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关键词： C-reactive protein   gastrointestinal cancer   interleukin 10   interleukin 6  

摘要： Gastrointestinal (GI) cancers represent a major global health burden, significantly impacts the digestive system. Recent research has focused on the relationship between interleukin-6 (IL-6), interleukin-10 (IL-10), and C-reactive protein (CRP) to deepen understanding of GI cancer-including esophageal, gastric, pancreatic, hepatobiliary, and colorectal cancers-pathogenesis and to enhance diagnostic and therapeutic strategies. Elevated levels of IL-6, IL-10, and CRP have been associated with advanced disease stages and poor prognosis, underscoring their potential utility as biomarkers for disease progression and outcome prediction. Moreover, these markers appear to modulate the sensitivity of GI cancer cells to chemotherapy, suggesting that their assessment in serum and tissue samples could aid therapeutic decision-making and predict treatment responses. In addition to their diagnostic and prognostic value, IL-6, IL-10, and CRP are being investigated as targets for preventive strategies. These findings highlight the potential role of anti-inflammatory interventions in chemoprevention. Overall, studying the interplay among IL-6, IL-10, and CRP has yielded valuable insights into the molecular mechanisms driving GI cancer development and progression. Continued research is essential to fully elucidate these complex interactions and to translate these findings into effective clinical applications for the management of GI malignancies.

关键词： Methicillin-resistant Staphylococcus aureus   Community-associated methicillin-resistant   Staphylococcus aureus   Social determinants of infectious disease   Bayesian hierarchical modeling   Counterfactual simulation   Mediation analysis   Incarceration   Health disparities   Racial disparities  

摘要： Purpose: Describe inequities in community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections and identify social factors contributing to these disparities. Methods: We characterized census tract-level risk factors for CA-MRSA infections in the Cook County Health (CCH) catchment population in Cook County, IL from 2009 to 2022 using hierarchical Poisson regression models. We conducted mediation analyses to estimate a) the total risk attributable to and b) proportion of between-tract disparities in CA-MRSA accounted for by census tract-level inequities in risk factors. Results: CCH patients living in majority Black census tracts in Cook County had double the rate of CA-MRSA infections as compared to CCH patients living in majority white census tracts. Socio-economic indicators such as public transportation use and the presence of homeless shelters in a census tract were associated with CA-MRSA rates in multivariate analyses. However, jail admission rates explained the largest proportion of CA-MRSA burden (30 %) and racial inequities in CA-MRSA incidence (69 %). Discussion: High risks of MRSA infection and colonization have consistently been documented among incarcerated and recently incarcerated individuals. Our results suggest that incarceration may also drive infections among non-incarcerated individuals living in communities with high levels of indirect exposure to jails, especially in majority Black census tracts.

关键词： berberine   pancreatic beta-cells   hormesis   p53 mediated apoptosis pathways   mitochondrial membrane potential  

摘要： Damage to pancreatic beta-cells serves as a critical pathological basis in the progression of diabetes. Berberine (BBR), an isoquinoline alkaloid, potentially protects pancreatic beta-cells, exerting hypoglycemic effects. However, the dose-response relationship and the specific protective mechanism are still unclear. Hormesis is a self-protective response triggered by mild stimuli and has been reported to determine the extent to which phytochemicals can combat diabetes. In this study, we found that BBR exhibited a typical hormetic effect in IL-1 beta-induced damage to pancreatic beta-cells, where low doses of BBR protect cells while high doses aggravate the damage. A model-based approach was used to describe dose-response relationships, as well as to detect and estimate hormetic effects. In addition, the regulatory effect of BBR in preventing apoptosis in pancreatic beta-cells was confirmed, and an appropriate dose of BBR stabilized the mitochondrial membrane potential and prevented DNA damage. Moreover, the results showed that the hormetic effect of BBR was closely related to p53 and apoptosis pathways. To further investigate the role of the p53-mediated apoptosis pathways, our study interfered with the p53 pathway, resulting in the attenuation of the hormetic effect of BBR. These results introduce the concept of hormesis to study the biphasic effects of berberine on damaged pancreatic beta-cells, while also exploring the relationship between the hormetic mechanism of BBR and the p53-mediated apoptosis pathway. These findings provide clues to explore the potential application of BBR in treating diabetes.

关键词： Non-HLA antibodies   Threshold cut off   Sensitization  

摘要： Background: Measuring non-HLA antibodies is a potentially important tool in assessing allograft dysfunction and needs to be correlated with clinical outcomes. Thus, determining the antibody distribution in healthy populations is important before correlating with clinical events. Using male blood donors, we selected a low immunological risk control cohort. Methods: We analyzed samples from 92 male, non-transfused blood donors (donors) to assess the detection of antibodies in a normal population cohort using a non-HLA 33 antigen multiplex commercial assay. Results: At manufacturer's suggested cutoff threshold (COT) of 75 % percentile, no donors had negative results and at 95 % percentile only three donors were negative across all 33 antigens. At each of the manufacturer's COT, the median (IQR) number positive antibody bead tests per donor was 13 (10-17), 11 (8-13) and 7 (5-10) at 75th, 85th and 95th percentile COT, respectively. There was poor correlation between manufacturer's COT and locally generated COT (range r = 0.520 to 0.595). The percentage of donors who had three or more positive antibody bead tests was: 98.9 % at 75th COT;95.7 % at 85th COT and 93.5 % at 95th COT. Conclusions: Considering the high proportion of positive results in a low immunological risk cohort, application of non-HLA antibody measurement in a diseased cohort is not optimal, and difficult to correlate with clinical events. Further studies to determine normal detection rates are needed for assay COT and clinical application in diseases.

关键词： autoimmunity   LADA   latent autoimmune diabetes in adults   T1D   type 1 diabetes   IFN-alpha   neutralizing antibody  

摘要： Context Autoantibodies against interferon-alpha (AAb-IFN-alpha) might be associated with the less aggressive autoimmunity in latent autoimmune diabetes in adults (LADA) compared to early-onset type 1 diabetes (T1D).Objective To investigate the presence and clinical relevance of the positivity to AAb-IFN-alpha in people with LADA compared to *** Design and Methods Serum levels of AAb-IFN-alpha isoforms were measured using a cell-based approach in 41 subjects with LADA and 90 subjects with *** The primary and secondary outcomes were the difference between LADA and T1D in the proportion of participants testing positive for autoantibodies (AAb) against >= 2 and against 3 interferon-alpha (IFN-alpha) isoforms, respectively. The presence and levels of AAb-IFN-alpha were related to clinical and biochemical features of participants with *** Seven (17.1%) and 5 (12.2%) participants with LADA and 3 (3.3%) and 0 participants with T1D showed positivity for AAb against >= 2 and 3 IFN-alpha isoforms (P = .011 and P = .0025, respectively). Fasting blood glucose and hemoglobin A1c levels were numerically lower among people with LADA testing positive for AAb against >= 2 IFN-alpha isoforms than among those who were either negative or positive for AAb against 1 IFN-alpha isoform. Among LADA-positive individuals, levels of AAb-IFN-alpha 2 isoform were inversely correlated with glutamic acid decarboxylase antibodies levels (rho = -0.513;P = .025).Conclusion Autoimmunity against IFN-alpha is peculiar to autoimmune diabetes and appears to be distinctive to its slowly progressive forms. Understanding the underlying molecular mechanisms and clinical significance of this novel autoimmunity could lead to the development of new therapeutic strategies in autoimmune diseases, advancing personalized medicine.

关键词： Non-classical MHC   L lineage   Salmonids   Molecular evolution  

摘要： Non-classical MHC class I molecules, which are encoded by a diverse gene family, have a wide range of functions that can be immune-or non-immune related. From an evolutionary perspective, different non-classical MHC class I genes are typically specific to smaller phylogenetic groups and are often not well conserved among species within these groups rendering non-classical MHC phylogeny difficult to establish. Here we perform a comparative analysis spanning non-classical MHC class I L lineage gene content, organization, phylogeny and variability across divergent salmonid species, providing insight into L lineage immune system variation and species-specific adaptations. Based on evolutionary relationships and sequence analysis, salmonid L lineage genes can be classified into three clades, each with distinct features. Clade I gene sequences exhibit significant variation within species, comprising multiple haplotypes and null alleles, as well as notable variations between species, including highly flexible gene numbers and patterns of pseudogenization. Clade I genes comprise eleven subclades, each displaying separate evolutionary patterns, characteristic phylogenetic marker motifs and subclade specific promoter regions, indicative of unique regulatory patterns and subclade specific functional roles. Our study reveals two distinct phylogenetic patterns among these genes: some subclades display a high degree of flexibility, as demonstrated by species specific expansions and contractions, whereas others have been maintained as mono-genic subfamilies with remarkably few changes in their nucleotide sequence across divergent species. Comparably, clade II L lineage genes consist of four subclades, among which LIA and LLA genes are full length genes with species specific pseudogenization patterns. We report compelling evidence that the LIA gene lineage is highly conserved and present in all 23 Salmonidae species examined as well as in representative Esociformes. This suggests t

关键词： HLA   HLA‐DRB1*13:371   next‐generation sequencing   novel allele  

摘要： The novel allele HLA-DRB1*13:371 differs from HLA-DRB1*13:02:01:01 by one nucleotide substitution in codon 127 in exon 3.

关键词： Molecular dynamics  

摘要： Interleukin-37b (IL-37b) has emerged as a potential therapeutic agent for inflammatory diseases. However, IL-37b tends to self-assemble into a dimeric form, which compromises its anti-inflammatory efficacy. Furthermore, the currently active monomeric variants of IL-37b are unstable, limiting their clinical utility. To address these challenges, we employed a series of in silico protein engineering strategies to design IL-37b variants with reduced dimerization propensity and enhanced monomeric stability. We identified and analyzed hot-spot residues critical for dimer formation using a double-alanine scanning approach, and subsequently mutated these residues in search of optimal mutations to block self-dimerization. Further, we expanded computational site-saturation mutagenesis to non-binding-site residues and evaluated their impact on monomer stability. Molecular dynamics (MD) simulations and structural analyses were performed to interpret the effects of these variants on stability. In total, we identified 36 mutations that block IL-37b dimer formation and 10 mutations that enhance monomer stability. The mutational effects of the two lists of mutations were independent, enabling potential multi-mutant combinations into dual-functional variants. The systematic in silico design approach presented for IL-37b in this work also provides a generalizable framework for the rational design of other cytokines and proteins.

关键词： AT1-AA   Interleukin-6   BK channel   NF-kappa B nuclear translocation  

摘要： The inflammatory phenotype of vascular smooth muscle cells (VSMCs) is an important factor in triggering vascular disease, and interleukin-6 (IL-6) is one of the earliest inflammatory cytokines upregulated in many inflammatory contexts. Angiotensin II-1 receptor autoantibody (AT1-AA) can promote the phenotypic transformation of VSMCs into macrophage-like cells, then synthesize abundant IL-6 to induce vascular inflammation. Previous studies suggested that abnormal BK channel function on the surface of VSMCs played an important role in the synthesis of IL-6, but the mechanism of abnormal BK channel involving in AT1-AA-induced IL-6 synthesis in VSMCs was unclear. In this study, the agonist NS1619 of the BK channel and the inhibitor Paxilline were used to reverse or exacerbate IL-6 synthesis in AT1-AA-induced VSMCs. It is known that NF-kappa B can enter the nucleus due to increased calcium ion concentration caused by BK channel dysfunction, thereby increasing IL-6 transcription. This study observed that Paxilline pretreatment significantly increased the residence time of AT1-AAinduced NF-kappa B in the nucleus, while NS1619 pretreatment showed the opposite trend. JSH-23 inhibiting NF-kappa B nuclear entry reversed the increase in IL-6 expression in VSMCs induced by AT1-AA. This study found that AT1AA enhanced NF-kappa B nuclear translocation by inhibiting BK channel function, which in turn promoted IL-6 transcription in VSMCs, increased IL-6 synthesis and induced vascular inflammation. This study revealed the importance of BK channel dysfunction in the process of AT1-AA increasing IL-6 synthesis and promoting vascular inflammation, and provided a new idea for alleviating vascular inflammatory diseases from the perspective of improving potassium channel function.

关键词： HLA‐DQB1*03   NGS   nonsynonymous mutation   novel allele  

摘要： Two novel HLA-DQB1*03 alleles, HLA-DQB1*03:581 and HLA-DQB1*03:582, have nonsynonymous mutations in exon 2 and exon 3, respectively.