Plutonium Loading of Prospective Grouped Actinide Extraction (GANEX) Solvent Systems based on Diglycolamide Extractants

The Grouped Actinide Extraction (GANEX) process is being developed for actinide recycling within future nuclear fuel cycles. Interactions between potential solvents and macro-concentrations of plutonium are one of the most important issues in defining the GANEX process. Surprisingly, plutonium loading of diglycolamide (DGA) based solvents such as tetra-octyl DGA (TODGA) causes precipitation rather than a conventional third phase, in direct contrast to results with U(VI), Th(IV) or lanthanide ions. Various DGA based solvent systems have been screened for their plutonium loading capacity and 0.2 M TODGA with 0.5 M DMDOHEMA in a kerosene diluent is selected as the optimum solvent formulation of those tested. Plutonium can be relatively easily stripped from this solvent using aqueous acetohydroxamic acid but this is very acid dependent in the low acidity region.     

Structure-activity relationship refinement and further assessment of indole-3-glyoxylamides as a lead series against prion disease

Structure–activity relationships within the indole‐3‐glyoxylamide series of antiprion agents have been explored further, resulting in discovery of several new compounds demonstrating excellent activity in a cell line model of prion disease (EC₅₀ <10 nM ). After examining a range of substituents at the para‐position of the N‐phenylglyoxylamide moiety, five‐membered heterocycles containing at least two heteroatoms were found to be optimal for the antiprion effect. A number of modifications were made to probe the importance of the glyoxylamide substructure, although none were well tolerated. The most potent compounds did, however, prove largely stable towards microsomal metabolism, and the most active library member cured scrapie‐infected cells indefinitely on administration of a single treatment. The present results thereby confirm the indole‐3‐glyoxylamides as a promising lead series for continuing in vitro and in vivo evaluation against prion disease.     

Protein engineering of cytochrome P450cam (CYP101) for the oxidation of polycyclic aromatic hydrocarbons

Mutations of the active site residues F87 and Y96 greatly enhancedthe activity of cytochrome P450_cam (CYP101) from Pseudomonasputida for the oxidation of the polycyclic aromatic hydrocarbonsphenanthrene, fluoranthene, pyrene and benzo[a]pyrene. Wild-typeP450_cam had low (<0.01 min^–1) activity with these substrates.Phenanthrene was oxidized to 1-, 2-, 3- and 4-phenanthrol, whilefluoranthene gave mainly 3-fluoranthol. Pyrene was oxidizedto 1-pyrenol and then to 1,6- and 1,8-pyrenequinone, with smallamounts of 2-pyrenol also formed with the Y96A mutant. Benzo[a]pyrenegave 3-hydroxybenzo[a]pyrene as the major product. The NADHoxidation rate of the mutants with phenanthrene was as highas 374 min^–1, which was 31% of the camphor oxidation rateby wild-type P450_cam, and with fluoranthene the fastest ratewas 144 min^–1. The oxidation of phenanthrene and fluoranthenewere highly uncoupled, with highest couplings of 1.3 and 3.1%,respectively. The highest coupling efficiency for pyrene oxidationwas a reasonable 23%, but the NADH turnover rate was slow. Theproduct distributions varied significantly between mutants,suggesting that substrate binding orientations can be manipulatedby protein engineering, and that genetic variants of P450_cammay be useful for studying the oxidation of polycyclic aromatichydrocarbons by P450 enzymes.     

Relationships of low serum vitamin D<Subscript>3</Subscript>with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity

Low serum 25 hydroxyvitamin D₃ (vitamin D₃) is known to perturb cellular function in many tissues, including the endocrine pancreas, which are involved in obesity and type II diabetes mellitus (TIIDM). Vitamin D₃ insufficiency has been linked to obesity, whether obesity is assessed by body mass index (BMI) or waist circumference (waist). Central obesity, using waist as the surrogate, is associated with the metabolic syndrome (MetSyn), insulin resistance, TIIDM and atherosclerotic cardiovascular disease (CVD). We tested how vitamin D₃ was related to measures of fat mass, MetSyn markers, haemoglobin A_1c (HbA_1c) and MetSyn in a cross-sectional sample of 250 overweight and obese adults of different ethnicities. There were modest inverse associations of vitamin D₃ with body weight (weight) (r = -0.21, p = 0.0009), BMI (r = -0.18, p = 0.005), waist (r = -0.14, p = 0.03), [but not body fat % (r = -0.08, p = 0.24)], and HbA_1c (r = -0.16, p = 0.01). Multivariable regression carried out separately for BMI and waist showed a decrease of 0.74 nmol/L (p = 0.002) in vitamin D₃ per 1 kg/m² increase in BMI and a decrease of 0.29 nmol/L (p = 0.01) per 1 cm increase in waist, with each explaining approximately 3% of the variation in vitamin D₃ over and above gender, age, ethnicity and season.     

4,4′BOX based catalysts: Synthesis,structure and catalytic application

The synthesis of two new 4,4′ bisoxazoline ligands is described. The use of copper complexes of these and three other recently described related ligands as catalysts in a cyclopropanation reaction is discussed. The first structural data on one such chiral copper complex is reported herein.     

The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A.     

Refactoring in Maintenance and Development of Z Specifications and Proofs

Once you have proved your refinement correct, that is not the end. Real products, and their accompanying specifications, develop over time, with new improved versions having added functionality. There are new maintenance issues that arise when altering and upgrading pre-existing large specifications and their respective proofs.We show how concepts from refactoring can be used to structure this process, and provide a means for well-defined, disciplined modifications. Additionally, we discuss how the analogy between proof and refactoring, as meaning preserving transforms, can be used to suggest the development of a refactoring toolset, and thence a refinement toolset.     

A workbook-based methodology for implementing concurrent engineering

Concurrent Engineering demands a new way of working and many organisations experience difficulty during implementation. The research described in this paper has the aim to develop a paper-based workbook style methodology that companies can use to increase the benefits generated by Concurrent Engineering, while reducing implementation costs, risk and time.

The three-stage methodology provides guidance based on knowledge accumulated from implementation experience and best practitioners. It encourages companies to learn to manage their Concurrent Engineering implementation by taking actions which expose them to new and valuable experiences. This helps to continuously improve understanding of how to maximise the benefits from Concurrent Engineering.

The methodology is particularly designed to cater for organisational and contextual uniqueness, as Concurrent Engineering implementations will vary from company to company. Using key actions which improve the Concurrent Engineering implementation process, individual companies can develop their own ‘best practice’ for product development. The methodology ensures that key implementation issues, which are primarily human and organisational, are addressed using simple but proven techniques.

This paper describes the key issues that the majority of companies face when implementing Concurrent Engineering. The structure of the methodology is described to show how the issues are addressed and resolved. The key actions used to improve the Concurrent Engineering implementation process are explained and their inclusion in the implementation methodology described.

Relevance to industry

Implementation of Concurrent Engineering concepts in manufacturing industry has not been a straightforward process. This paper describes a workbook-style tool that manufacturing companies can use to accelerate and improve their Concurrent Engineering implementation.