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(2021)ThesisMulti-layered waste packaging materials are widely used in the packaging industries due to their flexibility of applications, superior properties, and relatively lower cost. Despite the advantages accomplished by the polymer-metal multilayers packaging materials, recycling the waste in a traditional method is a very difficult task due to the complexities of multi-materials intrinsic behaviours during the processing of cast-off materials. In this study, a newly developed microrecycling technique (thermal disengagement technology, TDT) has been introduced and briefly demonstrated. Several outcomes are: (i) Polymer laminated Al packaging materials available from the local market was thermally disengaged by TDT into several useful products including ~98% pure Al, and graphitic C without any major emission (ii) laminated polymers in multi-layered packaging materials can be degraded into the graphitic C in an inert atmosphere. Degraded C can stay on Al surface to provide well protection against surface oxidation, (iii) TDT was utilised for different types of multilayer packaging materials consisting of multiple polymers and metallic contents (Al, Cu, & Fe) available in the local market. TDT is highly capable to recycle all different types of packaging materials irrespective to their inclusive materials. (iv) Al-containing packaging material was recycled in different media (air, nitrogen, & argon). Argon media was suitable to recycle Al into its original form and polymers into degraded graphitic C. Recycled Al was transformed into microparticles by non-traditional mechanical milling at cryogenic temperature (-196°C) created by liquid N2. Synthesised flake shaped, and micro-sized carbonaceous Al microparticles are contamination-free and thermally stable and can be useful in the fields of additive manufacturing, (v) A rapid transformation process was introduced where thermally disengaged Al from the TDT subsequently thermally transformed in an arc furnace at a very high temperature (~2000°C) in a short time period (~20s) in an inert and vacuum condition. As a result of this rapid transformation, ceramic reinforced Al alloy with an enhanced physical, microstructural, and mechanical properties was synthesised. The overall project of recycling polymer-metal multilayer packaging materials can be concluded with numerous green materials output along with some co-products and metallic alloys.
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(2021)ThesisThis thesis explores topological defects and topological defect transitions in epitaxial ultrathin ferroelectric heterostructures. Geometrical confinements in ultrathin films has enabled the realisation of several nontrivial topological polarisation arrangements in ferroelectrics, categorised as a range of topological defects such as bubble, meron, vortex, flux-closure domain, etc. These ferroelectric topological defects can be engineered by tuning depolarisation field, mechanical and electrical boundary conditions. Our model system is an ultrathin (001) oriented PbZrxTi1-xO3/ SrTiO3/ PbZrxTi1-xO3 heterostructure fabricated on La0.67Sr0.33MnO3 buffered SrTiO3 substrates. Several topological defects are realised under specific mechanical and electrical boundary conditions. Topological defect transitions are also achieved using different routes such as electric field, thickness variation, mechanical pressure and thin film milling. These topological defects have also gained immense technological interest on account of their emergent properties. This thesis further studies the functional properties in topological defects such as electrical conductivity in bubble domains. The motion of these bubble domains is also investigated. The results herein offer new insights on how to engineer topological defects and topological defect transitions in order to design multifunctional ferroelectric/multiferroic devices with enhanced operational speed, sensitivity and energy-efficiencies.
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(2021)ThesisSingle enzyme nanoparticles (SENs), which encapsulate individual enzymes in a thin permeable polymer network offer great control over the chemical and physical environment directly around the enzyme. SENs have exhibited great enzyme stability by restricting enzyme extensive unfolding motion under extreme conditions, like extreme pH and high temperature. However, up to date, the control over the chemistry of the shell is still quite limited. In this thesis, a new SEN formation strategy has been explored. In order to minimize the risk of enzyme deactivation during synthesis of the SENs, the weak electrostatic interaction was utilized to assemble charged polymers around the enzyme. Different lengths of charged polymers were pre-prepared via reversible addition−fragmentation chain-transfer polymerization (RAFT) and then attached to the surface of enzyme via electrostatic interactions. This strategy has been investigated for the different enzyme, including lysozyme, trypsin, protease, horseradish peroxidase, and glucose oxidase. Isothermal titration calorimetry (ITC) and asymmetric flow field-flow fraction (AF4) in combination with multiangle light scattering (MALS) reveal the binding number and strength of polymer chains / enzyme. The strength of binding can be tuned based on the charge density of the bound polymer. In this method, the trithiocarbonate group of a RAFT agent was placed close to the surface of the enzyme and the initiation of a free radical acrylamide / bisacrylamide polymerisation in solution can result in chain extension of the RAFT polymer and direct the formation of the newly formed hydrogel around the outside of the enzyme. AF4-MALS and small-angle X-ray scattering (SAXS) confirm the formation of a thin cross-linked shell around the enzyme. The mild conditions of this method of SEN formation, which avoids any covalent modification of the enzyme, results in no loss in activity on our model enzyme (glucose oxidase), and four-fold increase in thermal stability. The method is then utilized to probe the protective effect of trehalose close to the enzyme. Trehalose is generally assumed to be the most effective sugar to use as a protein stabilizer. In this method, trehalose molecules were placed close to enzyme surface by either assembling enzyme with charged trehalose polymers or crosslinking with trehalose monomer. In order to evaluate the effect of the trehalose in SENs on stabilizing enzyme, another disaccharide sucrose was treated in the same way for comparison. It was found that the core-shell structure, instead of the chemistry of the shell, was more important for stabilizing enzyme structure under heat treatment. This study offers a new technique for synthesis of SENs with ease of design and control of the shell chemistry of SENs, opening up new pathways for enzyme stabilization and application.
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(2021)ThesisThe purpose of my research is mainly focused on the Properties of CaO-Al2O3-based Mould Flux for High-Al Steel Continuous Casting. Mould flux is crucial to the continuous casting process for lubricating the strand as well as controlling the heat transfer between the mould and the steel strand. To reduce vehicle weight and obtain superior mechanical properties, a large amount of aluminium has been added to the steel. However, aluminium tends to react with silica-based mould flux during continuous casting, which could lead to a variety of casting problems, such as breakout prediction alarms, transverse and longitudinal depressions, etc. Therefore, it is crucial to limit the reaction between Al in the steel and SiO2 in the mould flux. This project aims to develop CaO-Al2O3-based mould fluxes for the continuous casting of the high-Al steel. The project will study melting properties, viscosity, structure, crystallisation behaviour and heat transfer of CaO-Al2O3-based mould fluxes to provide some strategy for the design of mould fluxes for the continuous casting of high-Al steel.
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(2021)ThesisBriquetting is a method of particles compaction where fine particles are densified to produce briquette with different sizes and shapes. In briquetting, loose particles are compressed two counter-rotating rolls. The structural and mechanical properties of briquettes are crucial to the downstream operations such as transportation, handling, and coating etc. Therefore, a better insight into those fundamentals governing of briquetting is of great importance to process control and optimization. This work aimed to develop numerical models at different scales to simulate the briquetting behaviour of fine particles. Two numerical techniques, finite element method (FEM) and discrete element method (DEM), were employed in the research. FEM considers compacts as continuum porous materials and can provide full scale simulations. On the other hand, DEM is a particle-based technique and can provide detailed information at the particle scale. The two complementary methods allow to analyse briquettes at different scales. A 2D FEM model was firstly developed to simulate the briquetting process. The Drucker-Prager Cap (DPC) model was adopted to characterize the mechanical response of powders. The model parameters were determined by conducting different experimental tests of die compaction of iron ore fines. The model was validated by comparing the simulation results with experimental data. The relative density and stresses of the briquettes showed inhomogeneous distributions in the flow direction. The parametric studies showed that the feed pressure affected the briquetting process considerably as both relative density and power draw increased almost linearly with increasing feed pressure. However, a non-linear trend was observed with increasing particle-wall friction. The 2D FEM model was later extended to 3D to consider the shape of roll pockets. The 3D simulation results showed that the Von Mises stress and hydrostatic pressure were more inhomogeneous compared to the 2D results. In the roll depth direction, both relative density and Von Mises decreased from the pocket periphery to the centre region. The effects of feed pressure, roll gap and roll speed were analysed. The roll force and relative density increased almost linearly with increasing feed pressure. A non-linear decline in roll force and relative density were observed as roll gap increased. However, roll speed showed limited impact on roll force and briquette mechanical properties. A DEM model with an elasto-plastic adhesion model was developed to simulate briquetting. The DEM model was firstly calibrated by comparing the die compaction results with experiments. In the DEM simulations of briquetting, the force-angular displacement curves showed the oscillatory patterns similar to those observed in the FEM simulations. The relative density at the final stage decreased in comparison with compression stage, and the contact force network was sparser and thinner. The effects of feed pressure and roll speed were studied. The force on the roll increased significantly, and the relative density and strength increased nonlinearly with increasing feed pressure. In contrast, the roll force, relative density, and strength declined as roll speed increased. The formed briquettes were compressed along two different directions to examine the strength and cracking phenomena. When compressed along the roll width, the crack started at the shoulder region and propagated to the centre part of the briquette. With increasing loading, the briquette broke into two parts along the vertical centre line. When compressed on the curve surface, the break force was much lower compared to the roll width direction and the crack initiated at the middle part of briquette and squeezed out vertically. Feed pressure of briquetting showed strong effect on the failure pattern and break force of briquettes. For both cases, the break force increased almost linearly with increasing feed pressure. Multiple cracks were observed for the loading direction along the roll width. However, a more distinct and clearer vertically squeezed crack at the middle periphery region was noticed along the curve surface. The effect of particle shape was investigated by simulating briquetting of tetrahedral particles. The roll force was much lower for the non-spherical particles and a lower relative density was observed for the tetrahedron particles. The force on the roll and the relative density was found to decrease with increasing the non-sphericity. On the other hand, both roll force and relative density increased with increasing feed pressure.
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(2021)ThesisTranscription factors (TFs) are proteins that bind to DNA in a sequence-specific manner and regulate gene transcription. ChIP-seq and other techniques have allowed a study of TF binding genome-wide but have shown that TFs bind to only a subset of in vitro predicted sites. This highlights that it is difficult to accurately predict which sites TF bind in vivo. In this current study, we have uncovered how the functional domains (FD, i.e., non-DNA binding domains) of TFs mediate protein-protein interactions that aid in TF genome localisation and investigate how DNA methylation affects the genomic localisation of TFs. This is important not only to better understand gene regulation but also to be able to develop next-generation artificial TFs. Analysis of ChIP-seq and RNA-seq data showed that disrupting the interaction between TF Krüppel -like factor 3 (KLF3) and its newly discovered FD co-partner WDR5 significantly impacted both KLF3 and WDR5 genomic localisation and gene activation. This demonstrated that protein-protein interactions with the FD can influence genome-wide TF binding. Next, we investigated how this finding translated to a family of TFs, the KLF family which all share a similar DNA binding domain (DBD) but bind and regulate different target genes across different tissues. Using publicly available ChIP-seq data, we showed that KLF family members have vastly different in vivo genome-wide binding profiles in HEK293 cells despite having similar consensus binding motifs. We then showed using ChIP-seq that replacing the KLF3 FD with the KLF1 FD reduces the number of binding sites and impacts genomic localisation. Taken together, these results demonstrate the importance of the FD in genome-wide binding and how FDs, by mediating specific protein-protein interactions, may allow TF families to achieve functional diversity despite their similar DBDs. We also investigated DNA methylation at the β-globin locus which is a model locus for studying transcriptional regulation where methylation has been identified to affect gene expression, but the underlying mechanisms are yet to be described. By measuring DNA methylation levels in human erythroid cell lines that show differential expression of HBG1/2 and HBB, we identified CpG sites at or near these genes that were differentially methylated and were close to regulatory regions and well-known TF binding sites. Future experiments will investigate whether these differences may directly affect TF binding leading to these gene-expression changes. Overall, my project has illuminated novel ways in which TF binding can be regulated in vivo to allow precise patterns of cellular gene expression, both by FD recruitment of partner proteins that regulate genomic localisation and by target site methylation that may alter TF binding.
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(2021)ThesisThis PhD thesis moves beyond conservation genetics/molecular ecology’s traditional consideration of genetic loci acting in isolation from other genetic loci, in a species that is acting in isolation from other species. I use modelling to explore these interactions, and produce some surprising results with implications for evolutionary biology and for conservation management. The first chapter presents a meta-analysis and simulations of recombination with epistatic selection – where a combination of alleles at different loci produces a fitness effect neither could produce alone. Epistasis is ubiquitous in nature, but difficult to detect. Additionally, mathematical models of recombination and epistatic interactions are typically intractable or contradictory. Consequently, epistatic interactions are often ignored. The main conclusion of the first chapter is that in Drosophila melanogaster, and in some models, lethal combinations of alleles at different loci tend to have a low recombination rate and thus break up less easily, though beneficial combinations show a different pattern. The second and third chapters use modelling to study correlations between species diversity and genetic diversity (SGDCs). If strong positive SGDCs are common, it may be possible to use one diversity measure in the place of another. Conversely, if strong negative SGDCs are common, conservation measures which target one diversity will negatively impact the other. There are theoretical arguments in support of positive and negative SGDCs, but little formal algebraic theory. Moreover, despite many SGDC studies, the results are equivocal. The second chapter shows that SGDCs which measure diversity using richness tend to be positive due to the construction of the SGDC as well as sampling bias but that assemblages with the same SGDCs can evolve very differently. Therefore, SGDCs may not be meaningful. However, many SGDC researchers use measures other than richness which weight rare variants differently from common ones. Therefore, the third chapter shows that the choice of weighting can seriously bias the interpretation of SGDC studies. In summary, this thesis lays the groundwork for a version of molecular ecology based upon a more thorough and accurate assessment of interactions of genes with one another, and with other species.
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(2021)ThesisImpedance cellular biosensors are amongst a promising type of label-free technologies in providing ongoing insights into physiological function of cells over a period ranging from several minutes to several days. However, detection of a highly specific biomolecular event using traditional impedance assays is technically challenging. The nature of impedance signal relies on the changes in the local ionic environment at the interface, providing many biochemical events at once lacking biomolecular specificity. The next decade is then likely to witness an interest in using developed impedance assays. Impedance-quartz crystal microbalance (QCM), impedance-surface plasmon resonance spectroscopy (SPR), and impedance-optical microscopy are the hybrid approaches that have been employed in the field. Integrating impedance biosensors to another sensing method, in particular new microscopies that enable identification of cellular structures and processes with a high degree of specificity, enhances the potential of traditional assays by providing additional relevant information. Herein an effective approach for accurate interpretation of impedance signal is presented. By development of optical/electrical multi-electrode chips, light was utilized for direct visualization of cell structures and processes on the surface of the microelectrode. It was essential to achieve both high throughput electrical results and high-resolution microscopy images to detect the transient changes inside the cells. Therefore, the strategy of simultaneous dual sensing was developed in three main steps. For the establishment of a reliable dual sensing readout, it was essential to use a commercial biosensing device (known as xCELLigence) in the first step. This approach enabled to compare the electrical results of developed dual biosensing device and a commercial device (as a high throughput assay for electrical measurement of subtle changes within the cell monolayer). The highly sensitive measurement of commercial device also made it possible to investigate the ongoing mechanism behind receptor/ligand activation. The signalling pathway was determined by using different pharmacological inhibitors. In a separate parallel experiment, fluorescence microscopy was used to visualise the specificity of histamine/HeLa cell interaction which was coupled to intracellular calcium rise. While it is assumed these two processes are connected, this could not be determined definitively by the sole biosensing device application. In the second step it was necessary to develop a setup with the capability of data acquisition in both the high throughput electrical setup and high-resolution fluorescence microscopy on a single platform. The first material of choice for the fabrication of this biosensor was ITO because of its electrical conductivity and optical transparency. It was shown that contribution of cells to the overall signal on the surface of ITO depends on the parameters including sensing area and width of microfingers. Furthermore, comparing the ITO results with the identical gold microelectrode revealed the ITO severely lacked sensitivity compared to gold. This was due to a better penetration of the electric field within the cell layer on the gold surface. The addition of a viewing window made a dual sensing readout possible on the gold microelectrode. Finally, the finding were used to maximize the system efficiency and precision for the detection of minute change of cells to the drug. The reduction of the microfingers down to the single cell level led to a more efficient distribution of electric field within cell monolayer. A high density of gold electrode arrays also increased the chance of individual cells blocking the current which was desirable. The added value of the developed biosensor was illustrated by studying GPCR activation in a more thorough manner using simultaneous fluorescence microscopy. The simultaneous optical/electrical experiment was performed as a powerful approach to translate specific intracellular biomolecular event contributing to the morphological changes in cell/drug interaction.
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(2021)ThesisIn this thesis, the main objective was to develop polymer-coated upconversion nanoparticles (UCNPs) for anticancer drug delivery. The ability of UCNPs to convert low energy near-infrared (NIR) light into high energy visible-ultraviolet light has resulted in its development as novel contrast agents for biomedical imaging-guided drug delivery. However, UCNPs succumb to poor colloidal stability in aqueous media, which can be alleviated by surface modifications. Adding a polymer cloak to the nanoparticle would ensure enhanced stability in biological media, playing an instrumental role in its biomedical applications. Firstly, poly(poly(ethylene glycol)methyl ether methacrylate)-block-poly(ethylene glycol methacrylate phosphate) (PPEGMEMAn-b-PEGMP3) polymers, where n = 26, 38 and 80, were prepared and attached to the UCNPs. The relationship between the length and grafting density of the polymer shell were then investigated for their effects on the physicochemical and biological properties of these core-shell UCNPs. The results showed that UCNPs coated with the longest PPEGMEMA chain, grafted at low brush density, were able to reduce the formation of the protein corona in vitro and in vivo whilst also showing the brightest upconversion luminescence in the solid-state. Secondly, the optimized chain length polymer was further introduced in polymethacrylic acid groups to attach the anticancer drug doxorubicin·HCl (DOX). To study the effect of drug loading amount on the biological activity of nanoparticles, a tri-block terpolymer poly (poly (ethylene glycol) methyl ether methacrylate) block polymethacrylic acid block polyethylene glycol methacrylate phosphate (PPEGMEMA80-b-PMAA20-b-PEGMP3) was synthesized to coat UCNPs and loaded different amounts of DOX (DOX-0 (0%), DOX-1 (1.32%), DOX-2 (4.06%), and DOX-3 (8.30%)). This study found that the effect of DOX loading on the biological behaviour of UCNPs was dominated by polymer shell hydration and protein corona. In addition to this, a particular protein corona was able to direct in vitro cellular association and in vivo biodistribution of the UCNPs. Finally, estrone ligand was introduced to PPEGMEMAx-b-PMAAy-b-PEGMP3 (x=7,15,33,80; y=16,20,18,18)-coated UCNPs with the expectation of enhancing the nanocarrier’s targeting ability towards estrogen receptor. In this study, the impact of the targeting ligand’s position, as well as PEGMEMA linker length, was studied for their effects on cellular uptake behaviour. The shortest polymer PPEGMEMA7-b-PMAA16-b-PEGMP3 appended with estrone at the end of the polymer chain was found to have the best cellular uptake behaviour in estrogen receptor α positive expression cell line MCF-7 and could efficiently improve the toxicity in estrogen receptor α positive expression cell lines and 3D spheroid model.
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(2021)ThesisBifunctional nitrogen mustards form DNA inter-strand crosslinks and are clinically important due to their broad-spectrum anti-tumour activity. However, the crosslinks are readily repaired by cancer cells, leading to fatal drug resistance, and their tendency to form monofunctional adducts exacerbates their carcinogenicity and mutagenicity. Equipping planar aromatic chromophores with alkylating groups to direct the alkylation of DNA by intercalation enhances alkylation efficacy, cytotoxicity, and modulates adduct specificity. Therefore, a N1,N6-bis(2-(aziridin-1-yl)ethyl)phenazine-1,6-dicarboxamide molecule named “Phenazir” was designed that bears aziridine groups at positions on the chromophore that predisposes them to nucleophilic attack by a guanine and adenine in the major and minor groove, respectively. It was anticipated that the resultant novel crosslinks would be difficult for cancer cells to repair, and therefore, Phenazir would be less susceptible to the development of resistance in a clinical setting. This thesis investigates the synthesis and biological activity of Phenazir and its analogues, and its binding to DNA through spectroscopic methods. Phenazir and its analogues were successfully synthesised and cytotoxicity measurements revealed that Phenazir had IC50 concentrations in the 5 to 25 nM range, and that it caused extensive DNA double strand breaks. Cytotoxicity measurements of other analogues, with different linker lengths and substitutions of the phenazine core, resulted in up to a 30-fold increase in activity. UV-Vis experiments demonstrated that the phenazine-1,6-carboxamide scaffold intercalated and alkylated DNA under mild conditions. NMR experiments were unsuccessful in obtaining solution structures of a Phenazir-oligomer complex, likely hindered by aggregation or polymerisation of Phenazir at high concentrations. However, molecular dynamics studies suggest that the aziridines in intercalated Phenazir are appropriately located to promote DNA alkylation. MALDI and nanoESI-MS were used to identify the alkylated adducts formed upon complexing a 5’ – TpG – 3’-containing oligomer with Phenazir, demonstrating that Phenazir alkylates efficiently at the TpG step with some evidence of interstrand crosslinking. Overall, the work in this thesis has led to the development of phenazine-1,6-carboxamides as a new class of highly active, DNA-targeting cytotoxic molecules that explore the previously untapped potential of threading bis-alkylation as a drug design approach.