Ghosts on the Tyne : the past as a resource for young working-class men in the post recessionary present

PhD ThesisThis thesis explores how young working-class men living in a former shipbuilding community – Walker in the East End of Newcastle-upon-Tyne - think about the interlinked and overlapping eras of industrialism and deindustrialisation. This includes the ways in which they remember industrial work and its loss, the strategies that they use to frame and comment upon this shared past, and how they draw on and invoke this history to help them understand the present and imagine the future. The experiences of thirty participants are explored to understand how their engagement with the shared past impacts upon their everyday lives and lived experiences in the post-industrial city. I argue that the young men who I researched remain connected to the past in multifarious ways and that they invoke and mobilise this history to help them navigate a socio-economic landscape whose contours have been shaped by the ‘Crisis Decades’ of deindustrialisation and our present ‘Age of Austerity’. This thesis makes three significant contributions. The first is demonstrating that the industrial past remains an important aspect of the lives of my participants. This builds on existing research and argues that although some of the young men with whom I worked tended towards thinking about the past in atavistic and reactionary ways, they were just as capable of engaging with it in a critical and nuanced manner. The second contribution explores the myriad of ways in which the participants remain connected with their shared past. These links to the past include familial connections, sensory recollections that are part of their personal biographies and engagements with material cultures of the home. Together this has established ongoing connections with industrial work in a community in which it is difficult to draw a clear division between an industrial past and a post-industrial present. The third contribution reveals how deindustrialisation represents an equally important part of the lived experiences of participants. Of particular interest is that although the closures and redundancies of industrial decline continue to cast a long shadow in Walker, the young men with whom I worked engaged with in creative ways, drawing on the past to imagine themselves as more than passive and victimised cogs in the machinery of capital

Mitochondrial dysfunction in the pathogenesis of osteoporosis

Ph. D. Thesis.Osteoporosis is a skeletal disease, characterised by reduced bone mass and altered microarchitecture, with subsequent loss of strength, increased fragility and risk of fragility fractures. Hip fractures alone cost the NHS £2 billion per year and have associated high morbidity and mortality. The pathogenesis of falling bone mineral density, ultimately leading to a diagnosis of osteoporosis is incompletely understood but the disease is currently thought to be multifactorial. Humans are known to accumulate mitochondrial mutations with age and mounting evidence suggests that this may be intrinsic to changes in phenotype with advancing age and pathogenesis of age-related disease. Mitochondrial mutations have been shown to occur from the age of 30 years in tissues such as colon, which interestingly correlates with commencement of decline in bone mineral density. This work has demonstrated the presence of mitochondrial DNA mutations in individual human stem cells and respiratory chain deficiency in human osteoblasts for the first time using novel techniques including single-cell PCR, flow cytometry and imaging mass cytometry. Work with the Polgmut/mut mouse model which acquire mitochondrial mutations at an enhanced rate, has demonstrated significantly higher levels of osteoblast respiratory chain deficiency compared to age matched wild type controls. This was associated with significantly reduced osteoblast population densities, reduced bone formation and increased osteoclast activity. Through these novel techniques, this work has demonstrated that underlying mitochondrial pathology directly affects mesenchymal stem cells and osteoblast potentially contributing to osteoporosis which will lead the way for development of new treatment modalities

Monitoring and modelling antibiotic resistance in Southeast Asian rivers

PhD ThesisPinpointing environmental antibiotic resistance (AR) hotspots in rivers in low-and-middle income countries (LMICs) is hindered by a lack of available and comparable AR monitoring data relevant to such settings. Addressing this problem, a comprehensive spatial and seasonal assessment of water quality and AR conditions in a Malaysian river catchment was preformed to identify potential 'simple' surrogates that mirror elevated AR. This included screening for β-lactam resistant coliforms, 22 antibiotics, 287 AR genes and integrons, and routine water quality parameters, covering absolute concentrations and mass loadings. Novel approaches were developed and applied to advance environmental microbiome and resistome research. To investigate relationships, standardised 'effect sizes' (Cohen's D) were introduced for AR monitoring to improve comparability of field studies. Quantitative microbiome profiling (QMP) was applied to overcome biases caused by relative taxa abundance data. In addition, Hill numbers were introduced as a unified diversity framework for environmental microbiome research. Overall, water quality generally declined, and environmental AR levels increased as one moved downstream the catchment without major seasonal variations, except total antibiotic concentrations that were higher in the dry season (Cohen's D > 0.8, P < 0.05). Among simple surrogates, dissolved oxygen (DO) most strongly correlated (inversely) with total AR gene concentrations (Spearman’s ρ 0.81, P < 0.05). This is suspected to result from minimally treated sewage inputs, which also contain AR bacteria and genes, depleting DO in the most impacted reaches. Thus, although DO is not a measure of AR, relatively lower DO levels reflect wastewater inputs, flagging possible AR hot spots. Furthermore, DO is easy-to-measure and inexpensive, already monitored in many catchments, and exists in many numerical water quality models (e.g., oxygen sag curves). Therefore, combining DO data and prospective modelling (e.g., with the watershed model HSPF) could guide local interventions, especially in LMIC rivers with limited data

The Role of Phosphate Acquisition in Promoting Stress Resistance and Virulence in a Major Human Fungal Pathogen

Ph. D. Thesis.The ability of pathogenic fungi to obtain essential nutrients from the host is vital for virulence. In Candida albicans, acquisition of the macronutrient phosphate (Pi) is regulated by the Pho4 transcription factor, which is important for both virulence and resistance to diverse and physiologically important stresses. A key aim of this work was to investigate the regulation of Pho4, and the roles of Pho80-Pho85 cyclin dependent kinase (CDK) signalling and inositol polyphosphates were explored. As reported in the model yeast Saccharomyces cerevisiae, the Pho80 cyclin functions as a negative regulator of Pho4 in C. albicans. However, in contrast to S. cerevisiae, the CDK inhibitor Pho81 also negatively regulates C. albicans Pho4; Pho4 accumulates in the nucleus in pho81Δ cells and Pi acquisition strategies are activated under Pi replete conditions. With regard to inositol polyphosphates, in contrast to that reported in S. cerevisiae, IP7 synthesis by the Kcs1 inositol pyrophosphate synthase was found to be largely dispensable for Pi homeostasis with Vip1-derived IP7 synthesis playing a more prominent role in C. albicans. The synthesis of the Pi storage molecule polyphosphate (polyP) is also regulated by Pho4. Previous work found that mobilization of Pi from polyP is one of the first responses evoked in response to Pi starvation and precedes activation of the Pho4 transcription factor. A further aim of this thesis was to investigate the importance of polyP mobilisation in the pathobiology of C. albicans. It was found that two polyphosphatases, Ppn1 and Ppx1, function redundantly in C. albicans to release Pi from polyP. Strikingly, it was shown that polyP mobilisation plays a role in Pho4 activation and stress resistance in C. albicans. Blocking polyP mobilisation also resulted in significant morphological defects. Consistent with these findings, data is also presented illustrating that polyP mobilisation is important for the virulence of C. albicans. Given the links between Pi acquisition and virulence, a further aim was to explore whether Pi acquisition could be exploited as a novel antifungal strategy. High-throughput screening of compound libraries revealed potential candidates directly targeting the PHO pathway, which present an exciting avenue for future work. Taken together, the findings presented in this thesis reveal novel insight into Pi homeostasis mechanisms in C. albicans and the potential of targeting this important virulence trait in the development of future therapeutic strategies

Advanced modelling and design considerations for interconnects in ultra- low power digital system

PhD ThesisAs Very Large Scale Integration (VLSI) is progressing in very Deep submicron (DSM) regime without decreasing chip area, the importance of global interconnects increases but at the cost of performance and power consumption for advanced System-on- Chip (SoC)s. However, the growing complexity of interconnects behaviour presents a challenge for their adequate modelling, whereby conventional circuit theoretic approaches cannot provide sufficient accuracy. During the last decades, fractional differential calculus has been successfully applied to modelling certain classes of dynamical systems while keeping complexity of the models under acceptable bounds. For example, fractional calculus can help capturing inherent physical effects in electrical networks in a compact form, without following conventional assumptions about linearization of non-linear interconnect components. This thesis tackles the problem of interconnect modelling in its generality to simulate a wide range of interconnection configurations, its capacity to emulate irregular circuit elements and its simplicity in the form of responsible approximation. This includes modelling and analysing interconnections considering their irregular components to add more flexibility and freedom for design. The aim is to achieve the simplest adaptable model with the highest possible accuracy. Thus, the proposed model can be used for fast computer simulation of interconnection behaviour. In addition, this thesis proposes a low power circuit for driving a global interconnect at voltages close to the noise level. As a result, the proposed circuit demonstrates a promising solution to address the energy and performance issues related to scaling effects on interconnects along with soft errors that can be caused by neutron particles. The major contributions of this thesis are twofold. Firstly, in order to address Ultra-Low Power (ULP) design limitations, a novel driver scheme has been configured. This scheme uses a bootstrap circuitry which boosts the driver’s ability to drive a long interconnect with an important feedback feature in it. Hence, this approach achieves two objectives: improving performance and mitigating power consumption. Those achievements are essential in designing ULP circuits along with occupying a smaller footprint and being immune to noise, observed in this design as well. These have been verified by comparing the proposed design to the previous and traditional circuits using a simulation tool. Additionally, the boosting based approach has been shown beneficial in mitigating the effects of single event upset (SEU)s, which are known to affect DSM circuits working under low voltages. Secondly, the CMOS circuit driving a distributed RLC load has been brought in its analysis into the fractional order domain. This model will make the on-chip interconnect structure easy to adjust by including the effect of fractional orders on the interconnect timing, which has not been considered before. A second-order model for the transfer functions of the proposed general structure is derived, keeping the complexity associated with second-order models for this class of circuits at a minimum. The approach here attaches an important trait of robustness to the circuit design procedure; namely, by simply adjusting the fractional order we can avoid modifying the circuit components. This can also be used to optimise the estimation of the system’s delay for a broad range of frequencies, particularly at the beginning of the design flow, when computational speed is of paramount importance.Iraqi Ministry of Higher Education and Scientific Researc

Low-grade Heat Recovery for Sustainable Automotive Manufacturing

PhD ThesisIn response to the need for UK manufacturing to decarbonise its production processes and become more sustainable, an increasing interest has been given to low-grade heat recovery technologies able to energy-efficiently control the temperature and humidity of the air supplied for product-specific applications. This study aims to investigate the novel use of liquid desiccant technology in automotive painting. The work includes a literature review on automotive manufacturing and painting to analyse processes, energy consumption, waste heat sources and the importance of temperature and humidity control, identifying how the liquid desiccant technology could match these conditions. Based on the knowledge of the main operating factors of the liquid desiccant technology, a framework for the techno-economic feasibility analysis of different heat recovery scenarios was developed. The techno economic analysis proposed new correlations for the analysis of the heat and mass transfer in the dehumidifier and regenerator of the liquid desiccant system able to predict the performance of the system under different conditions. Novel configurations for the use of liquid desiccant technology in the field of low-grade heat recovery and painting processes were designed and case studies were carried out to estimate the energy and economic performance of the designed novel configurations. Also, the performance of the technology in different outdoor air conditions, such as hot and humid climates, was estimated and compared with the UK. The case studies showed that the potential for heat recovery from transformers, compressors and thermal oxidisers and its use for air-conditioning, painting operation and air dehydration are high enough to achieve significant energy savings in terms of natural gas and electricity. Also, significant energy savings for cooling and dehumidification are achievable by employing the technology in hot and humid climates. Potential innovative solutions to increase the energy and economic performance of the liquid desiccant technology for automotive painting were also recommended. It was concluded that energy-efficient use of low-grade heat sources to drive the liquid desiccant technology could help the automotive industry to reduce its energy consumption and increase the sustainability of its production process

Reactive coupling for biodiesel production with integrated glycerol valorisation

Ph. D. Thesis.The increasing production of biodiesel globally over the last 20 years has increased the supply of “crude” glycerol. Initially, glycerol was a valuable by-product but is now low value or a waste product, due to mismatch between supply and demand. Valorisation of glycerol is an obvious route to improving the process economics. In this work, we investigated glycerols in situ valorisation by conversion to various oligomers (used in the pharmaceutical, food, and cosmetics industries) and glycerol ethers (used as oxygenated compounds to improve fuel combustion in Diesel engines). This is an example of "reactive coupling", a technique in which the by-product of one reaction is simultaneously converted to an added value product in a second reaction (in a single "pot"), thereby reducing the number of process steps. The main objective for this work is to produce glycerol free biodiesel with reduced methanol usage and fast triglyceride conversion using reactive coupling as a novel technique. This work will for the first time demonstrate the production of biodiesel and glycerol ethers in a single pot. This aimed to reduce glycerol byproduct and methanol recycling. First, the study the convert glycerol in a stainless steel reactor. Reactive coupling was then performed to convert triglyceride with simultaneous conversion of the glycerol to added value products. Sulfuric acid was used as catalyst for the reaction, as it is compatible with all the desired reactions. It is also cheap and can tolerate triglyceride with high FFA levels during biodiesel production. High temperature in transesterification results in fast conversion of triglyceride. The catalyst and temperatures used are suitable for both biodiesel reaction and glycerol etherification. Highest conversion of glycerol achieved was 68%, with over 90% selectivity to diglycerol in 5h. To avoid producing undesired by-products (such as acrolein) and higher oligomers (such as pentaglycerol), the recommended conditions are 3 wt% catalyst concentration, and a temperature of less than 150 oC. Furthermore, a kinetic model was fitted to the experimental data with activation energy of 112 kJmol-1 and pre-exponential factor of 2.18x1011 L.mol-1s-1. The thermodynamic analysis showed the reaction to be endothermic, less disordered, and non-spontaneous with an enthalpy (ΔH) 109 kJmol-1, entropy (ΔS) – 38.1 Jmol-1K-1, and Gibbs free energy (G) 125 kJmol-1 respectively. Reactive coupling achieved complete conversion of triglycerides and 100% FAME yield in 1h. About 60% of the glycerol was converted in parallel, with approximately 90% selectivity to glycerol ether and 10% to diglycerol. A temperature of not more than 150 oC is sufficient for this process with 3 wt% catalyst concentration and molar ratio 4:1 – 6:1. Some of the benefits of the reactively coupled process vs conventional processing are the rapid separation of the biodiesel phase from the glycerol phase, low alcohol to oil ratios, and the production of value-added products from the crude glycerol. The model should make scale-up of this process more predictable and robust. Combined reactive extraction and reactive coupling were also studied, i.e., reactive coupling on the oilseeds, rather than the oil. Over 90% of biodiesel production was achieved and complete conversion of the glycerol to glycerol ether and polyglycerol. However, a substantially higher molar ratio of methanol to oil (400:1) was required, likely to be uneconomic. There were various non-triglyceride products in the extract, which would probably necessitate extra downstream processing. In summary, for the first time, this work demonstrates reactive coupling to produce biodiesel, polyglycerol, and glycerol ether production using sulfuric acid as catalyst. The main advantages of this technique were: i. Reduced glycerol by-product by up to 60%. ii. Reduced methanol usage, from 20:1 to 4:1 – 6:1. This will remove/reduce downstream processing. iii. Rapid conversion of triglyceride. iv. Easy/fast separation of glycerol phase from FAME phase. Furthermore, this study demonstrated proof-of-concept for combined reactive extraction and reactive coupling. Hence, oil in seeds can be converted directly to biodiesel, glycerol, and added-value products. This study’s success shows that the glycerol by-product can be converted to a useful product directly during biodiesel production. Potentially, this will reduce waste generation and diversify the market of biodiesel producers.Petroleum Technology Development Fund (PTDF), Nigeri

Development of Novel PET-MRI Methodologies for Dementia Research

Ph. D. Thesis.Changes to cerebral mitochondrial function have been implicated in neurodegenerative pathology and in the process of healthy ageing. Phosphorus MR spectroscopy (31P-MRS) with magnetisation transfer (MT) can be used to make direct in vivo measurements of mitochondrial function. By combining 31P-MT with simultaneous FDG-PET imaging it is possible to assess the relationship between glucose hypometabolism, which is a characteristic feature of Alzheimer’s disease, and mitochondrial function. The primary aim of this project was to develop and evaluate the methodology for simultaneously measuring glucose metabolism and mitochondrial function with PETMR. An accelerated technique for 31P-MT was implemented, utilising kinetic modelling to reduce the acquisition time. This facilitates a multi-voxel implementation, allowing the rate of the creatine kinase reaction, k1, to be measured in multiple locations across the brain within a single scanning session. This approach was tested in phantoms and in vivo through an assessment of repeatability and comparison with a more established technique. The methodology for performing PET attenuation correction with non-standard MR RF coils was also developed and evaluated. The 31P-MT methodology was applied to investigate regional changes in mitochondrial function during the healthy ageing process. A global reduction in k1 was observed between young and middle-aged subjects, followed by a stabilisation between the middle-aged and elderly groups. This pattern is driven by voxels in the anterior region of the brain, with mitochondrial function remaining consistent across the age groups in the posterior region. This suggests that normal cognitive function in old age is associated with the maintenance of k1 in the posterior region of the brain. The combined PET-MRS methodology was applied in a small number of healthy subjects to demonstrate the approach to probing cerebral bioenergetics. This methodology has the potential to provide new insights into the pathological mechanisms of mitochondrial disease and Alzheimer’s disease.GE Healthcar

Predicting seizure spread andneurosurgical outcomes in epilepsy bycombining neuroimaging, machinelearning, and computer modelling

PhD ThesisBackground: Epilepsy is a neurological disorder of abnormal brain network in which seizures originate and spread via patient-specific spatial and temporal pathways. Disrupting these epileptic networks can enable seizure control; therefore, it is crucial to map, quantify, and understand these networks. This thesis aims to quantify the whole-brain structural network abnormalities of patients with focal and generalised epilepsy along with patientspecific network disruptions caused by epilepsy surgery. Method: We developed a novel patient-specific metric to quantify structural network abnormality at every brain region by standardising whole-brain structural networks of patients with healthy structural networks. To quantify local changes in the white-matter structure, we applied quantitative neuroimaging techniques and a computational model for making predictions on mechanisms of epilepsy development. We combined the network-based measures in robust cross-validated machine learning models to predict neurosurgical outcomes and seizure spread. Results: In drug-resistant focal epilepsy patients, structural network abnormality associated with post-surgical seizure recurrence and patient history of focal to bilateral tonic-clonic seizures. Combined with routinely acquired clinical variables, we predicted the patientspecific probability of seizure recurrence after surgery. In patients with idiopathic generalised epilepsy, we found localised abnormalities in major white-matter fascicles. The thalamocortical computer model of spike-wave seizures implicated the role of cortico-reticular connections in mechanism of epileptogenesis. Significance: This thesis highlighted the heterogeneity between patients that may be making them susceptible to a varied response for the same treatment. We offer practical tools to quantify these heterogeneities to complement clinical decision-making for effective patient stratification and tailored treatments

Modelling the dynamics of the upper ocean in the Eastern Tropical Pacific and its interactions with the tropical atmosphere

Ph. D. Thesis.The physical behaviour of the central and eastern tropical Pacific regions is characterized by a complex variety of multi-scale interacting processes. The Madden-Julian Oscillation (MJO) is the primary mode of intraseasonal variability in the tropical atmosphere. Although convection, together with related cloudiness and precipitation, tends to dissipate east of the 180º meridian, the MJO wind signal continues to progress eastward across the eastern Pacific and South America and into the tropical Atlantic. This research explores numerically the response of the upper ocean in the central and eastern tropical Pacific regions to MJO forcing. We use a global, intermediate resolution configuration of the Nucleus for European Modelling of the Ocean (NEMO) framework version 3.6, referred to as ORCA1-LIM3, forced with daily atmospheric forcing from the Coordinated Oceanic Reference Experiments (CORE) dataset version 2, for the period 1990 to 2000. The results show a strong influence of the MJO on temperature, salinity, zonal currents, and vertical currents in the first 300 m of depth, particularly at the equator. The intraseasonal wind is the key forcing factor that modulates the impact of the MJO. This is except for the temperatures at the mixed layer depth, the halocline, and the pycnocline, in the regions of the Central American Pacific coast and the southwestern Mexican coast where the influence of the MJO can be observed even in the absence of intraseasonal wind forcing. The impact of the MJO on the ocean's internal intraseasonal variability is analysed in the case of tropical instability waves. We show that the barotropic and baroclinic conversion terms that control the eddy kinetic energy levels in the region vary in magnitude with the phases of the MJO. These results have ramifications for understanding ocean intraseasonal variability, which is a critical step towards improving our ability to make more reliable mid-range ocean weather and ocean climate forecasts for the region.Ministry of Science, Technology, and Communications of Costa Ric