Repurposing of intestinal defensins as multi-target,dual-function amyloid inhibitors via cross-seeding

Amyloid formation and microbial infection are the two common pathological causes of neurogenerative diseases, including Alzheimer''s disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While significant efforts have been made to develop different prevention strategies and preclinical hits for these diseases, conventional design strategies of amyloid inhibitors are mostly limited to either a single prevention mechanism (amyloid cascade vs. microbial infection) or a single amyloid protein (Aβ, hIAPP, or hCT), which has prevented the launch of any successful drug on the market. Here, we propose and demonstrate a new “anti-amyloid and anti-bacteria” strategy to repurpose two intestinal defensins, human α-defensin 6 (HD-6) and human β-defensin 1 (HBD-1), as multiple-target, dual-function, amyloid inhibitors. Both HD-6 and HBD-1 can cross-seed with three amyloid peptides, Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC), to prevent their aggregation towards amyloid fibrils from monomers and oligomers, rescue SH-SY5Y and RIN-m5F cells from amyloid-induced cytotoxicity, and retain their original antimicrobial activity against four common bacterial strains at sub-stoichiometric concentrations. Such sequence-independent anti-amyloid and anti-bacterial functions of intestinal defensins mainly stem from their cross-interactions with amyloid proteins through amyloid-like mimicry of β-sheet associations. In a broader view, this work provides a new out-of-the-box thinking to search and repurpose a huge source of antimicrobial peptides as amyloid inhibitors, allowing the blocking of the two interlinked pathological pathways and bidirectional communication between the central nervous system and intestines via the gut–brain axis associated with neurodegenerative diseases.

Amyloid formation and microbial infection are the two common pathological causes of neurogenerative diseases. Here, we proposed a new “anti-amyloid and anti-bacteria” strategy to repurpose two intestinal defensins as multiple-target, dual-function amyloid inhibitors.     

气相生长氮化铝单晶的新方法

通过在钨坩埚盖开小孔的方法改变氮化铝结晶衬底上的温度场分布,在开孔处形成局部低温区;由于孔的几何尺寸的限制和氮化铝晶体生长的各向异性,开孔处的氮化铝晶体单晶化;随后,开孔处的单晶起籽晶的作用,逐渐长成较大尺寸、较高质量的氮化铝单晶.目前用该方法已经制备出直径大于2mm的氮化铝单晶体.     

用化学溶液方法在Ni-5at%W基底上制备La2Zr2O7过渡层的研究

La2Zr2O7(LZO)过渡层以其独特的物理化学性质越来越受到人们的关注。本文以乙酰丙酮镧和乙酰丙酮锆为前驱盐,丙酸为溶剂配置前驱液,用化学溶液方法(CSD)在具有立方织构的Ni-5at%W基底上制备了LZO过渡层薄膜。研究了前驱液成分、性质以及退火温度对LZO成相以及取向的影响。用常规XRD和X射线四环衍射仪分析了LZO薄膜的相成分和织构。结果显示,在1050℃下退火可以获得强立方织构的LZO薄膜,其中(222)峰的Phi扫描半高宽值为8.95°;(400)峰的Chi扫描半高宽值为6.8°。用高分辨扫描电子显微镜(FE-SEM)观察到LZO薄膜表面均匀致密,没有裂纹和空洞。     

Determination of Acetonitrile Volume Fraction in Mobile Phase by HPLC

This paper reports the development and validation of an assay for the determination of acetonitrile in the recycled mobile phase using high performance liquid chromatography（HPLC）. The method is based on that the retention in reversed-phase liquid chromatography increases with decreasing concentration of organic phase in the mobile phase. The natural logarithm of the capacity ratio for a given solute is linearly related to the volume fraction of the organic modifier in the mobile phase. For dimethylphthalate and diethylphthalate, the linearity range is 30%--60%, and for biphenyl and terphenyl, the range is 60%--95%. Precision values（RSD） were both 〈1% and the accuracy（RE） was in the range of ±1%. The assay was successfully applied to the determination of acetonitrile concentration of recycled mobile phase after the distillation of the column eluent in our laboratory.     

PVC/MBS/纳米 BaSO4 复合材料的制备及其性能

采用熔融共混法制备聚氯乙烯(PVC)/甲基丙烯酸甲酯-丁二烯-苯乙烯共聚物(MBS)/纳米重晶石(nano-BaSO4)三元复合材料,考察其力学性能和热稳定性能,并用扫描电镜观察冲击断面的形态.结果表明:MBS 与 nano-BaSO4 可协同增韧 PVC;当 MBS、nano-BaSO4 的含量分别为 10%、1%时,材料的韧性和刚性可同时得以改善,其冲击断面表现出典型的韧性断裂特征;热重分析显示添加 1%nano-BaSO4 可显著提高 PVC/MBS 的热稳定性能,其第一降解阶段的初始分解温度和最快分解温度分别提高了 10℃和14℃.     

高效液相色谱法和硫氰酸钾滴定法检测煤中氯的比较研究

比较了测定煤中氯的高效液相色谱(HPLC)法和硫氰酸钾滴定法。以密闭氧弹燃烧或艾氏卡剂熔融分解样品，分别以高效液相色谱法和硫氰酸钾滴定法测定煤中氯，通过对国家标准物质GBW11118、GBW11119、GBW11120分析结果的比较及t检验，表明两方法无显著性差异。     

基于一维标定物和改进进化策略的相机标定

为了解决运动参数光电探测过程中的相机标定问题,制作一种两端及中间各安装一个红外反光标记球的一维标定物.不需要其它复杂标定装置,只要将这种特制的一维标定物在测量空间内多次随意移动并摄取其图像,即可实现标定.算法首先假定主点位于像面中心附近的某个位置,再求出焦距、旋转矩阵、平移向量和比例因子,最后通过评价函数将相机标定转换成寻找两相机最佳主点对的非线性最小化问题.在传统进化策略中引进个体的自我改进系数、个体间距离等概念,提出了求取子代个体间的欧式距离并排序的方法,设计了搜索最佳主点对的改进型进化策略算法.与传统标定方法相比,基于一维标定物的方法克服了多相机场合的遮挡问题,改进进化策略的引入打破了一维标定物需做某种特殊运动的限制,使一维标定物自由运动时相机内、外参数的同时求解成为可能,改进的模拟退火进化策略改善了算法的全局收敛性能并加快了收敛速度.     

Dynamic synovial fibroblasts are modulated by NBCn1 as a potential target in rheumatoid arthritis

Rheumatoid arthritis (RA) is an autoimmune disease characterized by aggressive fibroblast-like synoviocytes (FLSs) and pannus formation. Various therapeutic strategies have been developed against inflammatory cytokines in RA in recent decades. Based on the migratory features of FLSs, we examined whether modulation of the migratory module attenuates RA severity. In this study, inflamed synovial fluid-stimulated FLSs exhibited enhanced migration and migratory apparatus expression, and sodium bicarbonate cotransporter n1 (NBCn1) was identified in primary cultured RA-FLSs for the first time. The NBC inhibitor S0859 attenuated the migration of FLSs induced with synovial fluid from patients with RA or with TNF-α stimulation. Inhibition of NBCs with S0859 in a collagen-induced arthritis (CIA) mouse model reduced joint swelling and destruction without blood, hepatic, or renal toxicity. Primary FLSs isolated from the CIA-induced mouse model also showed reduced migration in the presence of S0859. Our results suggest that inflammatory mediators in synovial fluid, including TNF-α, recruit NBCn1 to the plasma membrane of FLSs to provide dynamic properties and that modulation of NBCn1 could be developed into a therapeutic strategy for RA.Subject terms: Chemotaxis, Bone, Ion channel signalling, Rheumatoid arthritis, Drug development     

Rapid Detection of Five Estrogens Added Illegally to Dietary Supplements by Combining TLC with Raman Imaging Microscope

Estrogens added illegally to dietary supplements are hazardous to human health. Traditional detection and analysis methods have many limitations, and we have developed an assay that combines thin-layer chromatography with Raman imaging microscopy (TLC-RIM). The five estrogens (estrone, estradiol, estriol, ethinyl estradiol, and diethylstilbestrol) were initially separated by TLC, then detected by area scanning Raman imaging with a 532 nm laser under a microscope. Raman spectra were obtained for each estrogen, which were used for detecting estrogen illegally added to botanical dietary supplements. The LOD of each estrogen was 0.4, 1.0, 0.8, 0.2, and 0.2 mg/mL, respectively. The matrix in the real sample did not interfere with the detection of estrogens. The method was fast, sensitive, stable, specific, and reliable.     

Effect of Coconut Protein and Xanthan Gum,Soybean Polysaccharide and Gelatin Interactions in Oil-Water Interface

We report on our study of the interactions between coconut protein extracted from coconut meat and three hydrocolloids (gelatin, xanthan gum, and soybean polysaccharide) and their interfacial adsorption and emulsification properties. We used Zeta potential, fluorescence spectroscopy scanning and ITC to investigate the interactions between a fixed concentration (1%) of coconut protein and varying concentrations of hydrocolloid. Through the interfacial tension and interfacial viscoelasticity, the interfacial properties of the hydrocolloid and coconut protein composite solution were explored. The physical stability of the corresponding emulsion is predicted through microstructure and stability analysis. Xanthan gum forms a flocculent complex with coconut protein under acidic conditions. Soy polysaccharides specifically bind to coconut protein. Under acidic conditions, this complex is stabilized through the steric hindrance of soy polysaccharides. Due to gelatin-coconut protein interactions, the isoelectric point of this complex changes. The interfacial tension results show that as time increases, the interfacial tensions of the three composite solutions decrease. The increase in the concentration of xanthan gum makes the interfacial tension decrease first and then increase. The addition of soybean polysaccharides reduces the interfacial tension of coconut protein. The addition of xanthan gum forms a stronger elastic interface film. Emulsion characterization showed that the gelatin-added system showed better stability. However, the addition of xanthan gum caused stratification quickly, and the addition of soybean polysaccharides also led to instability because the addition of polysaccharides led to a decrease in thermodynamic compatibility. This research lays the foundation for future research into coconut milk production technology.