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.     

Macrophage Immunomodulation Through New Polymers that Recapitulate Functional Effects of Itaconate as a Power House of Innate Immunity

Itaconate (ITA) is an emerging powerhouse of innate immunity with therapeutic potential that is limited in its ability to be administered in a soluble form. A library of polyester materials that incorporate ITA into polymer backbones resulting in materials with inherent immunoregulatory behavior is developed. Harnessing hydrolytic degradation release from polyester backbones, ITA polymers result in the mechanism specific immunoregulatory properties on macrophage polarization in vitro. In a functional assay, the polymer-released ITA inhibits bacterial growth on acetate. Translation to an in vivo model of biomaterial associated inflammation, intraperitoneal injection of ITA polymers demonstrate a rapid resolution of inflammation in comparison to a control polymer silicone, demonstrating the value of sustained biomimetic presentation of ITA.     

Analysis of phosphorus removal and anaerobic selector performance in a full-scale activated sludge process in Singapore.

This paper analyses the performance of the anaerobic selector (A/O process) in a full-scale activated sludge process receiving mostly industrial sewage discharge (> 60%) in Singapore. In addition to the sludge settleability, enhanced biological phosphorus removal (EBPR) was studied. The sludge volume index (SVI) reduced from 200 to 80 ml g(-1) and foaming was suppressed significantly, indicating the effectiveness of the anaerobic selector in improving sludge settleability. The phosphorus removal efficiency was 66%, and 7.5 mg HAc-COD was consumed per mg PO4(3-) -P removed. In the anaerobic compartment, 31% of the SCOD and 73% of the acetic acid in the settled sewage were removed with PO4(3-) -P release of 14.1 mg PO4(3-)-P l(-1). The linear correlation between PO4(3-) -P release in the anaerobic compartment and PO4(3-) -P uptake in the aerobic compartment indicates that there is about 0.8 mg PO4(3-) -P release in the anaerobic compartment per mg PO34(3-) -P uptake in the aerobic compartment. The fates of volatile fatty acids (VFAs) and its short chain acids (SCAs) in the process were studied and discussed.     

A power-driven multiplication instruction-set design method for ASIPs

This paper presents a novel power-driven multiplication instruction-set design method for application-specific instruction-set processors (ASIPs). Based on a dual-and-configurable-multiplier structure, our proposed method devises a multiplication instruction set for low-power ASIPs. Our method exploits the execution sequences of multiplication instructions and effective bit widths of variables to reduce power consumed by redundant multiplication bits while minimizing the multiplication execution time. Experimental results on a set of DSP programs demonstrate that our proposed method achieves significant power reduction (up to 18.53%) and execution time improvement (up to 10.43%) with 18% area overhead.     

New hybrid fuzzy controller for direct torque control induction motor drives

A new hybrid fuzzy controller for direct torque control (DTC) induction motor drives is presented in this paper. The newly developed hybrid fuzzy control law consists of proportional-integral (PI) control at steady state, PI-type fuzzy logic control at transient state, and a simple switching mechanism between steady and transient states, to achieve satisfied performance under steady and transient conditions. The features of the presented new hybrid fuzzy controller are highlighted by comparing the performance of various control approaches, including PI control, PI-type fuzzy logic control (FLC), proportional-derivative (PD) type FLC, and combination of PD-type FLC and I control, for DTC-based induction motor drives. The pros and cons of these controllers are demonstrated by intensive experimental results. It is shown that the presented induction motor drive is with fast tracking capability, less steady state error, and robust to load disturbance while not resorting to complicated control method or adaptive tuning mechanism. Experimental results derived from a test system are presented confirming the above-mentioned claims.     

Modeling node mobility for reliable packet delivery in mobile ip networks

In this paper, we analyze node mobility for reliable packet delivery in mobile IP networks. In mobile IP, packets destined to roaming nodes are intercepted by their home agents and delivered via tunneling to their care of addresses (CoA). A mobile node may roam across multiple subnets. At each boundary crossing, a handoff is initiated such that the CoA is updated and a new tunnel is established. We consider both basic mobile IP handoff and smooth handoff. We find that reliable packet delivery in mobile IP networks can be modeled as a renewal process, because the retransmission over a new tunnel after each boundary crossing is independent of the previous history. We then derive the probability distribution of boundary crossings for each successful packet, based on which the packet reliable delivery time can be obtained. Our analytical model is derived based on a general distribution of residence time in a subnet and a general distribution of successful retransmission attempts in each subnet. The results can be readily applied to any distributions for both items. We also provide numerical examples to calculate the probability distribution of boundary crossings, and conduct simulations to validate our analytical results     

Microstrip stepped impedance resonator bandpass filter with an extended optimal rejection bandwidth

Bandpass filters with an optimal rejection bandwidth are designed using parallel-coupled stepped impedance resonators (SIRs). The fundamental (f/sub o/) and higher order resonant harmonics of an SIR are analyzed against the length ratio of the high-Z and low-Z segments. It is found that an optimal length ratio can be obtained for each high-Z to low-Z impedance ratio to maximize the upper rejection bandwidth. A tapped-line input/output structure is exploited to create two extra transmission zeros in the stopband. The singly loaded Q(Q/sub si/) of a tapped SIR is derived. With the aid of Q/sub si/, the two zeros can be independently tuned over a wide frequency range. When the positions of the two zeros are purposely located at the two leading higher order harmonics, the upper rejection band can be greatly extended. Chebyshev bandpass filters with spurious resonances up to 4.4f/sub o/, 6.5f/sub o/, and 8.2f/sub o/ are fabricated and measured to demonstrate the idea.     

RFA—300型自动分析仪检测总植物碱的改进

对连续流动法测定烟草及烟草制品中总植物碱的各影响因素进行了试验研究,并根据试验结果对仪器管路进行相应的改造。实验结果表明,烟草制品中总植物碱的连续流动法测定,改进后方法的回收收率高、重现性好。     

Non-equilibrium particle motion in the vicinity of a single blade

The motion of sand particles close to a single moving blade was investigated using Positron Emission Particle Tracking (PEPT) during the period in which the free bed surface profile was evolving to an equilibrium shape. The area affected by the blade was divided into active and inactive regions and these were analysed separately. The characteristic heart-shape of the active region in the plan view was determined. An approximately 10-particle-diameter wide velocity transition zone is found between the two regions. While the tracer particle is in the inactive region moving away from the blade, the time dependence of the axial displacement is well described by a logarithmic relationship. The probability of particle movement towards the centre of the blade was quantified using a “central tendency” index. The calculated central tendency shows maxima at each side of the blade. The separation of the two maxima, which indicates the width of the active region, increases with fill level but is independent of rotational speed.