西南医科大学

Introduction: Psoriasis is a chronic immune-mediated inflammatory skin disease with a complex genetic background, susceptible to psoriatic arthritis as a complication. However, interpretation of genetic associations from bulk tissue analyses is limited by cellular heterogeneity, hindering mechanistic inference. This study aimed to explore cell-type-specific causal regulatory mechanisms between psoriasis and periodontitis. Methods: We integrated psoriasis and periodontitis genome-wide association data with three single-cell expression quantitative trait locus (sc-eQTL) datasets (OneK1K, sc-eQTLGen, and dynamic CD4+ T-cell activation). Two-sample Mendelian randomization (MR) was supplemented by bulk eQTL, plasma protein QTL, and Steiger directionality analyses. Prioritized genes were further examined using single-cell transcriptomics, network-based in silico perturbation, functional enrichment, drug-signature analysis, and molecular docking. Results: Cell-type-resolved MR analyses revealed heterogeneous and context-dependent genetic effects across immune cell subsets, with both concordant and discordant associations between psoriasis and periodontitis. Among the prioritised candidates, LRRC25 showed nominally significant MR associations with both diseases, although these associations were not corrected for multiple testing. Bulk blood-derived eQTL analyses showed consistent inverse associations with both diseases, whereas naive B cell-specific MR analyses showed associations in the opposite direction. Single-cell RNA sequencing showed that LRRC25 expression was predominantly detected in monocytes, whereas only a small proportion of naive B cells expressed LRRC25 . In silico LRRC25 perturbation in monocytes produced concordant transcriptional changes across psoriasis and periodontitis, with FCGR3A identified as a central network hub. Functional enrichment analyses implicated innate immune, type I interferon and Fc receptor-related pathways. Conclusions: LRRC25 emerged as a putative shared immunoregulatory candidate, although evidence varied across molecular levels and immune cell contexts. No statistically significant shared protein-level association was identified. Our findings suggest that bulk eQTL inference may obscure cell-type-specific regulatory signals and highlight the value of single-cell-informed gene prioritization. Further experimental validation is needed.

Introduction Psoriasis is a chronic immune-mediated inflammatory skin disease with a complex genetic background, susceptible to psoriatic arthritis as a complication. However, interpretation of genetic associations from bulk tissue analyses is limited by cellular heterogeneity, hindering mechanistic inference. This study aimed to explore cell-type-specific causal regulatory mechanisms between psoriasis and periodontitis. Methods We integrated psoriasis and periodontitis genome-wide association data with three single-cell expression quantitative trait locus (sc-eQTL) datasets (OneK1K, sc-eQTLGen, and dynamic CD4+ T-cell activation). Two-sample Mendelian randomization (MR) was supplemented by bulk eQTL, plasma protein QTL, and Steiger directionality analyses. Prioritized genes were further examined using single-cell transcriptomics, network-based in silico perturbation, functional enrichment, drug-signature analysis, and molecular docking. Results Cell-type-resolved MR analyses revealed heterogeneous and context-dependent genetic effects across immune cell subsets, with both concordant and discordant associations between psoriasis and periodontitis. Among the prioritised candidates, LRRC25 showed nominally significant MR associations with both diseases, although these associations were not corrected for multiple testing. Bulk blood-derived eQTL analyses showed consistent inverse associations with both diseases, whereas naive B cell-specific MR analyses showed associations in the opposite direction. Single-cell RNA sequencing showed that LRRC25 expression was predominantly detected in monocytes, whereas only a small proportion of naive B cells expressed LRRC25. In silico LRRC25 perturbation in monocytes produced concordant transcriptional changes across psoriasis and periodontitis, with FCGR3A identified as a central network hub. Functional enrichment analyses implicated innate immune, type I interferon and Fc receptor-related pathways. Conclusions LRRC25 emerged as a putative shared immunoregulatory candidate, although evidence varied across molecular levels and immune cell contexts. No statistically significant shared protein-level association was identified. Our findings suggest that bulk eQTL inference may obscure cell-type-specific regulatory signals and highlight the value of single-cell-informed gene prioritization. Further experimental validation is needed.

As representatives of degenerative orthopedic diseases, intervertebral disc degenerative disease (IVDD) and osteoarthritis (OA) involve the spine and peripheral articular cartilage, respectively. Their comorbidity rate in individuals over 60 years exceeds 40

Knee osteoarthritis (KOA) is a chronic degenerative joint disease characterized by cartilage degradation, subchondral bone remodeling, osteophyte formation, and synovial inflammation. Emerging evidence indicates that immune-inflammatory responses, particularly macrophage polarization and pyroptosis, play central roles in KOA pathogenesis. In the synovial microenvironment, macrophages exhibit functional heterogeneity beyond the classical M1/M2 paradigm, with M1-like macrophages predominating and promoting pro-inflammatory signaling through metabolic and epigenetic reprogramming. Concurrently, M2-like macrophages are reduced and functionally impaired, failing to resolve inflammation or support tissue repair. Pyroptosis, a highly inflammatory form of programmed cell death mediated by inflammasomes and Gasdermin D (GSDMD), is significantly activated in KOA synovium. M1 macrophages display heightened susceptibility to pyroptosis, releasing IL-1β, IL-18, and damage-associated molecular patterns (DAMPs), which further reinforce M1 polarization and synovial inflammation, forming a self-amplifying “inflammation–pyroptosis–re-inflammation” loop. This maladaptive feedback between macrophage polarization and pyroptosis drives chronic synovitis, cartilage matrix degradation, subchondral bone abnormalities, and persistent pain. Targeting key nodes of this network, including NLRP3, caspase-1, GSDMD, HMGB1/RAGE, and macrophage metabolic pathways, may offer novel therapeutic strategies for KOA. Understanding the interplay between macrophage heterogeneity and pyroptotic signaling provides a mechanistic framework for precision interventions aimed at restoring immune homeostasis and mitigating joint degeneration in KOA.

While impaired decision-making and reduced impulsive control have been repeatedly reported in individuals with Internet Gaming Disorder (IGD), there was accumulating evidence that controlled gaming exposure may be beneficial in certain aspects of perceptual decision-making. This study aimed to investigate perceptual decision and metacognition processing in IGD applying a post-decision wagering paradigm and drift-diffusion modeling (DDM). Results demonstrated that individuals with IGD exhibited enhanced decision accuracy and elevated drift rates during perceptual decision-making. Yet, no group differences were observed in comparison of metacognitive ability and metacognitive bias, indicating preserved metacognition in IGD. Notably, drift rates were positively correlated with anxiety and depression symptoms in the IGD group, but was negatively correlated with general self-efficacy in healthy controls (HCs), indicating compromised self-regulatory capacity and maladaptive metacognitive resource allocation patterns in IGD individuals. These findings demonstrated enhanced performance and elevated evidence accumulation efficiency during perceptual decision-making, as well as preserved metacognitive abilities in individuals with IGD, suggesting gaming may induce certain cognitive enhancement during perceptual decision-making in clinically diagnosed IGD.