The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response

The strong association with the Major Histocompatibility Complex (MHC) class I genes represents a shared trait for a group of autoimmune/autoinflammatory disorders having in common immunopathogenetic basis as well as clinical features. Accordingly, the main risk factors for Ankylosing Spondylitis (AS), prototype of the Spondyloarthropathies (SpA), the Behçet’s disease (BD), the Psoriasis (Ps) and the Birdshot Chorioretinopathy (BSCR) are HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02, respectively. Despite the strength of the association, the HLA pathogenetic role in these diseases is far from being thoroughly understood. Furthermore, Genome-Wide Association Studies (GWAS) have highlighted other important susceptibility factors such as Endoplasmic Reticulum Aminopeptidase (ERAP) 1 and, less frequently, ERAP2 that refine the peptidome presented by HLA class I molecules to CD8⁺ T cells. Mass spectrometry analysis provided considerable knowledge of HLA-B*27, HLA-B*51, HLA-C*06:02 and HLA-A*29:02 immunopeptidome. However, the combined effect of several ERAP1 and ERAP2 allelic variants could generate an altered pool of peptides accounting for the “mis-immunopeptidome” that ranges from suboptimal to pathogenetic/harmful peptides able to induce non-canonical or autoreactive CD8⁺ T responses, activation of NK cells and/or garbling the classical functions of the HLA class I molecules. This review will focus on this class of epitopes as possible elicitors of atypical/harmful immune responses which can contribute to the pathogenesis of chronic inflammatory diseases.     

Interleukin-1β Modulation of the Mechanobiology of Primary Human Pulmonary Fibroblasts: Potential Implications in Lung Repair

Pro-inflammatory cytokines like interleukin-1β (IL-1β) are upregulated during early responses to tissue damage and are expected to transiently compromise the mechanical microenvironment. Fibroblasts are key regulators of tissue mechanics in the lungs and other organs. However, the effects of IL-1β on fibroblast mechanics and functions remain unclear. Here we treated human pulmonary fibroblasts from control donors with IL-1β and used Atomic Force Microscopy to unveil that IL-1β significantly reduces the stiffness of fibroblasts concomitantly with a downregulation of filamentous actin (F-actin) and alpha-smooth muscle (α-SMA). Likewise, COL1A1 mRNA was reduced, whereas that of collagenases MMP1 and MMP2 were upregulated, favoring a reduction of type-I collagen. These mechanobiology changes were functionally associated with reduced proliferation and enhanced migration upon IL-1β stimulation, which could facilitate lung repair by drawing fibroblasts to sites of tissue damage. Our observations reveal that IL-1β may reduce local tissue rigidity by acting both intracellularly and extracellularly through the downregulation of fibroblast contractility and type I collagen deposition, respectively. These IL-1β-dependent mechanical effects may enhance lung repair further by locally increasing pulmonary tissue compliance to preserve normal lung distension and function. Moreover, our results support that IL-1β provides innate anti-fibrotic protection that may be relevant during the early stages of lung repair.     

Design,Synthesis, and in vitro Evaluation of P2X7 Antagonists

The P2X7 receptor is a promising target for the treatment of various diseases due to its significant role in inflammation and immune cell signaling. This work describes the design, synthesis, and in vitro evaluation of a series of novel derivatives bearing diverse scaffolds as potent P2X7 antagonists. Our approach was based on structural modifications of reported (adamantan-1-yl)methylbenzamides able to inhibit the receptor activation. The adamantane moieties and the amide bond were replaced, and the replacements were evaluated by a ligand-based pharmacophore model. The antagonistic potency of the synthesized analogues was assessed by two-electrode voltage clamp experiments, using Xenopus laevis oocytes that express the human P2X7 receptor. SAR studies suggested that the replacement of the adamantane ring by an aryl-cyclohexyl moiety afforded the most potent antagonists against the activation of the P2X7 cation channel, with analogue 2-chloro-N-[1-(3-(nitrooxymethyl)phenyl)cyclohexyl)methyl]benzamide ( 56 ) exhibiting the best potency with an IC₅₀ value of 0.39 μM.     

基于多尺度的贝叶斯模型显著性检测

针对传统基于贝叶斯模型的显著性检测算法存在准确率不理想的问题,提出了一种基于多尺度的贝叶斯模型显著性检测算法。通过超像素分割算法(SLIC)将原图分割成不同尺度的超像素,根据超像素边界信息得到背景种子,进而通过距离计算和多尺度融合得到背景先验;对原图进行颜色增强,采用Harris算子对增强图进行检测角点求得凸包,融合不同尺度下的超像素得到凸包先验;融合背景先验和凸包先验得到最终先验;利用颜色直方图和凸包计算似然概率;将最终先验和似然概率通过贝叶斯模型计算显著图。在公开数据集MSRA1000、ECSSD上与多种传统算法进行准确率和召回率对比,该算法有更好的表现。     

基于主动学习的离群点集成挖掘方法研究

离群点检测任务通常缺少可用的标注数据，且离群数据只占整个数据集的很小一部分，相较于其他的数据挖掘任务，离群点检测的难度较大，尚没有单一的算法适合于所有的场景。因此，结合多样性模型集成和主动学习思想，提出了一种基于主动学习的离群点集成检测方法OMAL（Outlier Mining based on Active Learning）。在主动学习框架指导下，根据各种基学习器的对比分析，选择了基于统计的、基于相似性的、基于子空间划分的三个无监督模型作为基学习器。将各基学习器评判的处于离群和正常边界的数据整合后呈现给人类专家进行标注，以最大化人类专家反馈的信息量；从标注的数据集和各基学习器投票产生的数据集中抽样，基于GBM（Gradient BoostingMachine）训练一个有监督二元分类模型，并将该模型应用于全数据集，得出最终的挖掘结果。实验表明，提出方法的AUC有了较为明显的提升，且具有良好的运行效率，具备较好的实用价值。     

面向连续查询的敏感语义位置隐私保护方案

针对连续查询位置服务中构造匿名区域未考虑语义位置信息导致敏感隐私泄露问题，通过设计[(K,θ)]-隐私模型，提出一种路网环境下面向连续查询的敏感语义位置隐私保护方案。该方案利用Voronoi图将城市路网预先划分为独立的Voronoi单元，依据用户的移动路径和移动速度，选择具有相似特性的其他[K-1]个用户，构建匿名用户集；利用匿名用户集用户设定的敏感语义位置类型和语义安全阈值，以及用户所处语义位置的Voronoi单元，构建满足[(K,θ)]-隐私模型的语义安全匿名区域，可以同时防止连续查询追踪攻击和语义推断攻击。实验结果表明，与SCPA算法相比，该方案在隐私保护程度上提升约15%，系统开销上降低约20%。     

基于条件信息卷积生成对抗网络的图像识别

传统的图像识别方法需要大量有标签样本进行训练，且模型训练难以达到稳定。针对这些问题，结合条件生成网络和信息最大化生成网络的结构优势建立了条件信息卷积生成网络（C-Info-DCGAN）。模型增加图像的类别信息和潜在信息作为输入数据，然后利用Q网络去更好地发挥类别信息和潜在信息对训练的引导作用，并且利用深度卷积网络来加强对图像特征的提取能力。实验结果表明，该方法能够加快模型训练收敛速度，并有效提高图像识别的准确率。     

结合预训练模型和语言知识库的文本匹配方法

针对文本匹配任务,该文提出一种大规模预训练模型融合外部语言知识库的方法。该方法在大规模预训练模型的基础上,通过生成基于WordNet的同义—反义词汇知识学习任务和词组—搭配知识学习任务引入外部语言学知识。进而,与MT-DNN多任务学习模型进行联合训练,以进一步提高模型性能。最后利用文本匹配标注数据进行微调。在MRPC和QQP两个公开数据集的实验结果显示,该方法可以在大规模预训练模型和微调的框架基础上,通过引入外部语言知识进行联合训练有效提升文本匹配性能。