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.     

单晶SiC的电助光催化抛光及去除机理

为满足电子半导体等领域对SiC超光滑、无损伤和材料高效去除的要求，提出了电助光催化抛光SiC的新方法。研究了光催化剂种类及其pH值对抛光液氧化性和抛光效果的影响，讨论了材料的去除机理。结果表明：以p25型TiO2为光催化剂配制抛光液所获得的最大氧化还原电位为633.11 mV，材料去除率为1.18 μm/h，表面粗糙度Ra=0.218 nm；抛光后SiC表面氧化产物中，Si-C-O、Si-O和Si4C4O4的含量明显增加，SiC表面被氧化并被机械去除是主要的材料去除方式。     

11-苄硒基十一羧酸铵盐的双重刺激响应性质

合成了一种对氧化还原(Redox)和CO_2/N_2具有双重刺激响应的表面活性剂11-苄硒基十一羧酸铵盐(BSeUA),分别利用傅里叶红外光谱、核磁共振和电喷雾质谱等手段研究了BSeUA在Redox和CO_2/N_2刺激响应前后的分子结构变化特征。结果表明,在过氧化氢和水合肼交替作用下,BSeUA分子中二价硒醚基团(-Se-)与相应的四价硒亚砜基团(-Se=O)之间可以氧化还原可逆互变,在CO_2和N_2交替作用下,BSeUA分子中羧酸根(-COO-)与相应的羧酸(-COOH)之间可以可逆互变,从而实现BSeUA对Redox和CO_2/N_2具有双重刺激响应。分别在Redox和CO_2/N_2刺激作用下,由BSeUA稳定的乳液可以在破乳和再乳化2种状态下开关可逆循环至少5次,且乳液粒径和稳定性未发生明显变化。     

Revisiting CO2 emissions convergence in G18 countries

This study revisits whether CO₂ emissions converge in G18 countries over the period of 1950–2013. To work on this empirical analysis, we employ a more powerful quantile unit root test with per capita CO₂ emissions. While conventional unit root tests fail to reject convergence in CO₂ emissions in these G18 countries, quantile unit root test results demonstrate CO₂ emissions converged in 5 of these G18 countries (i.e., Australia, Brazil, Canada, Germany, and India). Our empirical results have important policy implications for the governments of G18 countries to direct efficient and effective energy policies to reduce the CO₂ emissions.     

宁夏红寺堡盆地隐伏古隆起成因机制及其对区域沙漠化的影响

目前对于青藏高原东北缘活动构造研究多集中于活动断裂带的活动性,而对夹持于其间的沉积盆地构造格架及活动性研究甚少。以夹持于烟筒山断裂与牛首山—罗山断裂之间的宁夏红寺堡盆地为研究对象,采用重力资料重处理解译、音频大地电磁测深(AMT)和地震勘探相结合,揭示红寺堡盆地隐伏构造特征,并进一步采用盆山一体化思路分析隐伏构造的成因机制及其对区域沙漠化的控制作用。结果表明:青藏高原在中新世末发生强烈的NE向推挤、扩展和隆升,红寺堡盆地由坳陷盆地转变为挠曲盆地; 在青藏高原NE向扩展的影响下,烟筒山断裂发生强烈的逆冲作用,古生代—中生代基底逆冲于古近系—新近系之上,受构造变形影响的最新地层为中新统彰恩堡组; 红寺堡盆地内的隐伏古隆起呈NW—SE向,与烟筒山构造带具有相同的构造动力学背景,受青藏高原NE向扩展影响形成于中新世末,并且至今仍具有活动性; 隐伏古隆起周缘断裂的活动破坏了地表稳定性、蓄水能力和地表植被,导致区域沙漠化呈现有规律的NW—SE向带状展布。该研究成果对于宁夏红寺堡盆地区域稳定性评价及沙漠化的综合治理具有现实指导意义。     

Retention of Eucalyptol,a Natural Volatile Insecticide,in Delivery Systems Based on Hydroxypropyl‐β‐Cyclodextrin and Liposomes

Eucalyptol (Euc) is a natural monoterpene with insecticide effects. Being highly volatile and sensitive to ambient conditions, its encapsulation would enlarge its application. Euc‐loaded conventional liposomes (CL), cyclodextrin/drug inclusion complex, and drug‐in‐cyclodextrin‐in‐liposomes (DCL) are prepared to protect Euc from degradation, reduce its evaporation, and provide its controlled release. The liposomal suspension is freeze‐dried using hydroxypropyl‐β‐cyclodextrin (HP‐β‐CD) as cryoprotectant. The liposomes are characterized before and after freeze‐drying. The effect of Euc on the fluidity of liposomal membrane is also examined. A release study of Euc from delivery systems, in powder and reconstituted forms, is performed by multiple head extraction at 60 °C after 6 months of storage at 4 °C. CL and DCL suspensions are homogeneous, show nanometric vesicles size, spherical shape, and negative surface charge before and after freeze‐drying. Moreover, HP‐β‐CD does not affect the fluidity of liposomes. CL formulations present a weak encapsulation for Euc. The loading capacity of eucalyptol in DCL is 38 times higher than that in CL formulation. In addition, freeze‐dried DCL and HP‐β‐CD/Euc inclusion complex show a higher retention of eucalyptol than CL delivery system. Both carrier systems HP‐β‐CD/Euc and Euc‐loaded DCL decrease Euc evaporation and improve its retention. Practical Applications: Eucalyptol is a natural insecticide. It is highly volatile and poorly soluble in water. To enlarge its application, its encapsulation in three delivery systems (conventional liposomes, cyclodextrin/drug inclusion complex, combined system composed of cyclodextrin inclusion complex and liposome) is studied. In this paper it is proved that cyclodextrin/eucalyptol inclusion complex and eucalyptol‐in‐cyclodextrin‐in‐liposome are effective delivery systems for encalyptol encapsulation, retention, and release.