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关键词： anxiety   body mass index   cortisol   executive functions   TNF alpha  

摘要： Overweight and obesity are associated with poorer executive functions (EF). The underlying mechanisms contributing to this relationship are not yet conclusive, but cortisol, anxiety, and inflammation are likely among the contributing factors. Our objective was to evaluate whether fibrinogen, tumour necrosis factor alpha (TNF alpha), cortisol, and anxiety significantly mediate the association between body mass index (BMI) z-score and EF (i.e., working memory, inhibition, cognitive flexibility, and a latent EF component) in both adolescents and adults. In this cross-sectional study, 268 participants aged 11-49 years with BMI values ranging from normal-weight to obesity were medically and neuropsychologically evaluated. Moderated multiple mediation analyses with mediators in parallel were conducted (X: BMI z-score;M: cortisol, anxiety, TNF alpha, and fibrinogen;Y: executive functions;Moderator: adolescent and adult groups). Our results suggested that TNF alpha mediated the association between BMI z-score and working memory only in adolescents (indirect effect = 0.09, 95% CI [0.03, 0.19]), whereas in adults, cortisol (indirect effect = -0.06, 95% CI [-0.13, -0.01]) and anxiety (indirect effect = 0.02, 95% CI [0.0001, 0.07]) mediated this association. Additionally, in adults, anxiety also mediated the relationship between BMI z-score and the latent EF component (indirect effect = 0.03, 95% CI [0.004, 0.08]). In the full sample, TNF alpha significantly mediated the relationship between BMI z-score and inhibition (indirect effect = -0.03, 95% CI [-0.06, -0.002]). In conclusion, our study suggests that inflammation, cortisol, and anxiety are biologically and psychologically plausible mechanisms through which BMI may influence cognitive performance. Large-scale longitudinal studies are needed to confirm these findings and to determine whether the observed associations are age-dependent.

关键词： HLA-G 14-bp   meta-analysis   polymorphism   recurrent spontaneous abortion  

摘要： We performed a meta-analysis to study the relationship between HLA-G 14-bp insertion/deletion polymorphism and recurrent spontaneous abortion (RSA). All literature was searched from PubMed, Web of Science, Embase and Wanfang databases. Statistical analyses were performed by the STATA software (Version 16.0). A total of 35 studies were analysed which included 3652 women with RSA and 3331 normal control subjects. The current meta-analysis revealed that 14-bp insertion/deletion polymorphism has a significant association with RSA (I vs. D: OR: 1.17;95% CI (1.05-1.30);II + ID vs. DD: OR: 1.33;95% CI (1.11-1.59);II vs. DD: OR: 1.34;95% CI (1.07-1.66);ID vs. DD: OR: 1.30;95% CI (1.08-1.58)). Subgroup analysis by the number of abortions indicated that there was no significant association between HLA-G 14-bp insertion/deletion polymorphism and RSA risk in women with two or more abortions. However, HLA-G 14-bp insertion/deletion polymorphism was associated with the risk of RSA in women with three or more abortions as well as the overall population (I vs. D: OR: 1.26;95% CI (1.04-1.52);II + ID vs. DD: OR: 1.47;95% CI (1.09-1.98);II vs. DD: OR: 1.52;95% CI (1.08-2.13);ID vs. DD: OR: 1.45;95% CI (1.06-1.99)). Subgroup analysis by ethnicity indicated that HLA-G 14-bp insertion/deletion polymorphism increased RSA risk in both Asian ancestry group (II + ID vs. DD: OR: 1.35;95% CI (1.06-1.73);ID vs. DD: OR: 1.37;95% CI (1.06-1.78)) and European ancestry group (I vs. D: OR: 1.25;95% CI (1.08-1.45);II vs. ID + DD: OR: 1.48;95% CI (1.14-1.91);II vs. DD: OR: 1.61;95% CI (1.19-2.18)). A pOR value of < 0.05 was considered statistically significant for these analyses. Our current meta-analysis demonstrated that the HLA-G 14-bp insertion/deletion polymorphism increased the risk of RSA in Asian ancestry group and European ancestry group.

关键词： CXCL11   interferon-gamma   respiratory syncytial virus   T-cell immune response   viral replication  

摘要： Respiratory syncytial virus (RSV) is the leading cause of childhood respiratory infections worldwide. However, no vaccine is available for children, and treatment options are limited. Identification of host factors pivotal to viral replication or immune-inflammatory regulation may inform the development of novel therapies, prophylaxes, or diagnoses. The chemokine (C-X-C motif) ligand 11 (CXCL11), which is drastically increased in RSV-infected respiratory tract samples, was previously found via a metatranscriptome screen, suggesting that CXCL11 may play an important role in RSV infection. In this study, we found that the CXCL11 expression level was negatively associated with the clinical disease severity of RSV infection. Using a CRISPR-Cas9-mediated knockout A549 cell line and a knockout mouse model, we investigated the role of CXCL11 in the pathogenesis of RSV. Our study indicated that CXCL11 restricted RSV infection by interfering with its polymerase activity to inhibit the RSV replication process. Additionally, CXCL11 was crucial for optimizing the IFN-gamma response. With a knockout mouse model, we confirmed that CXCL11 not only restricted RSV infection in vivo but was also associated with the severity of lung pathology. In addition, we found out that CXCL11 was indispensable for regulating Th1/Th2 balance, and the cytotoxic and antiviral phenotypes of the CD8+ T-cell response during RSV infection. Finally, we observed that supplementation with recombinant CXCL11 significantly improved the clinical outcomes of RSV infection in mice, as evidenced by reduced weight loss, lower viral titers, and attenuated lung inflammation. Overall, our studies suggested that CXCL11 functions in controlling RSV infection.

关键词： Retinal Pigment Epithelium   DNA Repair   Serine and Arginine Rich Splicing Factor 1   Interleukin-6  

摘要： Chronic inflammation has been associated with the progression of age-related macular degeneration (AMD) and diabetic retinopathy (DR), and the levels of various inflammatory factors are significantly increased in intraocular fluids of patients with AMD and DR. Therefore, elucidating the roles of inflammatory factors in the oxidative damage of RPE cells will help uncover the pathogenesis of AMD and DR. We have previously demonstrated that E2F1 plays an important role in the antioxidant capacity of RPE cells. Here, our transcriptome analysis shows that E2F1 affected the expressions of DNA repair genes in RPE cells. In addition, we found that E2F1 transactivated the splicing factor SRSF1. SRSF1 knockdown promoted DNA oxidative damage and apoptosis and decreased the mRNA stability of DNA repair genes XRCC2, POLK and LIG4 in RPE cells. Moreover, we found that SRSF1 could bind to the RNA stabilizing factor MATR3, and knockdown of the latter affected the mRNA stability of these DNA repair genes. Notably, interleukin-6 (IL-6), an inflammatory factor upregulated in intraocular fluids of patients with AMD and DR, decreased SRSF1 expression by inducing acetylation of E2F1 at the K125 position. Consistently, SRSF1 overexpression relieved IL-6-induced DNA oxidative damage and apoptosis in RPE cells. In vivo experiment results also confirmed that IL-6 could aggravate retinal oxidative damage. In conclusion, high levels of IL-6 in the eyes of patients with AMD and DR destabilize the mRNAs of DNA repair genes by disrupting the expression of SRSF1, leading to abnormal repair of DNA oxidative damage in RPE cells.

关键词： duck   Ii   MHC   localization   binding interaction  

摘要： Objective To investigate the intracellular localization and binding of duck invariant chain (Ii) to major histocompatibility complex (MHC) class I alpha or MHC class II beta molecules. Methods First, the genes of duck Ii, MHC I alpha, and MHC II$ were amplified by PCR, cloned into expression plasmids, and then sequenced to compare homology between ducks and selected agricultural species. Second, Rosetta or 293T cells were transfected with plasmids encoding Ii, MHC I alpha, and MHC II beta either alone or in combination to interrogate bind-ing following expression. The fluorescent reporter molecules used to tag/image transfected cells and expressed pro-tein were identified by western blot. Additionally, the binding interaction of the expressed products was observed by affinity purification using pull-down assay and coimmunoprecipitation. Finally, intracellular colocalization was observed by laser confocal microscopy. Results The results of western blots demonstrated that all constructed plasmids successfully expressed proteins. Pull down and coimmunoprecipitation revealed that Ii could bind I alpha or II beta, forming Ii-I alpha or Ii-II beta complexes, and they dissoci-ated into single molecules after SDS treatment. In 293T cells, Ii interacts with MHC I alpha or MHC II beta chains and colo-calizes intracellularly. Confocal fluorescence microscopy assay indicated that MHC I alpha and II beta were located in the endoplasmic reticulum and endosome. Conclusions Both MHC and Ii proteins exhibit direct interactions and can colocalize in the endoplasmic reticulum and endosomes. Clinical Relevance This study investigates the relationship between duck Ii and MHC proteins, offering a theoretical foundation for exploring the role of Ii in immune responses and advancing the development of Ii-vectored avian vaccines.

关键词： Heritability   Genetic correlation   GWAS   Diverse populations   HLA  

摘要： The human leukocyte antigen (HLA) region is a critical genetic locus associated with diverse complex traits, yet its intricate genetic architecture poses significant challenges to elucidation. Leveraging recent advances in regional heritability estimation and extensive datasets from the Million Veteran Program (MVP), we conducted a comprehensive investigation of the HLA region's genetic architecture. This involved heritability estimation and genetic correlation analyses within the HLA region across European Americans (EAs) and African Americans (AAs). Our analyses demonstrated that in EAs, the HLA region exhibited significantly greater local heritability than other genomic regions of comparable length for lipid metabolic traits (triglycerides [TG], total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL]), anthropometric measures (body mass index [BMI]), and suicide-related traits (suicidal ideation without suicide attempts [IDE] and suicidal thoughts and behaviors [SITB]) (false discovery rate [FDR]-adjusted empirical p-values < 0.05). Notably, this enrichment was not observed in AAs. Genetic correlation analyses revealed disparities between local HLA and genome-wide findings. EAs exhibited 16 significant local HLA correlations and 32 genome-wide correlations. Conversely, AAs displayed more significant local genetic correlations within the HLA region (14 pairs) than genome-wide (3 pairs), with two pairs (IDE-SITB, LDL-TC) concordantly significant. These findings underscore the HLA region's substantial contribution to the variance of these lipid metabolic traits, BMI, and suicide-related traits. Further investigation into the genetic mechanisms by which HLA-mediated pathways influence these phenotypes is crucial for elucidating the complex role of this region, particularly concerning lipid metabolism and suicidal behaviors.