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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.

关键词： WGA   IMDA   PCR-SSP   HLA ligands   Dengue patients  

摘要： BackgroundHigh-throughput DNA sequencing technologies have revolutionized genetic studies of populations and diseases. These methods provide deeper insights into gene structure and variation, offering more comprehensive immunogenetic data with stronger relevance to protein function and biological impact. However, the widespread adoption of high-resolution sequencing is hindered by factors such as cost and limited accessibility. Furthermore, successful implementation requires high-quality and sufficient quantities of genomic *** and resultsThis study addresses the challenges of limited DNA yields, a common issue in clinical samples, by employing whole-genome amplification (WGA) with isothermal multiple displacement amplification (IMDA). We investigated HLA ligands in 253 dengue samples with low DNA quantity. A multiplex PCR-SSP method was developed to determine HLA ligands in population, including HLA-C1, HLA-C2, HLA-A (Bw4), HLA-Bw4 (I80), HLA-Bw4 (T80), and HLA-A*11. The study successfully demonstrates the applicability of a multiplex PCR-SSP method for HLA genotyping in a large cohort of dengue patients. Our findings highlight the high prevalence of HLA-C1 (92.1%) and HLA-A*11:03 (78.3%) in dengue patients, providing valuable data for further investigations into the role of HLA polymorphisms in *** study demonstrates the utility of our approach for investigating HLA ligands in clinical samples with limited DNA. WGA-IMDA effectively overcomes the challenge of low DNA availability, making this approach suitable for resource-constrained settings. The multiplex PCR-SSP method provides a simple and cost-effective solution for immunogenetic studies.

关键词： IL-1β   Nociception   TRPV1   dorsal root ganglion   inflammasome   leishmaniasis   local inflammation  

摘要： Leishmaniasis is a group of neglected diseases that cause significant mortality and disability. In Brazil, the most prevalent form is cutaneous leishmaniasis, which is characterized by painless lesions despite intense inflammation and ulceration. While BALB/c mouse models exhibit hypersensitivity to inflammatory stimuli, C57BL/6 mice better mimic human-like lesion progression and nociception. This study aimed to investigate the mechanisms underlying nociception in cutaneous leishmaniasis using the C57BL/6 model. Following infection with , behavioral and nociceptive tests revealed unaltered mechanical nociception and motor capacity, although thermal hyperalgesia was observed during the chronic phase. Elevated IL-1β production in lesions and upregulation of TRPV1 in dorsal root ganglia (DRG) neurons were detected via ELISA and RT-qPCR. Mice deficient in IL-1β signaling components exhibited increased thermal thresholds, highlighting the role of IL-1β in thermal hyperalgesia during chronic infection. Histological analysis of chronic lesions revealed tissue deformities, indicating desensitization to mechanical and inflammatory stimuli due to nerve terminal alterations and fibroplasia resulting from regenerative processes. Conversely, thermal hyperalgesia in the chronic phase is driven by the effects of IL-1β on thermal nociceptive DRG neurons. These findings suggest that IL-1β and TRPV1 contribute to thermal hyperalgesia, whereas structural changes in lesions underlie mechanical desensitization. This model provides insight into the complex nociceptive mechanisms of cutaneous leishmaniasis.

关键词： TNFR1 signaling   Body-brain interaction   Metabolic inflammation   Necroptosis   Blood-brain barrier (BBB) permeability   Therapeutic targeting  

摘要： Body-brain interaction (BBI) plays a critical role in coordinating the communication between peripheral organs and the brain, contributing to the comorbidity of metabolic disorders and neurological disorders. In the context of obesity, one of the key mediators driving systemic and neuroinflammatory responses is the soluble form of tumor necrosis factor (TNF), which primarily signals through TNF receptor 1 (TNFR1) to regulate inflammation and cell death. In this review, we examine how TNF/TNFR1-mediated metabolic inflammation in obesity disrupts cellular homeostasis across multiple organ systems, including the brain. In peripheral tissues, TNF is overproduced and secreted by activated macrophages, leading to lipid dysmetabolism, insulin resistance, and metabolic dysfunction in key cell types such as adipocytes and hepatocytes. Elevated circulating TNF also increases the permeability of the blood-brain barrier, enabling peripheral inflammatory mediators to infiltrate the brain and activate glial cells, thereby amplifying neuroinflammation. Within the brain, TNF induces metabolic and autolysosomal dysfunction in neurons, resulting in elevated reactive oxygen species, accumulation of toxic protein aggregates, and impaired insulin signaling, contributing collectively to neuronal death and the progression of neurodegeneration. We further highlight the metabolic-inflammatory crosstalk within the BBI as a potential therapeutic target, focusing on anti-inflammatory strategies that modulate TNF/TNFR1 signaling. Lastly, we provide future perspectives on the implications of body-brain axes, cell type-specific mechanisms, and disease comorbidities in the context of obesity.

关键词： Inborn Errors of Immunity   IL10RA Deficiency   Hematopoietic cell Transplantation   Japan   Fludarabine   Busulfan   Melphalan  

摘要： Background IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. Methods We retrospectively analyzed patients with IL10RA deficiency in Japan. Results Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT;one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. Conclusion In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250)

关键词： acute viral myocarditis   children   immune factors   interleukin  

摘要： The study examines variations of serum interleukin (IL)-6, IL-17, and transforming growth factor-beta (TGF-beta) in pediatric viral myocarditis. One hundred and twenty children diagnosed with acute viral myocarditis were divided into survival (n = 60) and death (n = 60) groups according to their prognosis. Troponin I, serum IL-6, IL-17, TGF-beta, creatine kinase isoenzyme MB, and brain natriuretic peptide levels were significantly increased on admission and gradually increased during 1 week of immune monitoring, of which TGF-beta and IL-6 peaked in the second week and IL-17 peaked in the fourth week. The above-mentioned indices were significantly lower in the survival group than those in the death group (P < .05). The survival group exhibited significantly higher left ventricular ejection fraction (LVEF) (P < .05) and significantly lower brain natriuretic peptide (BNP) level (t = -0.408, P = .72) than the death group. The serum levels of IL-6, IL-17, and TGF-beta were significantly increased in children with acute viral myocarditis, and the LVEF was the main influencing factor leading to poor prognosis.