Somatic mutations accumulate throughout life and have been hypothesized to drive organismal decline. Yet whether these mutations are distributed randomly or whether cells shield their most critical components has remained unresolved. Here we analyze over a million somatic mutations across thirteen human tis-sues, finding that the aging genome exhibits organized vulnerability, captured by the existence of hypo-mutated genes and longevity-associated pathways that have significantly lower mutation burden. Highly connected network hubs are systematically protected from mutation, while peripheral, condition-specific genes accumulate disproportionate burdens. We show that this organized vulnerability arises from the interplay of two independent mechanisms: transcription-coupled repair, and selective filtering. Finally, we validate our findings under experimental mutagenesis, demonstrating intrinsic mechanisms of protection rather than tissue-specific confounders. These findings reframe the somatic mutation hypothesis: organismal decline may not reflect total mutational burden, but where those mutations fall within the cellular network.
The safety risks associated with urban rail transit equipment are characterized by multi-source heterogeneity and dynamic evolution. Traditional expert-driven static management models often fail to meet the proactive prevention demands in complex scenarios, leading to critical issues such as ambiguous risk identification and insufficiently targeted prevention measures. This study proposes a novel risk assessment and inference method that integrates knowledge graphs with Bayesian networks. First, a safety risk knowledge graph is constructed based on historical accident case reports. Then, a mapping method is proposed to convert the knowledge graph into a Bayesian network. Subsequently, data-driven statistical approaches are employed to estimate the network parameters. Finally, a case study involving equipment failures in urban rail transit is conducted to validate the proposed method. Experimental results demonstrate that the proposed method effectively identifies key risk factors and accurately traces accident causes through backward inference. The method also significantly outperforms traditional approaches in terms of practical accuracy. The findings provide intelligent decision support for the risk management of urban rail transit equipment.
Cross-view geo-localization between drone and satellite images is severely challenged by rapid weather variations, which induce appearance shifts, occlusions, and texture degradation. Inspired by human foveal attention, we propose the Fovea Attention Network (FANet), a robust dual-branch framework comprising: 1) the Weather-Adaptive Global Branch (WAGB) that explicitly injects weather cues (e.g., 'rain/snow') into the feature space via a style-modulation encoder, then captures large-scale structural consistency through a Learnable Region Reassembly (LRR) mechanism; and 2) the Local Semantic Attention Branch (LSAB) that leverages a pretrained segmentation model to generate high-confidence masks, distilling discriminative features from salient regions. An adaptive fusion strategy module fuses global context with fine-grained semantic cues. We further adopt multi-weather adaptive training, treating weather types as related tasks with shared parameters to reduce cross-weather confounding. Extensive experiments on University-1652, SUES-200, and CVUSA show that FANet achieves competitive Recall@1 across all conditions, attaining the highest overall mean with the lowest variance. Notably, it improves Recall@1 by 6.79% under severe low-illumination ('dark') conditions, demonstrating robustness and stability. Our code is available at https://github.com/Jahawn-Wen/FANet.
Nucleosome assembly protein 1-like 1 (NAP1L1), a canonical member of the NAP1 family, orchestrates chromatin architecture and nucleosome dynamics to regulate cell cycle progression, development and proliferation. NAP1L1 is mainly expressed in actively growing cells, and its dysregulation is closely associated with the occurrence of a variety of diseases, including neurodevelopmental disorders, cardiovascular diseases and cancers. Recent studies have revealed that NAP1L1 can influence disease progression by modulating multiple classic signaling pathways such as cGAS-STING, PI3K/AKT and WNT pathways, highlighting its complex involvement in cellular signaling networks. In this review, we systematically summarized the discovery, structural features, and multifaceted biological functions of NAP1L1, with a particular focus on its pathogenic roles in cancer and cardiovascular diseases. We evaluated its potential as a druggable target by integrating computational biology approaches with structural and pharmacological evidence, identifying conserved ligandable pockets and predicting plausible interactions with known bioactive compounds. These findings position NAP1L1 as a potential druggable target with promising prospects at the intersection of chromatin plasticity and signal transduction, and provide comprehensive insights into the therapeutic potential of targeting NAP1L1, providing information and advancement for future clinical strategies.
Cardiac fibrosis is a major pathological feature of cardiovascular diseases and a key driver of ventricular remodeling and heart failure, yet effective therapeutic strategies remain limited due to incomplete mechanistic understanding. Heme oxygenase-1 (HO-1), a key redox-regulating enzyme, has recently been implicated in cardiac injury. However, its role in cardiac fibrosis, particularly through the regulation of ferroptosis, remains poorly understood. This study systematically investigated the effects of HO-1-mediated ferroptosis on the progression of cardiac fibrosis. Myocardial infarction was induced by ligation of the left anterior descending coronary artery, and cardiac fibroblasts were stimulated with transforming growth factor-β1 (TGF-β1) to induce fibrosis. Ferroptosis was markedly activated, accompanied by increased ferrous iron (Fe2+) accumulation, enhanced reactive oxygen species (ROS) generation, and elevated levels of lipid peroxidation. Inhibition of ferroptosis significantly alleviated fibrotic responses and improved cardiac function. Mechanistically, ferroptosis suppression restored autophagic flux by correcting lysosomal abnormalities and normalizing LC3B and p62 accumulation. Furthermore, HO-1 was markedly upregulated in fibrotic conditions, promoting ferroptosis and myocardial fibrosis. Activation of HO-1 induced myocardial fibrosis by triggering ferroptosis-associated autophagic dysfunction, whereas HO-1 inhibition mitigated ferroptotic injury, restored autophagic homeostasis, and attenuated fibrosis. Blocking autophagy abolished the protective effects of HO-1 suppression, demonstrating that the antifibrotic role of HO-1-mediated ferroptosis is dependent on autophagic activity. These findings reveal a novel mechanism by which HO-1-mediated ferroptosis impairs autophagic homeostasis to drive cardiac fibrosis, highlighting HO-1 inhibition as a potential therapeutic strategy for attenuating cardiac fibrosis.
The architectural optimization of multifunctional components within MoS2-based nanohybrids demonstrates potential for amplifying cooperative catalytic effects in biomimetic catalytic systems. Employing APTES@MoS2 composites as specialized sorbents, their inherent amine coordination ability and surface negative charge were exploited to investigate their efficacy in adsorbing transition metal ions such as Ni2+, Fe3+, and Co2+ ions. High-temperature carbonization treatment gradually converted the amorphous APTES polymer into N-doped carbon (denoted as CAPTES), while simultaneously enhancing crystallinity and enabling transition metal doping in MoS2 nanosheets (NSs) through thermal treatment, leading to enhanced catalytic performance. Dense decoration of palladium nanoparticles (Pd NPs) is incorporated to amplify the hydrophilicity and the catalytic efficiency of CAPTES@Fe-MoS2 nanocomposites. Benefiting from the hierarchical hollow configuration with extensively exposed edge sites, optimized charge transfer dynamics, and homogeneously distributed active centers, the engineered tubular heterostructures demonstrate exceptional catalytic performance in both 4-nitrophenol (4-NP) reduction and biomimetic enzymatic reactions. This template-directed synthesis strategy provides a scalable platform for manufacturing heterostructured MoS2-based materials with tunable synergistic functionalities, enabling advanced catalytic solutions for environmental and analytical applications.
The advancement of highly efficient, selective catalysts stands as a pivotal challenge in methanol steam reforming (MSR) for hydrogen production. In conventional Ni-based catalysts, metallic Ni0 acts as the active site, synergizing with abundant surface oxygen vacancies of the oxide support and generating the intermediate *OCH₂ tends to directly decompose into CO, which further reacts with *H generated from H₂O activation to form CH₄, resulting in poor product selectivity. Herein, we propose a novel Ni/In₂O₃ catalyst that significantly enhances the selectivity of CO₂, increasing it from less than 10% to 90%. Comprehensive characterizations including XRD, XPS, H₂-TPR, UV-vis and TPSR reveal that, unlike conventional Ni0-based catalysts, the Ni/In₂O₃ catalyst forms a very active and selective Ni₂In₃ alloy phase that enables highly dispersed Ni species while endowing the catalyst with excellent capability for H₂O activation. Combined with further theoretical calculations, the catalytic reaction mechanisms of the CH₃OH and CH₃OH-H₂O systems on the catalyst surface are elucidated in detail. Density functional theory (DFT) calculations demonstrate that the d-p orbital hybridization in the Ni₂In₃ alloy effectively alters the electronic structure of Ni species and tunes the adsorption strength of reaction intermediates and balances the surface coverage of CH₂O* and *OH species, facilitating the critical HO-CH₂O* coupling step for CO₂ generation during methanol steam reforming and thereby improving the CO₂ selectivity of the Ni/In₂O₃ catalyst. The study presented in this work indicates that the formation of Ni-In active alloy phase may effectively overcome the inherent product selectivity issue of conventional Ni-based catalysts by regulating the surface coverage of the critical intermediate and therefore reaction pathway during methanol steam reforming.
Engineering organoids that faithfully replicate the intricate architecture and region-specific features of bodily organs and extraembryonic tissues remains a significant scientific challenge. Previously, we demonstrated that craniofacial skin organoids (cSkOs), containing epidermis, dermis, and hair, could be generated by co-developing epidermal progenitors with cranial mesenchyme. Building on this approach, we precisely adjusted cellular composition and signaling environments to generate ventral skin or-ganoids (vSkOs) with lateral plate mesoderm (LPM) progenitors, successfully recapitulating features of abdominal or groin skin. Modulating early BMP and FGF signaling redi-rected these vSkOs toward an extraembryonic fate, producing human amnion-like tis-sues, termed Amnioids. Like native human amnion, Amnioids rapidly expanded into large, avascular, hairless cysts, in sharp contrast to the primitive vasculature and abundant hair follicles of vSkOs. Single-cell RNA sequencing identified divergent molecular signatures and developmental trajectories, highlighting key roles for NOTCH, WNT, and YAP/Hippo signaling pathways. Functional studies further underscored mesenchymal-epithelial interactions and mechanical forces as critical regulators of epithelial expansion. Together, these models provide potent tools to investigate human development at the embryonic-extraembryonic interface, offering critical insights into congenital skin and amniotic disorders and opening new avenues for precision regenerative therapies.
Electronic skin (e-skin) faces challenges in achieving long-term signal stability and wearability due to the poor breathability, sweat accumulation, and limited sensitivity. This paper reports a multifunctional nanofibrous e-skin (PTZ-PPPB-PPT) fabricated via layer-by-layer electrospinning, integrating a hydrophobic layer (PVDF-TrFE/ZnO), a piezoelectric enhancement layer (PAN/PVP/PDA@BTO), and a thermochromic layer (PAN/PVP/TCM). Benefited from the asymmetric wettability and hierarchical fiber structure, the device enables unidirectional sweat transport (contact angle reduces from 132.8° to 0° within 5.72 s) while blocking reverse osmosis (hydrostatic resistance of 40 mmH₂O). When the piezoelectric sensor operates under excessive sweating conditions, the unidirectional sweat transport maintains skin surface dryness, thereby ensuring stable piezoelectric output during movement. Notably, the E-skin achieves a high output voltage (40 V at 30 N with a sensitivity of 0.825 V/N), exhibits rapid response/recovery (100/80 ms). It also demonstrates reversible thermochromism (25-40 °C) for real-time temperature visualization. Additionally, the device ensures superior comfort during prolonged wear by maintaining exceptional air permeability (8.05 mm/s) and outstanding mechanical flexibility (187.75 % elongation at break). This multifunctional integrated E-skin synergizes sweat management with temperature visualization, holding promising potential for applications in wearable healthcare, human-computer interaction, and dynamic environmental monitoring.
Here, we reported a novel and efficient method for the synthesis of S-alkyl substituted sulfilimines by employing a base-promoted ring-opening reaction of sulfonium salts with sulfenamides. This reaction proceeds smoothly under transition metal-free conditions and under an air atmosphere, allowing facile access to the corresponding products in good to excellent yields through selective C-S bond cleavage and simultaneous formation of a new C-S bond. This strategy features a broad substrate scope and holds promise for applications in late-stage functionalization.
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Modulating intratumoral copper homeostasis to trigger cuproptosis is a promising copper‑based anticancer strategy, but its clinical translation is hindered by the absence of precise spatiotemporal control over intracellular copper levels and ATP7A‑mediated active copper efflux. Here we report an ultrasound-activated copper molybdate nanoregulator, HCu1.5MoO5 (HCMO), that releases copper on demand and reprograms copper flux in tumor cells under ultrasound. Once internalized, ultrasound activates HCMO to release copper ions, providing a sustained intracellular copper supply. In parallel, HCMO also generates reactive oxygen species that impair mitochondrial function and depress cellular ATP, thereby attenuating the activity of the ATP-dependent exporter ATP7A and narrowing copper efflux. This dual-axis imbalance, in situ copper supplement, and efflux limitation significantly disrupt cellular copper homeostasis, interrupt the tricarboxylic-acid cycle, induce mitochondrial dysfunction, further enhance copper accumulation, and eventually cause irreversible cuproptosis. Together with apoptosis and necroptosis, the coordinated damage releases damage-associated molecular patterns and induces immunogenic cell death. Overall, this spatiotemporally programmable strategy links materials, physical fields, and immunity in a closed framework to coordinately disrupt copper homeostasis, offering a generalizable route to on-demand cuproptosis therapy.
Recovery of medium-chain carboxylic acids (MCCA) from food waste is constrained by low efficiency and instability. This study validated a short-term aerobic pretreatment (AP) strategy to enhance fungi-bacteria synergy. In batch tests, AP (0.2 vvm) achieved optimal caproate titers of 22.32 ± 1.56 g COD/L. The pretreatment enriched ethanol-producing yeasts and lactate-producing bacteria, establishing a robust co-electron donor pool. Metagenomic analysis revealed that this synergy suppressed the competing tricarboxylic acid cycle, redirecting carbon flux towards reverse β-oxidation (RBO) pathway and providing essential precursors for Clostridium_sensu_stricto_12. In a 134-day semi-continuous operation, AP sustained high titers (17.2-22.1 g COD/L) through a specialized guild dominated by the Ruminococcaceae bacterium BL-6, avoiding the systemic performance deterioration observed in controls. Life cycle assessment (LCA) confirmed a >60% carbon footprint reduction compared to conventional routes. Short-term aerobic pretreatment effectively regulates microbial succession to stabilize low-carbon MCCA production from food waste.
Template-mediated strategies are a versatile and scalable approach for fabricating one-dimensional (1D) tubular composites, while molybdenum trioxide (MoO3) micro/nanorods have emerged as promising templates for engineering hollow nanostructures. In this minireview, we systematically introduce recent advancements in a series of MoO3-based micro/nanorods for guiding the formation of 1D tubular composites with different structural characteristics. We summarize the various rational design strategies, such as hard-templating and self-templating methodologies, as well as derivative strategies with organic polymer coating and functional oxide coating for MoO3-derived 1D tubular composites. Notably, the architectures, structures, compositions, and morphologies of these composites are discussed for their applications in catalysis, protein adsorption, and enzyme-mimic reactions, among others. Finally, we critically evaluate the prospects, challenges, and opportunities for advancing MoO3-derived 1D tubular nanostructures toward next-generation nanocatalytic and environmental remediation technologies.
An isolated ulna referable to Docodon, from the Upper Jurassic Morrison Formation of Wyoming, resembles the ulna of Borealestes in the presence of a small facet for the radial condyle of the humerus that is confined to the middle of the lateral side of the facet for the ulnar condyle of the humerus and a prominent tubercle on the latter. These taxa and Haldanodon are characterized by the presence of a deep, slit-like lateral fossa for one of the ligaments of the elbow joint. These features are currently only known for Docodonta. However, the ulna of Docodon differs from those of Borealestes and Haldanodon in the lack of an anterior curvature at its proximal end. It shows the most plesiomorphic morphology currently known for docodontans, suggesting that this taxon lacks specialized fossorial or aquatic adaptations.
Multimodal sarcasm detection involves identifying sarcasm across multiple modalities, with the key challenge being modeling incongruity within and between modalities. Current methods often focus on inter-modal incongruity while underexploring intra-modal semantic information. To address this, we propose the Granularity-Based Inter and Intra-Modal Fusion Network (GIIFN). We leverage pre-trained visual and language models to extract semantic features from images and text, and introduce a learnable granularity grouping module to adaptively partition features into multiple semantic granularities. Furthermore, we design a bidirectional cross-attention mechanism to fuse intra-modal and inter-modal features at each granularity level. Experiments demonstrate that our approach achieves state-of-the-art performance.
Although nanozymes have been widely adopted in the field of colorimetric detection of heavy metal contaminants as well as disease markers, it still has development potential to develop a catalyst with high enzyme activity for application in tri-mode: UV-vis, smartphone and Raman. In this study, flower-like Ag/MgMn2O4 microspheres were fabricated via an integrated solvothermal and chemical reduction approach, demonstrating remarkable oxidase-like activity. Leveraging the exceptional oxidase-like activity of Ag/MgMn2O4, we developed a tri-mode (UV-vis-smartphone-Raman) sensing platform with multiplex analytical capability for GSH/Cu2+ detection. The system demonstrated broad linear responses (GSH: 0.5-300 μM; Cu2+: 0.1-300 μM) achieving ultrasensitive detection limits of 0.086 μM (GSH) and 0.062 μM (Cu2+). Furthermore, mechanistic investigations into the target detection revealed that the sulfhydryl groups in glutathione (GSH) readily coordinate with metal sites, thereby suppressing the catalytic activity of the catalyst. This phenomenon demonstrates promising potential for urinary analysis applications in clinical diagnostics. Conversely, the formation of Complex formed by Cu2+ and GSH effectively inhibits the coordination between GSH and metal atoms, which provides great helpful for quantitative detection of Cu2+ in environmental lake water. Therefore, the tri-mode sensor based on Ag/MgMn2O4 oxidase-like activity has a wide application prospect in biomedical fields and environmental detection fields.
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Small-diameter vascular grafts face limited success due to thrombosis, intimal hyperplasia, and insufficient remodeling. Here, we developed a tubular graft composed of aligned core-sheath structured PLCL fibers with sodium tanshinone IIA sulfonate (STS)-loaded polyethylene oxide (PEO) cores. The graft exhibited uniform structures, appropriate porosity, and matched mechanical properties. In vitro, aligned fibers enhanced smooth muscle cell (VSMC) proliferation and promoted a contractile phenotype (α-SMA, SM-MHC). Simultaneously, STS delivery modulated macrophage polarization, suppressing iNOS (M1-like) and enhancing CD206 (M2-like) expression. Co-culture assays revealed reciprocal regulation between VSMCs and macrophages, where VSMCs aligned and matured under macrophage-mediated anti-inflammatory cues, while contractile VSMCs reinforced M2-like polarization. These interactions effectively reduced intimal hyperplasia by preventing excessive smooth muscle cell proliferation and promoting a stable, anti-inflammatory microenvironment. In vivo rat implantation confirmed patency, endothelialization, and organized extracellular matrix resembling native vessels. These findings highlight the combined effect of graft design, macrophage and smooth muscle cell modulation, and cell-cell crosstalk in preventing intimal hyperplasia and driving vascular regeneration, offering a versatile strategy for functional small-diameter vascular grafts.