Discovery of Novel Small-Molecule Inhibitors of PD-1/PD-L1 Interaction via Structural Simplification Strategy

Blockade of the programmed cell death 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) interaction is currently the focus in the field of cancer immunotherapy, and so far, several monoclonal antibodies (mAbs) have achieved encouraging outcomes in cancer treatment. Despite this achievement, mAbs-based therapies are struggling with limitations including poor tissue and tumor penetration, long half-life time, poor oral bioavailability, and expensive production costs, which prompted a shift towards the development of the small-molecule inhibitors of PD-1/PD-L1 pathways. Even though many small-molecule inhibitors targeting PD-1/PD-L1 interaction have been reported, their development lags behind the corresponding mAb, partly due to the challenges of developing drug-like small molecules. Herein, we report the discovery of a series of novel inhibitors targeting PD-1/PD-L1 interaction via structural simplification strategy by using BMS-1058 as a starting point. Among them, compound A9 stands out as the most promising candidate with excellent PD-L1 inhibitory activity (IC₅₀ = 0.93 nM, LE = 0.43) and high binding affinity to hPD-L1 (K_D = 3.64 nM, LE = 0.40). Furthermore, A9 can significantly promote the production of IFN-γ in a dose-dependent manner by rescuing PD-L1 mediated T-cell inhibition in Hep3B/OS-8/hPD-L1 and CD3-positive T cells co-culture assay. Taken together, these results suggest that A9 is a promising inhibitor of PD-1/PD-L1 interaction and is worthy for further study.     

广义特征值问题的并行EBE向量迭代法

本文利用ＥＢＥ策略和共轭梯度法，将广义特征值问题向量迭代法中各步的计算在单元级上进行，避免了总刚度和总质量矩阵的组集，大大节省了存储量。由此建立的ＥＢＥ向量迭代法尤其适宜于并行处理。数值算例结果表明无论是串行、还是并行计算，这类ＥＢＥ向量迭代法都能有效提高计算速度。     

基于博弈论混合策略下的路径选择模型

为了缓解交通拥挤的状况,预测出行者路径选择行为是一项值得研究的工作.在混合策略下,根据出行者之间的博弈关系,定义了混合策略下的得益函数,并引入求解混合策略纳什均衡的一种新方法,即极值法,对出行者的路径选择博弈模型进行了求解,有效弥补了传统划线法的不足,最终得到每个出行者的最优选择,实现了博弈各方的平衡.通过算例,有效地说明了混合策略下出行者最可能做出的路径选择.     

含有免疫策略的一类计算机病毒模型稳定性分析

建立计算机病毒的动力学数学模型,可以更好地揭示计算机病毒流行的原因.考虑到免疫策略对计算机病毒动力学模型的重要影响,对一类SEIR模型进行了改进.得到了模型的无感染平衡点和感染平衡点的存在性,并分别求得两类平衡点的渐近稳定条件,通过数值模拟展示了理论成果.     

High-order adaptive Gegenbauer integral spectral element method for solving non-linear optimal control problems

In this work, we propose an adaptive spectral element algorithm for solving non-linear optimal control problems. The method employs orthogonal collocation at the shifted Gegenbauer–Gauss points combined with very accurate and stable numerical quadratures to fully discretize the multiple-phase integral form of the optimal control problem. The proposed algorithm relies on exploiting the underlying smoothness properties of the solutions for computing approximate solutions efficiently. In particular, the method brackets discontinuities and ‘points of nonsmoothness’ through a novel local adaptive algorithm, which achieves a desired accuracy on the discrete dynamical system equations by adjusting both the mesh size and the degree of the approximating polynomials. A rigorous error analysis of the developed numerical quadratures is presented. Finally, the efficiency of the proposed method is demonstrated on three test examples from the open literature.     

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This paper assumes that company's asset process follows a non-linear model, which reflects the relationship between the operation costs and the size business. Suppose that the company can control the asset process by changing the size of business, paying dividends and raising money dynamically. Meanwhile, it bears both fixed and proportional transaction costs during the control processes. Under the objective of maximizing the company's value, we obtain the explicit solutions of optimal strategies and value function by using the optimal control method. The results illustrate that the optimal strategies depend on the parameters of the model. The company should expand the business scale with the increasing of asset. Dividends should be paid out according to the impulse control strategy. Financing is profitable to avoid bankruptcy if and only if the transaction costs are relatively low.     

Comparative evaluation of a one‐pot strategy for the preparation of β‐cyclodextrin‐functionalized monoliths: Effect of the degree of amino substitution of β‐cyclodextrin on the column performance

To further evaluate the feasibility and applicability of the one‐pot strategy in monolithic column preparation, two novel β‐cyclodextrin‐functionalized organic polymeric monoliths were prepared using two β‐cyclodextrin derivatives, i.e. mono(6‐amino‐6‐deoxy)‐β‐cyclodextrin and heptakis(6‐amino‐6‐deoxy)‐β‐cyclodextrin. In this improved method, mono(6‐amino‐6‐deoxy)‐β‐cyclodextrin or heptakis(6‐amino‐6‐deoxy)‐β‐cyclodextrin reacted with glycidyl methacrylate to generate the corresponding functional monomers and were subsequently copolymerized with ethylene dimethacrylate. The polymerization conditions for both monoliths were carefully optimized to obtain satisfactory column performance with respect to column efficiency, reproducibility, permeability, and stability. The obtained poly(glycidyl methacrylate‐mono(6‐amino‐6‐deoxy)‐β‐cyclodextrin‐co‐ethylene dimethacrylate) and poly(glycidyl methacrylate‐heptakis(6‐amino‐6‐deoxy)‐β‐cyclodextrin‐co‐ethylene dimethacrylate) monoliths exhibited a uniform structure, good permeability, and mechanical stability as indicated by scanning electron microscopy and micro‐high‐performance liquid chromatography experimental results. Because of the probable existence of multi‐glycidyl methacrylate linking spacers on the poly(glycidyl methacrylate‐heptakis(6‐amino‐6‐deoxy)‐β‐cyclodextrin‐co‐ethylene dimethacrylate) monolith, the effect of the ratio of glycidyl methacrylate/heptakis(6‐amino‐6‐deoxy)‐β‐cyclodextrin was especially studied, and satisfactory reproducibility could still be achieved by strictly controlling the composition of the polymerization mixture. To investigate the effect of the degree of amino substitution of β‐cyclodextrin on column performance, a detailed comparison of the two monoliths was also carried out using series of analytes including small peptides and chiral acids. It was found that the β‐cyclodextrin‐functionalized monolith with mono‐glycidyl methacrylate linking spacers demonstrated better chiral separation performance than that with multi‐glycidyl methacrylate linking spacers.     

Estimation of Flat‐topped Gaussian distribution with application in system identification

Uniformly distributed uncertainty exists in industrial process; additive error introduced by quantization is an example. To be able to handle additive uniform and Gaussian measurement uncertainty simultaneously in system identification, the Flat‐topped Gaussian distribution is considered in this paper as an alternative to the Gaussian distribution. To incorporate this type of uncertainty in the maximum likelihood estimation framework, the explicit form of its density function is of necessity. This work proposes an approach for obtaining both the functional structure and corresponding parameter estimation of Flat‐topped Gaussian distribution by a moment fitting strategy. The performance of the proposed approximation function is verified by comparison to the Flat‐topped Gaussian distributed random variable with different Gaussian and uniform components. Results of numerical simulations and industrial applications in system identification are presented to verify the effectiveness of the Flat‐topped Gaussian distribution for noise distribution in handling additional uniform uncertainty.     

A strategy to develop fast RP-HPLC methods using monolithic silica columns

Since the appearance of monolithic silica, much work has been done describing the properties of monolithic silica columns. Meanwhile the transferability of analytical methods from conventional to monolithic silica columns has been intensively investigated [1-5]. RP HPLC method development strategies for conventional columns should be updated or scaled to meet the higher performing monolithic column technology. Because of the high permeability of monolithic silica columns it should be possible to decrease the time for method development by applying high isocratic flow rates. Here we suggest a clear strategy for method development using monolithic columns. The strategy will be applicable for various sample compositions, e. g., acidic, basic, or neutral. The applicability of monolithic columns for especially complex separations of basic mixtures without the need of using a highly basic mobile phase that harms the column will be pointed out in this work. This work will describe in detail the actual method development process. For better understanding of our strategy, the influence of flow rate, column length, mobile phase composition, pH, and temperature will be discussed. Details about the application of a flow program will be mentioned.