach enabled lap joints to achieve a high dry shear strength of 6.2 MPa, exceeding that of natural wood. Notably, this strategy utilized water to facilitate the regeneration and performance retention of the interface, allowing the material to retain 97% of its strength even after two boiling water cycles. Furthermore, the mechanical properties were optimized through pressure control, thereby yielding specific flexural strength (276.2 MPa cm³ g^-1) and specific flexural modulus (24 000 MPa cm³ g^-1) that were comparable or even superior to those of certain metals, construction materials, and engineering plastics. This work provides useful insights into the design of high-performance, sustainable wood-based structural materials suitable for outdoor environments.

Esophageal cancer (EC) is highly lethal due to late diagnosis, and accurate non-invasive tools for early detection and subtyping remain lacking. Circulating cell-free mitochondrial DNA (ccf-mtDNA) fragmentomics offers a promising biomarker source. In this large multi-center study enrolling 1,260 participants spanning healthy control (HC), benign esophageal diseases (BED), precancerous lesions and EC patients, we developed two machine learning models based on plasma ccf-mtDNA fragmentomic profiles: an EC detection (ED) model and a pathological subtyping prediction (PSP) model. The ED model achieved an AUC of 0.9706 (EC vs. non-EC) in the training cohort, with high performance in internal (0.9762), external (0.9748), and Chinese minority (0.9668, Uyghur and Kazakh) validation cohorts. At the optimal cut-off, it yielded 92.16% sensitivity for stage I EC in the combined validation cohort and correctly identified 93.10% of early EC cases missed by preoperative biopsy. It also discriminated high-grade intraepithelial neoplasia from non-EC with an AUC of 0.9597. The PSP model distinguished ESCC from EAC with 89.71% accuracy, improving to 90.74% after integrating key clinical parameters. In summary, ccf-mtDNA fragmentomics provides a robust, non-invasive platform for early EC detection, precancerous risk stratification, and histological subtyping, demonstrating strong potential to transform clinical management.

Bone marrow mesenchymal stem cells (BMSCs) support bone formation through osteogenic differentiation and pro-angiogenic paracrine activity, but the mechanisms coordinating these functions remain incompletely understood. Here, we identified dual-specificity phosphatase 26 (DUSP26) as a regulator of BMSC osteogenesis and mitochondrial homeostasis. DUSP26 expression increased during osteogenic differentiation and was reduced in osteoporotic femoral tissues. p300 gain- and loss-of-function experiments, together with analysis of the Yin Yang1(YY1) K183R mutant, supported the conclusion that p300-regulated YY1 lactylation contributes to DUSP26 transcriptional activation. DUSP26 interacted with the mitochondrial processing peptidase subunit beta(PMPCB) and reduced its tyrosine phosphorylation, with mass spectrometry and mutational analyses implicating Y141 as involved in this regulation. Functional assays supported a model in which DUSP26 limits mitochondrial processing peptidase (MPP)-mediated PTEN-induced kinase 1 (PINK1) processing and promotes PINK1-dependent mitophagy, thereby supporting mitochondrial homeostasis. DUSP26 enhanced osteogenic differentiation and the pro-angiogenic activity of BMSC-conditioned medium(CM), whereas its knockdown impaired bone formation and reduced type H vessels in vivo. Furthermore, BMSC-derived exosomes carrying a runt-related transcription factor 2 (RUNX2) promoter-driven DUSP26 plasmid produced preferential transgene expression in osteogenic-lineage cells and attenuated ovariectomy-induced bone loss in mice. These findings link lactylation-associated transcriptional regulation to mitochondrial protein processing and support further preclinical evaluation of DUSP26-directed approaches for osteoporosis.

Developing strategies that simultaneously overcome chemoresistance and immune suppression remains a major challenge for improving transarterial chemoembolization (TACE) in hepatocellular carcinoma (HCC). Inspired by clinically used CaCO₃ microspheres in TACE, we propose an "extracellular buffering-intracellular metabolic disruption" strategy to precisely regulate lactate homeostasis for targeted therapy. Herein, we engineered multifunctional embolic microspheres (SDCa-MSs) co-loaded with calcium carbonate nanoparticles (CaNPs), syrosingopine (Syr), and doxorubicin (DOX) for TACE application. Within the acidic tumor microenvironment, SDCa-MSs buffer extracellular acidity while disrupting intracellular lactate metabolism, thereby simultaneously remodeling extracellular and intracellular pH homeostasis. This coordinated regulation enhances DOX efficacy, induces calcium dyshomeostasis and immunogenic cell death, and ultimately stimulates robust antitumor immunity. In multiple murine HCC models, SDCa-MSs markedly suppress tumor growth, remodel the tumor immune microenvironment, and synergistically enhance the therapeutic efficacy of anti-PD-L1 immunotherapy. By integrating metabolic regulation, chemotherapy, and immune activation into a single embolic platform, this work establishes an acid-base homeostasis-regulating strategy for potentiating TACE and provides a conceptual framework for improving locoregional cancer immunotherapy.

Obesity is a major risk factor for insulin resistance and type 2 diabetes. Adipocyte stress responses can either promote metabolic dysfunction or preserve insulin action, but the contribution of the p38 MAPK activator MKK3 to adipose tissue physiology remains poorly understood. Here, we show that adipose MKK3 expression increases early during high-fat feeding and is also elevated in human obesity. In human visceral adipose tissue, MKK3 expression was positively associated with body mass index and leptin and inversely associated with HbA1c in unadjusted analyses. Using germline, Fabp4-Cre, and Adipo-Cre Mkk3-deficient mice, together with p38β-deficient mice and primary adipocytes, we found that loss of adipocyte MKK3 impairs insulin responsiveness. Adipo-Cre;Mkk3^fl/fl (Adipo^Mkk3) mice displayed reduced insulin-stimulated glucose uptake selectively in subcutaneous white adipose tissue despite unchanged body composition and basal brown adipose tissue activity. Mechanistically, MKK3 or p38β deficiency increased p70S6K activity and inhibitory IRS1 Ser307 phosphorylation, reduced GLUT4 translocation and Akt activation, and these defects were partially rescued by rapamycin or the selective p70S6K inhibitor PF-4708671. Together, these findings identify an adipocyte MKK3-p38β-p70S6K axis that helps preserve insulin signaling during nutritional stress.