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关键词： Maternal obesity   fetal programming   vascular function   endothelial homeostasis   hypertension  

摘要： This study investigated the impact of maternal high-fat diet on vascular function and endothelial homeostasis in offspring. We found that offspring exposed to maternal high-fat diet exhibited elevated blood pressure, impaired abdominal aortic vascular function, and endothelial homeostasis imbalance. These changes were accompanied by increased levels of reactive oxygen species (ROS) and upregulation of pro-inflammatory cytokines (including IL-1 beta, TNF-alpha, IL-6, and IL-10). Treatment with NLRP3 or IL-1 beta inhibitors prevented the deterioration in vascular function, reduced endothelial NO production, and inflammation induced by maternal high-fat diet exposure compared to the control group. The findings suggest that during pregnancy, mitigating the vascular impairments in offspring induced by maternal high-fat diet can be achieved by inhibiting the NLRP3/IL-1 beta pathway.

关键词： rs641153   Complement   Evolution   Factor B   HLA   Primates   Complotype   MHC   Bf   C2   C4   Disease   Orangutan   Immunity   Chimpanzee auroimmunity  

摘要： BackgroundMajor Human Histocompatibility complex (MHC or HLA in humans) has been associated to autoimmune diseases. However, only statistical phenomenological and no pathogenetic description has been reached after decades. This shows that MHC single locus association studies are probably useless for HLA/diseases association. Extended HLA (class I and class II genes) haplotypes should also be studied conjointly with class III or complement alleles (complotypes). Complotypes in humans are defined as alleles belonging to C2, C4 and Bf (Factor B) genes/proteins (class III). Also, the placing of MHC class I and class II genes close together with complement genes from at least birds to humans shows existence of a strong selection to gather conjointly these loci that fight microbes, help self-maintenance and avoid autoimmunity. In this paper we aim to study Bf alleles in primates in order to rise again interest to study the role of Bf alleles together with other MHC genes in their physiopathology and *** (Pongo pygmaeus, Popy) cell lines RNA from 6 different individuals were retrotranscribed, PCR amplified, cloned and DNA sequenced in order to study Bf *** Bf allele identical to that found in chimpanzee (Patr-Bf*A01) and human (rs641153) was found in two of the six studied orangutans: Popy-Bf*A01 and Popy-Bf*A02. This polymorphism is placed in Factor B codon 32 that defines BF*S and Bf*F proteins in man and produce Leu instead of Arg (Bf*S) or Gln (Bf*F). In addition, each new orangutan allele present synonymous differences with each other at codon 25: Popy-Bf*A01 shows ACG while Popy-Bf*A02 bears ACA, both codifying for *** selection for about 15 million years (time gap of evolutionary appearance between orangutan and hominids) shows the importance of this particular allele conservation in immune and self defense in primates. The complotypes (Bf,C2 and C4 loci) alleles together with other MHC class I and Cass II loci alle

关键词： Asthma   Airway inflammation   Decline   Eosinophils   Lung Diseases  

摘要： Background Asthma is associated with accelerated rate of FEV1 decline. ObjectiveTo determine predictive factors associated with accelerated FEV1 decline in adult asthma and evaluate sputum cytokines as potential biomarkers for airflow decline. Methods We recruited 125 asthmatics evaluated at the asthma clinic of Li & egrave;ge and reevaluated them at least 5 years later. Clinical, functional and inflammatory characteristics were compared between patients with accelerated decline (FEV1 decline > 0.85% pred.y(-1)) and others. Predictive factors were highlighted with linear regression analysis. Sputum EGF, VEGF, FGF, IL5, IL8, TGF-beta, and IgE levels were measured in 58 of these patients at both visits by Human XL cytokine Luminex Performance assay and Elisa. Results Post-BD FEV1 decline was 0.06 +/- 2.44% pred.y-1 in the overall population. Median (IQR) time between visits was 66 (62 - 86) months. The multivariable analysis showed that an increase in blood eosinophils over time (Delta BEC) (Reg. Coef. (95%CI): 0.002 (0.001 to 0.004), p = 0.005)) and onset of asthma (0.04 (0.003 to 0.07), p = 0.036) were independently associated with FEV1 decline. IL8 levels measured at baseline were higher (499 (408-603) pg/ml, p = 0.0040) in patients with accelerated decline compared to others (143 (88-308) pg/ml). Conclusion In this study, we have confirmed that an increase in blood eosinophil counts over a follow-up of at least 5 years and later onset of asthma are associated with accelerated annual FEV1 decline. Moreover, high sputum IL8 levels could be a risk factor for accelerated decline in asthma patients.

关键词： DNA extraction   Microtube   PCR-SSOP   HLA typing  

摘要： Background The purity of the extracted DNA is critical for successful molecular testing. This study aimed to compare the effect of various DNA extraction methods, extraction processes, and sources of consumables, such as microtubes, on PCR results. Methods DNA extraction from whole blood was performed using four different approaches utilizing four types of microtubes: chloroform-based, sodium perchlorate-based, heat-assisted salting out, and solid-phase extraction. Extracted DNA was evaluated by nanodrop spectrophotometry and used in PCR-based methods for human leukocyte antigens (HLA) typing. Results The lowest and highest concentrations of extracted DNA were observed in the column-based and heat-assisted methods, respectively. The mean ratios of A260/A230, represents chemical contamination, were significantly lower in all extraction methods using all types of microtubes versus "A" microtube. We observed the highest mean ratio of A260/A230 (> 1.9) in the sodium perchlorate method by using the "A" microtube compared to other types of microtubes and extraction methods. Extracted DNA samples using microtube "A" showed acceptable results for HLA typing compared to other microtubes that represented uninterpretable results in the PCR using the sequence-specific oligonucleotide probe (PCR-SSOP) method. Conclusion Our findings indicate that the chemical contaminations derived mainly from microtubes can decrease the quality of DNA and consequently interfere with the amplification or hybridization reactions in the PCR-SSOP method for HLA typing. Although, technical issues and extraction processes may also influence the quality of DNA.

关键词： Fusobacterium   colorectal cancer   comparative genomics   intestinal microbiota   novel species   pangenome  

摘要： Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel species, sp. nov. (), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the genus, with as its closest neighbor. is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to is rare for most members. displays a metabolic profile and antibiotic resistance repertoire consistent with other species. has adherent and immunomodulatory capabilities, as it intimately associates with human colon cancer epithelial cells and promotes IL-8 secretion. An analysis of the prevalence and abundance of in > 20,000 human metagenomic samples shows that it is a rarely detected member within human stool with variable relative abundance, found in both healthy controls and patients with colorectal cancer (CRC). Our study sheds light on a novel bacterial species isolated directly from the human CRC tumor niche and given its interaction with cancer epithelial cells suggests that its role in human health and disease warrants further investigation.

关键词： Cancer immunotherapy   Epitope prediction   HLA   Machine learning   MHC  

摘要： Cancer immunotherapy hinges on accurate epitope prediction for advancing vaccine development. VaxOptiML (available at https://***/) is an integrated pipeline designed to enhance epitope prediction and prioritization. This study aims to develop and deploy a robust tool for accurate prediction and prioritization of highly immunogenic and optimized MHC-I and MHC-II T-cell epitopes for cancer vaccine development and immunotherapy. Utilizing a curated dataset of experimentally validated epitopes and employing sophisticated machine learning techniques, VaxOptiML features three models: epitope prediction from target sequences, personalized HLA typing, and prioritization the predicted epitopes based on immunogenicity scores. Our rigorous data extraction, cleaning, and feature extraction processes, coupled with model building, yield exceptional accuracy, sensitivity, specificity, and F1 score, surpassing existing prediction methods. Comprehensive visual representations underscore VaxOptiML's robustness and efficacy in accelerating epitope discovery and vaccine design for cancer immunotherapy. Deployed via Streamlit for public use, VaxOptiML enhances accessibility and usability for researchers and clinicians, demonstrating significant potential in cancer immunotherapy.

关键词： Inborn Errors of Immunity   IL10RA Deficiency   Hematopoietic cell Transplantation   Japan   Fludarabine   Busulfan   Melphalan  

摘要： Background IL10RA (IL10 receptor subunit alpha) deficiency is an autosomal recessive disease that causes inflammatory bowel disease during early infancy. Its clinical course is often fatal and the only curative treatment is allogeneic hematopoietic cell transplantation (HCT). In Japan, only case reports are available, and there are no comprehensive reports of treatment outcomes. Methods We retrospectively analyzed patients with IL10RA deficiency in Japan. Results Two newly identified and five previously reported patients were included in this study. Five patients underwent HCT;one untransplanted patient survived to age 14, and one died of influenza encephalopathy before transplantation. All five HCT recipients underwent HCT at the age before 2 years. They all were conditioned with fludarabine/busulfan- or fludarabine /melphalan-based regimens. The donor source was human leukocyte antigen haploidentical donor bone marrow (BM) for two patients and unrelated umbilical cord blood (CB) for two patients. One patient experienced graft failure with unrelated CB and required a second transplant with unrelated BM. All patients who underwent HCT survived and demonstrated an improved performance status. Conclusion In cases of IL10RA deficiency, the need for transplantation should be promptly assessed, and early transplantation should be considered. (190/250)

关键词： Platelet transfusion refractoriness   anti-HLA antibody   anti-HLA-C autoantibody   hematologic disorders  

摘要： OBJECTIVES:Platelet transfusion refractoriness (PTR) is a frustrating clinical problem, and primary and persistent (P/P) PTR who experienced persistent PTR since the first transfusion was failed to be well recognized. This study aims to investigate the incidence and risk factors for P/P PTR. METHODS:Patients with hematologic disorders who underwent HLA high-resolution genotyping and donor-specific HLA antibody or panel reactive antibody (PRA) testing between January 2019 and March 2023 were reviewed. Clinical data including infection history, splenomegaly, frequency and quantity of blood transfusions, and transfusions response were delineated and subsequently analyzed. RESULTS:114 patients were included retrospectively, and 1071 transfusions were recorded. The overall incidence of PTR was 28.95% (33/114), with 63.63% (21/33) being P/P PTR. Anti class I HLA (anti-HLA-I) antibody was identified as an independent risk factor for ineffective platelet transfusion through multivariate logistic regression analysis ( = .034). Interestingly, anti-HLA-C autoantibodies were first found in six patients, and both anti-HLA-A and C autoantibodies were detected in one case, comprising a total of 10.71% (6/56) of HLA-I antibody-positive patients. Further analysis revealed that anti-HLA-C autoantibody was identified as an independent risk factor for P/P PTR ( = .039). Among patients with positive anti-HLA-C antibodies, significant differences in the effectiveness of ABO, D-matched and cross-matching transfusions were observed between patients with or without anti-HLA-C autoantibodies ( < .001 and  = .017). Notably, platelet transfusions independence was achieved by two of the four patients who received rituximab. CONCLUSIONS:This work emphasized the significance of anti-HLA-C autoantibody for P/P PTR in hematological patients, and rituximab may therapeutic.

关键词： Renal ischemia/reperfusion   Remote ischemic pre-conditioning   Apelin   Inflammation   Oxidative stress  

摘要： Background Remote limb ischemic pre-conditioning (RIPreC) can invoke potent renal protection. The involvement of oxidative stress and inflammatory pathways in renal ischemia/reperfusion injury (I/RI) was also confirmed. This study was designed to investigate the RIPreC effects on IRI-induced kidney dysfunction in rats through NF kappa B/TNF-alpha/TGF-beta/apelin signaling *** Renal I/RI was induced by occluding the kidney arteries for 45 min, then reperfusion for 24 h. Four similar cycles of left femoral artery ischemia (2 min)/reperfusion (3 min) before the onset of kidney ischemia were performed to create RIPreC. Animals were randomly divided into three groups: sham, I/R, and RIPreC + I/R. Following the reperfusion phase, urine and blood samples were taken, and the kidney was removed for functional, molecular, and histological *** When compared to sham rats, renal IRI resulted in decreased creatinine clearance and increased sodium fractional excretion, lower antioxidant enzyme activities, higher malondialdehyde content and higher nuclear factor-kappa B (NF-kappa B), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-betta (TGF-beta), and Apelin expression levels, and histologically damaged kidney tissue. All of the alterations, as mentioned earlier, were alleviated using the RIPreC *** Thus, RIPreC can protect against renal dysfunction after renal I/RI via modulation of the TNF-alpha/NF-kappa B/TGF-beta Apelin signaling pathway and strengthening the antioxidant defense system.