Adsorption of the pulmonary surfactant at interfaces and the associated bio logical effects

&nbsp; &nbsp; 肺表面活性剂是由II 型肺泡细胞合成和分泌的脂质蛋白质复合物质，可以吸附在肺泡的表面，在界面处形成单层膜， 这一层膜能够将肺泡的表面张力降低到非常低 ，以维持正常的呼吸作用 。肺表面活性剂膜也是抵御吸入的纳米颗粒的第一道屏障。当纳米颗粒与肺表面活性剂膜接触时，它们可以吸附肺表面活性剂的磷脂脂和蛋白质，从而在其表面上形成称之为脂蛋白冕的结构 。该脂蛋白冕赋予了纳米颗粒新的生物识别身份，并影响纳米颗粒的生物效应。因此， 研究肺表面活性剂在表面或界面（包括空气水界面和纳米颗粒表面）上的吸附，对于研究肺表面活性剂的生物物理功能和生物效应至关重要。 &nbsp; &nbsp; 尽管目前已有许多关于肺表面活性剂 在界面或表面吸附的实验研究， 揭示肺表面活性剂在界面上的动态吸附过程仍然具有很大的挑战性。通过受限液滴表面张力测量法（ Constrained Drop Surfactometry , CDS ）和粗粒化分子动力学模拟，本文首先研究了肺表面活性剂 的主要成分二棕榈酰磷脂酰胆碱（dipalmitoylphosphatidylcholine DPPC ）在 水气界面吸附的生物物理机制。我们发现从囊泡吸附的 DPPC 膜表现出明显比通过有机溶剂铺展的 DPPC 单层膜更高的平衡表面张力 。模拟显示，只有 DPPC 囊泡的外层能够在水气界面打开并铺展，而内层保持完整并在界面处形成反胶束的结构 。这种反胶束增加了单层膜的局部曲率，从而导致了磷脂在水气界面 的松散排序，进而形成了更高的平衡表面张力。 &nbsp; &nbsp; 通过粗粒化分子动力学模拟研究了多组分肺表面活性剂在水气界面的吸附。我们发现具有比 DPPC 更大头部基团的磷脂 在水气界面的吸附可以达到较低的表面张力。不饱和的尾巴和胆固醇可以通过稳定吸附结构的曲率以及增强倒置胶束中尾部之间的相互作用，帮助吸附的肺表面活性剂的表面张力降低到更低的值。通过包括梯度离心和高效液相色谱 质谱在内的实验技术，定量分析了纳米颗粒上吸附的天然肺表面活性剂的磷脂成分。我们发现肺表面活性剂的吸附是由肺表面活性剂薄膜和纳米颗粒表面之间的粘附能驱动的，该粘附能可以通过纳米颗粒的表面性质以及外力来调节。 同样，脂蛋白冕中的磷脂的成分不同于原始的肺表面活性剂成分，这可能是由于纳米颗粒与特定脂质之间的吸引力或脂质的弯曲模量所决定。 &nbsp; &nbsp; 使用耗散粒子动力学模拟研究了肺表面活性剂在纳米颗粒上的吸附的生物效应，即细胞膜与修饰了肺表面活性剂的纳米颗粒之间的相互作用。我们研究了肺表 面活性剂脂质和蛋白质的物理化学特性如何分别影响吸入纳米颗粒的细胞膜的 响应 。我们指出了细胞膜对脂质纳米颗粒内吞作用的几个关键因素，包括修饰脂质的变形，脂质的变形，修饰修饰脂质的密度和配体脂质的密度和配体--受体结合强度。进一步的研究表明，修修饰饰脂质的变形消耗了能量，但另一方面却促进了脂质的变形消耗了能量，但另一方面却促进了修饰的修饰的配体更紧密地与受体结合。修饰的 脂质密度控制了配体的数量和脂质纳米颗粒的疏水性，分别通过特异性和非特异性相互作用影响内吞作用 。 我们还发现与脂质相关的疏水性表面活性剂蛋白可以加速纳米颗粒的内吞过程，但是内吞作用效率主要取决于被覆表面活性剂脂质的密度。</p

肺表面活性剂修饰的纳米颗粒与细胞膜相互作用的分子模拟研究

呼吸系统是纳米颗粒进入人体的重要途径,吸入的纳米颗粒首先会与肺泡表面的肺表面活性剂作用,吸附其中的磷脂以及蛋白质分子,在其表面形成一层脂蛋白冠。脂蛋白冠将会取代原始颗粒的表面性质,决定纳米颗粒的生物效应,如与细胞膜的相互作用。目前,关于纳米颗粒表面吸附的肺表面活性剂如何影响此类相互作用的分子机制尚不明确。在此,我们通过粗粒化分子模拟,研究了肺表面活性剂修饰的纳米颗粒与细胞膜之间的相互作用。结果表明,多种因素会影响细胞膜与肺表面活性剂修饰的纳米颗粒的相互作用。首先,修饰在颗粒表面的磷脂的弹性变形会使磷脂提供的配体与细胞膜上的受体更紧密地结合,从而促进细胞膜内吞纳米颗粒。其次,修饰磷脂的密度会改变颗粒表面的亲疏水性以及配体密度,分别通过非特异性和特异性作用影响细胞膜对纳米颗粒的摄入。最后,修饰的疏水性肺表面活性剂蛋白通过与细胞膜磷脂的强粘附作用,加速细胞膜对纳米颗粒的内吞,但细胞膜对纳米颗粒的内吞行为主要取决于修饰的磷脂。我们的模拟结果有助于更好地理解现有的实验现象,对于评估吸入纳米颗粒的毒性以及设计呼吸给药具有重要意义

PEG修饰纳米颗粒穿过肺表面活性剂的分子动力学模拟

金纳米颗粒(AuNP)用作纳米药物载体一直广受关注。而如何设计Au NP使其更容易穿过肺表面活性剂(PS)的磷脂单层膜、同时又最大程度地减少甚至杜绝对磷脂膜的破坏成为一个亟待解决的问题。有实验发现,聚乙二醇(PEG)修饰纳米颗粒穿越磷脂双层膜取得了很好的效果[1]。但关于PEG为什么有助于纳米颗粒穿膜的相关机理性研究相对缺乏。因此,本文采用Martini粗粒化模型、全面模拟了PEG修饰的Au NP穿过PS的过程。我们的结果为PEG修饰Au NP提供了指导、同时也一定程度上揭示了其穿过PS的机理

Nanoparticle translocation across the lung surfactant film regulated by grafting polymers

Nanoparticle-based pulmonary drug delivery has gained significant attention due to its ease of administration, increased bioavailability, and reduced side effects caused by a high systemic dosage. After being delivered into the deep lung, the inhaled nanoparticles first interact with the lung surfactant lining layer composed of phospholipids and surfactant proteins and then potentially cause the dysfunction of the lung surfactant. Conditioning the surface properties of nanoparticles with grafting polymers to avoid these side effects is of crucial importance to the efficiency and safety of pulmonary drug delivery. Herein, we perform coarse-grained molecular simulations to decipher the involved mechanism responsible for the translocation of the polymer-grafted Au nanoparticles across the lung surfactant film. The simulations illustrate that conditioning of the grafting polymers, including their length, terminal charge, and grafting density, can result in different translocation processes. Based on the energy analysis, we find that these discrepancies in translocation stem from the affinity of the nanoparticles with the lipid tails and heads and their contact with the proteins, which can be tuned by the surface polarity and surface charge of the nanoparticles. We further demonstrate that the interaction between the nanoparticles and the lung surfactant is related to the depletion of the lipids and proteins during translocation, which affects the surface tension of the surfactant film. The change in the surface tension in turn affects the nanoparticle translocation and the collapse of the surfactant film. These results can help understand the adverse effects of the nanoparticles on the lung surfactant film and provide guidance to the design of inhaled nanomedicines for improved permeability and targeting

Interfacial behavior of phospholipid monolayers revealed by mesoscopic simulation

A mesoscopic model with molecular resolution is presented for dipalmitoyl phosphatidylcholine (DPPC) and pal-mitoyl oleoyl phosphatidylcholine (POPC) monolayer simulations at the air-water interface using many-body dissipative particle dynamics (MDPD). The parameterization scheme is rigorously based on reproducing the physical properties of water and alkane and the interfacial property of the phospholipid monolayer by comparison with experimental results. Using much less computing cost, these MDPD simulations yield a similar surface pressure-area isotherm as well as similar pressure-related morphologies as all-atom simulations and experiments. Moreover, the compressibility modulus, order parameter of lipid tails, and thickness of the phospholipid monolayer are quantitatively in line with the all-atom simulations and experiments. This model also captures the sensitive changes in the pressure-area isotherms of mixed DPPC/POPC monolayers with altered mixing ratios, indicating that the model is promising for applications with complex natural phospholipid monolayers. These results demonstrate a significant improvement of quantitative phospholipid monolayer simulations over previous coarse-grained models

Computational Investigations of the Interaction between the Cell Membrane and Nanoparticles Coated with a Pulmonary Surfactant

When inhaled nanoparticles (NPs) come into the deep lung, they develop a biomolecular corona by interacting with the pulmonary surfactant. The adsorption of the phospholipids and proteins gives a new biological identity to the NPs, which may alter their subsequent interactions with cells and other biological entities. Investigations of the interaction between the cell membrane and NPs coated with such a biomolecular corona are important in understanding the role of the biofluids on cellular uptake and estimating the dosing capacity and the nanotoxicology of NPs. In this paper, using dissipative particle dynamics, we investigate how the physicochemical properties of the coating pulmonary surfactant lipids and proteins affect the membrane response for inhaled NPs. We pinpoint several key factors in the endocytosis of lipid NPs, including the deformation of the coating lipids, coating lipid density, and ligand-receptor binding strength. Further studies reveal that the deformation of the coating lipids consumes energy but on the other hand promotes the coating ligands to bind with receptors more tightly. The coating lipid density controls the amount of the ligands as well as the hydrophobicity of the lipid NPs, thus affecting the endocytosis kinetics through the specific and nonspecific interactions. It is also found that the hydrophobic surfactant proteins associated with lipids can accelerate the endocytosis process of the NPs, but the endocytosis efficiency mainly depends on the density of the coating surfactant lipids. These findings can help understand how the pulmonary surfactant alters the biocompatibility of the inhaled NPs and provide some guidelines in designing an NP complex for efficient pulmonary drug delivery

Adsorption of Phospholipids at the Air-Water Surface

Phospholipids are ubiquitous components of biomembranes and common biomaterials used in many bioengineering applications. Understanding adsorption of phospholipids at the air-water surface plays an important role in the study of pulmonary surfactants and cell membranes. To date, however, the biophysical mechanisms of phospholipid adsorption are still unknown. It is challenging to reveal the molecular structure of adsorbed phospholipid films. Using combined experiments with constrained drop surfactometry and molecular dynamics simulations, here, we studied the biophysical mechanisms of dipalmitoylphosphatidylcholine (DPPC) adsorption at the air-water surface. It was found that the DPPC film adsorbed from vesicles showed distinct equilibrium surface tensions from the DPPC monolayer spread via organic solvents. Our simulations revealed that only the outer leaflet of the DPPC vesicle is capable of unzipping and spreading at the air-water surface, whereas the inner leaflet remains intact and forms an inverted micelle to the interfacial monolayer. This inverted micelle increases the local curvature of the monolayer, thus leading to a loosely packed monolayer at the air-water surface and hence a higher equilibrium surface tension. These findings provide novel insights, to our knowledge, into the mechanism of the phospholipid and pulmonary surfactant adsorption and may help understand the structure-function correlation in biomembranes

动车组传动齿轮模糊稳健修形设计

考虑到齿轮的修形参数和性能参数受制造和使用过程中各影响因素的扰动影响，提出了一种基于改进容差模型和模糊理论的动车组传动齿轮稳健修形设计方法。确定了齿轮稳健修形设计中的可控因素与不可控因素，结合正交试验设计与Romax运动仿真获取试验样本点；利用多项式函数拟合传动误差峰峰值的响应面近似模型。在此基础上，引入模糊理论，基于改进容差模型建立齿轮稳健修形优化数学模型，采用NSGA-III算法寻优求解，并将其与其他修形方案进行比较，最后对各修形方案进行仿真验证。结果表明，基于改进容差模型的齿轮稳健修形结果要优于传统容差模型；在基于改进容差模型的齿轮稳健修形设计中考虑模糊因素的影响，不仅改善了齿面偏载情况，还提高了修形结果的稳健性和合理性

RELATIONSHTP OF ECO-ENVIRONMENTAL CHANGE AND NATURAL EROSION AND MAN-MADE ACCELERATED EROSION

黄土高原大部分地区因严重的土壤侵蚀，已丧失原有的自然景观，子午岭林区为追溯研究自然侵蚀和人为加速侵蚀与生态环境演变提供了研究基地。通过典型区考察和定位试验研究及实验室分析测试，分析研究了子午岭林区植被破坏与恢复对土壤侵蚀演变的影响；自然生态平衡下自然侵蚀和人为破坏植被耕垦的加速侵蚀特征及人为加速侵蚀与土壤退化过程等

我国珍稀濒危植物保护红线的划定

本文依据《国家生态保护红线——生态功能基线划定技术指南(试行)》原则和植物保护的具体情况,探讨了我国珍稀濒危植物保护红线划定的原则与方法。研究选取《国家重点保护野生植物名录》中收录的所有物种作为研究对象。将其定义为红线保护植物,其中的I级保护植物定义为红线关键植物,并基于文献资料及标本记录等数据建立了我国植物的属性数据库和地理分布数据库。在GIS支持下,以建立的数据库为基础研究了我国红线保护植物的地理分布特征;基于保护生物学理论,结合我国自然保护区的就地保护现状进行了分析和评价;以热点地区和GAP分析为理论基础,在其分布地中识别具有代表性的热点区域以及不同属性植物分布的重点区域,进而结合土地利用和人类干扰因素,划定我国珍稀濒危植物生境整体保护的红线。通过在全国尺度上的分析,得出我国珍稀濒危植物的整体保护红线面积为71.63万km2,占陆域国土面积的7.45%。植物生境保护红线划定的原则、方法和划定方案的研究对于更准确地划定生态安全预警红线具有重要意义,同时可以为我国国土生态安全格局的构建提供依据