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关键词： Co-localisation   IL-2   IL-6   Mendelian randomisation   TYK2   Type 1 diabetes  

摘要： Aims/hypothesisWe aimed to investigate the genetic evidence that supports the repurposing of drugs already licensed or in clinical phases of development for prevention of type 1 *** obtained genome-wide association study summary statistics for the risk of type 1 diabetes, whole-blood gene expression and serum protein levels and investigated genetic polymorphisms near seven potential drug target genes. We used co-localisation to examine whether the same genetic variants that are associated with type 1 diabetes risk were also associated with the relevant drug target genetic proxies and used Mendelian randomisation to evaluate the direction and magnitude of the associations. Furthermore, we performed Mendelian randomisation analysis restricted to functional variants within the drug target ***-localisation revealed that the blood expression levels of IL2RA (encoding IL-2 receptor subunit alpha [IL2RA]), IL6R (encoding IL-6 receptor [IL6R]) and IL6ST (encoding IL-6 cytokine family signal transducer [IL6ST]) shared the same causal variant with type 1 diabetes liability near the corresponding genes (posterior probabilities 100%, 96.5% and 97.0%, respectively). The OR (95% CI) of type 1 diabetes per 1-SD increase in the genetically proxied gene expression of IL2RA, IL6R and IL6ST were 0.22 (0.17, 0.27), 1.98 (1.48, 2.65) and 1.90 (1.45, 2.48), respectively. Using missense variants, genetically proxied TYK2 (encoding tyrosine kinase 2) expression levels were associated with type 1 diabetes risk (OR 0.61 [95% CI 0.54, 0.69]).Conclusions/interpretationOur findings support the targeting of IL-2, IL-6 and TYK2 signalling in prevention of type 1 *** availabilityThe analysis code is available at https://***/jkoskenniemi/T1DSCREEN, which also includes instructions on how to download the original GWAS summary statistics.

关键词： iNOS   NF-kappa B p105   ERK   c -Jun   Nuclear translocation  

摘要： Inducible nitric oxidase (iNOS) encoded by Nos2 is a representative IFN gamma-inducible effector molecule that plays an important role in both innate and adaptive immunity. In the present study, we demonstrated that full-length NF-kappa B p105 (p105), which is a precursor of NF-kappa B p50 (p50), is required for full activation of IFN gamma-induced iNOS expression in the RAW264.7 mouse macrophage cell line. In comparison to wild-type (WT) RAW264.7 cells, p105 KO RAW264.7 (p105 KO) cells completely lost IFN gamma-induced iNOS expression. Despite the limited effect of exogenous expression of p50 in p105 KO cells on IFN gamma-induced Nos2 promoter activity, p105 expression fully restored IFN gamma-induced Nos2 promoter activity to a level comparable to that of WT cells, suggesting an important role for full-length p105 in IFN gamma-induced iNOS expression. While the expression and phosphorylation of JAK1 and STAT1 were rather enhanced in p105 KO cells, the phosphorylation of c-Jun downstream of MAPK signaling was decreased. IFN gamma-induced phosphorylation of ERK, a kinase for IFN gamma-induced c-Jun phosphorylation, was not significantly reduced in p105 KO cells, although the nuclear activity of ERK was significantly decreased due to its reduced translocation to the nucleus. Expression of iNOS, nuclear translocation of ERK, and phosphorylation of cJun were restored by stable supplementation of p105 in p105 KO cells. These results suggest that p105 is required for the nuclear translocation of ERK and the subsequent phosphorylation of c-Jun, which are necessary for full activation of IFN gamma-induced iNOS expression. Reduced nuclear translocation of ERK in p105 KO cells was also observed in the activation of ERK following serum starvation, further suggesting that the involvement of p105 in ERK nuclear translocation is not limited to IFN gamma-stimulated cells but is a more general function of p105.

关键词： Cutaneous Leishmaniasis   IFN-gamma Serum level   IFN-gamma polymorphisms  

摘要： Leishmaniasis, a broad range of parasitic diseases, caused by Leishmania which is a flagellated intracellular protozoan parasite of the family Trypanosomatidae. The severity of leishmaniasis diseases ranges from minor cutaneous lesions to severe visceral illnesses that can be disfiguring and life-threatening. Cytokines are glycoprotein molecules produced by various cells in response to various immunological triggers. They regulate the body's innate and adaptive immunological responses. The aim of this study was to clarify the association of serum level and polymorphisms of IFN-gamma with susceptibility to cutaneous leishmaniasis (CL). The whole blood 200 samples were collected from patients and controls from Diyala Governorate/ Iraq from October 2022 to February 2023 which were used to measure IFN-gamma polymorphisms using High Resolution Melting technique. Enzyme-linked immunosorbent assay was used to detect the serum level of IFN-gamma. The findings of this investigation showed that the IFN-gamma serum concentration elevated significantly in patients compared to controls (P < 0.01). Also, the study found that the highest mean level IFN-gamma concentrations were found in adults aged 46-55 years old for patients compared with controls with significant differences (P < 0.01). While, no significant differences were observed in the rest age groups except children aged 5-15 years old. Additionally, significant differences between patients and controls were revealed by polymorphisms data in all genetic models for genotypes GA, AA, (GA + AA) and allele A with (P < 0.01) and OR > 1. However, the distribution of IFN-gamma serum levels by SNP (rs2069705) demonstrated no differences between genotypes except GG genotype which has significant differences for patients comparing to the same genotype in controls. Taking together, the SNP for IFN gamma (rs2069705) could be a risk factor for susceptibility infection with CL. Also, considered the mutant allele A as a risk allele and

关键词： canine   ELISA   immune response   leishmaniosis   cytokine  

摘要： Canine leishmaniosis (CanL) is a zoonotic disease caused by Leishmania infantum, where increased interferon-gamma (IFN-gamma) levels are associated with controlling the infection and mild to moderate disease. Therefore, monitoring IFN-gamma concentrations is essential for monitoring the immune responses in CanL. This study compared a faster, cost-effective IFN-gamma release whole blood assay in tubes (WBA-T) with a standardized version (WBA-S) in 41 dogs at different states of L. infantum infection. WBA-T was performed at 24, 48, and 72 h of incubation with three conditions: blood, blood with L. infantum-soluble antigen (LSA), and blood with mitogen ConA. WBA-S was performed in plates, with blood diluted and incubated for five days using the same conditions. Supernatants (WBA-S) or plasma (WBA-T) were harvested for IFN-gamma measurement by ELISA. No significant differences were observed in terms of IFN-gamma concentration between WBA-T and WBA-S under LSA conditions. However, the 48 h incubation period during WBA-T showed the highest median of IFN-gamma concentration compared to other incubation periods and WBA-S. The IFN-gamma concentrations under ConA stimulation in WBA-S were significantly higher than in WBA-T at all incubation times studied. In conclusion, WBA-T stimulated with LSA at 48 h incubation time was shown to be the most appropriate for assessing IFN-gamma production.

关键词： IL37   Molecular dynamics simulations   Dimer   Stability   In silico protein engineering  

摘要： IL37 plays important roles in the regulation of innate immunity and its oligomeric status is critical to these roles. In its monomeric state, IL37 can effectively inhibit the inflammatory response of IL18 by binding to IL18Ra, a capacity lost in its dimeric form, underlining the pivotal role of the oligomeric status of IL37 in its anti-inflammatory action. Until now, two IL37 dimer structures have been deposited in PDB, reflecting a substantial difference in their dimer interfaces. Given this discrepancy, we analyzed the PDB structures of the IL37 dimer (PDB IDs: 6ncu, 5hn1) along with a AF2-multimer prediction by molecular dynamics (MD) simulations. Results showed that the 5hn1 and AF2-predicted dimers have the same interface and stably maintained their conformations throughout simulations, while the recent IL37 dimer (PDB ID: 6ncu) with a different interface did not, proposing a possible issue with the recent IL37 dimer structure (6ncu). Next, focusing on the stable dimer structures, we have identified five critical positions of V71/Y85/I86/E89/S114, three new positions compared to the literature, that would reduce dimer stability without affecting the monomer structure. Two quintuple mutants were tested by MD simulations and showed partial or complete dissociation of the dimer. Overall, the insights gained from this study reinforce the validity of the 5hn1 and AF2 multimer structures, while also advancing our understanding of the IL37 dimer interface through the generation of monomer -locked IL37 variants.

关键词： Cytokines   Inflammatory pain   Hyperalgesia   Cholinergic system   Antinociception  

摘要： Introduction: Tissue injury results in the release of inflammatory mediators, including a cascade of algogenic substances, which contribute to the development of hyperalgesia. During this process, endogenous analgesic substances are peripherally released to counterbalance hyperalgesia. The present study aimed to investigate whether inflammatory mediators TNF-alpha, IL-1 beta, CXCL1, norepinephrine (NE), and prostaglandin E2 (PGE2) may be involved in the deflagration of peripheral endogenous modulation of inflammatory pain by activation of the cholinergic system. Methods: Male Swiss mice were subjected to paw withdrawal test. All the substances were injected via the intraplantar route. Results: The main findings of this study were as follows: (1) carrageenan (Cg), TNF-alpha, CXCL-1, IL1-beta, NE, and PGE2 induced hyperalgesia;(2) the acetylcholinesterase enzyme inhibitor, neostigmine, reversed the hyperalgesia observed after Cg, TNF-alpha, CXCL-1, and IL1-beta injection;(3) the non-selective muscarinic receptor antagonist, atropine, and the selective muscarinic type 1 receptor (m1AChr) antagonist, telenzepine, potentiated the hyperalgesia induced by Cg and CXCL-1;(4) mecamylamine, a non-selective nicotinic receptor antagonist, potentiated the hyperalgesia induced by Cg, TNF-alpha, CXCL-1, and IL1-beta;(5) Cg, CXCL-1, and PGE2 increased the expression of the m1AChr and nicotinic receptor subunit alpha 4protein. Conclusion: These results suggest that the cholinergic system may modulate the inflammatory pain induced by Cg, PGE2, TNF-alpha, CXCL-1, and IL1-beta.

关键词： Adaptive immunity   cGAS-STING   DNA-damage response (DDR)   IFN   Innate immunity  

摘要： When cells proliferate, stress on DNA replication or exposure to endogenous or external insults frequently results in DNA damage. DNA-Damage Response (DDR) networks are complex signaling pathways used by multicellular organisms to prevent DNA damage. Depending on the type of broken DNA, the various pathways, Base-Excision Repair (BER), Nucleotide Excision Repair (NER), Mismatch Repair (MMR), Homologous Recombination (HR), Non-Homologous End-Joining (NHEJ), Interstrand Crosslink (ICL) repair, and other direct repair pathways, can be activated separately or in combination to repair DNA damage. To preserve homeostasis, innate and adaptive immune responses are effective defenses against endogenous mutation or invasion by external pathogens. It is interesting to note that new research keeps showing how closely DDR components and the immune system are related. DDR and immunological response are linked by immune effectors such as the cyclic GMP-AMP synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway. These effectors act as sensors of DNA damage-caused immune response. Furthermore, DDR components themselves function in immune responses to trigger the generation of inflammatory cytokines in a cascade or even trigger programmed cell death. Defective DDR components are known to disrupt genomic stability and compromise immunological responses, aggravating immune imbalance and leading to serious diseases such as cancer and autoimmune disorders. This study examines the most recent developments in the interaction between DDR elements and immunological responses. The DDR network's immune modulators' dual roles may offer new perspectives on treating infectious disorders linked to DNA damage, including cancer, and on the development of target immunotherapy.

关键词： Epstein-Barr virus   BZLF1   IL-2   BCG   Tumor  

摘要： In this research, a recombinant Bacillus Calmette Guerin (rBCG) vector vaccine carrying a human IL-2 and EBV BZLF1 fusion gene (IL-2-BZLF1-rBCG) was constructed. The IL-2-BZLF1-rBCG construct was successfully generated and stably expressed the IL-2 and BZLF1 proteins. IL-2-BZLF1-rBCG activated the immune system and promoted the secretion of IFN-gamma and TNF-alpha by CD4(+) and CD8(+) T cells. IL-2-BZLF1-rBCG activated lymphocytes to effectively kill EBV-positive NPC cells in vitro. Additionally, IL-2-BZLF1-rBCG stimulated the proliferation of NK cells and lymphocytes in vivo, activated related immune responses, and effectively treated EBV-positive NPC. The immune response to and pharmacological effect of IL-2-BZLF1-rBCG were explored in vitro and in vivo to provide a theoretical and experimental basis for the prevention and treatment of EBV-positive tumors with an rBCG vector vaccine.

关键词： HLA   Allele   Haplotype   Zhejiang Han  

摘要： The Zhejiang Han population, a subgroup of the Southern Han ethnic group, resides in Zhejiang Province, situated on the southeast coast of China. In this study, we conducted HLA genotyping for 813 voluntary umbilical cord blood donors from the Zhejiang Han population, targeting 11 HLA loci, namely HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3/4/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1, using the next-generation sequencing method. Our analysis of the alleles and haplotypes revealed a high degree of polymorphism within these loci. A total of 289 unique HLA alleles were identified, with the HLA-B locus exhibiting the most significant diversity, while HLA-DRB4 displayed the lowest variation. Due to the inherent limitations of the sequencing method, some unresolvable alleles in the specific loci, such as HLA-DRB1, HLA-DPA1, and HLA-DPB1, were assigned as G group designation. In our comprehensive analysis across all 11 HLA loci, a total of 1204 haplotypes were estimated. The distribution of these alleles was similar to those of the Chinese Southern Han population while highly different from the Caucasian population. These findings contribute to a deeper understanding of the genetic characteristics of HLA loci within the Chinese Southern Han population.