Investigating the modulation of oral drug absorption using in vitro models

Dipeptides can be absorbed into cells via the dipeptide transporter (which also transported tripeptides and dipeptide derivatives). The optimum conditions for measuring the inhibition of Gly-Pro uptake in Caco-2 cells were identified. A number of structure-activity relationships were identified. These included the effects of increasing the amino-acid chain-length, and the presence of a thiol or hydroxyl group in the side-chain increased IC50 while the presence of a hydroxyl group did not. The benzyl esters had lower or equal IC50 values compared to the parent dipeptides while the methyl esters had higher values. These results indicated that while molecular properties did affect IC50, the size, charge and composition of three particular groups caused the most significant effects, supporting the structure-activity relationship identified. An assay was developed using calcein-AM to show the inhibition of p-glycoprotein activity. There was no significant change due to the presence of mannitol but there was in the presence of clyclosporin A (p<0.01). Incubating the cells with the test solution for 30 minutes before the addition of the ester resulted in a significant (p<0.001) difference. The assay was specific for p-glycoprotein, as the presence MRP inhibitors had no effect (p>0.05). The modified protocol allowed the identification of p-glycoprotein inhibitors quickly and simply using a cell suspension of unmodified cells. The clinically relevant buffering of grapefruit juice to pH 7 led to a four-fold increase in intracellular calcein and hence significant inhibition of p-glycoprotein. Buffered orange and lemon juices had no effect on the assay. Flavone derivatives had previously been found to be inhibitors of CYP3A4 yet neither naringin nor naringenin had any significant effect at concentrations found in grapefruit juice. Of the other (non-grapefruit) flavone derivatives tested, hesperidin, found in orange juice, had no significant effect, kaempferol and rutin also had no effect while genistein significantly inhibited p-glycoprotein (results that support previous studies). Hydroxycinnamic acids had no effect on p-glycoprotein. Studies on other compounds found that the balance between inhibiting p-glycoprotein and disrupting cell membranes depends on the compound containing an oxygen atom and the size of the negative charge on it, as well as three-dimensional arrangement of the atoms.

Computer aided manufacturing of geometric models

As systems for computer-aided-design and production of mechanical parts have developed, there has arisen a need for techniques for the comprehensive description of the desired part, including its 3-D shape. The creation and manipulation of shapes is generally known as geometric modelling. It is desirable that links be established between geometric modellers and machining programs. Currently, unbounded APT and some bounded geometry systems are being widely used in manufacturing industry for machining operations such as: milling, drilling, boring and turning, applied mainly to engineering parts. APT systems, however, are presently only linked to wire-frame drafting systems. The combination of a geometric modeller and APT will provide a powerful manufacturing system for industry from the initial design right through part manufacture using NC machines. This thesis describes a recently developed interface (ROMAPT) between a bounded geometry modeller (ROMULUS) and an unbounded NC processor (APT). A new set of theoretical functions and practical algorithms for the computer aided manufacturing of 3D solid geometric model has been investigated. This work has led to the development of a sophisticated computer program, ROMAPT, which provides a new link between CAD (in form of a goemetric modeller ROMULUS) and CAM (in form of the APT NC system). ROMAPT has been used to machine some engineering prototypes successfully both in soft foam material and aluminium. It has been demonstrated above that the theory and algorithms developed by the author for the development of computer aided manufacturing of 3D solid modelling are both valid and applicable. ROMAPT allows the full potential of a solid geometric modeller (ROMULUS) to be further exploited for NC applications without requiring major investment in new NC processor. ROMAPT supports output in APT-AC, APT4 and the CAM-I SSRI NC languages.

Teallach - a flexible user - interface development environment for object database applications

The Teallach project has adapted model-based user-interface development techniques to the systematic creation of user-interfaces for object-oriented database applications. Model-based approaches aim to provide designers with a more principled approach to user-interface development using a variety of underlying models, and tools which manipulate these models. Here we present the results of the Teallach project, describing the tools developed and the flexible design method supported. Distinctive features of the Teallach system include provision of database-specific constructs, comprehensive facilities for relating the different models, and support for a flexible design method in which models can be constructed and related by designers in different orders and in different ways, to suit their particular design rationales. The system then creates the desired user-interface as an independent, fully functional Java application, with automatically generated help facilities.

Random distributed feedback fibre lasers

The concept of random lasers exploiting multiple scattering of photons in an amplifying disordered medium in order to generate coherent light without a traditional laser resonator has attracted a great deal of attention in recent years. This research area lies at the interface of the fundamental theory of disordered systems and laser science. The idea was originally proposed in the context of astrophysics in the 1960s by V.S. Letokhov, who studied scattering with "negative absorption" of the interstellar molecular clouds. Research on random lasers has since developed into a mature experimental and theoretical field. A simple design of such lasers would be promising for potential applications. However, in traditional random lasers the properties of the output radiation are typically characterized by complex features in the spatial, spectral and time domains, making them less attractive than standard laser systems in terms of practical applications. Recently, an interesting and novel type of one-dimensional random laser that operates in a conventional telecommunication fibre without any pre-designed resonator mirrors-random distributed feedback fibre laser-was demonstrated. The positive feedback required for laser generation in random fibre lasers is provided by the Rayleigh scattering from the inhomogeneities of the refractive index that are naturally present in silica glass. In the proposed laser concept, the randomly backscattered light is amplified through the Raman effect, providing distributed gain over distances up to 100km. Although an effective reflection due to the Rayleigh scattering is extremely small (~0.1%), the lasing threshold may be exceeded when a sufficiently large distributed Raman gain is provided. Such a random distributed feedback fibre laser has a number of interesting and attractive features. The fibre waveguide geometry provides transverse confinement, and effectively one-dimensional random distributed feedback leads to the generation of a stationary near-Gaussian beam with a narrow spectrum. A random distributed feedback fibre laser has efficiency and performance that are comparable to and even exceed those of similar conventional fibre lasers. The key features of the generated radiation of random distributed feedback fibre lasers include: a stationary narrow-band continuous modeless spectrum that is free of mode competition, nonlinear power broadening, and an output beam with a Gaussian profile in the fundamental transverse mode (generated both in single mode and multi-mode fibres).This review presents the current status of research in the field of random fibre lasers and shows their potential and perspectives. We start with an introductory overview of conventional distributed feedback lasers and traditional random lasers to set the stage for discussion of random fibre lasers. We then present a theoretical analysis and experimental studies of various random fibre laser configurations, including widely tunable, multi-wavelength, narrow-band generation, and random fibre lasers operating in different spectral bands in the 1-1.6μm range. Then we discuss existing and future applications of random fibre lasers, including telecommunication and distributed long reach sensor systems. A theoretical description of random lasers is very challenging and is strongly linked with the theory of disordered systems and kinetic theory. We outline two key models governing the generation of random fibre lasers: the average power balance model and the nonlinear Schrödinger equation based model. Recently invented random distributed feedback fibre lasers represent a new and exciting field of research that brings together such diverse areas of science as laser physics, the theory of disordered systems, fibre optics and nonlinear science. Stable random generation in optical fibre opens up new possibilities for research on wave transport and localization in disordered media. We hope that this review will provide background information for research in various fields and will stimulate cross-disciplinary collaborations on random fibre lasers. © 2014 Elsevier B.V.

Integrating OpenMI and Uncertweb:managing uncertainty in OpenMI models

OpenMI is a widely used standard allowing exchange of data between integrated models, which has mostly been applied to dynamic, deterministic models. Within the FP7 UncertWeb project we are developing mechanisms and tools to support the management of uncertainty in environmental models. In this paper we explore the integration of the UncertWeb framework with OpenMI, to assess the issues that arise when propagating uncertainty in OpenMI model compositions, and the degree of integration possible with UncertWeb tools. In particular we develop an uncertainty-enabled model for a simple Lotka-Volterra system with an interface conforming to the OpenMI standard, exploring uncertainty in the initial predator and prey levels, and the parameters of the model equations. We use the Elicitator tool developed within UncertWeb to identify the initial condition uncertainties, and show how these can be integrated, using UncertML, with simple Monte Carlo propagation mechanisms. The mediators we develop for OpenMI models are generic and produce standard Web services that expose the OpenMI models to a Web based framework. We discuss what further work is needed to allow a more complete system to be developed and show how this might be used practically.

XPS and XMCD study of Fe3O4/GaAs interface

Ultrathin Fe oxide films of various thicknesses prepared by post-growth oxidation on GaAs(100) surface have been investigated with X-ray photoelectron spectroscopy (XPS), X-ray absorption spectroscopy (XAS), and X-ray magnetic circular dichroism (XMCD). The XPS confirms that the surfaces of the oxide are Fe3O4 rather than Fe2O3. XAS and XMCD measurements indicate the presence of insulating Fe divalent oxide phases (FeO) beneath the surface Fe3O4 layer with the sample thickness above 4 nm. This FeO might act as a barrier for the spin injection into the GaAs.

Bridging large and small scales of water models using hybrid Molecular Dynamics/Fluctuating Hydrodynamics framework

This thesis presents a two-dimensional water model investigation and development of a multiscale method for the modelling of large systems, such as virus in water or peptide immersed in the solvent. We have implemented a two-dimensional ‘Mercedes Benz’ (MB) or BN2D water model using Molecular Dynamics. We have studied its dynamical and structural properties dependence on the model’s parameters. For the first time we derived formulas to calculate thermodynamic properties of the MB model in the microcanonical (NVE) ensemble. We also derived equations of motion in the isothermal–isobaric (NPT) ensemble. We have analysed the rotational degree of freedom of the model in both ensembles. We have developed and implemented a self-consistent multiscale method, which is able to communicate micro- and macro- scales. This multiscale method assumes, that matter consists of the two phases. One phase is related to micro- and the other to macroscale. We simulate the macro scale using Landau Lifshitz-Fluctuating Hydrodynamics, while we describe the microscale using Molecular Dynamics. We have demonstrated that the communication between the disparate scales is possible without introduction of fictitious interface or approximations which reduce the accuracy of the information exchange between the scales. We have investigated control parameters, which were introduced to control the contribution of each phases to the matter behaviour. We have shown, that microscales inherit dynamical properties of the macroscales and vice versa, depending on the concentration of each phase. We have shown, that Radial Distribution Function is not altered and velocity autocorrelation functions are gradually transformed, from Molecular Dynamics to Fluctuating Hydrodynamics description, when phase balance is changed. In this work we test our multiscale method for the liquid argon, BN2D and SPC/E water models. For the SPC/E water model we investigate microscale fluctuations which are computed using advanced mapping technique of the small scales to the large scales, which was developed by Voulgarakisand et. al.

The development of attenuation compensation models of fluorescence spectroscopy signals

This study examines the effect of blood absorption on the endogenous fluorescence signal intensity of biological tissues. Experimental studies were conducted to identify these effects. To register the fluorescence intensity, the fluorescence spectroscopy method was employed. The intensity of the blood flow was measured by laser Doppler flowmetry. We proposed one possible implementation of the Monte Carlo method for the theoretical analysis of the effect of blood on the fluorescence signals. The simulation is constructed as a four-layer skin optical model based on the known optical parameters of the skin with different levels of blood supply. With the help of the simulation, we demonstrate how the level of blood supply can affect the appearance of the fluorescence spectra. In addition, to describe the properties of biological tissue, which may affect the fluorescence spectra, we turned to the method of diffuse reflectance spectroscopy (DRS). Using the spectral data provided by the DRS, the tissue attenuation effect can be extracted and used to correct the fluorescence spectra.