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关键词： uterine leiomyoma   L17A, TNF, IL1B, IL6, and IL8 combined genotypes   single nucleotide polymorphism  

摘要： Genetic analysis of DNA samples from 180 patients with uterine leiomyoma (UL) and 98 women of the control group without UL showed that the frequency of homozygous AA variant of IL17A -197G/A gene polymorphism was significantly increased in UL (odds ratio, OR = 4.33;p = 0.0096). The frequency of this variant was even more increased when it is combined with homozygote variants GG at positions 238 and 308 of the TNF gene. The combination of the genotypes of these polymorphisms in the AA-GG-GG positions is not only widespread among patients with UL (OR = 12.22;p = 0.0054), but also was not detected in the control group. On the contrary, heterozygous IL17A -197 GA in combination with TNF-863C/A, TNF-308G/A, TNF-238G/A, IL1B-31T/C, IL6-174C/G, and IL8-251T/A are detected significantly less frequently among patients with UL than in the control, with taking into account Bonferroni's correction for the multiplicity of comparisons. The results obtained can be used in the personalized prognosis of predisposition to UL.

关键词： adipose-derived mesenchymal stem cells   interleukin-10   autoimmune dacryoadenitis   microRNA   T follicular helper cells  

摘要： PURPOSE. Mesenchymal stem cells (MSCs) represent a promising therapeutic strategy in clinical research for dry eye, and their immunomodulatory effects can be enhanced through genetic modification. In this study, we constructed interleukin-10 (IL-10) gene-modified adipose-derived MSCs (IL-10-ADSCs) and investigated their protective effects and underlying mechanisms on rabbit autoimmune dacryoadenitis, an animal model of autoimmune dry eye. METHODS. ADSCs were isolated from rabbit adipose tissue and transduced with IL-10 overexpressing lentivirus. Then the preventive and therapeutic effects of IL-10-ADSCs on rabbit autoimmune dacryoadenitis were evaluated. Flow cytometry and Western blot were performed to assess the immunomodulatory effects of IL-10-ADSCs on T follicular helper (Tfh) cells. Bioinformatic analyses and functional gain and loss assays were used to determine the molecular mechanism underlying the effects of IL-10-ADSCs on Tfh responses. RESULTS. We demonstrated that IL-10-ADSCs maintain the cell surface phenotype and multi-differentiation potentials of MSCs. Intravenous injection of IL-10-ADSCs markedly attenuated autoimmune dacryoadenitis, yielding significantly superior clinical and pathological improvements compared to ADSCs. Further investigation revealed that IL-10-ADSCs administration significantly suppressed Tfh cell responses in vivo and in vitro, contributing to reduced inflammation and improved tissue damage. Mechanistically, IL-10-ADSCs exert their suppressive function on Tfh cells partially through the miR-142-5p/RC3H1 axis. Notably, IL-10-ADSCs subconjunctivally administered after disease onset efficiently ameliorated the severity of autoimmune dacryoadenitis. CONCLUSIONS. IL-10-ADSCs ameliorate autoimmune dacryoadenitis by suppressing Tfh cell responses via suppressing the miR-142-5p/RC3H1 axis. The enhanced therapeutic effects of IL-10-ADSCs could be of significant value in improving the effectiveness of stem cell therapy in autoimmune dry

关键词： IFN-γ   IFN-γ receptor   viral IFN-binding protein   biased agonist   generative artificial intelligence  

摘要： IFN-gamma is a pleiotropic antiviral cytokine that coordinates innate and adaptive immune responses and induces both immunostimulatory and immunosuppressive activities, limiting its use in the clinic. Due to its antiviral role, several viruses express proteins that bind IFN-gamma, blocking its interaction with the IFN-gamma receptor (IFNGR). However, varicella zoster virus glycoprotein C binds IFN-gamma and induces the expression of a subset of specific ISGs, similar to biased IFN-gamma agonists generated based on the crystal structure of the IFN-gamma - IFNGR complex. Here, we propose using structural and mechanistic information from viral proteins and biased agonists to design novel IFN-gamma agonists that fine-tune IFN-gamma - IFNGR activity, reducing the immunosuppres sive and toxic effects of this cytokine.

关键词： cattle   high-throughput sequencing   MHC  

摘要： Due to factors such as lower biosecurity, greater wildlife/farm animal interfaces, and environmental challenges, cattle in sub-Saharan Africa are exposed to more diverse and intensive bacterial, viral and protozoan pathogen challenges than cattle in Europe and other high-income regions of the world. Classical class I genes of the major histocompatibility complex (MHC) contribute to protection from diseases caused by these pathogens by refining a huge pool of potential pathogen-derived peptide ligands into a smaller ensemble for presentation to CD8+ T cells. Knowledge of population-prevalent MHC alleles is therefore critical for evidence-based approaches to vaccine design and improved understanding of pathogen resistance. Whereas variation in MHC molecules is understood in most detail for European Bos taurus, the alleles expressed by Africa's cattle remain poorly defined. We have leveraged recent improvements in the accuracy of PacBio high-fidelity (HiFi) circular consensus sequencing (CCS) and adapted stringent sequence filtering algorithms to identify hundreds of as yet uncharacterised fully phased BoLA-I alleles from multiple populations of African taurine (Ankole) and indicine (Zebu) cattle in East Africa. The analysis highlights a convergence of population-prevalent class I MHC allelic repertoires in taurine and indicine cattle, likely due to the similar pathogen-driven selective pressures. Our analysis of the anchor residue accommodating pockets of these prevalent alleles revealed extremely high levels of polymorphism, which contrast with Holstein alleles that exhibit a more limited repertoire of MHC specificity-determining pocket residues, potentially constraining the breadth of peptide presentation. However, in the context of considerable sequence and physicochemical variation in the pocket-forming residues, it was possible to discern overlaps in the predicted peptide binding spectrum. Interrogation of potential differences in peptide binding specificities wi

关键词： 100   CXCL8   CXCR1 Ab   gentamicin   IL-17 Ab   lysozyme   neutrophil degranulation   septic arthritis  

摘要： AimThe main objective of this study is to elucidate the role of CXCR1 Ab, IL-17 Ab, and gentamicin in protecting septic arthritis by regulating neutrophil functional responses while evaluating the contribution of the CXCL8-CXCR1 ***-four experimental swiss albino mice were utilized to study septic arthritis. They were divided into eight groups. After developing sepsis, respective mice groups were treated with CXCR1 Ab, IL-17 Ab, and gentamicin doses. Doses were administered on days 1, 8, and 13 of the experimental schedule. At the early, middle, and late phases of the experiment i.e. at 3, 10, and 15 DPI (Days Post Infection), mice were sacrificed and blood and tissues were collected for further experimental evaluations. Different functional studies were performed on isolated blood neutrophils, spleen, and synovial tissues. Histological evaluation, immunofluorescence study, sepsis profile, and downstream signaling pathway analysis were done to obtain *** mice group exhibited high inflammatory responses while treatment helped to mitigate them. IL-17 neutralization helped to lower bacterial burden, neutrophil ROS activity, MPO activity, and ALP activity. However, the combined neutralization of CXCR1 and IL-17 greatly influenced PMN chemotactic activity and lysozyme activity. At the early phase of the experiment, IL-17 neutralization's impact was more prominent, while later, CXCR1 neutralization gained the upper *** can conclude that IL-17 Ab in combination with gentamicin is potent in modulating neutrophil activities positively to cure sepsis, while CXCR1 Ab, through the CXCL8/CXCR1 pathway, regulates neutrophil functional activities by impacting different downstream signaling cascades.

关键词： HLA   HLA-DRB1*11:343   new allele   NGS   peptide-binding domain  

摘要： HLA-DRB1*11:343 differs from HLA-DRB1*11:03:01 by a single nucleotide substitution in codon 12 in exon 2.

关键词： Alzheimer's disease   BMAL1   circadian rhythm   DNA methylation   IL-17A  

摘要： Circadian disruptions and neuroinflammation impact nearly all people with Alzheimer's disease (AD), but their relationships with each other and the impact of their interaction on AD remain to be addressed. Here, we found that amyloid (A)-beta treatment downregulated brain and muscle aryl hydrocarbon receptor nuclear translocator-like (BMAL) 1 through the hypermethylation of its promoter region in HT22 cells and that the inhibition of DNA methylation ameliorated circadian rhythm disorders and restored BMAL1 protein expression by reversing its hypermethylation in APPswe/PSEN1dE9 (APP/PS1) mice. Critically, increased levels of interleukin (IL)-17A contributed to BMAL1 downregulation through the hypermethylation of its promoter region, thus leading to circadian disruptions in APP/PS1 mice. Moreover, we revealed that the mitogen-activated protein kinase (MAPK) pathway was responsible for IL-17A-induced DNA methyltransferase (DNMT) 1 upregulation. Taken together, we elucidate a new mechanism connecting IL-17A with altered DNA methylation of Bmal1, which results in circadian disturbances in an AD mouse model.

关键词： Football   Physical fitness   Sprint   Jump ability   Strength   AGT   IL-6  

摘要： Background: The present investigation aims to elucidate the physical fitness attributes inherent in male football players about the Angiotensinogen (AGT) rs699 and Interleukin-6 (IL-6) rs1800795 gene polymorphisms. Methods: Twenty-two male football players, aged 18 to 35 years, voluntarily enrolled in the study conducted within the North Macedonian Super League. Genomic DNA was extracted from oral epithelial cells. Genotyping procedures were then executed using real-time polymerase chain reaction (RT-PCR). All participants were actively involved in an intensive training program six days a week throughout the six-week pre-season preparation phase. The male football players underwent physical assessments both before and after the training program. Statistical analysis involved the use of the Paired-Sample t-Test to discern differences between the pre-test and post-test measurements of the male football players. Results: When stratifying the outcomes according to the IL-6 genotype and AGT genotype variables, statistically significant differences were not observed in Squat Jump (SJ), 5 m sprint, 30 m sprint, Counter Movement Jump (CMJ), Drop Jump (DJ) evaluations, and body fat percentage (p > 0.05). In contrast, statistically significant differences were observed in the Yo-Yo Intermittent Recovery Test Level 2 (Yo-Yo IRT 2), 10 m sprint, and One Repetition Maximum (1RM) bench press variables (Yo-Yo IRT 2: CC and CT p = 0.005, <0.001;10 m sprint: CT p = 0.024;and 1RM bench press: CC, CT and TT p < 0.001, <0.001, 0.045, respectively). Significant differences were also identified in the Yo-Yo IRT 2, 10 m sprint, and 1RM bench press measurements (Yo-Yo IRT 2: CC, CG and GG p = 0.002, 0.021, 0.001;10 m sprint: CC and GG p = 0.020, 0.028;and 1RM bench press: CC, GG p = 0.001, 0.001, respectively). Conclusions: In summary, the AGT rs699 and IL-6 rs1800795 gene polymorphisms may play a role in the adaptations induced by training in male football players.

关键词： CD4+CD25-T cells   diabetes mellitus   corneal nerve degeneration   interferon-gamma (IFN-gamma)  

摘要： PURPOSE. This study aimed to explore the relationship between corneal nerve degeneration and elevated dendritic cells (DCs) in diabetic keratopathy. METHODS. Corneas from diabetic and healthy mice were analyzed using single-cell RNA sequencing. Corneal nerve density and DC and T-cell infiltration were quantified through whole-mount corneal staining. Freshly isolated mouse trigeminal ganglion (TG) neurons were co-cultured with immature DCs, mature DCs, activated CD8+ T cells, and CD4+CD25- T cells. TG neurite outgrowth was assessed to identify potential effector cells driving corneal nerve degeneration. In addition, interferon-gamma (IFN-gamma) and blocking antibodies were used to evaluate their effects on TG neurite outgrowth and corneal nerve degeneration in mice. RESULTS. Compared with age-matched healthy mice, diabetic mice exhibited a significant reduction in corneal nerve density and sensitivity, along with increased infiltration of DCs, CD4+ T cells, and CD8+ T cells. In vitro co-culture experiments revealed that CD4+CD25- T cells, rather than DCs and CD8+ T cells, significantly inhibited TG neurite outgrowth. Among cytokines, elevated IFN-gamma in diabetic corneas impaired TG neurite outgrowth and induced corneal nerve degeneration, whereas IL-4 and IL-17 had no such effect. Blocking IFN-gamma alleviated CD4+CD25- T-cell-induced inhibition of TG neurite outgrowth and corneal nerve degeneration in diabetic mice. CONCLUSIONS. CD4+CD25- T cells, but not DCs or CD8+ T cells, contribute to corneal nerve degeneration in diabetic mice, a process partially mediated by IFN-gamma.