The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a number of disorders. The link between CCK and anxiety was the basis for this research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed. 1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3- position of the benzodiazepine scaffold varied, and substituted 3-anilino benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

Composite materials impact damage detection using neural networks

This thesis considers two basic aspects of impact damage in composite materials, namely damage severity discrimination and impact damage location by using Acoustic Emissions (AE) and Artificial Neural Networks (ANNs). The experimental work embodies a study of such factors as the application of AE as Non-destructive Damage Testing (NDT), and the evaluation of ANNs modelling. ANNs, however, played an important role in modelling implementation. In the first aspect of the study, different impact energies were used to produce different level of damage in two composite materials (T300/914 and T800/5245). The impacts were detected by their acoustic emissions (AE). The AE waveform signals were analysed and modelled using a Back Propagation (BP) neural network model. The Mean Square Error (MSE) from the output was then used as a damage indicator in the damage severity discrimination study. To evaluate the ANN model, a comparison was made of the correlation coefficients of different parameters, such as MSE, AE energy, AE counts, etc. MSE produced an outstanding result based on the best performance of correlation. In the second aspect, a new artificial neural network model was developed to provide impact damage location on a quasi-isotropic composite panel. It was successfully trained to locate impact sites by correlating the relationship between arriving time differences of AE signals at transducers located on the panel and the impact site coordinates. The performance of the ANN model, which was evaluated by calculating the distance deviation between model output and real location coordinates, supports the application of ANN as an impact damage location identifier. In the study, the accuracy of location prediction decreased when approaching the central area of the panel. Further investigation indicated that this is due to the small arrival time differences, which defect the performance of ANN prediction. This research suggested increasing the number of processing neurons in the ANNs as a practical solution.

Fibre Bragg grating strain sensors

The fabrication of in-fibre Bragg gratings (FBGs) and their application as sensors is reported. The strain and temperature characteristic results for a number of chirped and uniform gratings written into three different host fibres are presented. The static and dynamic temperature response of a commercially available temperature compensated grating is reported. A five sensor wavelength division multiplexed fibre Bragg grating strain measurement system with an interrogation rate of 25 Hz and resolution of 10 was constructed. The results from this system are presented. A novel chirped FBG interrogation method was implemented in both the 1.3 and 1.5 m telecommunication windows. Several single and dual strain sensor systems, employing this method, were constructed and the results obtained from each are reported and discussed. These systems are particularly suitable for the measurement of large strain. The results from a system measuring up to 12 m and with a potential measurement range of 30 m are reported. This technique is also shown to give an obtainable resolution of 20 over a measurement range of 5 000 for a dual sensor system. These systems are simple, robust, passive and easy to implement. They offer low cost, high speed and, in the case of multiple sensors, truly simultaneous interrogation. These advantages make this technique ideal for strain sensing in SMART structures. Systems based on this method have been installed in the masts of four superyachts. A system, based on this technique, is currently being developed for the measurement of acoustic waves in carbon composite panels. The results from an alternative method for interrogating uniform FBG sensors are also discussed. Interrogation of the gratings was facilitated by a specifically written asymmetric grating which had a 15 nm long linearly sloped spectral edge. This technique was employed to interrogate a single sensor over a measurement range of 6 m and two sensors over a range of 4.5 me. The results obtained indicated achievable resolutions of 47 and 38 respectively.

Zwitterionic and charge-balanced (polyampholyte) copolymer hydrogels

Zwitterionic compounds, or zwitterions, are electrically neutral compounds having an equal number of formal unit charges of opposite sign. In common polyzwitterions the zwitterionic groups are usually located in pendent groups rather than the backbone of the macromolecule. Polyzwitterions contain both the anion and cation in the same monomeric unit, unlike polyampholytes which can contain the anion and cation in different monomeric units. The use of cationic and anionic monomers (or monomers capable of becoming charged) in stoichiometric equivalent proportions produces charge-balanced polyampholyte copolymers. Hydrogel materials produced from zwitterionic monomers have been proposed for use and are used in many biomaterial applications but synthetic charge-balanced polyampholyte are less common. Certain properties of hydrogels which are important for their successful use as biomaterials, these include the equilibrium water content, mechanical, surface energy, oxygen permeability, swelling and the coefficient of friction. The zwitterionic monomer N,N-dimethyl-N-(2-acryloylethyl)-N-(3-sulfopropyl) ammonium betaine (SPDA) was synthesized with 2-hydroxyethly acrylate (HEMA) as the comonomer to produce a series of polyzwitterion hydrogels. To produce charged-balanced copolymer hydrogels two “cationic” monomers were selected; 2-(diethylamino) ethyl methacrylate (DMAEMA) and 3-(dimethylamino) propyl methacrylamide (DMAPMA) and an anionic monomer; 2-acrylamido 2,2 methylpropane sulphonic acid (AMPS). Two series’ of charge-balanced copolymers were synthesized from stoichiometric equivalent ratios of DMAEMA or DMAPMA and AMPS with HEMA as a terpolymer. The zwitterionic copolymer and both charge-balanced copolymers produced clear, cohesive hydrogels. The zwitterionic and charge-balanced copolymers displayed similar EWC’s along with similar mechanical and surface energy properties. The swelling of the zwitterionic copolymer displayed antipolyelectrolyte behavior whereas the charge-balanced copolymers displayed behaviour somewhere between this and a typical polyelectrolyte. This work describes some aspects of the polymerisation and properties of SPDA copolymers and charge-balanced (polyampholyte) copolymers relevant to their potential as biomedical / bioresponsive materials. The biomimetic nature of SPDA together with its compatibility with other monomers makes it a useful and complimentary addition to the building blocks of biomaterials.

ALEX:mobile language assistant for low-literacy adults

Basic literacy skills are fundamental building blocks of education, yet for a very large number of adults tasks such as understanding and using everyday items is a challenge. While research, industry, and policy-making is looking at improving access to textual information for low-literacy adults, the literacy-based demands of today's society are continually increasing. Although many community-based organizations offer resources and support to adults with limited literacy skills, current programs have difficulties reaching and retaining those that would benefit most from them. To address these challenges, the National Research Council of Canada is proposing a technological solution to support literacy programs and to assist low-literacy adults in today's information-centric society: ALEX© – Adult Literacy support application for EXperiential learning. ALEX© has been created together with low-literacy adults, following guidelines for inclusive design of mobile assistive tools. It is a mobile language assistant that is designed to be used both in the classroom and in daily life, in order to help low-literacy adults become increasingly literate and independent.

Chapter 1 : nucleobases with designed patterns of hydrogen bonding

The chemistry used in key bond-forming steps to prepare nucleobases with designed patterns of hydrogen bonding is surveyed. Incorporation of the nucleobases into DNA and RNA oligomers is achieved either chemically using building blocks such as nucleoside phosphoramidites or enzymatically using nucleotide triphosphates. By varying the hydrogen bonding pattern within nucleobases, and by incorporating additional substituents, new structures have been designed that "reach over" so that contacts with both strands in targeted duplex DNA can be made in antigene strategies to control gene expression. Various new base-pairing systems have been evaluated that expand the genetic alphabet beyond Watson-Crick base pairs A.T and G.C. For example, benzo-homologated analogs of the natural DNA bases represent a new genetic set of orthogonal, size-expanded derivatives that have been shown to encode amino acids of a protein in a living organism.

Investigating polymer-peptide conjugates and electrospinning for the production of advanced materials

This thesis describes the production of advanced materials comprising a wide array of polymer-based building blocks. These materials include bio-hybrid polymer-peptide conjugates, based on phenylalanine and poly(ethylene oxide), and polymers with intrinsic microporosity (PIMs). Polymer-peptides conjugates were previously synthesised using click chemistry. Due to the inherent disadvantages of the reported synthesis, a new, simpler, inexpensive protocol was sought. Three synthetic methods based on amidation chemistry were investigated for both oligopeptide and polymerpeptide coupling. The resulting conjugates produced were then assessed by various analytical techniques, and the new synthesis was compared with the established protocol. An investigation was also carried out focussing on polymer-peptide coupling via ester chemistry, involving deprotection of the carboxyl terminus of the peptide. Polymer-peptide conjugates were also assessed for their propensity to self-assemble into thixotropic gels in an array of solvent mixtures. Determination of the rules governing this particular self-assembly (gelation) was required. Initial work suggested that at least four phenylalanine peptide units were necessary for self-assembly, due to favourable hydrogen bond interactions. Quantitative analysis was carried out using three analytical techniques (namely rheology, FTIR, and confocal microscopy) to probe the microstructure of the material and provided further information on the conditions for self-assembly. Several polymers were electrospun in order to produce nanofibres. These included novel materials such as PIMs and the aforementioned bio-hybrid conjugates. An investigation of the parameters governing successful fibre production was carried out for PIMs, polymer-peptide conjugates, and for nanoparticle cages coupled to a polymer scaffold. SEM analysis was carried out on all material produced during these electrospinning experiments.

Composite cell support membranes based on collagen and polycaprolactone for tissue engineering of skin

The preparation and characterisation of collagen:PCL composites for manufacture of tissue engineered skin substitutes and models are reported. Films having collagen:PCL (w/w) ratios of 1:4, 1:8 and 1:20 were prepared by impregnation of lyophilised collagen mats by PCL solutions followed by solvent evaporation. In vitro assays of collagen release and residual collagen content revealed an expected inverse relationship between the collagen release rate and the content of synthetic polymer in the composite that may be exploited for controlled presentation and release of biopharmaceuticals such as growth factors. DSC analysis revealed the characteristic melting point of PCL at around 60°C and a tendency for the collagen component, at high loading, to impede crystallinity development within the PCL phase. The preparation of fibroblast/composite constructs was investigated using cell culture as a first stage in mimicking the dermal/epidermal structure of skin. Fibroblasts were found to attach and proliferate on all the composites investigated reaching a maximum of 2×105/cm2 on 1:20 collagen:PCL materials at day 8 with cell numbers declining thereafter. Keratinocyte growth rates were similar on all types of collagen:PCL materials investigated reaching a maximum of 6.6×104/cm2 at day 6. The results revealed that composite films of collagen and PCL are favourable substrates for growth of fibroblasts and keratinocytes and may find utility for skin repair. © 2003 Elsevier Ltd. All rights reserved.

Structure of glassy GeO2

The full set of partial structure factors for glassy germania, or GeO2, were accurately measured by using the method of isotopic substitution in neutron diffraction in order to elucidate the nature of the pair correlations for this archetypal strong glass former. The results show that the basic tetrahedral Ge(O-1/2)(4) building blocks share corners with a mean inter-tetrahedral Ge-O-Ge bond angle of 132(2)degrees. The topological and chemical ordering in the resultant network displays two characteristic length scales at distances greater than the nearest neighbour. One of these describes the intermediate range order, and manifests itself by the appearance of a first sharp diffraction peak in the measured diffraction patterns at a scattering vector k(FSDP) approximate to 1.53 angstrom(-1), while the other describes so-called extended range order, and is associated with the principal peak at k(PP) = 2.66( 1) angstrom(-1). We find that there is an interplay between the relative importance of the ordering on these length scales for tetrahedral network forming glasses that is dominated by the extended range ordering with increasing glass fragility. The measured partial structure factors for glassy GeO2 are used to reproduce the total structure factor measured by using high energy x-ray diffraction and the experimental results are also compared to those obtained by using classical and first principles molecular dynamics simulations.

Evaluation of Impact of Beam Size on Fibre Bragg Grating Fabrication

Fabrication of gratings has gone a long way since the onset by Kenneth Hill in 1976. Basic fabrication techniques such as holographic and phase-mask which have distinguishing advantages (variable wavelength, and high repeatability consecutively) have since been modified in an effort to combine the advantages of both methods. These basic methods are inherently simple and have few controls, they have been combined and modified over time to enable the possibility of fabricating gratings with complex modulation index and phase profiles.

Evaluation of impact of beam size on fibre Bragg grating fabrication

Fabrication of gratings has gone a long way since the onset by Kenneth Hill in 1976. Basic fabrication techniques such as holographic and phase-mask which have distinguishing advantages (variable wavelength, and high repeatability consecutively) have since been modified in an effort to combine the advantages of both methods. These basic methods are inherently simple and have few controls, they have been combined and modified over time to enable the possibility of fabricating gratings with complex modulation index and phase profiles.

Fatigue crack growth behaviour in molten-metal processed SiC particle-reinforced aluminium alloys

Fatigue crack initiation and subsequent short crack growth behaviour of 2014-5wt%SiC aluminium alloy composites has been examined in 4-point bend loading using smooth bar specimens. The growth rates of long fatigue cracks have also been measured at different stress ratios using pre-cracked specimens. The distributions of SiC particles and of coarse constituent particles in the matrix (which arise as a result of the molten-metal processing and relatively slow cooling rate) have been investigated. Preferential crack initiation sites were found to be SiC-matrix interfaces, SiC particles associated with constituent particles and the coarse constituent particles themselves. For microstructurally short cracks the dispersed SiC particles also act as temporary crack arresters. In the long crack growth tests, higher fatigue crack growth rates were obtained than for monolithic alloys. This effect is attributed to the contribution of void formation, due to the decohesion of SiC particles, to the fatigue crack growth process in the composite. Above crack depths of about 200 μm 'short' crack growth rates were in good agreement with the long crack data, showing a Pris exponent, m = 4 in both cases. For the long crack and short crack growth tests little effect of specimen orientation and grain size was observed on fatigue crack growth rates, but, specimen orientation affected the toughness. No effect of stress ratio in the range R = 0.2-0.5 was seen for long crack data in the Paris region.

The influence of ageing on fatigue crack growth in SiC-particulate reinforced 8090

A study of the influence of SiC-particulate reinforcement on ageing and subsequent fatigue crack growth resistance in a powder metallurgy 8090 aluminium alloy-SiC composite has been made. Macroscopic hardness measurements revealed that ageing at 170°C in the composite is accelerated with respect to the unreinforced alloy, though TEM studies indicate that this is not due to the enhanced precipitation of S′. Fatigue crack growth rates in the naturally aged condition of the composite and unreinforced matrix are similar at low to medium values of ΔK, but diverge above ≈ 8 MPa√m owing to the lower fracture toughness of the composite. As a result of the presence of the reinforcement, planar slip in the composite is suppressed and facetted crack growth is not observed. Ageing at or above 170°C has a deleterious effect on fatigue crack growth. Increased ageing time decreases the roughness of the fracture path at higher growth rates. These effect are though to be due to microstructural changes occurring at or near to the SiC/matrix interfaces, providing sites for static mode failure mechanisms to operate. This suggestion is supported by the observation that as ΔK increases, crack growth rates become Kmax dependent, implying the crack growth rate is strongly influenced by static modes.

Modular construction of dynamic nucleodendrimers

Isoguanosine-containing dendritic small molecules self-assemble into decameric nucleodendrimers as observed by 1D NMR spectroscopy, 2D DOSY, and mass spectrometry. In particular, apolar building blocks readily form pentameric structures in acetonitrile while the presence of alkali metals promotes the formation of stable decameric assemblies with a preference for cesium ions. Remarkably, co-incubation of guanosine and isoguanosine-containing nucleodendrons results in the formation of decameric structures in absence of added salts. Further analysis of the mixture indicated that guanosine derivatives facilitate the formation, but are not involved in decameric structures; a process reminiscent of molecular crowding. This molecular system provides a powerful canvas for the rapid and modular assembly of polyfunctional dendritic macromolecules. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Shear induced toughening in bonded joints:experiments and analysis

Bonded joint specimens were fabricated from composite adherends and either an epoxy or a urethane adhesive. In mixed-mode fracture experiments, the epoxy bonded specimens generally failed by subinterfacial fracture in the composite, while specimens bonded with urethane failed very close to the adhesive/substrate interface. For the epoxy bonded specimens, fracture toughness did not change significantly with mode-mix, but for urethane bonded joints, fracture toughness increased with increasing shear load. Finite element analysis, which modeled specimens bonded with the two adhesives, showed similar trends. The different toughening behaviors for the two bonded joints can be attributed to dissipation of energy through inelastic deformation, which was insignificant in the epoxy-bonded joints but substantial when the urethane was used as the bonding agent.