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关键词： IL-4 inducing peptides   ESM-2 model   Protein language model   SMOTE   ENN  

摘要： Despite progress in developing antiviral drugs and vaccines, infections continue to be a significant challenge. Interleukin-4 (IL-4) is crucial for regulating immune responses and mediating allergic reactions. This research aims to improve the predictive accuracy of IL-4-inducing peptides by tackling data imbalance and enhancing feature extraction. Specifically, we introduce a new approach that utilizes SMOTE and ENN for balancing the dataset and applies a 30-layer ESM-2 model for extracting deep features. The extracted features are subsequently processed through a Gated Recurrent Unit (GRU) model, which is optimized through hyperparameter tuning. Our method achieves notable improvements, with an AUC of 0.98 and an accuracy of 93.1 %, highlighting its potential to support future immunotherapy and vaccine development efforts. The PLM-IL4 web server is freely accessible at http://***/PLM-IL4, and the datasets used in this research are also available for download from the website.

关键词： STAT2   IRF3   IFN   Ubiquitination   Black carp  

摘要： Interferon (IFN) regulatory factor 3 (IRF3) is a critical transcription factor involved in inducing IFN production. However, the regulatory mechanisms of piscine IRF3 remain inadequately explored. Here, we report that the signal transducer and activator of transcription 2 (STAT2) of black carp (Mylopharyngodon piceus) functions as a positive regulator in the black carp IRF3 (bcIRF3)-mediated IFN signaling pathway. Knockdown of bcSTAT2 in vivo facilitates viral replications, and the mRNA levels of bcSTAT2 gene increase after IFN stimulation in host cells. Additionally, overexpression of bcSTAT2 promotes the activation of interferon stimulated response element (ISRE) ex vivo. Co-immunoprecipitation assays identify the interaction between bcSTAT2 and bcIRF3, and both molecules exhibit similar subcellular distributions in immunofluorescent staining assay. When co-expressed, bcSTAT2 improves the protein level of bcIRF3, and enhances the bcIRF3-mediated IFN production and antiviral capabilities. Mechanistically, we demonstrate that bcSTAT2 significantly enhances the nuclear translocation of bcIRF3. Besides, bcSTAT2 enhances K29-linked ubiquitination, while reduces K33-and K48-linked ubiquitination of bcIRF3. Taken together, our data concludes that bcSTAT2 positively regulates bcIRF3-mediated antiviral activity by regulating its ubiquitination and facilitating its nuclear translocation, which has shed a light on the regulation of IFN signaling.

关键词： Neuroinflammation   IL-6 trans-signalling   sgp130Fc   TDP-43 protein aggregates   Microglia  

摘要： Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by chronic inflammation in both the central nervous system (CNS) and peripheral tissues. Interleukin-6 (IL-6) has been implicated in ALS pathology;however, IL-6 exhibits both anti-inflammatory and pro-inflammatory functions. Notably, IL-6 trans-signalling possesses pro-inflammatory properties and is emerging as a key contributor to neuroinflammation during neurodegeneration. In this study, we aimed to characterize the expression of the IL-6 trans-signalling pathway in ALS mouse models and investigate its role in ALS protein aggregate-mediated inflammation in microglia and peripheral immune cells. Our results revealed that the protein expression level of a key IL-6 trans-signalling component, soluble IL-6 receptor (sIL-6R), was significantly increased in the spinal cord and tibialis anterior (TA) muscles of both SOD1G93A and rNLS8 TDP-43 transgenic mice. Additionally, using mouse primary microglia, human monocyte-derived microglia-like cells (MDMi), and blood peripheral immune cells, we demonstrated that recombinant TDP-43 protein elicits robust pro-inflammatory cytokine responses, including IL-6, TNF-alpha, IL-23, and MCP-1. These responses were attenuated when treated with a specific IL-6 trans-signalling inhibitor, sgp130Fc. Our findings suggest that the TDP-43-induced inflammatory response is, in part, IL-6 trans-signalling-dependent and highlight the role of IL-6 trans-signalling as a potential driver of chronic inflammation contributing to ALS pathology. These results support IL-6 trans-signalling as a promising therapeutic target for mitigating inflammation and slowing disease progression. Future research should explore the broader implications of modulating IL-6 trans-signalling in ALS.

关键词： Innate lymphoid cells (ILCs)   Leprosy   ILC1   ILC3   CCR6   IL-17   IFN-g  

摘要： Leprosy is a skin disease caused by Mycobacterium leprae, characterized by both localized and generalized immune responses. Th1/17 lymphocytes play a crucial role in the immune response against M. leprae. However, adaptive immunity alone is not sufficient to completely eradicate the pathogen, suggesting the involvement of other innate immune cells in pathogen removal. Therefore, we investigated innate lymphoid cells (ILCs), which are the innate counterparts of helper T cells in adaptive immunity and are known to produce IFN-gamma and IL-17. In the present study, we evaluated the expression of ILC1 and ILC3 in borderline tuberculoid (BT) and lepromatous leprosy (LL) lesional skin by flow cytometry and real time PCR. Further, the expression of various in-situ genes, including cytokines, chemokines, cytokine receptors chemokine receptors, and transcription factors by qPCR in skin lesions of leprosy patients were analyzed. The phenotypes of ILC1 and ILC3 cells were determined as CD3negCCR6+CD19negIFN-gamma+ and CD3negCCR6+CD19negIL-17A+, respectively, by flow-cytometry analysis. BT skin lesions represents high CCR6+expression on total ILCs as compared to LL patients. Our results clearly indicate that ILC1 and ILC3 were highly expressed in skin lesions of BT as compared to LL leprosy patients. Moreover, we observed that double positive (DP) CD3negCCR6+CD19negIFN-gamma+IL-17A+ ILCs were up-regulated in LL and showed a pathogenic role. The gene expression of IL-17A and IFN-gamma were found to be significantly positively correlated with the percentage of CCR6+ ILCs. On the other hand, CCR6neg ILCs were negatively correlated with ILC1 and ILC3 associated markers. Summarily our results clearly suggest that both ILC1 and ILC3 are important and immune-protective, on the contrary DP (IFN-gamma+IL-17A+) ILCs may promote progression and immunopathology of leprosy.

关键词： Antinuclear antibodies   Genetics   HLA   Genome wide association study   Autoimmune disease  

摘要： Background: The genetic basis, heritability, and genetic differences by patterns and titers of antinuclear antibodies (ANA) are still poorly understood. Methods: Within the Mass General Brigham Biobank, containing electronic health records (EHR) and genotyping for >65,000 consented patients, we identified individuals with HEp-2 immunofluorescence ANA results (1989-2022) and genetically predicted European ancestry. We performed genome-wide associated studies for ANA+ > 1:40, > 1:80, all and in speckled and homogeneous ANA patterns, for those only +1:40, and then excluding those with >1 of 9 ANA-associated autoimmune diagnoses, each compared to those ANA-and adjusted for age, sex, and 4 genetic principal components. The lability method estimated ANA+ heritability. We investigated HLA alleles using SNP2HLA imputation. Results: 7035 subjects were ANA+ at >1:40, 4279 at >1:80 and 5840 were ANA-. Associations were similar but stronger for ANA >1:80 than >1:40. Associations were stronger for speckled and homogeneous ANA patterns separately (each vs. all ANA-) and attenuated after excluding those with >1 autoimmune disease diagnosis. At both titers, HLA-DQB1:0201 had the strongest association, OR 1.3 (95 % CI 1.2-1.5, p 9.1 x 10-14 for ANA >1:80);HLA-B:08, HLA-DRB1:03, and HLA:C:0701 alleles also showed significant associations. The strongest non-HLA association was rs34748780 (chromosome 7) near IRF5/TNPO3, OR 1.2 (95 % CI 1.1-1.4, p 1.6 x 10-8 for ANA >1:80). ANA+ >1:40 heritability was 12 % (SE 0.03), p 1.0 x 10-8 and >1:80 was 19 % (SE 0.03), p 1.9 x 10-12. Conclusion: HLA-DQB1:0201, HLA-DRB1:03, HLA-B, and HLA-C were strong genetic factors for ANA+ in these European ancestry individuals.

关键词： Grass carp reovirus   VP6   TBK1   Autophagy  

摘要： The interferon (IFN) response serves as a powerful defense mechanism against viral infections in fish. However, grass carp reovirus (GCRV) is capable of evading the IFN system, although the specific mechanisms remain unclear. In this study, we report that GCRV VP6 employs an immune evasion strategy by degrading TANKbinding kinase 1 (TBK1) through the autophagy pathway, thereby inhibiting IFN activation. Firstly, overexpression of VP6 facilitated the replication of GCRV, while, it impeded the activation of the IFN promoter induced by polyinosinic-polycytidylic acid (poly I:C) and GCRV. In addition, VP6 was found to interact with TBK1 and suppress its expression. Treatment with autophagy pathway inhibitors was able to restore TBK1 degradation, indicating that VP6 degrades TBK1 through the autophagy pathway. Furthermore, VP6 significantly attenuated the cellular antiviral response mediated by TBK1, thereby suppressing IFN production. These results demonstrate how GCRV evades the host immune response by exploiting the host autophagy system and provide insight into the underlying molecular mechanisms involved.

关键词： Non-alcoholic fatty liver disease   IL-37   Lipid deposition   Ferroptosis   Macrophage polarization  

摘要： Non-alcoholic fatty liver disease (NAFLD), which acts as a predominant contributor to chronic liver disease, remains a pervasive global epidemic. Interleukin-37(IL-37) is documented to have protective effects against various liver diseases. This work focuses on investigating the role and relevant action mechanism of IL-37 in NAFLD. Immunofluorescence assay and Western blot(WB)were used to estimate M1 macrophage markers. For immunofluorescence analysis, images from five randomly selected fields per sample were captured using a confocal microscope (Leica). Fluorescence intensity was quantified by ImageJ software (version 1.53) with background subtraction, and data were normalized to DAPI-positive *** lipid Reactive Oxygen Species (ROS)and cell lipid droplet deposition were assessed via BODIPY 581/591 C11 staining and Oil Red O staining. Fe2 +, triglycerides and cholesterol levels were assessed utilizing appropriate assay kits. WB was adopted for the estimation of proteins associated with ferroptosis and apoptosis. Protein band intensities were quantified using Image Lab software (Bio-Rad) and normalized to beta-actin expression. Three technical replicates were analyzed for each biological replicate (n = 3). Our data revealed that IL-37 alleviated PA-stimulated (Palmitic acid-stimulaed)M1 macrophage polarization. It was also identified that IL-37 suppressed lipid accumulation and apoptosis in RAW264.7 cells through inhibiting the polarization of M1 macrophages. Collectively, IL-37 could improve PA-stimulated lipid accumulation and apoptosis in liver cells through suppressing M1 macrophage polarization, which might be mediated by ferroptosis.

关键词： Vaginal microbial infections   Inflammatory biomarkers   Bacterial vaginosis  

摘要： Microbial-associated vaginal infections are common among women of reproductive age and are linked to alterations in the local immune environment. Inflammatory biomarkers such as IL-6, IL-beta, and TNF-alpha, along with vaginal pH have emerged as potential indicators of microbial dysbiosis. This study aimed to statistically evaluate the ability of these specific inflammatory cytokines and vaginal pH to identify infection status. Cytokine concentrations and vaginal pH were measured in clinically characterized samples. The group differences were analyzed using Mann-Whitney U tests and Cliff's Delta for effect size. ROC-AUC analysis was also performed to assess the discriminative power, and correlation heatmaps explored marker synergy. The infected individuals showed increased levels of all cytokines (p < 0.001), with large effect size (Delta > 0.9 for IL-6, IL-1 beta, TNF-alpha). Vaginal pH also differed significantly (Delta = 0.60). In addition, the combination of IL-6 and vaginal pH achieved excellent discriminative performance (AUC = 0.98). These findings suggest that IL-6, IL-1 beta, and TNF-alpha, when combined with vaginal pH, can function as reliable non-invasive biomarkers for the early detection and improved diagnostic triaging of vaginal microbial infections.

关键词： Juvenile idiopathic arthritis   HLA class II alleles   treatment response   disease activity   prognostic marker  

摘要： to expedite the dissemination of scientific findings to the research community as soon as possible after acceptance following peer review and corresponding modification (where appropriate). An "Advanced Online" manuscript is published online prior to copyediting, formatting for publication and author proofreading, but is nonetheless fully citable through its Digital Object Identifier (doi (R)). Nevertheless, this "Advanced Online" version is NOT the final version of the manuscript. When the final version of this paper is published within a definitive issue of the journal with copyediting, full pagination, etc., the new final version will be accessible through the same doi and this "Advanced Online" version of the paper will disappear.

关键词： Ulcerative colitis   IL-10   Mitochondrial function   Intestinal barrier   Autophagy   ISG15  

摘要： Background: Interleukin-10 (IL-10), an anti-inflammatory cytokine, has shown therapeutic effect on autoimmune diseases, yet its effects on UC remain unclear. This study aims to investigate whether the administration of IL-10 can suppress disease flares in ulcerative colitis (UC). Methods: A UC model was established in mice using dextran sulfate sodium (DSS) to evaluate the therapeutic effect of IL-10. LPS-stimulated Caco-2 cells were utilized to explore the underlying molecular mechanisms, focusing on apoptosis, inflammation, and oxidative stress. Results: IL-10 administration significantly alleviated clinical symptoms in DSS-induced colitis, including promoting body weight recovery, increasing colon length, and reducing disease activity index scores. IL-10 repaired the intestinal mucosal barrier by inhibiting apoptosis of intestinal epithelial cells, downregulating proinflammatory cytokines (IL-6, Interferon-gamma, and IL-1 beta), and modulating oxidative stress markers, such as malondialdehyde (MDA) and superoxide dismutase (SOD). In LPS-stimulated Caco-2 cells, IL-10 protected against apoptosis, oxidative stress, and inflammation. Bioinformatics analysis of control and IL-10 knockout mice showed a significant upregulation of Interferon-Stimulated Gene 15 (ISG15) after IL-10 knockout. In contrast, ISG15 expression was downregulated in the LPS + IL-10 group but upregulated in LPS-stimulated Caco-2 cells. These results suggest that ISG15 is a target gene of IL-10 and plays a role in autophagy regulation. Furthermore, IL-10 enhanced autophagy by increasing the protein expression of ATG7, and the LC3-II/LC3-I ratio, thereby reducing apoptosis and oxidative stress in Caco-2 cells. Autophagy inhibition with 3-Methyladenine or overexpression of ISG15 diminished IL-10's protective effects. Conclusion: This study demonstrates that IL-10 administration inhibits the progression of UC by activating autophagy and modulating ISG15 expression. In the future, targeted delivery of