Causal link between type 1 diabetes mellitus and juvenile idiopathic arthritis in Europe
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The genetic and observational nexus between diabetes and arthritis: a national health survey and mendelian randomization analysis
Diabetes mellitus (DM) and arthritis are prevalent conditions worldwide. The intricate relationship between these two conditions, especially in the context of various subtypes of arthritis, remains a topic of interest.
Targeting macrophage polarization by inhibiting Pim2 alleviates inflammatory arthritis via metabolic reprogramming
Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis. Moreover, although previous studies have reported that the proviral integration of Moloney virus 2 (Pim2) kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells, its role in inflammatory arthritis remains unclear. In this study, we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization. Specifically, Pim2 directly phosphorylates PGK1-S203, PDHA1-S300, and PFKFB2-S466, thereby promoting glycolytic reprogramming. Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collagen-induced arthritis (CIA) model mice. Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization. Through molecular docking and dynamic simulation, bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization, thereby mitigating the progression of inflammatory arthritis. For targeted treatment, neutrophil membrane-coated bexarotene (Bex)-loaded PLGA-based nanoparticles (NM@NP-Bex) were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages, and these nanoparticles (NPs) exhibited superior therapeutic effects with fewer side effects. Taken together, the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance. NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.
Causation versus prediction in travel mode choice modeling
This study discusses and analyzes the difference between causal and predictive modeling to model travel mode choice. Causal modeling is expressed through causal discovery and causal inference, used to extract causal relationships in mode choice decision making and estimate causal effects between variables. Predictive modeling is expressed through artificial neural networks. When modeling travel mode choice in three Chicago neighborhoods, we find that both causal and predictive modeling approaches perform well and are useful for their modeling purposes. We also note that the study of mode choice behavior through causal modeling is under-explored while it could transform our understanding of mode choice behavior. Further research is needed to realize the full potential of these techniques in modeling mode choice.
Triangulation for causal loop diagrams: constructing biopsychosocial models using group model building, literature review, and causal discovery
The complex nature of many health problems necessitates the use of systems thinking tools like causal loop diagrams (CLDs) to visualize the underlying causal network and facilitate computational simulations of potential interventions. However, the construction of CLDs is limited by the constraints and biases of specific sources of evidence. To address this, we propose a triangulation approach that integrates expert and theory-driven group model building, literature review, and data-driven causal discovery. We demonstrate the utility of this triangulation approach using a case example focused on the trajectory of depressive symptoms in response to a stressor in healthy adults. After triangulation with causal discovery, the CLD exhibited (1) greater comprehensiveness, encompassing multiple research fields; (2) a modified feedback structure; and (3) increased transparency regarding the uncertainty of evidence in the model structure. These findings suggest that triangulation can produce higher-quality CLDs, potentially advancing our understanding of complex diseases.
Caspase-11 mediated inflammasome activation in macrophages by systemic infection of A. actinomycetemcomitans exacerbates arthritis
Clinical studies have shown that Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans) is associated with aggressive periodontitis and can potentially trigger or exacerbate rheumatoid arthritis (RA). However, the mechanism is poorly understood. Here, we show that systemic infection with A. actinomycetemcomitans triggers the progression of arthritis in mice anti-collagen antibody-induced arthritis (CAIA) model following IL-1β secretion and cell infiltration in paws in a manner that is dependent on caspase-11-mediated inflammasome activation in macrophages. The administration of polymyxin B (PMB), chloroquine, and anti-CD11b antibody suppressed inflammasome activation in macrophages and arthritis in mice, suggesting that the recognition of lipopolysaccharide (LPS) in the cytosol after bacterial degradation by lysosomes and invasion via CD11b are needed to trigger arthritis following inflammasome activation in macrophages. These data reveal that the inhibition of caspase-11-mediated inflammasome activation potentiates aggravation of RA induced by infection with A. actinomycetemcomitans. This work highlights how RA can be progressed by inflammasome activation as a result of periodontitis-associated bacterial infection and discusses the mechanism of inflammasome activation in response to infection with A. actinomycetemcomitans.
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