Drug and fatty acid hydroxylation by solubilized human liver microsomal cytochrome P-450--Phospholipid requirement

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22148/1/0000577.pd

Mechanistic Studies on Diamine Oxidase

To investigate the enzyme pea seedling diamine oxidase our studies concentrated on three main areas: 1. mechanistic studies of the oxidative deamination of primary diamines catalysed by diamine oxidase; 2. oxidation of aromatic compounds with amine side chains by pea seedling diamine oxidase; and 3. inhibition of pea seedling diamine oxidase. To make use of diamines synthesised within the research group a fourth area was studied: 4. synthesis of cisplatin analogues. Mechanistic Studies of the Diamine Oxidase-Catalysed Deamination of Diamines Diamine oxidase catalyses the oxidative deamination of diamines to their corresponding aminoaldehydes (Scheme A). To test the hypothesis that the diamine oxidase-catalysed oxidation proceeds via an enamine intermediate (i) we prepared a number of alpha,o-diamines labelled with deuterium at the beta-positions. The [2H4]-labelled diamines and the corresponding unlabelled diamines were incubated with pea seedling diamine oxidase and the products were trapped with benzoylacetic acid in situ. (Scheme B). This gave substituted acetophenone products (ii) which were analysed by NMR and mass spectrometry. From a comparison of the spectroscopic data we were able to show that the enamine intermediate (i) is not involved in the enzymatic process. 2. Oxidation of Aromatic Compounds with Amine Side Chains by Pea Seedling Diamine Oxidase A range of quinoline, pyridine, thiophene and pyrrole derivatives with amine side chains were synthesised and tested as substrates of pea seedling diamine oxidase using a spectrophotometric assay which measures the hydrogen peroxide by-product of the enzymatic reaction. From this assay Vmax and Km values were obtained for the oxidation of each substrate using diamine oxidase. The Vmax is the maximal rate of oxidation and gives an indication of the oxidation rate for the various substrates. The KM is a measure of the strength of the enzyme-substrate complex and determines the binding efficiency of the substrate to the enzyme. Analysis of this kinetic data provided information on the enzymatic process and the nature of the pea enzyme's active site. Comparison of the kinetic data obtained from the various aromatic substrates enabled us to study the effect on the binding affinity and rate of oxidation from changes to the ring size of the substrates. The role of the second amine group was also explored using nitrogen heterocycles with amine side chains. 3. Inhibition of Pea Seedling Diamine Oxidase Polyamines are known to be essential in the growth and replication of cells, and diamine oxidase plays a key role in the polyamine metabolism with the oxidative deamination of diamines. Inhibitors of diamine oxidase should therefore have a considerable effect on the polyamine metabolism and hence cell growth. With this in mind inhibitors of diamine oxidase may possess important biological activity. Compounds which were shown to be poor substrates but efficient binders of the pea seedling diamine oxidase from our initial studies were tested as inhibitors. These tests were carried out using the same spectrophotometric assay as before, but which had been modified to include the inhibitor. Most of the compounds tested were found to inhibit the diamine oxidase-catalysed deamination of putrescine and were shown to be competitive inhibitors. 4. The Synthesis of Cisplatin Analogues Cisplatin (iii) is a widely used anticancer drug, but its therapeutic value is limited by the number of toxic side effects which it exhibits. To make use of the diamines available from other studies, we attempted to make cisplatin analogues with various diamines used as bidentate ligands. As there were no examples of unsaturated diamines being used in cisplatin analogues we used cis-1.4-diaminobut-2-ene (iv) which had previously shown antibiotic activity. We made our target compound cis-1,4-diamino(dichloro)-platinum (II) (v), but were unable to make our second target cis-1,4-diaminobut-2-ene(1,1-cyclobutanedicarboxylato)platinum (II) (vi)

An approximate Riemann solver for shallow water equations and heat advection in horizontal centrifugal casting

AbstractAn approximate Riemann solver was developed for solving modified shallow water equations (SWE) and energy transport describing the average flow dynamics of a single layer spreading inside a horizontally rotating cylinder. The numerical model was particularly developed for simulating the horizontal centrifugal casting (HSC) of the outer shell of a work roll. The SWE were derived in the rotating frame of reference; therefore, fictitious forces (the centrifugal force and the Coriolis force) were considered. In addition, other forces such as the bed shear force, the force of gravity, the wind shear force and forces arising from the variable liquid/solid interface were taken into account. The Jacobian matrix of the nonlinear hyperbolic system of PDEs was decomposed into a set of eigenvalues and corresponding eigenvectors using standard and corrected Roe averages. A Harten–Hyman entropy fix was used to prevent expansion shocks (entropy violating solutions) typically occurring during transonic rarefactions. Source terms were applied as a stationary discontinuity and were physically bounded and well-balanced for steady states (producing non-oscillatory solutions). Each wave was upwinded using the explicit Godunov’s method. The high resolution corrections with flux limiters were used to achieve second order of accuracy and dispersion free solutions at discontinuities. In addition to the Riemann solver, a central scheme FV model was used to solve the heat diffusion inside the cylinder (mold) and partially solidified liquid layer, coupled with the solidification model. Several simulations were performed, results were analyzed and discussed

Towards Demisable Fiber Reinforced Plastics

For avoiding the Kessler syndrome, satellites in low Earth orbits must be removed in due time after the end of their service life by re-entering into the Earth's atmosphere. Active, controlled re-entry requires availability of thrusters and propellant at the end of the mission. Thus, the active re-entry comes at a high cost and reduces the available payload mass of a mission. It is accordingly desirable to leave the satellite to itself at the end of its life and allow it to re-enter in an uncontrolled way. Unfortunately, parts of such satellites can survive the destructive re-entry flight and may impact on the ground. These debris pose a risk to public safety if they go down over an inhabited area. Rules that limit the acceptable ground risk per mission to a specific threshold are therefore in place in many countries. The typical accepted risk is one incident in ten thousand missions (1:10 000). Fiber reinforced plastics (FRPs) have been considered easily demisable because of their organic matrices and the fact that they would be able to burn at ground conditions. However, wind tunnel tests have revealed that FRPs have a very high demise resistance and can act as an ablative heat shield. This results in FRPs generally being a problematic material in the ground risk assessment. The good news is that there have been material level tests that showed a desirable demise behavior, which resulted in higher demise rates. The goal of the COMP2DEM project is identifying the microscopic and macroscopic parameters that determine the demise process and phenomena and explaining the differences in the observed behavior. Based on this knowledge, new fiber-reinforced plastics with increased demisability shall be formulated. The presentation covers the first phase of the COMP2DEM project: the screening of different FRP variants by thermophysical material characterization and demise simulation in the arc heated wind tunnels of DLR. New FRPs with increased demisability are currently under development and an outlook on the developments in the project is given

DEVELOPING A FLEXIBLE THERMAL PROTECTION SYSTEM FOR MARS ENTRY: SYSTEMS ENGINEERING, MECHANICAL DESIGN AND MANUFACTURING PROCESSES

A flexible thermal protection system (FTPS) is needed to enable the use of deployable and inflatable hypersonic decelerators. These decelerators could increase entry vehicle drag area beyond that of a conventional rigid heatshield, enabling Mars missions with greater landed masses and higher-elevation landing sites than can be currently achieved. An FTPS is essential to protect the hypersonic decelerator and payload from atmospheric entry aerothermal loads; conventional rigid heatshields are constrained by the available space within the launcher fairing. An ESA technology development is ongoing to raise the European FTPS technology readiness level from 2 to 3 and to define an FTPS that may be integrated with a Mars-entry inflatable hypersonic decelerator. This paper presents the FTPS requirements, material selection, mechanical characterisation and manufacturing technique development

DEVELOPING A FLEXIBLE THERMAL PROTECTION SYSTEM FOR MARS ENTRY: THERMAL DESIGN AND TESTING

Flexible Thermal Protection Systems (FTPS) are a key technology needed to enable novel inflatable and deployable aerodynamic decelerators. A development campaign is underway to raise the European FTPS technology readiness level from 2 to 3, advancing design and test capability. An FTPS suitable for a reference Mars landing mission is being designed. The FTPS has three functional layers: outer layers of Nextel 440 BF-20 fabric; insulation layers of SIGRATHERM GFA5 graphite felt and Pyrogel XTE aerogel; and a silicone-coated Kevlar fabric gas barrier. The density, specific heat capacity and thermal diffusivity of candidate materials was measured. Results were then used in thermal simulations to define a baseline layup. The layup thermal conductance was assessed in thermocouple-instrumented layup tests. Layups including joints were also tested and found not to have significantly different conductance. Layup test thermal simulations showed good agreement with the experimental data. Future work will include arc-jet tests and thermal model optimisation

Barbarians at the British Museum: Anglo-Saxon Art, Race and Religion

A critical historiographical overview of art historical approaches to early medieval material culture, with a focus on the British Museum collections and their connections to religion