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关键词： Ancient DNA   European Neolithic   Population genetics   Admixture   Immune genes   HLA diversity  

摘要： BackgroundThe northern European Neolithic is characterized by two major demographic events: immigration of early farmers from Anatolia at 7500 years before present, and their admixture with local western hunter-gatherers forming late farmers, from around 6200 years before present. The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is *** analyzed genome-wide data of 125 individuals from seven archeological early farmer and late farmer sites located in present-day Germany. The late farmer group studied here is associated with the Wartberg culture, from around 5500-4800 years before present. We note that late farmers resulted from sex-biased admixture from male western hunter-gatherers. In addition, we observe Y-chromosome haplogroup I as the dominant lineage in late farmers, with site-specific sub-lineages. We analyze true HLA genotypes from 135 Neolithic individuals, the majority of which were produced in this study. We observe significant shifts in HLA allele frequencies from early farmers to late farmers, likely due to admixture with western hunter-gatherers. Especially for the haplotype DQB1*04:01-DRB1*08:01, there is evidence for a western hunter-gatherer origin. The HLA diversity increased from early farmers to late farmers. However, it is considerably lower than in modern *** early farmers and late farmers exhibit a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time.

关键词： Polyvinylidene fluoride composites   Fused deposition molding   Electrical properties  

摘要： The polar n phase of polyvinylidene fluoride (PVDF) is a desirable material for the fabrication of smart sensor devices, given that PVDF typically exists in its alpha phase under standard conditions. In this study, we developed a method to fabricate high dielectric PVDF composites by incorporating an ionic liquid (IL) modified barium titanate BaTiO3 (BT). This was achieved by leveraging the filling effect of F atoms in PVDF and oxygen vacancies in BT, as well as the ion-dipole interaction between the CF2 of PVDF and the imidazolium cation of IL. These synergistic effects induced a crystalline phase transition in the PVDF, leading to an increase in the content of the polar n-phase to 84.01 % and a peak dielectric constant of 36.3 (100 HZ), which is 4.5 times that of the pure PVDF. Furthermore, it was demonstrated that the n phase content of the composite material remains high during the Fused deposition molding(FDM) process, thereby providing a material foundation for one-time molding of the dielectric material. Based on the above method, the fully 3D printed triboelectric nanogenerator (TENG) has a stable signal output and achieves a balance between device structure and performance. These findings indicate that PVDF/BT/IL holds promise as an electronegative material in the realm of triboelectricity.

关键词： Interleukin 17 (IL-17)   invasive breast cancer (IBC)   immune microenvironment   prognostic biomarkers  

摘要： Background: Recently, interleukin 17 (IL-17) has been found to play a critical role in the development of breast cancer. However, its prognostic significance in invasive breast cancer (IBC) remains unclear. This study aims to determine the role of IL-17-related signatures in IBC to identify novel therapeutic options. Methods: IBC data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) were used to identify IL- 17-related prognostic genes. A predictive model was developed using TCGA data and validated using METABRIC data. The relationship between IL-17 scores and immune landscape, chemotherapy drug sensitivity [half maximal inhibitory concentration (IC50)], and immune checkpoint gene expression was analyzed. The quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate key gene expression in breast tumor and normal tissue samples. Results: The predictive model identified core IL-17-related prognostic genes and successfully estimated the prognosis of IBC patients. The model's validity was confirmed using METABRIC data. Patients with high IL-17 scores had worse overall survival (OS) compared to those with low IL-17 scores. Low IL-17 scores were associated with higher immune checkpoint gene expression and predicted enhanced responses to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1) therapies. Patients with low IL-17 scores exhibited a higher abundance of immune microenvironment components. Furthermore, qRT-PCR confirmed the lower expression of OR51E1, NDRG2, RGS2, and TSPAN7 in breast tumors compared to normal tissue. Conclusions: IL-17-related signatures are promising biomarkers for predicting the prognosis of IBC patients. These findings suggest that IL-17-related markers could be used to guide individualized therapeutic strategies, potentially improving outcomes for IBC patients.

摘要： Excessive inflammation and cytokine release are hallmarks of severe COVID-19. Certain programmed cell death processes can drive inflammation, however, their role in the pathogenesis of severe COVID-19 is unclear. Pyroptosis is a pro-inflammatory form of regulated cell death initiated by inflammasomes and executed by the pore-forming protein gasdermin D (GSDMD). Using an established mouse adapted SARS-CoV-2 virus and a panel of gene-targeted mice we found that deletion of the inflammasome (NLRP1/3 and the adaptor ASC) and pore forming proteins involved in pyroptosis (GSDMA/C/D/E) only marginally reduced IL-1 beta levels and did not impact disease outcome or viral loads. Furthermore, we found that SARS-CoV-2 infection did not trigger GSDMD activation in mouse lungs. Finally, we did not observe any difference between WT animals and mice with compound deficiencies in the pro-inflammatory initiator caspases (C1/11/12-/-). This indicates that the classical canonical and non-canonical pro-inflammatory caspases known to process and activate pro-IL-1 beta, pro-IL-18 and GSDMD do not substantially contribute to SARS-CoV-2 pathogenesis. However, the loss of IL-1 beta, but not the absence of IL-18, ameliorated disease and enhanced survival in SARS-CoV-2 infected animals compared to wildtype mice. Collectively, these findings demonstrate that IL-1 beta is an important factor contributing to severe SARS-CoV-2 disease, but its release was largely independent of inflammasome and pyroptotic pathways.

关键词： Prognosis   Diagnosis   Immune cell infiltrate   Aberrant methylation   Microarray   Biomarker identification  

摘要： PurposeColorectal cancer (CRC) is the third most common cancer globally, necessitating novel biomarkers for early diagnosis and treatment. This study proposes an efficient pipeline leveraging an integrated bioinformatics and machine learning framework to enhance the identification of diagnostic and prognostic biomarkers for *** selection of methylated differentially expressed genes (MeDEGs) and features (genes) was made using both statistical and Machine learning (ML) approaches from publically available datasets. These genes were subjected to STRING network construction and hub genes estimation, separately. Also, essential miRNAs (micro-RNAs) and TFs (Transcription factors) as regulatory elements were revealed and findings were validated through scRNA-seq analysis, promoter methylation, gene expression levels correlated with pathological stage, and interaction with tumor-infiltrating immune *** an integrated analysis pipeline, we identified 27 hub genes, among which CTNNB1, GSK3B, IL-1 beta, MYC, PXDN, TP53, EGFR, SRC, COL1A1, and TGBF1 showed better diagnostic behaviour. Machine learning approach includes the development of K-Nearest Neighbors (KNN), Artificial Neural Networks (ANN), and Random Forest (RF) models using TCGA datasets, achieving an accuracy range between 99 and 100%. The Area Under the Curve (AUC) value for each model is 1.00, signifying good classification performance. The high expression of some diagnostic genes was associated with poor prognosis, concluding IL-1 beta as both a prognostic and diagnostic biomarker. Additionally, the NF-kappa B and microRNAs (miR-548d-3p, miR-548-ac) and TFs (NF kappa B and STAT5A) play a major role in the comprehensive regulatory network for CRC. Furthermore, hub genes such as IL-1 beta, TGFB1, and COL1A1 were significantly correlated with immune infiltrates, suggesting their potential role in CRC ***, the elevated expression of IL-1 beta coupled with abnormal DNA

关键词： TGF-β1   EGFR突变   细胞因子   非小细胞肺癌   免疫组织化学  

摘要： 目的:探讨转化生长因子β(TGF-β)对表皮生长因子受体(EGFR)突变ⅢC-Ⅳ期非小细胞肺癌(NSCLC)患者血清细胞因子白细胞介素-2(IL-2)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)及肿瘤坏死因子-α(TNF-α)的影响.方法:选取2018年5月至2022年1月于我院行基因检测的117例ⅢC-Ⅳ期NSCLC患者作为研究对象,分为EGFR突变组(n=50)和EGFR未突变组(n=67),应用免疫组织化学(IHC)染色观察TGF-β1的蛋白表达情况,ELISA法检测血清细胞因子IL-2、IL-6、IL-10及TNF-α的水平,分析TGF-β1对EGFR突变ⅢC-Ⅳ期NSCLC患者血清细胞因子IL-2、IL-6、IL-10及TNF-α的影响.结果:EGFR突变组患者TGF-β1蛋白表达水平高于未突变组(P<0.05).与EGFR未突变组比较,突变组患者血清细胞因子IL-2在TGF-β1高表达时水平降低(P<0.05),IL-6、IL-10及TNF-α在TGF-β1高表达时水平均增高(P<0.05).结论:EGFR突变 ⅢC-Ⅳ期NSCLC患者TGF-β1表达上调可影响血清细胞因子IL-2、IL-6、IL-10及TNF-α的水平,改变肿瘤免疫微环境,加强肿瘤免疫逃逸.

关键词： peptide-MHC binding   MHC I and II   deep learning   uterine corpus endometrial carcinoma   neoantigen  

摘要： The key roles of Major Histocompatibility Complex (MHC) Class I and II molecules in the immune system are well established. This study aims to develop a novel machine learning framework for predicting antigen peptide presentation by MHC Class I and II molecules. By integrating large-scale mass spectrometry data and other relevant data types, we present a prediction model OnmiMHC based on deep learning. We rigorously assessed its performance using an independent test set, OnmiMHC achieves a PR-AUC score of 0.854 and a TOP20%-PPV of 0.934 in the MHC-I task, which outperforms existing methods. Likewise, in the domain of MHC-II prediction, our model OnmiMHC exhibits a PR-AUC score of 0.606 and a TOP20%-PPV of 0.690, outperforming other baseline methods. These results demonstrate the superiority of our model OnmiMHC in accurately predicting peptide-MHC binding affinities across both MHC-I and MHC-II molecules. With its superior accuracy and predictive capability, our model not only excels in general predictive tasks but also achieves significant results in the prediction of neoantigens for specific cancer types. Particularly for Uterine Corpus Endometrial Carcinoma (UCEC), our model has successfully predicted neoantigens with a high binding probability to common human alleles. This discovery is of great significance for the development of personalized tumor vaccines targeting UCEC.

关键词： 电针   干眼   泪腺   TLR4/NF-κB通路   Th1/Th2细胞因子  

摘要： 目的 探讨电针对干眼兔泪腺TLR4/NF-κB通路和Th1/Th2细胞因子的表达的影响，分析电针对干眼的作用机制。方法 取雌雄不拘的健康新西兰兔24只随机分为空白组、模型组、电针组，西药组，每组6只，空白组不作处理;其余三组以氢溴酸东莨菪碱2.0mg/kg-1，皮下注射4次/d，连续35d。电针组和西药组在第22天进行治疗，每天1次，共14d。不同时间段进行角膜荧光染色、泪膜破裂时间、泪液流量测定和光镜检测，Elisa法检测IL-4、IFN-γ含量，免疫组化法检测结膜、泪腺、角膜NF-κB蛋白表达，蛋白质印迹学检测泪腺、TLR4、NF-κB、iNOS蛋白的表达，PCR检测TLR4和iNOS的mRNA表达。结果 实验第27、35d同时段电针组与模型组相比角膜荧光染色和评分减少，泪膜破裂时间延长，泪液流量增多，差异均有统计学意义（均为 P＜0.05）；光镜示电针组与模型组相比结膜、泪腺。角膜组织损伤改善；Elisa结果示与模型组相比，电针组泪腺中IFN-γ含量降低，IL-4含量升高，差异均有统计学意义（P＜0.05）；免疫组化结果示与模型组比较，针刺组结膜、泪腺组织中NK-κBp65蛋白表达降低（P＜0.05）；蛋白质印迹学结果显示与模型组相比，电针组下调TLR4、p-NF-κBp65、iNOS的表达水平，差异均有统计学意义（P＜0.05）。PCR结果显示与模型组相比，电针组下调TLR4的表达水平，差异有统计学意义（P＜0.05）。结论 针灸可以改善兔干眼模型泪腺炎症和损伤，并且可以通过抑制TLR4/NF-κB通路和Th1/Th2细胞因子的表达的途径发挥作用。