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Bedford, MA, United States

Lam A.M.,Pharmasset Inc. | Edwards T.E.,Beryllium | Mosley R.T.,Pharmasset Inc. | Murakami E.,Pharmasset Inc. | And 7 more authors.
Antimicrobial Agents and Chemotherapy | Year: 2014

Resistance to the 2'-F-2'-C-methylguanosine monophosphate nucleotide hepatitis C virus (HCV) inhibitors PSI-352938 and PSI-353661 was associated with a combination of amino acid changes (changes of S to G at position 15 [S15G], C223H, and V321I) within the genotype 2a nonstructural protein 5B (NS5B), an RNA-dependent RNA polymerase. To understand the role of these residues in viral replication, we examined the effects of single and multiple point mutations on replication fitness and inhibition by a series of nucleotide analog inhibitors. An acidic residue at position 15 reduced replicon fitness, consistent with its proximity to the RNA template. A change of the residue at position 223 to an acidic or large residue reduced replicon fitness, consistent with its proposed proximity to the incoming nucleoside triphosphate (NTP). A change of the residue at position 321 to a charged residue was not tolerated, consistent with its position within a hydrophobic cavity. This triple resistance mutation was specific to both genotype 2a virus and 2'-F-2'-C-methylguanosine inhibitors. A crystal structure of the NS5B S15G/C223H/V321I mutant of the JFH-1 isolate exhibited rearrangement to a conformation potentially consistent with short primerlate RNA binding, which could suggest a mechanism of resistance accomplished through a change in the NS5B conformation, which was better tolerated by genotype 2a virus than by viruses of other genotypes. © 2014, American Society for Microbiology. All Rights Reserved. Source


Manufacturers add product variants in one product family to meet customers' different preferences. Components could be shared and reused to reduce costs. Demand and demand variance change with different sale prices under the stochastic and price-sensitive demand environment. Demand uncertainty has significant effects on costs and profits of the supply chain. With a numerical example involving a product family of cordless drills, a model is used to investigate the effect of supplier profit rate, cost reduction, and component commonality on the supply chain performance. Results show that saving in upstream suppliers due to component commonality could be passed to the manufacturer, retailer, and customers with appropriate coordination models such as quantity discount. With reduced procedure cost, a win-win pricing strategy for one supplier is to increase its profit at a rate while sell its products at a cheaper sale price based on the cost mark-up method considering the demand uncertainty from buyers or downstream suppliers in the supply chain. Copyright © 2011 Inderscience Enterprises Ltd. Source


Gelinas A.D.,SomaLogic | Davies D.R.,Beryllium | Janjic N.,SomaLogic
Current Opinion in Structural Biology | Year: 2016

Understanding the structural rules that govern specific, high-affinity binding characteristic of aptamer-protein interactions is important in view of the increasing use of aptamers across many applications. From the modest number of 16 aptamer-protein structures currently available, trends are emerging. The flexible phosphodiester backbone allows folding into precise three-dimensional structures using known nucleic acid motifs as scaffolds that orient specific functional groups for target recognition. Still, completely novel motifs essential for structure and function are found in modified aptamers with diversity-enhancing side chains. Aptamers and antibodies, two classes of macromolecules used as affinity reagents with entirely different backbones and composition, recognize protein epitopes of similar size and with comparably high shape complementarity. © 2016. Source


Zhang T.,Beryllium
Yejin Fenxi/Metallurgical Analysis | Year: 2013

The beryllium copper intermediate alloy sample was dissolved by nitric acid to determine the content of aluminum. The pH of solution was adjusted to 6-7 using ammonia water. The iron and aluminum were precipitated in form of hydroxide. After filtration and washing, they were separated from matrix copper. The precipitation was dissolved with hydrochloric acid. In HAc-NaAc buffer solution at pH 5.0, aluminum reacted with 8-hydroxyquinoline to form complex, which was extracted with chloroform. The maximum absorption wavelength of complex was at 393 nm, and the apparent molar absorptivity was 6.45×103 L·mol-1·cm-1. In chloroform coloring solution, the Beer's law was obeyed for aluminum ion with mass concentration of 0-4000 μg/L. The interference ions such as iron and copper were removed by cupron-chloroform extraction before coloring. This method was applicable for the determination of 0.0002%-0.5% aluminum in beryllium copper intermediate alloy. The results were consistent with those obtained by ICP-AES. The recoveries of standard addition were 98%-102%. Source


Morales A.,Beryllium | Hashiguchi D.,Beryllium
Advances in Powder Metallurgy and Particulate Materials - Proceedings of the 2015 International Conference on Powder Metallurgy and Particulate Materials, PowderMet 2015 | Year: 2015

Beryllium and aluminum beryllium alloys are used as light weight, high modulus materials for mechanical-optical systems. Hot isostatically pressed (HIP'd) powder is used in the value stream as a near net shape (NNS) manufacturing process to reduce both material and processing cost. A case study of a Seamless Iterative Process (SIP) will be presented in which input material was reduced by approximately 67%, reduced from 88 to 29 kilograms (195 to 64 pounds) using the SIP NNS HIP model. Other examples will be illustrated. The scope will encompass shaped HIP cans with a powder input range of 9 to 455 kilograms (20 to 1000 pounds). which roughly translates to an equivalent steel or copper powder input of 36-kilograms to 1815-kilograms (80 to 4000 pounds) per blank. Source

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