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关键词： HLA genotype   T cell donors   BK virus   Virus-specific T cells  

摘要： PurposeThe increasing application of virus-specific T cell therapy for treating BK virus infections in immunocompromised patients highlights the necessity for rapid identification of compatible cell donors with optimal BK-specific T cell response. This study aims to characterize the BK virus-specific T cell response in relation to demographic factors, blood group, serological status, and HLA genotypes using samples from a cell donor *** blood mononuclear cells from cell donors were stimulated with peptide pools derived from VP1 and LTA proteins, and the IFN-gamma production was analyzed using ELISpot and validated by flow *** findings provide an overview of the T cell response to BK virus proteins in healthy donors, revealing associations with demographic characteristics, RhD status, CMV or EBV serological status, and HLA alleles. Remarkably, RhD-negative, CMV-seronegative, and EBV-seronegative donors showed a major T cell response against BK virus proteins. Notably, certain HLA alleles were associated with either enhanced or diminished T cell response. Furthermore, our results suggest that HLA-B leader dimorphism, specifically the presence of threonine at position 2, influences the VP1-specific immune response, resulting in enhanced T cell *** study, beyond advancing our understanding of the relationship between donor characteristics and BK virus-specific T cell response, has significant implications for improving the selection of optimal cell donors for patient-specific adoptive therapy.

关键词： Vitiligo   Chronic unpredictable mild stress (CUMS)   Fibroblasts   Cellular senescence   IL-6  

摘要： BackgroundPsychological stress is the most common psychological comorbidity and a significant triggering factor of vitiligo. Moderate to severe psychological stress can markedly affect the efficacy of vitiligo treatment. However, the specific mechanisms underlying its involvement remain insufficiently *** unpredictable mild stress (CUMS)-induced major depressive disorder (MDD)-like behavior was modeled in C57BL/6 mice alongside wild-type mice to investigate differences in vitiligo pathogenesis. White spot tissues from mouse tails were subjected to high-throughput transcriptomic sequencing (RNA-seq). In vitro experiments utilized beta-galactosidase, P16, and P21 to assess IFN-gamma-induced senescence. The effects of exogenous IL-6 on fibroblast senescence were assessed, and the role of blocking the IL-6 autocrine loop with an IL-6R inhibitor in reversing IFN-gamma-induced fibroblast senescence was ***-induced MDD -like mice exhibited significantly lower body mass index and sugar-water preference index compared to wild-type mice, and their vitiligo severity was markedly increased. Transcriptomic sequencing revealed significant upregulation of cellular senescence and JAK-STAT signaling pathways in white spot tissues of depressive-like vitiligo mice. In vitro findings indicated that IFN-gamma induced fibroblast senescence via activation of the JAK2-STAT3 signaling pathway, which subsequently promoted melanocyte apoptosis and increased IL-6 secretion and IL-6R expression. Exogenous IL-6 further activated the JAK2-STAT3 signaling pathway, induced fibroblast senescence, and synergistically intensified IFN-gamma-induced fibroblast *** activation of the IL-6 autocrine loop, synergizing with IFN-gamma to aggravate fibroblast senescence and promote melanocyte apoptosis. Blocking the IL-6 autocrine loop may serve as an effective approach to mitigate the impact of CUMS on vitiligo pathogenesis and treatment efficacy

关键词： Psychiatric disorders   length of stay   Interleukin-6   Tumor Necrosis Factor Alpha   Insulin  

摘要： Hospital length of stay (LOS) is a widely used indicator of healthcare efficiency and a key metric for evaluating the performance of psychiatric services. This study aims to identify predisposing, needs-related, and enabling factors associated with LOS among patients with psychiatric disorders admitted through the psychiatric emergency room in Montreal, Canada. A total of 600 individuals with mental health disorders who were hospitalized between 2012 and 2018 were interviewed. Guided by the Behavioral Model for Vulnerable Populations, factors influencing LOS were assessed using a negative binomial regression model. Longer LOS was associated with patients aged 60 and older, those diagnosed with psychotic and/or personality disorders at admission, individuals with elevated interleukin-6 (IL-6) levels (a pro- and anti-inflammatory cytokine), and those with a history of hospitalization. In contrast, shorter LOS was observed among patients with common mental health symptoms, substance use disorders (SUD), suicidal ideation, among those with elevated levels of the proinflammatory cytokine tumor necrosis factor alpha (TNF-alpha) or insulin. Targeted interventions such as Assertive Community Treatment for patients with personality disorders, intensive home care for those with psychotic disorders, and crisis resolution teams for individuals experiencing suicidal ideation or common mental health symptoms may help reduce hospitalization durations. For patients with SUD, improved referral systems and harm reduction-oriented outpatient care are recommended. Circulating biomarkers such as IL-6, TNF-alpha, and insulin may aid in early identification of patients at risk for prolonged stays and hold promise for integration into clinical decision-making and treatment. Further research is needed to validate these findings across diverse psychiatric populations.

关键词： Aquaporin 1   Rheumatoid arthritis   Autophagy   Apoptosis   Proliferation   Fibroblast-like synoviocytes  

摘要： Objective Fibroblast-like synoviocytes (FLS) are key players in rheumatoid arthritis (RA) by resisting apoptosis via increased autophagy. Elevated synovial aquaporin 1 (AQP1) affects RA FLS behaviors, but its relationship with FLS autophagy is unclear. We aim to clarify that silencing AQP1 inhibits autophagy to exert its anti-RA effects. Methods We studied the effects and mechanisms of AQP1 silencing on autophagy in TNF-alpha-induced RA FLS and examined the crucial role of autophagy inhibition in its impacts on RA FLS pathogenic behaviors. We explored whether silencing synovial AQP1 relieved rat adjuvant-induced arthritis (AIA) by reducing synovial autophagy. Results TNF-alpha stimulation increased AQP1 expression and autophagy levels in RA FLS, with a positive correlation between them. AQP1 silencing inhibited autophagy in TNF-alpha-stimulated RA FLS, along with suppressing proliferation, promoting apoptosis, and mitigating inflammation. Notably, the inhibitory effects of AQP1 silencing on RA FLS pathogenic behaviors were cancelled by autophagy activation with rapamycin (Rapa) but enhanced by autophagy inhibition using 3-Methyladenine. Mechanistically, silencing AQP1 enhanced the binding of Bcl-2 to Beclin1 by decreasing Beclin1-K63 ubiquitination, thus inhibiting RA FLS autophagy. In vivo, silencing synovial AQP1 relieved the severity and development of rat AIA, alongside reducing Ki67 expression, promoting apoptosis, and decreasing autophagy within AIA rat synovium. Expectedly, the Rapa co-administration nullified the anti-AIA effects of silencing synovial AQP1. Conclusion These findings reveal that silencing AQP1 inhibits RA FLS pathogenic behaviors and attenuates rat AIA through autophagy inhibition. This study may help clarify the pathogenic role of AQP1 in enhancing autophagy during RA development.

关键词： Rheumatoid Arthritis   G. mellonella hemolymph   MiR-146a   Immunomodulators   Osteocalcin   In-silico simulation  

摘要： Rheumatoid arthritis (RA) is an inflammatory autoimmune illness that persistently and recurrently affects joints. In RA, miR-146a functions as a key regulator, modulating inflammation by targeting and downregulating cytokines that promote inflammation, such as TNF-alpha and IL-6, whereas osteocalcin, a bone metabolism marker, plays a role in bone remodeling and joint health. The interplay between these molecules significantly influences RA progression and severity by balancing inflammation and bone integrity. Conventional antirheumatic drugs often cause varying levels of side effects. As sustainable development initiatives grow, insects are gaining interest as sustainable food sources and potential medicinal agents. Notably, the increasing Galleria mellonella (G. mellonella) population has raised concerns about the spread of honeybee viruses, affects bee products and food security, and drives economic losses in the therapeutic market. Accordingly, hemolymph has crucial defensive and immunological effects in insects and has recently been investigated as an immunomodulatory agent in parasitic in-vitro and in-vivo rat models. This work was designed to elucidate the potential immunomodulatory impact of G. mellonella hemolymph on the crosstalk between miR-146a, IL-6, TNF-alpha, and osteocalcin in the context of RA, utilizing both computational molecular modeling and in-vivo validation. Computer-aided molecular simulation for immune and RA mediators is applied through specific cell annotation, targeted pathways, and in-silico protein-protein and gene-gene interactions with a gene relative-tissue expression heatmap, which is based on gas chromatographic-mass spectrometric analysis of hemolymph. Our study is the first to adapt a preliminary test to optimize hemolymph dosing and toxicity. The rats were subsequently divided into four groups: healthy control, Freund's adjuvant-induced arthritis (utilized as a model that mimics human RA), methotrexate-treated arthritis, and hem

关键词： Intrusion detection  

摘要： In cyberspace, intrusion and detection constitute dynamic and continuous game processes, where data streams are generated incrementally during intrusion. To mitigate intrusions and safeguard assets effectively, it is imperative to take prompt actions based on real-time detection and analysis of the currently available data streams. However, existing approaches that rely on complete and clean data struggle to keep pace with the continuous real-time flow of new network data. To address this issue, we introduce IL-IDS (Incremental Learning for Intrusion Detection Systems), a novel intrusion detection approach that utilizes incremental learning to enable accurate and timely detection of intrusions in real-world scenarios, where the need for real-time processing and learning from newly generated traffic data is paramount. IL-IDS performs in scenarios with limited data availability, where it initially transforms textual data streams into vectorized representations and leverages a variation autoencoder (VAE) to compress these vectors, efficiently extracting their latent features. Then a classifier is trained to distinguish attack and normal behaviors, and a three-way decision method is employed to establish a boundary for ambiguous data that pose challenges in direct classification. Concurrently, threat intelligence is integrated into this process to enhance the accuracy of decision-making. We validate the effectiveness and efficiency of IL-IDS with experiments on real-world deployments during an international activity, highlighting its robustness and reliability in intrusion detection applications, especially under conditions of confined data streams. Notably, IL-IDS has exhibited comparable accuracy and recall results, and attains exceptional 99.93% precision and 96.83% F1-score, which demonstrates a notable improvement of 5.27% and 2.59% respectively in comparison to intrusion detection models trained on complete and readily available data. © The Author(s) 2025.

关键词： miR-126b   IL-4R alpha 1   Th2 immune response   MAPK pathway   mTOR pathway   Large yellow croaker ( Larimichthys crocea )  

摘要： The closely related cytokines Interleukin-4 (IL-4) and IL-13 regulate the Th2 immune response by interacting with their specific receptor complexes. MicroRNAs (miRNAs) modulate various biological pathways through mechanisms that either repress mRNA translation or promote messenger RNA degradation. The miRNA miR-126b is implicated in fish embryonic development. However, its role in regulating the Th2 immune response remains unclear. Here, the mature sequence of miR-126b was identified in large yellow croaker (Larimichthys crocea), which is highly conserved among vertebrates. MiR-126b was confirmed to directly target the 3 '-UTR of LcIL-4R alpha 1. Overexpression of miR-126b in primary head kidney leukocytes (PKLs) resulted in a remarkable reduction of LcIL-4R alpha 1 mRNA levels. Upon transfection with miR-126b mimics and subsequent stimulation by LcIL-4/13A and LcIL-4/13B proteins, the phosphorylation levels of MEK1/2 and 4E-BP1, which serve as essential components of the MAPK and mTOR cascades, were notably decreased in PKLs. Furthermore, overexpression of miR-126b also attenuated the activation effects of LcIL-4/13A and LcIL-4/13B on both T cell proliferation and differentiation, as well as B cell proliferation. These results indicated that miR-126b regulates the Th2 immune response by targeting IL-4R alpha 1, thereby disrupting IL-4/13A and IL-4/13B-mediated signal transduction. These findings highlight a crucial regulatory role of miR-126b in the Th2 immunity in teleost fish.

关键词： KIF2C   Diffuse large B -cell lymphoma   Macrophage polarization   Tumor progression  

摘要： KIF2C is an oncogene highly expressed in various malignancies, but its role in diffuse large B-cell lymphoma (DLBCL) remains unclear. In this study, THP-1 cells were stimulated to differentiate into M0, M1, and M2 macrophages using the culture medium of OCI-LY3 DLBCL cells. KIF2C expression was upregulated during M2 polarization. Knockdown or overexpression of KIF2C in THP-1 cells revealed that KIF2C promoted M2 but not M1 polarization. Whether in the co-culture of THP-1_M0 cells with altered KIF2C levels and OCI-LY3 cells, or in OCILY3 cells with altered KIF2C levels. KIF2C knockdown inhibited OCI-LY3 proliferation, migration, and invasion, and promoted apoptosis. In contrast, KIF2C overexpression enhanced M2 polarization and tumor-promoting behaviors. Mechanistically, KIF2C knockdown reduced p-STAT3 (Tyr705) levels in macrophages. Application of STAT3 agonist colivelin TFA restored IL-10 expression and M2 polarization. KIF2C knockdown in tumor cells inhibited their growth and viability, both in vitro and in a subcutaneous xenograft model, in which M2 macrophage polarization, IL-10 expression, and tumor progression were reduced. These findings suggest that KIF2C in macrophages and/or tumor cells regulates DLBCL-associated M2 macrophage polarization and tumor progression through the STAT3/IL-10 axis, highlighting KIF2C as a potential therapeutic target in DLBCL.