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.     

Evaluation of expanded gamut software solutions for spot color reproduction

Expanded gamut printing is an approach in color reproduction that expands the color gamut of conventional CMYK printing processes via the use of additional colorants, such as Orange, Green, and Violet inks. This study evaluates the ability of commercial color management software to create an accurate solution for an expanded gamut printing system. In this study, two printing processes were used, an Epson SureColor P9000 inkjet printer/proofer and an HP Indigo 7900 digital production press, both with 7-color expanded gamut ink sets. Software solutions from Alwan, CGS ORIS, ColorLogic, GMG Color, Heidelberg, and Kodak were evaluated. The systems were tested to see how well they could reproduce the colors in the entire PANTONE+ Solid Coated spot color library. It is shown that the solutions are able to reproduce 89% to 94% of the spot colors on the Epson P9000 inkjet printer and 77% to 87% of the library on the Indigo 7900, both to less than two CIEDE2000 (a typical tolerance in label and packaging work). The number of color patches in expanded gamut characterization test charts was noted, as this is still an area of proprietary, nonstandardized working practice. There are many different colorant combinations that can make the same color in expanded gamut printing. The ink build created by the different software solutions was studied, as it relates to press stability through appropriate choice of colorants. Pantone and Adobe provide everyday commercial tools for expanded color workflows. The study identified some issues with products from these companies that could confuse a less-skilled user in a busy production environment. The conclusion of the study is that expanded gamut solutions for spot color printing produce totally acceptable results for digital printing processes; expanded gamut printing is ready, here and now. The findings show that expanded gamut printing can replace cumbersome conventional spot color workflows creating considerable savings and advantages, especially for label and packaging printers.     

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.     

Thaumasite––direct, woodfordite and other possible formation routes

Two main formation routes for thaumasite exist below 15 °C. One is the direct route from C–S–H reacting with appropriate carbonate, sulfate, Ca²⁺ ions and excess water. The other route is the woodfordite route from ettringite reacting with C–S–H, carbonate, Ca²⁺ ions and excess water, in which thaumasite arises through the intermediate formation of the solid solution woodfordite. The woodfordite route for thaumasite formation appears to be relatively quicker (although still slow) than the direct route, presumably because with the former the ettringite already has the octahedral [M(OH)₆] units that can facilitate the critical change from [Al(OH)₆]³⁻ to [Si(OH)₆]²⁻ groupings. Both routes are mutually dependent on each other. The presence of magnesium salts can modify the path to thaumasite formation. High pressure might be able to stabilise [Si(OH)₆]²⁻ groupings and allow thaumasite to become formed above 15 °C. This possibility is discussed.     

Unresolved controversies concerning psychopathy: Implications for clinical and forensic decision making.

At some point in their careers, clinicians who work or consult in forensic and correctional settings will almost certainly encounter individuals who exhibit psychopathic personality features. Because of the widespread use of this disorder to inform legal and clinical decision making, psychologists should be exceedingly familiar with the relevant research literature on this topic before venturing into these settings. This article reviews the empirical bases of several clinically relevant claims and assertions regarding psychopathy and concludes that many areas of research are decidedly more equivocal in their findings than is commonly perceived. Although there is much to be gained by assessing psychopathy in various contexts, clinicians need to be cautious about drawing overzealous and empirically questionable conclusions about an important disorder that also has great potential for abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Using an integrated process of data and modeling in HRA

The paper describes an approach taken to estimate the probabilities of failure associated with various railroad tasks to prevent accidents (principally collisions and derailments). These probabilities were estimated using an expert elicitation process that used partially relevant data available from a variety of databases and that were filtered and scaled to make them more directly relevant to the analyses being performed. Extensive qualitative studies were performed prior to the elicitation process to identify relevant contexts under which the tasks can be performed.