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Defect-stabilised Pt catalysts on UiO-66(NH2)
Get PDFThis thesis broadly explores the use of the metal organic framework (MOF) UiO-66(NH2) as a support material for photocatalytic hydrogen generation.
Hydrogen generation is an important reaction in sustainable catalysis, with the potential to create hydrogen fuel using sunlight energy, improving upon the current methods such as steam reforming, which produce CO2 emissions during hydrogen generation. Hydrogen is an ideal candidate for an energy carrier in a net-zero fuel economy, and its production using sunlight is a highly promising prospect to contribute to the global effort of circumventing CO2 emissions and reducing anthropogenic global warming.
UiO-66(NH2) is an analogue of the highly popular MOF UiO-66, where UiO-66(NH2) is composed of Zr6O4(OH)4 zirconium-oxo clusters and linkers of 2-amino terephtalate. These building units co-ordinate into extended macromolecules developing a crystal structure with networks of high porosity. UiO-66, and its analogues exhibit relatively high thermal and chemical stability, an essential trait for catalyst supports. These MOFs also display a very high tunability, with the ability to replace the metal and organic components with certain candidates, while maintaining the crystal structure. UiO-66 family MOFs are perhaps most distinguished by their ability to form defects, which have been observed to present in a variety of ways, with the possibility for both cluster and linker vacancies, and phases of the material which naturally incorporate defects.
This research aims to use UiO-66(NH2) catalysts to create more sustainable catalysts, by reducing sintering during catalysis. Sintering is a significant cause for loss of catalyst activity for catalysts where an active site is immobilised upon a support material. Agglomeration of the catalyst particles reduces the surface proportion of atoms, and therefore the proportion of catalytically active atoms.
Chapter 4 presents a body of work in which I introduce missing linker defects to UiO-66(NH2) in varying quantities, measuring the physical properties of the MOF using PXRD and SEM, and quantifying the missing linker concentrations by TGA. I explore the effects of missing linkers on catalytic activity towards photocatalytic hydrogen generation, and conduct post mortem analysis to measure nanoparticle sintering to assess the efficacy for missing linker defects introducing ‘anchor sites’ at which to stabilise catalyst nanoparticles.
Chapter 5 presents work which occurred in parallel with Chapter 4, developing and optimising a photocatalytic reactor cell to maximise the observed hydrogen generation from UiO-66(NH2) photocatalysts. This chapter investiagtes key design parameters in a photocatalytic reactor, and achieves large increases in the observed rate of photocatalysis by applying the same catalyst to a new reactor. The development of this reactor was key to highlight changes in rate of H2 generation in both Chapters 4 and 6.
Chapter 6 Investigates another approach to sustainable heterogeneous catalysis. Instead of stabilising Pt catalysts, I implemment Nickel and Nickel/ Platinum mixed metal catalysts, with the aim of using cheaper, more earth-abundant metals for photocatalysis
Mapping the architecture of three porosities: A study of urban decay and regeneration in Semarang old town, Indonesia
Get PDFThis PhD thesis is an architectural inquiry that proposes and explores the concept of architectural porosity as a framework for interpreting patterns of inhabitation within an urban heritage context. It aims to illuminate the diverse definitions and perceptions of porosity within heritage practice and in architectural and urban discourse more broadly.
The research begins by approaching porosity as an interdisciplinary concept, drawing on perspectives from the physical sciences, such as materials science and geology, to the social sciences and humanities, including archaeology, cultural heritage, and urban studies. These various interpretations of porosity are then reframed architecturally: on the one hand, rooted in the materiality of the urban fabric, and on the other, extending beyond its material existence to influence social and spatial dynamics. By applying the idea of porosity both literally and metaphorically, the study identifies three distinct modes or levels of operation: (1) material porosity, understood as a typically microscopic quality that reflects the capacity of architectural surfaces to retain traces of past events; (2) spatial porosity, observed through an analysis of inhabitable architectural boundaries; and (3) social porosity, proposed as a consequence of the preceding two, which denotes a potentially productive coexistence of planned and unplanned, human and non-human inhabitation—often marginalised or erased in conventional urban heritage revitalisation projects. These three forms of porosity are conceptualised collectively as a new definition of architectural porosity, offering a framework for reinterpreting urban heritage values and enhancing regeneration outcomes by enriching the diversity of spatial practices and patterns of inhabitation in the built environment.
The research includes an in-depth case study of the revitalised urban heritage site of Semarang Old Town in Indonesia—a historic colonial district comprising over one hundred heritage buildings. Since 2017, Semarang Old Town has undergone a significant revitalisation effort involving infrastructure upgrades and selective restoration of heritage buildings. These interventions have brought notable improvements to environmental quality, including enhanced drainage and redesigned streetscapes featuring new street furniture. However, the regeneration process has also sought to 'clean up' many of the informal practices that once occupied the streets, façades, and building edges—practices that had emerged following the area’s stagnation in the post-independence era. Given the site's complex and fragile socio-cultural context—including the uncertain legal status of some heritage buildings and the prevalence of economically driven informal activities—Semarang Old Town remains a mix of restored and decaying structures, with both formal and informal inhabitation continuing despite the revitalisation efforts. Nonetheless, these efforts persist in a direction that treats heritage sites as income-generating assets for a broader and more affluent market. This often entails restoring historical materials, erasing signs of decay, and suppressing informal modes of inhabitation.
This thesis proposes a framework for re-reading the value of heritage sites by developing a porosity index based on the three aforementioned categories. The porosity index maps the material, spatial, and social conditions of the heritage buildings studied, indicating their revitalisation status as well as the presence of both human and non-human forms of inhabitation. These three sets of mappings are examined relationally, as an assemblage of latent potentialities found within the urban heritage landscape. This analytical framework offers an alternative perspective within ongoing debates on heritage conservation, revitalisation, and gentrification, advocating for a more adaptable and inclusive approach that better acknowledges and preserves a broader spectrum of material, spatial, and social inhabitation practices
First time entrants to the youth justice system
No full textThis thesis provides an in-depth exploration related to First Time Entrants (FTEs) to the youth justice system. The thesis is driven by a research need in Nottingham City in particular, where the rates of FTEs are consistently the highest in England and Wales. A range of approaches are used to explore this issue, including a systematic review and both quantitative and qualitative primary research. Chapter one provides an introduction to the thesis and its key concepts, outlining the need for research in this area. Next, chapter two presents a systematic review of international literature related to the use of diversion measures, intended to keep children who have offended for the first time away from formal youth justice processes. It considers their effectiveness with respect to reducing reoffending and provides recommendations for practice. Chapter three then presents qualitative research exploring FTEs’ journeys prior to engaging in offending behaviour, to consider whether more could have been done to prevent them from entering the youth justice system in Nottingham. Interviews were conducted with children, their guardians and youth justice case managers and data was analysed using Interpretative Phenomenological Analysis. Following this, chapter four presents a quantitative analysis of data from 1,099 FTEs in Nottingham between 2016-2022. This provides insight into both the characteristics of FTEs and the factors associated with continued offending in this cohort. Data for this study were extracted from AssetPlus, the assessment tool most commonly used within the youth justice system. AssetPlus is critically evaluated in chapter five, considering its psychometric properties, alignment with current theory and practical utility. Finally, a discussion of the key findings of the thesis and implications for practice are provided in chapter six
Creating an E. coli-expressible luminescent protein
No full textPhotoproteins are a class of bioluminescent macromolecules consisting of one or more polypeptide chains, which stabilise a bound organic ligand capable of light emission in the visible wavelength region upon reaction with a chemical stimulant. Some photoproteins have been utilised as biosensors of biologically-relevant ions or compounds.
Pholasin® – a photoprotein isolated from the rock-boring mollusc Pholas dactylus – has been commercialised by Knight Scientific as an effective chemiluminescent detector of notable free radicals and non-radical oxidants produced by the mammalian immune system. To date, recombinant expression of the apoprotein of Pholasin®, and subsequent reconstitution with its covalent luminescent ligand, dehydrocoelenterazine 10, has not been successful in matching the reactivity of the mollusc-isolated photoprotein.
Utilising the literature report that the coelenterazine-binding protein (CBP) from the sea pansy Renilla muelleri has been heterologously expressed and co-crystallised with its native ligand, coelenterazine 5 as a starting point, we have investigated the possibility for generating an E. coli expressible analogue of the Pholasin® apoprotein. Four homology models of the R. muelleri CBP were created in silico. The effect of introducing cysteine residues in the binding site was investigated using the Schrödinger Maestro molecular docking platform, evaluating the mutants’ binding affinity for the endogenous coelenterazine 5 and the structurally similar dehydrocoelenterazine 10. Two
of the homology models (I62C-CBP, M130C-CBP) exhibited favourable calculated binding of the endogenous ligand coelenterazine, and of the proposed ligand dehydrocoelenterazine. Designed plasmids encoding each of these proteins bearing a protease-cleavable affinity tag were transformed into E. coli and expressed. The secondary structures of the purified tag-free proteins were compared to expressed R. muelleri CBP via circular dichroism spectroscopy. Lastly, combining published reactions from several sources, the luminophore coelenterazine 5 was synthesised at a yield of 18 % over four steps. Oxidation yielded the desired compound, dehydrocoelenterazine 10, although its complete purification was not achieved.
The luminescence of 10 was assessed using ABEL® Antioxidant Test Kit for Singlet Oxygen from Knight Scientific. Relative to an equimolar assay of Pholasin®, the peak light emission of 10 was approximately 44-times smaller. The results of this research have laid the foundation for creating an analogue of Pholasin® that: is expressible in E. coli; offers versatility, in the structure of the chromophore, and of the protein; and can potentially lead to bespoke options for a FRNO-triggered luminescent biosensor
Development and evaluation of new methods to optimise the Actiphage RapidTM assay for detection of mycobacteria
Get PDFPathogenic mycobacteria including M. tuberculosis complex and M. avium subspecies paratuberculosis are pathogens of global importance posing a risk to human health and contributing to large economic losses in the agricultural industry. Due to nature, severity and implications of mycobacterial infections, there is a need for rapid and sensitive diagnostics. The characteristic, slow-growing nature of pathogenic mycobacteria introduces a barrier to diagnosing infections quickly when using culture-based methods. Histology lacks the sensitivity to detect low cell numbers, nor does it allow for species specific identification. ELISA assays are most used for detection of mycobacteria due to their inexpensiveness and quick turnaround from sampling to results. Although ELISA tests are specific, they have low sensitivity, especially in early stages of infection. To overcome these issues with standard mycobacterial methods of detection, the Actiphage® assay was developed to provide a reasonably quick, sensitive identification method by using a broad host- range Mycobacteriophage to lyse mycobacterial cells recovered from white blood cells and using endpoint PCR to identify species-specific signature DNA sequences extracted from the mycobacteria.
This project was sponsored by PBD Biotech Ltd. to develop, evaluate and optimise Actiphage RapidTM-qPCR based approaches for detection of mycobacteria from clinical blood and milk samples. Whilst qPCR kits are currently commercially available for the detection of M. avium subspecies paratuberculosis, many of these kits have been optimised for detection from faecal, tissue or organ samples. Therefore, whether these kits were compatible with DNA samples prepared using mycobacteriophage lysis and containing substances from blood known to inhibit PCR amplification remained to be explored. Evaluation of the use of commercial qPCR kits to detect mycobacterial DNA prepared from the Actiphage® assay was carried out. The results highlighted issues with using commercial kits including the need to implement a ∆Cq analysis method due to unspecific binding events of the Actiphage RapidTM assay negative control. Results also showed that trouble shooting was difficult with commercial qPCR kits, therefore, the company decided to develop and optimise an in-house qPCR assay to allow for more control over assay development. Whilst there was success in designing and using a novel qPCR kit for the detection of M. avium subspecies paratuberculosis and M. tuberculosis complex, results show that more optimisation is needed to efficiently incorporate an internal amplification control within the assay, something that is essential for a diagnostic kit. Nevertheless, experiments to detect M. avium subspecies paratuberculosis from blood of farmed goats by Actiphage RapidTM assay and qPCR using a commercial qPCR kit demonstrated that Actiphage RapidTM-qPCR assay approaches offer a more sensitive detection of M. avium subspecies paratuberculosis than ELISA based assays.
A second area of research focused on elucidating further applications of the Actiphage RapidTM assay. Areas of interest were using Actiphage RapidTM assay as a physical lysin to extract mycobacterial DNA for sequencing experiments, investigating restriction fragment length polymorphisms found in M. avium complex and using Actiphage RapidTM assay to aid in herd management. Exploiting single nucleotide polymorphisms within an insertion sequence of M. avium complex to develop a high-resolution melting analysis approach allowed for differentiation of M. avium subspecies paratuberculosis subtype, something that can be beneficial as an epidemiological tool. Finally, through testing of bovine bulk milk and individual cattle with Actiphage RapidTM assay, results were used to successfully isolate M. tuberculosis complex infected animals from a herd to control disease and work towards a disease-free status for the farm, validating that Actiphage RapidTM assay is a useful diagnostic tool for control of mycobacterial disease
Part A – AI-Designed Protein Binders Tackle a Century-Old Challenge: Tc24 as a Universal Vaccine Antigen for Chagas Disease Part B – Expression, Purification and Biophysical Characterisation of de novo binders designed against the Flagellar Calcium Binding Protein, Tc24
Get PDFPart A – Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains one of the most
neglected tropical diseases, disproportionately affecting low-income, rural populations across
Latin America. Despite over a century since its discovery, there is still no effective vaccine and
therapies currently rely on the usage of nifurtimox and benznidazole, which have been linked
to severe side effects. This review explores the multifaceted challenges of developing both a
therapeutic and prophylactic treatment for Chagas disease. Particular attention is given to the
flagellar calcium-binding protein Tc24, a highly conserved, immunogen expressed across all
morphological stages of T. cruzi.
In parallel, this review examines how artificial intelligence (AI) and deep learning (DL)
platforms are revolutionising structural prediction and binder design. These technologies
enable the in silico development of both high-affinity and target-specific binders at low cost.
In summary, this review proposes the integration of conserved antigen targets, with AI-guided
binder design presents a novel framework for overcoming current barriers in vaccine
development, offering renewed hope for the prevention and management of Chagas disease.
Part B – Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, remains one of the most
neglected tropical diseases, disproportionately effecting affecting socioeconomically
impoverished regions across Latin America. Despite over a century of research since its
discovery, there is still no effective vaccine, and current therapies rely on the usage of
nifurtimox and benznidazole which have been linked to severe side effects. Tc24, a highly
conserved flagellar calcium binding protein remains an attractive vaccine candidate.
This study experimentally evaluated six RFdiffusion designed binders against Tc24. Although
no functional binders were identified, these results highlight limitations of current binder
design pipelines and emphasise the need for incorporating solubility parameters in future Tc24
binder development
The potential role of Peperomia pellucida (l.) Kunth in ameliorating hyperglycaemic and glycation-induced inflammation in human retinal pigment epithelial cell line (ARPE-19)
Get PDFDiabetic retinopathy (DR) is a microvascular complication that causes blindness. DR management is costly and accompanied with adverse effects. Peperomia pellucida (L.) Kunth is traditionally used for inflammation, but its effects on DR remain unexplored. This study aimed to elucidate the regulatory mechanism of P. pellucida against high glucose and glycation induced stress in human retinal pigment epithelial cell line (ARPE-19). P. pellucida was macerated with methanol, and fractionated with hexane, chloroform, ethyl acetate, n-butanol and water. Semi-quantitative colorimetric assays indicated that the ethyl acetate plant fraction demonstrated potent antioxidant, anti-inflammatory and anti-glycation activities, alongside significant (p<0.05) higher α-amylase and α-glucosidase inhibitory activities when compared to the standard anti-diabetic drug, acarbose. Both ethyl acetate fraction and crude methanolic plant extract significantly (p<0.05) restored the ARPE-19 cell viability under high glucose and glycation stress. High glucose and glycation induced the nuclear factor kappa B (NF-κB) p65 and signal transducer and activator of transcription 3 (STAT3) signalling pathways with significant (p<0.05) increase of gene (1.22-31.30 folds) and protein (1.39-7.79 folds) expression for angiogenic and inflammatory markers, including interleukin 8 (IL-8), matrix metalloproteinase 2, monocyte chemoattractant protein 1, receptor for AGE, and vascular endothelial growth factor in ARPE-19, as determined via reverse transcription real-time polymerase chain reaction and western blot. Conversely, the gene and protein (0.12-0.56 folds) expression of glutathione peroxidase were significantly reduced due to the suppression of peroxisome proliferator-activated receptor gamma (PPAR-γ). P. pellucida did not alter the biomarkers’ gene and protein expression under normal glucose condition except for IL-8 (0.75-0.89 folds). Although in vivo brine shrimp toxicity analysis revealed that crude methanolic extract and ethyl acetate fraction were mildly toxic, in vitro cell viability findings showed that they were non-cytotoxic towards ARPE-19. Dillapiole, 2,4,5-trimethoxystyrene, β-caryophyllene, β-santalene, methyl 9-octadecenoic acid and methyl pheophorbide-a were among the predominant phytochemicals identified in the crude methanolic extract via spectroscopic and spectrometric techniques. Notably, methyl pheophorbide-a was identified for the first time in P. pellucida. The current findings support P. pellucida as an alternative therapeutic source to mitigate high glucose and glycation-induced stress in DR by regulating the NF-κB p65, PPAR-γ and STAT3 signalling pathways
Rational inhibitor design, synthesis and evaluation as steps towards the discovery of new anti-tuberculosis drugs
No full textOf all the infectious diseases that have ever plagued humankind (and animal-kind), tuberculosis (TB) remains one of the deadliest, having claimed some 1.3 million human lives in 2022 alone, to say nothing of its impact on the other species with which our lives are intertwined. Being a bacterial infection, TB is treatable with appropriate antibiotics, but the few drugs capable of killing or suppressing the growth of the remarkably hardy bacteria that cause the disease (primarily Mycobacterium tuberculosis in humans, and M. bovis in other species, most notably cattle) are rapidly losing their overall efficacy as antibiotic resistance rises in prevalence. The long and onerous treatment regimens required even in drug-sensitive cases – six months of up to four drugs, increasing to nine months if relatively moderate drug resistance has been confirmed, and even to twenty in extreme cases – and the potentially unbearable adverse effects of some of the therapies involved tend to lead to suboptimal patient compliance, hastening this already inevitable process, which has created an urgent, unmet need for novel anti-TB drugs.
Starting from a recently reported, rationally designed inhibitor of InhA, an enoyl-acyl reductase involved in the synthesis of mycolic acids – crucial components of the mycobacterial cell wall – and a clinically validated target (the ultimate target of the first-line therapy isoniazid), a small library of seven compounds differing from each other at only one point (45 and 55-60) has been synthesised with the intention of generating a structure-activity relationship. Following computer simulations of their interactions with InhA and their pharmacokinetic and toxicological properties, their activity against M. smegmatis, a close relative of M. tuberculosis and M. bovis, has been assessed by multiple methods, and all seven appear to suppress bacterial growth to a similar and inconsistent degree, perhaps temporarily. Regrettably, they are also only sparingly soluble in water and have a tendency to form aggregates that rob them of their efficacy and interfere with some methods of evaluating biological activity. Nevertheless, there is crystallographic evidence that 58 may be capable of low-occupancy binding to its target, and some biochemical evidence of similarly weak binding between InhA and all but one of these compounds. Some refinement to the basic structure is needed to improve their solubility, but there is potential for these compounds to evolve into true drug leads.
In parallel, the activity of the fungal natural product atrofuranic acid (AFA) and some of its derivatives (67-69) against M. tuberculosis and InhA has been probed by similar computational, microbiological and biochemical means, and seem rather more promising. AFA has been proved to bind to InhA, and both it and compound 69 have been shown to suppress mycobacterial growth at relatively low concentrations (5 µg mL-1), without the problematically low solubility of the fully synthetic compounds. Progress has also been made towards chemoenzymatic synthesis of other AFA derivatives, generated by feeding unnatural aromatic amino acids to the relevant fungi or supplying appropriate isolated enzymes with the corresponding pyruvic acids; this work is still ongoing
A Quantum Graph Approach to Metamaterial Design
Get PDFSince the turn of the century, metamaterials have garnered significant attention for their ability to exhibit exotic properties such as cloaking and perfect lensing. This has led to a growing need for reliable mathematical models capable of describing these materials' complex behaviors. While various modeling techniques exist for studying and engineering metamaterials, this thesis introduces a novel approach based on the scattering formalism of quantum graph theory. The flexibility and mathematical simplicity of this framework make it an ideal tool for designing metamaterials with unique band structures and for exploring complex multi-layer configurations. This thesis begins by extending quantum graph theory's scattering formalism to study wave propagation in complex periodic and finite quantum systems. Green’s functions on quantum graphs are developed using a scattering approach, offering a powerful method for analyzing wave behavior on both closed and open graphs. Next, we apply this formalism to study acoustic metamaterials modeled as networks of interconnected waveguides, confirming the model's predictions through both simulations and experiments. Finally, the thesis explores the design of an angular Fourier filter using a periodic quantum graph with beyond-nearest-neighbor connections, demonstrating that quantum graphs can be used to model resonant wave transmission at discrete angles. The results were verified using COMSOL simulations in the acoustic regime, showing excellent agreement between theory, simulation, and experiment. This work establishes quantum graph theory as a new paradigm for metamaterial design, offering a versatile and intuitive framework for modeling wave behavior and guiding the development of future metamaterial technologies
Towards energy benchmarking in residential buildings in the Kingdom of Saudi Arabia
No full textCountries worldwide are facing the challenges of improving energy efficiency and reducing carbon emissions to mitigate climate change, conserve resources, achieve energy security, and reap economic benefits. Over recent decades, the Kingdom of Saudi Arabia has experienced a rapid increase in domestic energy consumption. Notably, residential buildings have emerged as significant consumers, accounting for approximately 50% of the total electricity consumption within the building sector. This sustained expansion in energy demand raises concerns regarding environmental impact. Sustainability has recently become a fundamental issue in the Kingdom of Saudi Arabia (KSA), as one of the cornerstones of Saudi Vision 2030. One of the key initiatives under Vision 2030 is the Saudi Green Initiative, which aims to significantly reduce carbon emissions and achieve net zero emissions by 2060. To support the goals of the Saudi Green Initiative and promote sustainable growth, it is essential to develop effective strategies and tools for improving energy efficiency in residential buildings. One of the key challenges here is the lack of a national benchmark values that may help stakeholders to evaluate the energy consumption of their buildings. In response, this research attempts to develop a benchmarking framework tailored explicitly to the Saudi Arabian context and establish an energy benchmarking for residential buildings.
The research is divided into five milestones. The first milestone involves a thorough review of energy consumption in the KSA, identifying factors contributing to energy demand, and reviewing the current energy benchmarking methods for buildings. This review provides a comprehensive insight into the energy consumption of residential buildings and identifies the most appropriate energy benchmarking methods, which can be adapted to the Saudi Arabian building context. The second research milestone involves collecting data from a representative sample of residential buildings in the Saudi Arabia. The third milestone involves improving the specifications of the representative sample buildings to comply with the Saudi Building Code (SBC) requirements. The fourth milestone concerns conducting statistical tests and analyses, which are necessary to ensure that the research is based on sound data and assumptions, contributing to the overall quality of the research. The last milestone involves developing energy benchmarks for villas and apartments in the KSA. The benchmark can contribute to improving building energy performance in the region. The benchmark provides insights into factors influencing energy use, enabling stakeholders to assess the energy efficiency of their buildings. The benchmark also educates the public about energy consumption patterns, influences building asset value, and aids policymakers in setting energy-efficiency standards and implementing incentives.
The main findings reveal that applying the SBC-602/2018 requirements to the buildings can improve the energy consumption of villas and apartments by up to 19% and 40%, respectively. Moreover, the findings suggest that the normalised energy use intensity (EUInorm) benchmarks for villas and apartments that meet the SBC requirements in the Riyadh region are 60 kWh/m2/Yr and 98 kWh/m2/Yr, respectively. These benchmarking values were based on normalising the significant variables that affect energy consumption
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