Strategies To Design Selective Histone Deacetylase Inhibitors

This review classifies drug-design strategies successfully implemented in the development of histone deacetylase (HDAC) inhibitors, which have many applications including cancer treatment. Our focus is on especially demanded selective HDAC inhibitors and their structure-activity relationships in relation to corresponding protein structures. The main part of the paper is divided into six subsections each narrating how optimization of one of six structural features can influence inhibitor selectivity. It starts with the impact of the zinc binding group on selectivity, continues with the optimization of the linker placed in the substrate binding tunnel as well as the adjustment of the cap group interacting with the surface of the protein, and ends with the addition of groups targeting class-specific sub-pockets: the side-pocket-, lower-pocket- and foot-pocket-targeting groups. The review is rounded off with a conclusion and an outlook on the future of HDAC inhibitor design.     

Rational Design of Potent Inhibitors of a Metallohydrolase Using a Fragment-Based Approach

Metallohydrolases form a large group of enzymes that have fundamental importance in a broad range of biological functions. Among them, the purple acid phosphatases (PAPs) have gained attention due to their crucial role in the acquisition and use of phosphate by plants and also as a promising target for novel treatments of bone-related disorders and cancer. To date, no crystal structure of a mammalian PAP with drug-like molecules bound near the active site is available. Herein, we used a fragment-based design approach using structures of a mammalian PAP in complex with the Maybridge^TM fragment CC063346, the amino acid L-glutamine and the buffer molecule HEPES, as well as various solvent molecules to guide the design of highly potent and efficient mammalian PAP inhibitors. These inhibitors have improved aqueous solubility when compared to the clinically most promising PAP inhibitors available to date. Furthermore, drug-like fragments bound in newly discovered binding sites mapped out additional scaffolds for further inhibitor discovery, as well as scaffolds for the design of inhibitors with novel modes of action.     

天然气水合物储层泥质细粉砂挡砂介质堵塞规律与微观挡砂机制

中国南海海域部分天然气水合物储层中地层砂为高泥质含量细粉砂，开采防控砂难度较大。针对高泥质细粉砂挡砂机制问题，使用粒度中值为10.13 μm的泥质细粉砂样品，模拟单向气液携砂流动条件，使用绕丝筛板、金属烧结网、金属纤维、预充填陶粒4类挡砂介质在20~80 μm挡砂精度下进行挡砂模拟实验，采用显微成像系统观察挡砂介质内部及表面砂粒沉积与堵塞动态，分析介质流通性能和挡砂性能变化，总结堵塞规律、微观挡砂机制与形态及其控制因素。研究结果表明，不同类型和精度的挡砂介质对泥质细粉砂的堵塞总体呈现堵塞开始、堵塞加剧和堵塞平衡3个阶段。随着驱替进行，挡砂介质渗透率逐渐降低，幅度会高达90%以上；同时过砂速度减缓，最终过砂率为5%~10%。根据堵塞规律和微观图像分析，提出了粗组分分选桥架、局部砂团适度挡砂、整体砂桥阻挡等挡砂介质对泥质细粉砂的3种微观挡砂机制。以粗组分分选桥架挡砂机制为主的挡砂工况下，挡砂介质堵塞渗透率较高，但过砂率超过15%，挡砂效果较差；以整体砂桥挡砂机制为主时，过砂率在10%以下，挡砂性能较好，但各类挡砂介质的堵塞渗透率不足1 D，流通性能较差。局部砂团适度挡砂机制为主时介质挡砂性能及流通性能介于两者之间。挡砂介质对天然气水合物储层泥质细粉砂的微观挡砂机制和形态受挡砂介质类型、精度、地层砂特征以及流动条件等因素控制，其规律对于水合物泥质细粉砂防控砂优化有指导意义。     

基于PMU的电力系统监控体系结构优化设计

文中提出了一种利用有限数量的相量测量单元(PMU)和相量数据集中器(PDC)设计最优监控结构的方法。通过在大量的设定值场景下,使电力系统可观测性曲线的期望值最大化,同时使通信基础设施成本最小化,最终确定PMU和PDC的最佳位置。提出了一种非线性动态扩展卡尔曼滤波(EFK)状态观测器。这种状态观测器可以将暂态行为转换为由代数微分方程描述的广域电力系统,而无需非线性反演技术。最后以IEEE-5电力系统为例,说明了该方法的有效性。     

Operation principles for hydrogen spark ignited direct injection engines for passenger car applications

The sustainable reduction of greenhouse gas emissions from road transport requires solutions to achieve net-zero carbon dioxide emissions. Therefore, in addition to vehicles with electrified powertrains, such as those implemented in battery electric of fuel cell vehicles, internal combustion engines fueled with e-fuels or biofuels are also under discussion. An e-fuel that has come into focus recently, is hydrogen due to its potential to achieve zero tank-to-wheel and well-to-wheel carbon dioxide emissions when the electrolysis is powered by electricity from renewable sources. Due to the high laminar burning velocity, hydrogen has the potential for engine operation with high cylinder charge dilution by e.g. external exhaust gas recirculation or enleanment, resulting in increased efficiency. On the other hand, the high burning velocity and high adiabatic flame temperatures pose a challenge for engine cooling due to increased heat losses compared to conventional fuels. To further evaluate the use of hydrogen for small passenger car engines, a series production 1 L 3 cylinder gasoline engine provided by Ford Werke GmbH was modified for hydrogen direct injection. The engine was equipped with a high pressure external exhaust gas recirculation system to investigate charge dilution at stoichiometric operation. Due to limitations of the turbocharging system, very lean operation, which can achieve nitrogen oxides raw emissions below 10 ppm, was limited to part load operation below BMEP = 8 bar. Thus, a reduction of the nitrogen oxides emission level at high loads compared to stoichiometric operation was not possible. At stoichiometric operation with external exhaust gas recirculation engine efficiency can be increased significantly. The comparison of stoichiometric hydrogen and gasoline operation shows a reduced indicated efficiency with hydrogen with significant faster combustion of hydrogen at comparable centers of combustion. However, higher boost pressures would allow to achieve even higher indicated efficiencies by charge dilution compared to gasoline engine operation.     

自重湿陷性黄土地基预钻孔浸水处理的可靠度设计方法

为解决传统预浸水法存在的浸水时间长、浸水处理范围难以确定等不足,基于土体中水分运移规律,依据可靠度理论、极限状态设计方法及复合 Poisson 过程原理,提出一种消除黄土湿陷性的处理浸水方法——预钻孔浸水法。给出了利用预钻孔浸水法对自重湿陷性黄土地基进行浸水时,水平向及竖直向浸水影响范围的确定模型;在此基础上结合达西定律给出了浸水孔设计参数如孔深、孔间距及浸水孔个数的确定方法。结合铜川某工程,设计进行了现场预钻孔浸水试验,对该方法的合理性进行了验证,并通过现场钻探、现场勘探、室内湿陷性试验等方法对该方法的处理效果进行了评价。该浸水方法具有浸水时间短、浸水影响范围可根据浸水孔布设进行控制等优点,且浸水处理效果良好,完全符合施工要求。     

毫米波三维异质异构集成技术的进展与应用

三维异质异构集成技术是实现电子信息系统向着微型化、高效能、高整合、低功耗及低成本方向发展的最重要方法,也是决定信息化平台中微电子和微纳系统领域未来发展的一项核心高技术。文章详细介绍了毫米波频段三维异质异构集成技术的优势、近年来的发展趋势以及面临的挑战。利用硅基MEMS 光敏复合薄膜多层布线工艺可实现异质芯片的低损耗互连,同时三维集成高性能封装滤波器、高辐射效率封装天线等无源元件,还能很好地处理布线间的电磁兼容和芯片间的屏蔽问题。最后介绍了一款新型毫米波三维异质异构集成雷达及其在远距离生命体征探测方面的应用。     

电信专业学术英文写作模块化教学实践

学术英文写作是当今电子信息专业研究生必修的一门课程。然而传统的以教师为中心的灌输式教学已不能跟上网络迅猛发展的趋势,尤其是当疫情来临的特殊形势下。此外,现有的学术英文写作教学研究仅提供宏观的设计,缺乏具体的实际可操作性。为此,本文以引言写作逻辑为教学模块案例,探索了如何充分利用网络资源的优势,开展以学生为中心的课前课中课下有机融合的灵活的教学设计。所探索的引言写作技巧和详实的教学设计,为模块化网络教学提供一个切实可行的参考方案。