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Traumatic brain injury (TBI) is a leading cause of mortality and long-term disability worldwide, producing acute neurological deficits and lasting cognitive impairment. Post-injury neuroinflammation is a principal driver of secondary damage and contributes substantially to TBI-induced cognitive dysfunction (TBI-CD), yet the cell-autonomous mechanisms operating within neurons remain incompletely characterised. The AIM2 inflammasome - a cytosolic sensor of double-stranded DNA that drives pro-inflammatory cytokine release and pyroptosis - has been studied primarily in myeloid cells, and its role within neurons after TBI is unclear. Here, using a controlled cortical impact (CCI) mouse model, an in vitro mechanical-injury model, AAV-mediated neuron-specific AIM2 knockdown and a comprehensive set of behavioural and molecular assays, we define a neuron-intrinsic, self-perpetuating GSDMD-mtDNA-AIM2 axis that drives neuronal pyroptosis and cognitive decline after TBI. CCI triggered acute (24 h) AIM2 inflammasome activation specifically in cortical and hippocampal neurons, neuronal pyroptosis and CA3 neuronal loss. AAV-mediated knockdown of AIM2 in hippocampal CA3 neurons significantly reduced neuronal loss in this region and rescued cognitive performance in the Y-maze, novel object recognition and Morris water maze at 14 and 28 days post-injury. Mechanistically, mechanical injury caused early (3-6 h) release of mitochondrial DNA (mtDNA) - but not nuclear DNA - into the neuronal cytosol, where it directly activated the AIM2 inflammasome and engaged caspase-1/GSDMD-dependent pyroptosis; ethidium bromide-mediated mtDNA depletion reversed each pyroptotic marker. Within the first 0.5-3 h post-injury, activated GSDMD N-terminal fragments (GSDMD-NT) translocated to mitochondria, disrupted mitochondrial membrane potential (ΔΨm) and promoted further mtDNA leakage; CRISPR knockout of GSDMD, but not of Bax, prevented this injury-induced mitochondrial dysfunction. Delayed pharmacological inhibition of caspase-1 (VX-765 applied 6 h after injury, after the first wave) selectively suppressed a discrete second wave of cytosolic mtDNA release at 9-12 h and attenuated late-phase LDH release, providing direct experimental evidence for a self-perpetuating second wave of mtDNA-driven AIM2 activation. These findings define a self-perpetuating, neuron-intrinsic GSDMD-mtDNA-AIM2 inflammasome-pyroptosis axis as a driver of TBI-CD, and identify neuron-targeted AIM2 silencing as a candidate therapeutic strategy for limiting post-TBI neuroinflammation and cognitive decline.

Voriconazole (VCZ)-induced hepatotoxicity lacks effective early biomarkers and targeted interventions. This study investigated the role of triggering receptor expressed on myeloid cells-1 (TREM1) as a central integrator of macrophage-driven inflammation and metabolic dysregulation in voriconazole-associated hepatic steatosis. Clinical correlations between plasma soluble TREM1 (sTREM1) and liver injury severity were assessed in patients treated with voriconazole. Mechanistic studies utilized macrophage-specific depletion, macrophage-specific Trem1 knockout and overexpression models, macrophage-hepatocyte co-cultures, and integrated multi-omics profiling. VCZ-TREM1 binding was validated through molecular docking, surface plasmon resonance (SPR), and co-immunoprecipitation (Co-IP), with pathway inhibition assays conducted using the LR12 peptide. In patients, elevated sTREM1's levels correlated with the severity of liver injury, indicating its potential as an early diagnostic marker. VCZ directly bound to TREM1, promoting the formation of TREM1-Toll-like receptor 4 (TLR4) complexes, which activated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)-nuclear factor kappa-B (NF-κB)-NOD-like receptor thermal protein domain associated protein 3 (NLRP3)-interleukin-1beta (IL-1β) signaling cascade. The resulting overproduction of IL-1β induced hepatocyte lipid accumulation through reactive oxygen species (ROS)-mediated activation of sterol regulatory element-binding protein 1 (SREBP1)-driven lipogenesis. Pharmacological inhibition of TREM1 (LR12 peptide) suppressed TREM1 signaling and attenuated both inflammatory and metabolic alterations in murine models. This study elucidated a TREM1-centered signaling network linking VCZ-induced inflammation to steatosis. sTREM1 showed potential as a translational biomarker for early detection of liver injury, and TREM1 inhibition (LR12) offers a promising therapeutic strategy for antifungal-related hepatotoxicity.

Osteosarcoma (OS) suffers from stagnant survival rates due to high metastatic potential and genomic complexity. Here, we present a high-resolution single-cell transcriptomic atlas of the OS ecosystem using single-cell fixed RNA profiling (FLEX) of 40,401 cells across four clinical stages: treatment-naïve, post-chemotherapy, recurrent, and lung metastatic. We identified a metastasis-enriched malignant subpopulation, OB_3, characterized by aggressive transcriptional signatures and governed by ADAMTS12, which we validated as a prognostic marker for reduced overall survival. Functional in vitro experiments further demonstrated that ADAMTS12 silencing significantly reduced the migratory capacity of HOS and 143B OS cells and suppressed AKT and ERK phosphorylation, thereby supporting its role as an active driver of metastatic progression. Within the microenvironment, metastatic progression was defined by the emergence of RNASE1+ M2-like tumor-associated macrophages, an expansion of highly immunosuppressive S100A4+ regulatory T cells, and the specialization of PLVAP+ stalk endothelial cells driving tumor angiogenesis. Integrative interactome analysis revealed that these populations function as central coordinating hubs, utilizing MIF, SPP1, and Galectin signaling to orchestrate the metastatic niche. Our findings, validated across multiple external cohorts and tissue microarrays, delineate a coordinated multi-cellular network involving ADAMTS12+, RNASE1+, S100A4+, and PLVAP+ cells. This study clarifies how malignant and microenvironmental components co-evolve to facilitate systemic dissemination, providing a translational framework for precision risk stratification and the development of next-generation therapeutic strategies to counteract metastatic OS.

This study aims to examine how religiosity moderates the influence of attitude and electronic word of mouth (E-WOM) on purchase decisions in Indonesia's modest fashion market. It seeks to provide empirical evidence on how cognitive, social, and spiritual factors interact in shaping Muslim consumers' purchasing behavior. A quantitative research approach was employed using Structural Equation Modeling (SEM) with data collected from 320 Muslim consumers in Jakarta and surrounding areas. The constructs (attitude, E-WOM, religiosity, and purchase decision) were measured using validated multi-item scales adapted from previous studies. The results indicate that both attitude and E-WOM have significant positive effects on purchase decisions, with E-WOM being the most dominant factor. Religiosity exerts a direct positive influence and strengthens the relationship between attitude and purchase decision, but does not moderate the effect of E-WOM. These findings highlight that while religiosity enhances value-driven behavior, digital influence transcends religious intensity. The study suggests that modest fashion marketers should integrate syariah-compliant values with credible digital engagement strategies to foster consumer trust and loyalty. Balancing faith-based authenticity with modern digital communication can enhance brand relevance in the halal fashion market. This study extends the Theory of Planned Behavior (TPB) by incorporating religiosity as a moderating factor within the context of Islamic consumer behavior. It contributes to the growing body of Islamic marketing literature by revealing how faith and digital interaction jointly shape purchase decisions in the modest fashion industry.

The insect microbiome can influence host physiology and responses to infection, yet how it changes during interactions with pathogens remains underexplored. The Indianmeal moth, Plodia interpunctella, a major global pest of stored food products, can be targeted for biological control using the entomopathogenic nematodes (EPNs) Heterorhabditis bacteriophora. Understanding whether H. bacteriophora infection alters the P. interpunctella larval microbiome is crucial, since changes in microbial diversity, measured by alpha diversity indices (Faith's Phylogenetic diversity, Observed Amplicon Sequence Variants, Shannon diversity, and Pielou's evenness), can affect how the infection develops and influence the success of the EPNs as biological control agents. However, the response of the P. interpunctella larval microbiome to H. bacteriophora infection has not been well-characterized. Here, we investigated how the P. interpunctella larval microbiome changes following infection with either symbiotic (carrying the symbiotic bacteria Photorhabdus luminescens) or axenic (lacking bacterial symbionts) H. bacteriophora. Beta diversity analyses (Bray-Curtis dissimilarity, PERMANOVA) revealed shifts in ASV richness (number of observed amplicon sequence variants) and community evenness in the P. interpunctella larvae infected with either symbiotic or axenic nematodes. P. interpunctella larvae were sampled at 36h and 60h post-infection for 16s rRNA sequencing (READS/SAMPLE). We analyzed 150 P. interpunctella larval microbiomes per time point (60 larvae infected with symbiotic H. bacteriophora, 60 larvae infected with axenic H. bacteriophora, and 30 uninfected larvae). Illumina paired-end sequencing of 16S rRNA V3-V4 libraries yielded a mean sequencing depth of approximately 3.76 × 10^5 read pairs per sample. The UpSet analyses of shared ASVs across uninfected larvae and larvae infected with either symbiotic or axenic H. bacteriophora identified distinct ASVs unique to each infection type. LEfSe analysis further identified differentially expressed taxa observed in the microbiome of larvae infected with either symbiotic or axenic H. bacteriophora. Notably, larvae infected with symbiotic H. bacteriophora showed the highest number of unique ASVs, indicating that larval microbiome restructuring correlates with the presence of the symbiotic bacteria P. luminescens. These results indicate that the bacterial symbiont associated with EPNs is an important driver of host microbiome changes during infection, which may influence infection outcomes and the effectiveness of EPN-based biological control.

Lenvatinib resistance is a notable clinical challenge in advanced hepatocellular carcinoma (HCC). Androgen receptor (AR) upregulation has been associated with poor prognosis and high invasiveness, particularly in AR-high HCC, yet its specific role in lenvatinib resistance remains unclear. The present study investigated whether AR confers resistance through regulating the circular RNA hsa_circ_0011385. Bioinformatic screening and experimental validation identified hsa_circ_0011385 as significantly upregulated in HCC tissues and AR-high cell lines. In established lenvatinib-resistant cells (MHCC97H-LR), AR, hsa_circ_0011385 and Akt3 were upregulated, while miR-212-5p was downregulated. Mechanistically, AR directly bound to the promoter of eukaryotic translation initiation factor 3 subunit I (EIF3I), the host gene of hsa_circ_0011385 and promoted its transcription. The upregulated hsa_circ_0011385 acted as a molecular sponge for miR-212-5p, thereby relieving its inhibition of the downstream oncogene Akt3. Functional assays showed that AR knockdown sensitized resistant cells to lenvatinib, inhibiting proliferation and migration while promoting apoptosis, whereas overexpressing hsa_circ_0011385 reversed these effects. To the best of our knowledge, the present study revealed for the first time that in AR-high HCC, AR drives lenvatinib resistance by activating the EIF3I/hsa_circ_0011385/miR-212-5p/Akt3 axis. This finding provides a new theoretical basis and potential therapeutic targets for overcoming lenvatinib resistance in this patient subset.

Long-term ecosystem development includes a build-up phase followed by a decline (retrogressive) phase characterized by reduced plant productivity and belowground process rates due to reduced nutrient availability. In boreal forests, retrogression is accompanied by soil organic matter (SOM) accumulation, especially in the prolonged absence of fire. However, the role of bacterial communities in SOM dynamics during ecosystem retrogression has been little explored. Using a 5000-year post-fire boreal forest chronosequence, we investigated how long-term succession and retrogression shapes soil bacterial community structure and functional specialization. While the Actinomycetota phylum dominated communities across all chronosequence stages, a significant family-level shift within this phylum occurred in the later (retrogressive) phase, characterized by a transition from Mycobacteriaceae to Streptosporangiaceae. The recovery of metagenome-assembled genomes (MAGs) revealed distinct life-history trade-offs between these families. Streptosporangiaceae MAGs were significantly enriched in genes for degrading phenolics, cellulose, and lignin, and exhibited potential for chitin, lipid and peptide degradation. This positions them as potential decomposers of the primary constituents of stored soil carbon, including plant-derived complex carbohydrates and fungal necromass, during retrogression when fungal activity declines. In contrast, Mycobacteriaceae MAGs are likely to prioritize inorganic phosphate (P i ) uptake-by pstS gene enrichment, reflecting adaptation to P availability changes during ecosystem development. Collectively, our results demonstrate that long-term ecosystem retrogression drives shifts in the bacterial communities and functions within the Actinomycetota. These shifts may indicate possible divergent strategies, i.e. recalcitrant carbon turnover versus nutrient scavenging, which could explain shifts in the microbial community as the ecosystem transitions toward retrogressive, nutrient-limited states.

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Intracerebral hemorrhage (ICH) frequently triggers acute lung injury (ALI) via sympathetic overactivation. We aimed to investigate the neuroinflammatory mechanisms driving this brain-lung crosstalk and evaluate targeted neuromodulatory interventions via the mechanosensor PIEZO2. We utilized an ICH mouse model and norepinephrine (NE)-stimulated MLE12 cells. Pathological mechanisms were explored using transcriptomics, calcium imaging, and Vps35 knockdown. Therapeutic efficacies were assessed via central sympathetic blockade (stellate ganglion block, SGB) and peripheral PIEZO2 inhibition (D-GsMTx4). NE release exacerbated neurogenic ALI post-ICH. Mechanistically, NE upregulated VPS35, which simultaneously promoted PIEZO2 membrane trafficking and impaired ATP2A2-dependent endoplasmic reticulum (ER) calcium clearance. This induced massive intracellular calcium influx, triggering widespread ER stress and NLRP3/GSDMD-mediated pyroptosis in alveolar epithelial cells. Vps35 knockdown attenuated these effects in vitro. Crucially, targeted interventions with SGB or D-GsMTx4 successfully blocked this lethal central-peripheral cascade, alleviating pulmonary pyroptosis and improving in vivo outcomes. Sympathetic overactivation drives neurogenic ALI post-ICH via the VPS35/PIEZO2-ER stress-pyroptosis axis. Dual-node neuromodulation (SGB or PIEZO2 inhibition) offers a promising therapeutic strategy for secondary multiorgan complications following acute brain injury.

To investigate the impact of distinct socioeconomic status (SES) patterns on the risk of thyroid diseases in pregnant women against the background of adequate iodine nutrition. A cross-sectional study was conducted in Xinjiang from 2021 to 2022, enrolling 1,166 pregnant women. Fasting venous blood and urine samples were collected to assess thyroid function and iodine nutritional indicators. Long-term and short-term iodine intake were evaluated using a food frequency questionnaire and a 3-day 24-h dietary recall, respectively. Latent class analysis (LCA) was used to identify socioeconomic-environmental patterns based on region, income, education, occupation, and passive smoking status. Multivariable regression models were constructed to analyze the association between SES patterns and thyroid outcomes, adjusting for maternal and environmental covariates. Mediation analysis models were used to assess the mediating effect of iodine nutritional indicators. Three SES patterns were identified: Pattern A (Northern Xinjiang-Housewife-dominant Low SES, 37.14%), Pattern B (Southern Xinjiang-Housewife-dominant Low-to-Middle SES, 41.60%), and Pattern C (Highly Educated-Professional Women-High SES, 21.27%). Compared with Pattern A, Pattern C was significantly associated with lower TSH levels (β = -0.17, 95% CI: -0.32 - -0.03, p = 0.019). In the logistic regression models, Pattern B was significantly associated with lower odds of thyroid nodules compared with Pattern A (OR = 0.32, 95% CI: 0.14-0.74, p = 0.008). No statistically significant associations were observed between SES patterns and other thyroid disease outcomes after adjustment. Mediation analysis suggested that although dietary iodine intake and urinary iodine-to-creatinine ratio differed across SES patterns, these iodine nutritional indicators did not show statistically significant mediation in the associations between SES patterns and thyroid-related outcomes (p > 0.05). Against the overall background of adequate iodine nutrition, differences in socioeconomic patterns were independently associated with thyroid disease outcomes in pregnant women in Xinjiang, and this influence is not dependent on differences in iodine intake. This study suggests that prevention and control strategies for perinatal thyroid diseases should extend beyond single nutritional interventions towards psychological support and comprehensive environmental management targeting specific social roles.

Capnocytophaga ochracea, an early colonizer of oral biofilms associated with gingivitis, plays an incompletely understood role in periodontal pathogenesis. While sialidases are established virulence factors in late-colonizing 'red-complex' pathogens, their function in early colonizers, such as C. ochracea, remains unknown. To address this knowledge gap, we identified and characterized Co-NanH, the sole sialidase of C. ochracea. We performed phylogenetic and structural analyses to compare it with known sialidases. Enzymatic assays were conducted using recombinant Co-NanH to determine its pH optimum, substrate specificity, and kinetic parameters. Furthermore, we utilized sialidase inhibitors (such as DANA) and generated a nanH genetic deletion mutant (ΔnanH) to assess the enzyme's role in planktonic growth, biofilm formation, and interactions with human gingival epithelial cells (adhesion and internalization). Phylogenetic and structural analyses revealed that Co-NanH shares significant homology with a sialidase from Tannerella forsythia but possesses a distinct Sec/SPI signal peptide and a monomeric structure. Recombinant Co-NanH exhibited optimal activity at pH 5.5 and cleaved both α2,3- and α2,6-linked sialic acids, with kinetic parameters comparable to those of red-complex pathogen sialidases. Inhibitors like DANA potently suppressed its activity and reduced C. ochracea biofilm formation. Crucially, genetic deletion of nanH abolished sialidase activity without affecting planktonic growth. The ΔnanH mutant exhibited severely impaired biofilm formation, characterized by reduced biomass, thickness, and initial attachment. Furthermore, the mutant showed significantly reduced adhesion to and internalization by human gingival epithelial cells compared with wild-type and complemented strains. These findings establish Co-NanH as a key mediator of C. ochracea in biofilm maturation and host cell interactions, revealing a functional parallel between early colonizers and classical periodontal pathogens. This work provides functional evidence that sialidase activity in an early colonizer contributes to oral dysbiosis by facilitating biofilm development and priming the host environment for disease progression.

Nitrogen loss during straw composting substantially undermines nutrient recycling efficiency and the agronomic value of finished compost products. Clarifying how different nitrogen sources mediate nitrogen transformation and nitrogen retention in organic fractions is therefore essential for improving compost maturity and nitrogen retention. This study evaluated how three nitrogen-rich amendments with divergent chemical characteristics (chicken manure, fish meal, and soybean powder) influenced nitrogen transformation, organic nitrogen fractionation, enzyme dynamics, and microbial succession during static pile composting of rice straw. Compost maturity varied significantly among treatments (P < 0.05), with germination indices of 100% for soybean powder, 90.1% for fish meal, and 84.9% for chicken manure. Chicken manure primarily promoted a mineralization-oriented nitrogen transformation pattern characterized by rapid ammonium accumulation and subsequent nitrification, accompanied by elevated urease activity and enrichment of Firmicutes. In contrast, fish meal and soybean powder were associated with nitrogen transformation patterns involving stronger proteolytic and oxidative enzyme activities and greater nitrogen retention in relatively stable organic fractions, resulting in significant increases in amine nitrogen and hydrolysable unknown nitrogen (HUN), a relatively stable organic nitrogen fraction, by 45.1-139% relative to the control (P < 0.05). Coordinated proteolytic and oxidative enzyme activities, together with enrichment of Thermobifida, Actinobacteriota, and Aspergillus, were strongly associated with HUN formation. Overall, protein-rich nitrogen sources were more conducive to microbial-enzymatic interactions associated with organic nitrogen stabilization, whereas chicken manure favored nitrogen mineralization. These findings demonstrate that nitrogen sources can shape nitrogen transformation toward greater inorganic nitrogen production or higher organic nitrogen retention, thereby providing practical insights for improving nitrogen retention and compost quality in straw composting systems.