Biomineralization, the biologically controlled formation of minerals by living organisms, is central to the development, maintenance, and repair of dental hard tissues. This perspective summarizes the current understanding of the molecular and cellular mechanisms governing enamel and dentin mineralization, with particular emphasis on the regulatory roles of amelogenins, enamel matrix proteins, dentin matrix proteins, and non-collagenous phosphoproteins. The clinical implications for dental caries, periodontal bone loss, and dentin hypersensitivity are critically evaluated in the context of biomineralization-based preventive and restorative strategies. Emerging technologies, including microbially induced carbonate precipitation (MICP), bioactive glass-mediated remineralization, and biomimetic peptide-guided mineralization, are assessed for their translational potential in next-generation dental therapeutics. Two new conceptual frameworks are proposed: (i) a comparative mechanistic model distinguishing enamel versus dentin biomineralization pathways, and (ii) a translational pipeline mapping laboratory biomineralization strategies to clinical dental applications. This perspective identifies key knowledge gaps and future research directions at the intersection of biomineralization science and clinical dentistry.
Hirudin is a potent thrombin inhibitor limited by short circulation half-life and bleeding complications. We engineered an FXa-activatable hirudin thrombus-targeted prodrug, yet the N-terminal IEGR peptide introduced unwanted basal activity. After further screening, we found this residual function was fully silenced by a P-selectin-binding peptide upstream of IEGR, with no compromise to FXa-mediated cleavage. Our final construct PXHV2 incorporates both peptides, C-terminal human serum albumin to extend half-life, and an albumin-embedded cyclic RGD sequence for constitutive platelet recruitment. PXHV2 remains catalytically inert until FXa proteolysis restores thrombin-suppressive capacity. In murine electrical and laser-induced thrombosis models, PXHV2 delayed arterial and microvascular occlusion and maintained 120 min pre-injury antithrombotic protection, unlike rapidly ineffective free hirudin. PXHV2 elicited no increase in tail bleeding relative to saline controls. Our data identify PXHV2 as a long-lived, thrombus-selective prodrug with durable efficacy and minimal bleeding risk.
The use of cover crops (CCs) is increasingly promoted to diversify cropping systems and advance agricultural sustainability. Yet, CC adoption can involve context-dependent trade-offs, including resource competition and elevated greenhouse gas (GHG) emissions. In this opinion article, we propose enhanced rock weathering (ERW) as a complementary strategy to improve biogeochemical synchrony within CC systems. By synthesizing emerging evidence, we show how CC-ERW interactions can synergistically enhance carbon sequestration, nutrient cycling, GHG mitigation, and soil food-web functioning, mainly via root-driven weathering processes and soil feedbacks. We further outline opportunities for application across diverse agroecosystems and highlight key challenges for scaling, including weathering thresholds, potential metal risks, and governance constraints. Overall, harnessing the CC-ERW nexus offers a promising pathway toward climate-resilient and multifunctional agriculture.
Designing healthy, palatable foods is a grand challenge in materials science, particularly in quest for low-sodium products where flavor is often compromised. The central problem is not merely replacing NaCl, but re-engineering the food matrix itself to manage off-flavors and retain desirable aromas. Here, an AI-informed framework demonstrates how the biopolymer κ-Carrageenan (KC) can sculpt the myofibrillar protein (MP) architecture for enhanced aldehyde capture and bitterness masking in low-sodium systems. Results showed KC acts as a molecular scaffold, transforming the protein from a rigid state into a porous, aggregated network. This remodeling significantly boosted binding for key flavor aldehydes (3-methylbutanal < pentanal < hexanal < heptanal). KC modulated MP-heptanal interactions primarily involved hydrogen bonding, whereas other aldehydes interacted mainly via hydrophobic forces. Concurrently, KC's sulfate groups sequestered K+, masking bitterness while enhancing saltiness and umami. To decipher this interplay, an interpretable machine learning model (R2 > 0.9) quantitatively linked conformational changes to flavor. SHAP analysis then revealed aldehyde concentration, protein solubility, and thiol group availability as the most critical features governing aldehyde absorption and bitterness perception. This work pioneers a structure-driven, Al-based strategy for flavor design, offering a new paradigm for the rational formulation of next-generation healthy foods.
Chronic nonspecific low back pain (CNLBP) is a major global driver of disability, with increasing attention toward individualized, evidence-based, and function-oriented interventions. To delineate the global CNLBP research landscape, we conducted a bibliometric and visualization analysis covering the period from 1996 to 2025. Publications were retrieved from the Web of Science Core Collection, and VOSviewer, CiteSpace, and the R package bibliometrix were used to examine publication growth, author output, contributions by countries and institutions, journal influence, keyword co-occurrence patterns, and citation burst signals. A total of 937 peer-reviewed articles were identified, authored by 4,336 individuals across 288 journals and 65 countries. The largest share of publications was contributed by the United States, while Australia demonstrated strong international collaboration and citation impact. Institutions such as Vrije Universiteit Amsterdam, University of Southern Denmark, and University of Sydney played leading roles in CNLBP research output. Influential authors included Peter O'Sullivan and Kieran O'Sullivan, noted for contributions to psychosocial modeling and individualized rehabilitation. Keyword co-occurrence analysis identified four thematic clusters: (1) disease definition and epidemiology; (2) evidence-based management and health systems; (3) neuromechanical rehabilitation strategies; and (4) psychosocial dimensions and patient-centered outcomes. Burst keyword analysis revealed recent focus on "motor control" (2021-2024), "Tampa scale" (2023-2025), and "quality of life" (2023-2025), reflecting the shift toward precision rehabilitation and multidimensional assessment. A comprehensive overview of the evolving CNLBP research landscape was provided through this bibliometric analysis. Findings underscore the transition from diagnostic exploration to integrated clinical interventions, with growing emphasis on function, psychological well-being, and personalized care pathways.
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Capsular polysaccharides (CPS) of the human gut microbiota are structurally diverse surface glycopolymers whose monosaccharide composition, linkage patterns, charge properties, and strain-specific modifications directly encode multifaceted biological functions. This review systematically examines the CPS structural landscape across major gut commensals, including Bacteroides spp., Lacticaseibacillus spp., Bifidobacterium spp., Enterococcus spp., and members of the Enterobacteriaceae family. We integrate recent findings to show how CPS architecture governs three interconnected functional domains: environmental fitness (resistance to gastric acid, bile salts, antibiotics, and phage predation), immune modulation (engagement of TLR2, Dectin-1, DC-SIGN, Siglecs, and MHC-II pathways to orchestrate regulatory T- and B-cell responses, macrophage polarization, and epithelial barrier maintenance), and ecological integration (cross-feeding and carbon reservoir functions). We identify critical knowledge gaps-most notably, the lack of high-resolution structure-activity relationships that link three-dimensional CPS conformations to specific immunological outcomes, compounded by a persistent Bacteroides-centric bias and underexplored ecological functions. Emerging tools, including cryo-electron microscopy, solid-state nuclear magnetic resonance, glycan arrays, and machine learning, offer unprecedented potential to advance the nascent field of CPS structure-activity relationships. We propose that a deeper understanding of CPS structural features, once achieved, may eventually inform the rational design of precision interventions that harness host-microbe mutualism for therapeutic benefit.
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Current decay of alkaline ethanol electrooxidation on Pt-Au/NF due to electrolyte-mediated losses and adsorbate-associated surface restructuring is primarily caused by alkalinity loss and acetaldehyde/acetate accumulation.
Breastfeeding anchors infant immunity and long-term health, but its benefits are threatened by Staphylococcus aureus (S. aureus) mastitis, an increasingly prevalent condition driven by antimicrobial resistance and therapeutic limitations. Beyond compromising maternal wellness, mastitis threatens the safety and continuity of breast milk, highlighting a critical need for innovative intervention strategies. Herein, we demonstrated that α‑ketobutyrate (α-KB), a metabolite of the transsulfuration pathway, mitigated S. aureus‑induced inflammation, oxidative stress, and blood-milk barrier (BMB) disruption both in vivo and in vitro. α‑KB enhanced macroautophagic/autophagic responses, marked by increased ATG5, BECN1 (beclin 1), and LC3-II:LC3-I conversion and reduced SQSTM1/p62, through a RIPK1-lactate-TFEB axis. Specifically, it directly bound and stabilized RIPK1, elevated lactate production, and drove TFEB nuclear translocation to activate macroautophagy/autophagy and promote intracellular bacterial clearance. Molecular docking and molecular dynamics simulations suggested stable α‑KB and RIPK1 binding via hydrophobic and hydrogen bond interactions; RIPK1 knockout abolished α‑KB-induced autophagy and lactate generation, effects rescued by lactate supplementation. This study identifies a novel immunometabolic circuit linking a metabolite to RIPK1-lactate-TFEB-mediated autophagy, offering therapeutic potential against antibiotic‑resistant S. aureus mastitis and presenting a new paradigm for safeguarding breastfeeding quality and infant health.
Transmembrane protein 41B (TMEM41B) serves as a critical host factor for various coronavirus infections, providing a potential target for developing antiviral gene-edited animals. However, TMEM41B is a gene essential for mammalian embryonic development, with complete knockout resulting in embryonic lethality. Consequently, it is of paramount importance to identify its critical functional domains that are amenable to deletion. In this study, we demonstrated that TMEM41B is involved in the replication stage of porcine deltacoronavirus (PDCoV), an emerging zoonotic coronavirus that infects various animals and even humans, but not in the attachment, internalization, or release steps. Through the construction of truncated mutants and cell lines stably expressing or precisely lacking the functional domains of TMEM41B, we confirm that, in addition to the VTT domain, the sixth transmembrane (TM6) domain of TMEM41B is also required for coronavirus infection. Using CRISPR/Cas9 technology, we generated a C57BL/6J mouse model with a deletion of the TMEM41B TM6 domain. Animal experiments demonstrated that the deletion of the TM6 domain significantly inhibited viral infection in vivo and mitigated liver tissue damage caused by mouse hepatitis virus (MHV), thereby increasing the survival rate of mice after MHV infection. Taken together, this study is the first to report a requirement of TMEM41B TM6 domain for coronavirus infection, deepening our understanding of TMEM41B function and providing novel insights for the development of antiviral gene-edited animals.IMPORTANCETMEM41B is a proviral host factor for pan-coronaviruses, making it an ideal target for developing antiviral gene-edited animals. However, the essential role of TMEM41B in mammalian embryonic development poses a major obstacle to this goal. Identifying its critical functional domains or key amino acids that are amenable to deletion is pivotal for evaluating TMEM41B as a viable target for developing antiviral gene-edited animals. Our present study demonstrates that the sixth transmembrane (TM6) domain of TMEM41B is critical for the infection of PDCoV and other coronaviruses, without obviously compromising the function of its conserved VTT domain. Furthermore, a mouse infection model provides strong evidence that deletion of TM6 suppresses viral infection and attenuates virus-induced liver damage. Collectively, we identify TM6 as a crucial domain for coronavirus infection both in vitro and in vivo, providing new insights into the structure-function relationship of TMEM41B and proposing a novel strategy for antiviral animal development.
Diapause in Coridius chinensis is a complex survival strategy that enables them to survive under prolonged cold stress. To elucidate the mechanisms of temperature regulation during diapause, we conducted multi-omics analyses, including gut metagenomics, brain transcriptomics, and fat body metabolomics, under both normal (25 °C) and diapause conditions (4 °C). Gut microbiome analysis revealed an extreme polarization during diapause, dominated by the endosymbionts Pantoea endophytica (52%) and Rickettsia bellii (47.4%), while functional microbiota such as Pantoea and Dietzia were significantly reduced. This shift suggests a trade-off where microbial metabolic diversity is sacrificed in favor of intracellular symbionts that may regulate host mitochondrial activity and suppress energy consumption. Brain transcriptomic analysis indicated a downregulation of neural signaling pathways related to feeding suppression, stress resistance, and circadian rhythm regulation. Fat body metabolomics identified the coordinated activation of 13 core pathways that link energy storage with stress adaptation, with dynamic changes ranging from rapid stress responses (0-300 AU) to energy storage dominance (300-500 AU), and finally to a state of homeostasis (>500 AU). Notably, dysregulated choline metabolism was significantly correlated with necrotic features (r = 0.78, p < 0.001), while catecholamine biosynthesis derived from tyrosine emerged as a corrective pathway, revealing the mechanistic link between metabolic flexibility and survival. Adults primarily utilize plants within the Cucurbitaceae, Fabaceae, and Solanaceae families as hosts, underpinned by long-standing folk traditions in specific localities regarding their dietary consumption or therapeutic application.
Tumour-node-metastasis staging does not fully explain prognostic heterogeneity in non-small cell lung cancer. We evaluated whether haematoxylin-and-eosin whole-slide images could estimate histological subtype, pathological stage probabilities, survival risk and spatially grounded biological associations. SparseAGE-MTL, a weakly supervised multi-task multiple-instance learning model with a shared projection-topology encoder and endpoint-specific heads, was trained and benchmarked in 954 The Cancer Genome Atlas cases using seven pathology feature spaces and 18 comparator models. External evaluation used 948 tissue-microarray and 324 whole-slide cases. Attention maps were co-registered with 10x Visium spatial transcriptomics and integrated with bulk transcriptomics, immune-infiltration estimates and ESTIMATE scores. Analyses included paired model comparisons, false-discovery-rate correction, Cox models, calibration assessment and decision curve analysis. In the CONCH feature space, SparseAGE-MTL achieved 93.73% accuracy, 98.19% area under the receiver-operating-characteristic curve and 93.08% F1-score for adenocarcinoma/squamous cell carcinoma classification in internal benchmarking; external area-under-the-curve values were approximately .91 and .82. Stage estimation had lower discrimination, with external overall area under the curve approximately .70 and cohort-dependent calibration. Risk-score-defined groups differed in overall survival in both histological subtypes and showed similar external trends. High-attention regions were enriched at tumour-stroma or tumour-immune interfaces and were associated with B-cell, fibroblast, C1QC, COL1A1, epithelial-mesenchymal transition, metastasis and hypoxia signals. Higher risk cases showed malignant pathway activation, lower immune/stromal scores, higher tumour purity and subtype-specific immune/stromal differences. Adding the risk score to the clinical model increased external pooled concordance index from approximately .620 to .672. In retrospective cohorts, SparseAGE-MTL generated subtype-classification, stage-probability and survival-risk outputs from routine pathology images. Subtype classification had higher numerical performance than stage estimation. Survival-risk and attention outputs were associated with outcome and spatial/transcriptomic features, but prospective, treatment-annotated validation is required before clinical use. SparseAGE-MTL is a weakly supervised multi-task MIL framework that jointly performs NSCLC subtype classification, stage prediction, and survival risk estimation from routine H&E slides using only slide-level labels. The model achieves stable competitive performance across seven feature spaces and 18 comparators, with external validation demonstrating robust generalization to independent WSI and TMA cohorts. Attention hotspots co-localize with tumor-stroma/immune interfaces and spatial transcriptomic signatures of EMT, hypoxia, and C1QC/COL1A1 enrichment, providing biologically grounded interpretability. High-risk groups exhibit activated malignant pathways, lower immune/stromal scores, higher tumor purity, and incremental prognostic value beyond clinical variables.
Tracheal, bronchus, and lung cancer remains a major global cancer burden, but cross-national comparisons using composite proxy indicators are limited. Using Global Burden of Disease 1990-2021 estimates, we constructed a quality-of-care index (QCI) from incidence, mortality, prevalence, and disability outcomes; assessed temporal and geographic patterns; modeled associations with linear mixed models; and compared older adults with the overall population. Age-standardized incidence and death rates declined globally, but QCI remained highly unequal across 204 countries. QCI was higher in high-development settings, lower in low-development settings, and generally lower among older adults than in the overall population. Socioeconomic development was positively associated with QCI, whereas older age was negatively associated with QCI. These findings identify persistent inequities in this outcome-based proxy indicator and support SDI-stratified and aging-responsive lung cancer care strategies.
Worldwide, diabetic retinopathy (DR) stands as a leading cause of vision loss. However, the involvement of PANoptosis-a form of inflammatory cell death that combines features of apoptosis, pyroptosis, and necroptosis-in the development of DR has not been fully elucidated. This study investigated the molecular mechanisms underlying high glucose (HG)-induced PANoptosis in human retinal microvascular endothelial cells (hRMECs), focusing on the scavenger receptor CD36 and NOTCH/MAML signaling. HG specifically induced PANoptosis in hRMECs, evidenced by concurrent activation of apoptotic, pyroptotic, and necroptotic markers, along with PANoptosome complex formation and morphological validation via terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. HG significantly upregulated CD36 expression and activated the NOTCH/MAML pathway. CD36 overexpression exacerbated PANoptosis by enhancing cell death, inflammatory responses, and oxidative stress, whereas CD36 knockdown conferred protection. Mechanistically, CD36 promoted PANoptosome assembly through NOTCH/MAML pathway activation, as demonstrated by increased NICD-MAML1 nuclear colocalization and enhanced NOTCH component expression. We further verified that the CD36-NOTCH axis regulates PANoptosis through the modulation of NLRP3, a core component of the PANoptosome. Pharmacological NOTCH inhibition using DAPT ameliorated HG-induced PANoptosis, whereas NOTCH activation mimicked CD36 overexpression effects. These results establish a novel CD36-NOTCH/MAML-NLRP3-PANoptosis regulatory pathway in diabetic retinal endothelial cells. This discovery provides crucial insights into DR pathogenesis and pinpoints potential targets for therapeutic intervention.
Recently, link prediction (LP) based on graph neural networks (GNNs) methods has achieved notable successes in biological networks (BNs), since it can reveal the organizational principles, functional mechanisms, and dynamic properties of biological systems. However, these LPs still face some significant challenges that need to be addressed in BNs. The first is the complex and heterogeneous characteristics of BNs. Moreover, BN structures often have the dynamic addition and removal of nodes and edges over time or across physiological states. Afterward, there are asymmetries and hierarchical modularity in the structures of BNs. Finally, high computational complexity has resulted from the above challenges in BNs. Therefore, this article proposes a novel GNN-based LP model via local clustering and subgraphs, termed LCS in short, to address these issues in BNs. LCS introduces a subgraph-based GNN approach to effectively address the heterogeneous characteristics inherent in complex BNs, along with the consequent challenges of asymmetry and hierarchical modularity. Furthermore, LCS designs a dynamic local subgraph extraction (SE) mechanism based on heat kernel diffusion and the Chopper pruning algorithm. This mechanism leverages the effective local clustering properties of heat diffusion and uses Chopper to achieve linear-time SE, mitigating subgraph size explosion and enhancing LP efficiency. Additionally, by imposing diversity regularization constraints, the method reduces computational complexity and improves generalization performance. Experimental results on four BN benchmarks demonstrate that LCS achieves significant improvements over existing state-of-the-art LP methods. The implementation of LCS is publicly available at https://github.com/XL0104/LCS-Model.git.
To investigate whether periodontitis (PD) induces microstructural alterations in specific WM tracts, particularly the corticospinal tract (CST), which is associated with motor function. Based on genome wide association study (GWAS) summary statistics from PD (45 563 samples) and CST imaging-derived phenotypes (IDPs) (31 356 samples), two-sample Mendelian randomization (MR) analysis was performed. The primary analysis was conducted using inverse variance weighted (IVW) method, supplemented by weighted median (WM), MR-Egger regression, robust adjusted profile score (MR-RAPS), and constrained maximum likelihood and model averaging bayesian information criterion (cML). Sensitivity analysis was performed using Cochran Q test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO), and leave-one-out (LOO) analysis. MR analysis revealed positive associations between PD and CST fractional anisotropy (FA)(β=0.07, P=6.11×10-3) and negative associations with mean diffusivity (MD)(β=-0.06, P=3.90×10-2). These findings remained consistent across sensitivity analysis. PD led to an increase in FA values and a decrease in MD within the CST, indicating that the integrity of the CST was compromised. PD has a detrimental causal impact on the integrity of CST microstructures, potentially increasing the risk of CST lesions. Therefore, this study suggests that effective clinical prevention and treatment of PD are necessary.
Nesfatin-1 is an 82-amino acid polypeptide derived from the precursor protein nucleobindin 2 (NUCB2), which is a conserved multifunctional peptide in vertebrates that plays a key role in metabolic regulation, inflammatory response and ferroptosis. Although Nesfatin-1 has been characterized in various vertebrates, from mammals to teleosts, its structural and functional characteristics in primitive vertebrates remain unclear. In this study, Nesfatin-1 orthologs from the most primitive jawless vertebrate lamprey (Lethenteron camtschaticum) were cloned and identified, designated as Lc-Nesfatin-1. Bioinformatic analysis revealed that Nesfatin-1 of lamprey is relatively conserved in both sequence similarity and three-dimensional (3D) structure compared to that of higher vertebrates. Lc-Nesfatin-1 was significantly upregulated under lipopolysaccharide (LPS) stimulation, which also markedly induced the expression of pro-inflammatory cytokines, the key signaling molecule NF-κB, and anti-inflammatory cytokines. Notably, Flow cytometry analysis showed that Lc-Nesfatin-1 did not significantly inhibit LPS-induced intracellular ROS production. Furthermore, Nesfatin-1 serves as an effective negative regulator that significantly inhibits ferroptosis. These results reveal that Lc-Nesfatin-1 plays a critical role in modulating both LPS-induced inflammatory responses and ferroptosis. This study has successfully elucidated the characteristics and functions of Nesfatin-1 in primitive vertebrates and provided valuable insights into the investigation of inflammatory responses and ferroptosis in jawless vertebrates.
Fumonisin B1 (FB1) poses serious health concerns to human health. In this research, the cardiotoxic effects of FB1 were comprehensively evaluated through in vitro experiments using H9C2 cardiomyocytes and in vivo assays utilizing zebrafish. In H9C2 cells, exposure to 40 mg/L FB1 resulted in marked mitochondrial damage and apoptotic cell death. Transcriptomic profiling identified 1292 differentially expressed genes, with significant enrichment in pro-inflammatory signaling pathways, containing TNF, NOD-like receptor, and MAPK pathways. These findings were corroborated by the elevated expression of inflammatory mediators, i.e., IL-6, IL-8, and NF-κB, along with elevated phosphorylation of NF-κB p65 and MAPK ERK proteins, indicating the activation of these signaling cascades. In zebrafish, FB1 (40 mg/L) induced pronounced oxidative stress, cardiac malformations, functional disruptions, and heightened inflammatory responses. These molecular and functional disturbances ultimately resulted in compromised cardiac gene expression and physiological impairment, offering novel mechanistic insights into FB1-induced cardiovascular toxicity and underscoring its potential risk to cardiac health.