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1.
Peter K. Windsor Stephen P. Plassmeyer Dominic S. Mattock Jonathan C. Bradfield Erika Y. Choi Bill R. Miller III Byung Hee Han 《International journal of molecular sciences》2021,22(6)
Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the π–π interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease. 相似文献
2.
Raquel Cano Jos L. Prez Liss Angarita Dvila ngel Ortega Yosselin Gmez Nereida Josefina Valero-Cedeo Heliana Parra Alexander Manzano Teresa Isabel Vliz Castro María P. Díaz Albornoz Gabriel Cano Joselyn Rojas-Quintero Maricarmen Chacín Valmore Bermúdez 《International journal of molecular sciences》2021,22(9)
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required. 相似文献
3.
Sobha Karuthedom George Lucia Laukov Ren Weiss Vladislav Semak Birgit Fendl Victor U. Weiss Stephanie Steinberger Günter Allmaier Carla Tripisciano Viktoria Weber 《International journal of molecular sciences》2021,22(8)
Growing interest in extracellular vesicles (EVs) has prompted the advancements of protocols for improved EV characterization. As a high-throughput, multi-parameter, and single particle technique, flow cytometry is widely used for EV characterization. The comparison of data on EV concentration, however, is hindered by the lack of standardization between different protocols and instruments. Here, we quantified EV counts of platelet-derived EVs, using two flow cytometers (Gallios and CytoFLEX LX) and nanoparticle tracking analysis (NTA). Phosphatidylserine-exposing EVs were identified by labelling with lactadherin (LA). Calibration with silica-based fluorescent beads showed detection limits of 300 nm and 150 nm for Gallios and CytoFLEX LX, respectively. Accordingly, CytoFLEX LX yielded 40-fold higher EV counts and 13-fold higher counts of LA+CD41+ EVs compared to Gallios. NTA in fluorescence mode (F-NTA) demonstrated that only 9.5% of all vesicles detected in scatter mode exposed phosphatidylserine, resulting in good agreement of LA+ EVs for CytoFLEX LX and F-NTA. Since certain functional characteristics, such as the exposure of pro-coagulant phosphatidylserine, are not equally displayed across the entire EV size range, our study highlights the necessity of indicating the size range of EVs detected with a given approach along with the EV concentration to support the comparability between different studies. 相似文献
4.
5.
This work describes the procedure used to define the measurement uncertainties of horizontal two-phase air-water flow experiments conducted to determine influences due to pipe diameter on pressure gradient on such flows. These experiments were performed with 4 different pipe diameters, always using the same test section length, therefore varying the length-to-diameter (L/D) ratio. Several parameters were measured, such as volumetric/mass flow rate, pressures, temperatures and pressure drop; other parameters were calculated, such as the superficial velocities of each fluid, as well as their corresponding properties. The main parameters studied were the flow patterns for different velocity configurations and the two-phase pressure drop to be used for model improvement, thus the importance of uncertainties analysis. The sources of uncertainty were defined, detailed, systematically studied and quantified. Also, the reproducibility capacity of the experimental setups were analysed through the uncertainty analysis and proving them to be able for future similar studies. The flow maps with their uncertainties could help understand the thresholds for each defined flow pattern region, and the plots of two-phase pressure drop variation with diameter confirmed the homogeneous model as a possible approach to calculate pressure drop if the uncertainties are considered. 相似文献
6.
拉臂机构作为拉臂式垃圾车的关键部位,直接决定整车的可靠运行与人员操作体验,文中在分析拉臂机构的力学特性基础上,计算出在装卸工况下的载荷,利用有限元分析软件,对拉臂机构关键部位进行静态有限元分析与模态分析,分析结果表明拉臂机构符合动态性能要求,但其工作时强度不足,需对此进行结构优化。通过对拉臂机构进行局部修改,采取必要的辅助措施,使其达到符合静态性能要求的目的。在满足拉臂机构静动态性能要求上,装箱工况最大应力降低了23.3%,卸箱工况最大应力降低了24.9%,较好地达到了提高拉臂机构安全性能的目的。 相似文献
7.
针对某一体式夹紧器工作原理,以及根据打开周期、有无气缓冲、气缓冲形式、负载因素不同,定义不同工况,制定一体式夹紧器下盖冲击的测试方案。可调节工装设计为模拟不同负载工况提供了便捷条件;搭建测试和信号采集平台,获得夹紧器在不同工况条件下冲击力和动态性能——爬行、反弹、撞击;确定下盖冲击力主要影响因素——打开周期、负载、气缓冲效果,并对其敏感性进行量化分析。通过工况1,4的数据记录对比得出,现有的缓冲结构可以减少160%~290%的下盖冲击力。实验结论为V63夹紧器设计和气缓冲设计提供依据,为V63夹紧器标准工况应用条件提供量化分析数据支撑。 相似文献
8.
基于能量法和Archard磨损模型,提出了一种考虑磨损的齿轮啮合刚度数值计算方法。根据展成法原理,建立了精确的齿廓曲线方程。利用能量法计算齿轮单齿啮合刚度,并通过分段1阶傅里叶级数拟合获得齿轮总啮合刚度。以Archard磨损模型为基础,计算得到齿面法向磨损量与啮合点处压力角的关系。计算分析了不同磨损量对齿轮啮合刚度的影响。结果表明,磨损量在齿根、齿顶处较大,在节点处的理论磨损量为0 mm,随着压力角的逐渐增加,磨损量先减小后增大;齿面非均匀磨损会降低齿轮啮合刚度,随着磨损量的逐渐增加,啮合刚度逐渐减小。该方法为考虑磨损的齿轮系统动力学建模提供了理论基础。 相似文献
9.
采用硬度计、轮廓仪、光学显微镜、扫描电子显微镜等对服役后的U71Mn钢轨气压焊接头的硬度、裂纹形貌及显微组织进行测试与观察,分析接头不同区域的损伤行为。结果表明:焊接接头两侧距接头中心30~50 mm处存在低凹区域,其位置与软化区位置吻合;轮轨接触使接头硬度提高,但是软化区的硬度始终低于母材;根据珠光体形态,接头从中心向两侧热影响区可依次分为层片状珠光体区域、部分珠光体球化区Ⅰ、珠光体球化区、部分珠光体球化区Ⅱ;软化区位于珠光体球化区;珠光体球化区与部分珠光体球化区的裂纹深度和裂纹尖端扩展角都较大,这是由于粒状珠光体对裂纹扩展的阻力较小导致的。 相似文献
10.