Sofosbuvir Selects for Drug-Resistant Amino Acid Variants in the Zika Virus RNA-Dependent RNA-Polymerase Complex In Vitro

The nucleotide analog sofosbuvir, licensed for the treatment of hepatitis C, recently revealed activity against the Zika virus (ZIKV) in vitro and in animal models. However, the ZIKV genetic barrier to sofosbuvir has not yet been characterized. In this study, in vitro selection experiments were performed in infected human hepatoma cell lines. Increasing drug pressure significantly delayed viral breakthrough (p = 0.029). A double mutant in the NS5 gene (V360L/V607I) emerged in 3 independent experiments at 40–80 µM sofosbuvir resulting in a 3.9 ± 0.9-fold half- maximal inhibitory concentration (IC₅₀) shift with respect to the wild type (WT) virus. A triple mutant (C269Y/V360L/V607I), detected in one experiment at 80 µM, conferred a 6.8-fold IC₅₀ shift with respect to the WT. Molecular dynamics simulations confirmed that the double mutant V360L/V607I impacts the binding mode of sofosbuvir, supporting its role in sofosbuvir resistance. Due to the distance from the catalytic site and to the lack of reliable structural data, the contribution of C269Y was not investigated in silico. By a combination of sequence analysis, phenotypic susceptibility testing, and molecular modeling, we characterized a double ZIKV NS5 mutant with decreased sofosbuvir susceptibility. These data add important information to the profile of sofosbuvir as a possible lead for anti-ZIKV drug development.     

The Critical Role of Passive Permeability in Designing Successful Drugs

Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients.     

探针馈电圆柱共形微带天线阻抗特性的FDTD法分析

将圆柱坐标系下非分裂式理想匹配层吸收边界条件(UPML)引入到圆柱共形微带天线的全波分析中，并给出了其中的场量迭代方程，明显地减小了计算空间，简化了编程；提出了圆柱坐标系下考虑有限尺寸探针半径的新算法，使得计算结果更加精确；应用GPOF方法预估了时域晚时响应，使计算时间减少了70％～90％。本文给出的模型能够对任意多层圆柱共形结构的微带天线进行计算，因此对此类天线的CAD设计具有实际意义。     

Fabrication of Schottky barrier MOSFETs using self-assembly CoSi2 nanopatterning and spacer gate technologies

A self-assembly patterning method for generation of epitaxial CoSi₂ nanostructures was used to fabricate 50 nm channel-length MOSFETs. The transistors have either a symmetric structure with Schottky source and drain or an asymmetric structure with n⁺-source and Schottky drain. The patterning technique is based on anisotropic diffusion of Co/Si atoms in a strain field during rapid thermal oxidation. The strain field is generated along the edges of a mask consisting of 20 nm SiO₂ and 300 nm Si₃N₄. During rapid thermal oxinitridation (RTON) of the masked silicide structure, a well-defined separation of the silicide layer forms along the edge of the mask. These highly uniform gaps define the channel region of the fabricated device. The separated silicide layers act as metal source and drain. A poly-Si spacer was used as the gate contact. The asymmetric transistor was fabricated by ion implantation into the unprotected CoSi₂ layer and a subsequent out-diffusion process to form the n⁺-source. I–V characteristics of both the symmetric and asymmetric transistor structures have been investigated.     

Computational analysis of thin coating layer failure using a cohesive model and gradient plasticity

Thermal barrier coatings (TBC) are widely used to prevent transient high temperature attack and allow components high durability. Due to strong inhomogeneous material properties the TBC failure often initiates near the interface between the brittle oxide layer and the ductile substrate. A reliable prediction of the TBC failure requires detailed information about the crack tip field and the consequent fracture criteria. In the present paper both cohesive model and gradient plasticity are used to simulate the failure process and to study interdependence of the interface stress distribution with the specific fracture energies. Computations confirm that combination of the two models is able to simulate different failure mechanisms in the TBC system. The computational model has the potential to give a realistic prediction of the crack propagation process.     

An Exploratory Study of E-Business Success Factors

E-business success factors are Important for traditional enterprises to implement e-business. This topic is attracting more and more researchers to study. This paper makes an exploratory study on the factors influencing e-business success. Firstly, based on the literature review, 52 factors are suggested. Secondly, two rounds of survey with Delphi method are conducted. Qualitative and quantitative analysis are used to identify 57 factors. This is the foundation of empirical study.     

STATIONARY TANGENT: THE DISCRETE AND NON-SMOOTH CASE

Abstract. In Keich (2000 ),we define a stationary tangent process, or a locally optimal stationary approximation, to a real non-stationary smooth Gaussian process. This paper extends the idea by constructing a discrete tangent – a `locally' optimal stationary approximation – for a discrete time, real Gaussian process. Analogously to the smooth case, our construction relies on a generalization of the recursion formula for the orthogonal polynomials of the spectral distribution function. More precisely, we use a generalization of the Schur parameters to identify the stationary tangent. By way of discretizing, we later demonstrate how this tangent can be used to obtain `good' local stationary approximations to non-smooth continuous time, real Gaussian processes. Further, we demonstrate how, analogously to the curvatures in the smooth case, the Schur parameters can be used to determine the order of stationarity of a non-smooth process.     

Enhanced thermal stability of a sputtered titanium-nitride film as a diffusion barrier for capacitor-bottom electrodes

The effect of a thin RuO_x layer formed on the Ru/TiN/doped poly-Si/Si stack structure was compared with that on the RuO_x/TiN/doped poly-Si/Si stack structure over the post-deposition annealing temperature ranges of 450–600°C. The Ru/TiN/poly-Si/Si contact system exhibited linear behavior at forward bias with a small increase in the total resistance up to 600°C. The RuO_x/TiN/poly-Si/Si contact system exhibited nonlinear characteristics under forward bias at 450°C, which is attributed to no formation of a thin RuO_x layer at the RuO_x surface and porous-amorphous microstructure. In the former case, the addition of oxygen at the surface layer of the Ru film by pre-annealing leads to the formation of a thin RuO_x layer and chemically strong Ru-O bonds. This results from the retardation of oxygen diffusion caused by the discontinuity of diffusion paths. In particular, the RuO_x layer in a nonstoichiometric state is changed to the RuO₂-crystalline phase in a stoichiometric state after post-deposition annealing; this phase can act as an oxygen-capture layer. Therefore, it appears that the electrical properties of the Ru/TiN/poly-Si/Si contact system are better than those of the RuO_x/TiN/poly-Si/Si contact system.     

一种基于小波逼近的稳定直接自适应控制算法

针对一类未知不稳定非线性系统,基于小波逼近理论,提出了一种直接自适应控制 算法,并由Lyapnov理论证明了整个控制闭环系统的稳定性.