Doctor of Philosophy

dissertationThe unique plasmonic properties of noble metal nanocrescents were investigated using optical spectroscopy techniques and correlated with tunable structural features. Multiple characteristics were observed that offer advantages for increased sensitivity a

Clinical and experimental studies on the role of APC in neoplasia

The adenomatous polyposis coli gene (APC) is located at human chromosome 5q21. Germline mutations in the APC gene characterise the Mendelian dominant inherited disorder, familial adenomatous polyposis coli (FAP). FAP patients develop numerous adenomas within the large intestine, some of which ultimately progress to carcinoma. A more general role for APC mutations in neoplasia is suggested by the fact that FAP patients are at risk of developing tumours of the brain, thyroid, bone and focal proliferative lesions ( "desmoid tumours ") of the connective tissue. Furthermore, mutations in the APC gene and / or loss of heterozygosity (LOH) at 5q21 have been reported in a range of sporadic tumours including tumours of the lung.This thesis firstly investigated the occurrence of LOH at chromosome 5q21 in subtypes of human non -small cell lung cancer (NSCLC). Allele loss was compared in adenocarcinoma (ADC) and squamous cell carcinoma (SCC), the most common forms of NSCLC. Further sub -classification of the ADC subgroup was carried out to compare ADC arising in the bronchus versus the parenchyma, as determined by histology. Four genetic polymorphisms in the APC and MCC (mutated in colorectal cancer) genes at chromosome 5q21 were analysed for LOH in 92 consecutive primary SCC and ADC of the lung. Loss of heterozygosity was identified in at least two polymorphic loci in 40% (27/68) of informative cases. There was no significant difference in the frequency of LOH between SCC and ADC cases (Chi- squared test, df=1, p= 0.446) or within the ADC subgroups; bronchial and parenchymal origin (Fisher's exact test; two -tailed test p= 0.237). Results revealed that the frequency of LOH within the SCC group and the ADC remained similar at each tumour stage, Fisher's exact test (two -tailed test; p >0.2 in all cases). This result suggests that loss of 5q21 does not promote metastatic spread in these histological groups. Following the subdivision of ADC into site of origin, results revealed that LOH was not associated with increasing tumour stage in the parenchymal or bronchial subgroups, as determined by Fisher's exact test (two -tailed test; p >0.2 in all cases), or that the frequency of LOH differed between subgroups at each tumour stage, Fisher's exact test, two tailed test; p >0.2 in all cases.Thirty tumours showing LOH at one or more polymorphic sites were examined for mutations in the mutation cluster region (MCR) of APC by single- strand conformational polymorphism (SSCP) analysis. Mutations were not detected in any of these cases. These results suggest that it is likely that a tumour suppressor gene on 5q other than APC is involved in the pathogenesis of lung cancer.Secondly, this thesis examined ADC of parenchymal or bronchial origin by the independent criterion of K -RAS mutation, a known feature in pulmonary ADC. Sixty -five surgically resected primary pulmonary adenocarcinomas were screened for mutations at codon 12 of the K -RAS gene by a PCR based method. Mutations in position 1 or position 2 of codon 12 were detected in 16 tumours (25 %). When analysed by site of origin, mutations were seen in 9/26 (35 %) parenchymal and in 0/12 bronchial ADC. This difference is significantly different, as determined by Fisher's exact test (two -tailed test; p= 0.0355). No association was noted between the presence ofK -RAS mutation at tumour stage, indicating that K -RAS mutations are not associated with metastatic spread. K -RAS mutations were also detected in 5 out of 32 foci of alveolar atypical hyperplasia (AAH), a lesion considered on histological grounds to be the precursor to parenchymal ADC. DNA sequencing showed that the great majority of mutations in both ADC and AAH were G -T transversions. These findings provide support for the classification of pulmonary ADC into bronchial and parenchymal subtypes and also provide molecular evidence to support the importance of AAH in the development of parenchymal cancers.Finally, this thesis described the generation and initial characterisation of a murine APC transgenic founder line designed as a model to investigate the effects of aberrant expression of APC. Several Apc mutant murine models of FAP already exist. These all carry a heterozygous mutation in the Apc gene. The Min mouse (multiple intestinal neoplasia) is an example and carries a mutation at codon 850. All current models however are of limited use as mice homozygous for Apc mutations die at approximately 5 6.6 days post coitum, limiting analysis to Apc heterozygotes. Homozygous loss of Apc therefore depends upon additional somatic events that are not under direct experimental control and this may be associated with additional, undisclosed genetic events. Here a transgenic approach was taken to generate animals where the expression of the APC transgene is conditionally inactivated using the Cre -loxP recombination system of the bacteriophage P 1. APC cDNA was flanked by loxP sequences and the promoter sequence of the ubiquitously expressed murine phosphoglycerate kinase (Pgk) gene cloned upstream of the APC cDNA to drive the expression of the transgene. Pro -nuclear injection was used to deliver the APC transgene into oocytes of wildtype mice (F1 (C57BL /6 x CBA)). A transgene positive founder line was established and transcription of the APC cDNA confirmed in a wide variety of tissues using reverse transcription polymerase chain reaction (PCR). To date, transgene positive mice on an Apc wildtype background show no gross phenotype. Embryonic fibroblasts were derived and Cre- recombinase delivered by infection with a replication deficient adenovirus. APC cDNA excision was confirmed by PCR. The founder line was crossed with the C57BL /6 Apc +/min line. Transgene positive Apc +Irvin mice were interbred and offspring screened to identify whether the APC transgene can rescue the Apc M II lethal phenotype. To date embryonic rescue has not been identified

Engineering For One Planet: Resources For Infusing Sustainability And Leadership Competencies Across All Engineering Disciplines

Engineering for One Planet (EOP) is an initiative to transform engineering education and equip all future engineers across all disciplines with the fundamental skills and principles of social and environmental sustainability. Catalyzed by The Lemelson Foundation and VentureWell in collaboration with hundreds of sustainability advocates across sectors, the EOP initiative envisions a world in which all engineers play a critical role in ensuring that the solutions of today do not become the problems of tomorrow, restoring and regenerating our environment, and improving lives for all. EOP is accelerating curricular transformation by supporting faculty change efforts and fostering collaboration among stakeholders across sectors. Experts from academia, civil society and government co-developed the EOP Framework in 2020, including an adaptable and adoptable menu of core and advanced sustainability and leadership learning outcomes. Five universities pilot tested the EOP Framework in curricular changes over two years, and the EOP Framework was revised in 2022. In 2023, EOP launched companion teaching guides with step-by-step guidance and free teaching resources for integrating learning outcomes from the EOP Framework. To date, more than 120 faculty have used the EOP Framework to generate curricular changes in dozens of diverse engineering disciplines and programs, impacting thousands of students. EOP makes its teaching tools available for free and is designed for flexible adoption and adaptation to encourage rapid expansion of sustainability into engineering education. This presentation will enable participants to learn about the resources available through EOP, gain ideas from successful curricular change approaches and get involved in EOP’s growing global community

How To Use New Tools To Integrate Sustainability Into Engineering Teaching

Recently, three projects have addressed the challenge that while many excellent resources on sustainability education exist, there aren’t many that explicitly guide engineering educators to integrate these into their teaching, or indeed that are intended to upskill engineering academics to be able to deliver this teaching. These projects are the Reimagined Degree Map project undertaken by Engineers Without Borders UK (sponsored by the Royal Academy of Engineering), the Sustainability Toolkit project undertaken by the UK’s Engineering Professors’ Council (sponsored by Siemens and the Royal Academy of Engineering), and the Engineering for One Planet Framework and two companion guides, co-created by hundreds of engineering education stakeholders (sponsored The Lemelson Foundation). All aim to build the capacity of educators to embed sustainability knowledge, skills and mindsets in their modules, courses or curriculum that will enable students to become competent in globally responsible engineering practice. In cooperation with academic, industry, and advocacy group leaders, these projects have resulted in the development of several educational tools that are presented in the workshop

Modeling Quantum Enhanced Sensing on a Quantum Computer

Quantum computers allow for direct simulation of the quantum interference and entanglement used in modern interferometry experiments with applications ranging from biological sensing to gravitational wave detection. Inspired by recent developments in quantum sensing at the Laser Interferometer Gravitational-wave Observatory (LIGO), here we present two quantum circuit models that demonstrate the role of quantum mechanics and entanglement in modern precision sensors. We implemented these quantum circuits on IBM quantum processors, using a single qubit to represent independent photons traveling through the LIGO interferometer and two entangled qubits to illustrate the improved sensitivity that LIGO has achieved by using non-classical states of light. The one-qubit interferometer illustrates how projection noise in the measurement of independent photons corresponds to phase sensitivity at the standard quantum limit. In the presence of technical noise on a real quantum computer, this interferometer achieves the sensitivity of 11\% above the standard quantum limit. The two-qubit interferometer demonstrates how entanglement circumvents the limits imposed by the quantum shot noise, achieving the phase sensitivity 17\% below the standard quantum limit. These experiments illustrate the role that quantum mechanics plays in setting new records for precision measurements on platforms like LIGO. The experiments are broadly accessible, remotely executable activities that are well suited for introducing undergraduate students to quantum computation, error propagation, and quantum sensing on real quantum hardware.Comment: 11 pages, 8 figure

Neuropeptides, amines and amine receptors in the human spinal cord: the effects of Parkinson's disease

The aims of this study were to investigate (i) the levels of catecholamines, indoleamines, substance P and thyrotrophin-releasing hormone (TRH) in the post-mortem spinal cord of subjects who had died with Parkinson's disease and to compare them with those of control subjects (ii) adrenergic and serotonergic receptors in the post-mortem Parkinsonian and control spinal cord and (iii) the effects of subject age and sex and the interval between death and post-mortem (PMI) on the levels of neurotransmitters and neuropeptides and on receptor binding in post-mortem tissue. To perform these investigations (i) a sensitive radioimmunoassay which is specific for substance P and has low cross-reactivity with other similar peptides and (ii) a common extraction medium for the concomitant extraction of catecholamines, indoleamines, substance P and TRH from CNS tissue were developed. The main findings were: There were significant correlations between the levels of 5HT, TRH and α2-adrenoceptor binding and both subject age and the PMI. In Parkinson's disease compared with control subjects: (i) the levels of noradrenaline were significantly reduced in the thoracic ventral region of the spinal cord,(ii) dopamine levels were higher in the thoracic ventral and dorsal spinal cord,(iii) in the lumbar spinal cord 5HT levels were significantly reduced in the dorsal horn with an increase in the ratio of 5HIAA/5HT, (iv) noradrenaline levels were reduced in both dorsal and ventral horns of the lumbar spinal cord and (v) there were no differences between the levels of substance P and TRH in any spinal cord region. There were no measurable 5HT1A or 5HT2 binding sites in the human spinal cord under the conditions used. However, specific α2-adrenoceptor binding was defined in terms of binding affinity and number of receptors in the spinal cord

Digital Energetics

Media and energy require joint theorization as they are bound together across contemporary informational and fossil regimes. Digital Energetics traces the contours of a media analytic of energy and an energy analytic of media across the cultural, environmental, and labor relations they subtend. Focusing specifically on digital operations, its authors analyze how data and energy have jointly modulated the character of data work and politics in a warming world

Exploring the Impact of Patient and Public Involvement in a Cancer Research Setting

An enduring theme in the literature exploring patient and public involvement (PPI) in research has been the focus on evaluating impact, defined usually in terms of participants’ practical contribution to enhancing research processes. By contrast, there has been less emphasis on the perspectives and experiences of those involved in PPI. Drawing on qualitative data with people involved in the National Cancer Research Network in the United Kingdom, we report on what motivated participants to get involved and their experiences of involvement in this setting. We highlight how those involved in PPI often espoused the notion of the “good citizen,” with PPI in research being a natural extension of their wider civic interests. However, our findings also highlight how PPI was an important resource, utilized by participants to make sense of living with chronic illness. We suggest that PPI in research also offers spaces for the reconfiguration of self and identity

Neuropeptides, amines and amine receptors in the human spinal cord: the effects of Parkinson's disease

The aims of this study were to investigate (i) the levels of catecholamines, indoleamines, substance P and thyrotrophin-releasing hormone (TRH) in the post-mortem spinal cord of subjects who had died with Parkinson's disease and to compare them with those of control subjects (ii) adrenergic and serotonergic receptors in the post-mortem Parkinsonian and control spinal cord and (iii) the effects of subject age and sex and the interval between death and post-mortem (PMI) on the levels of neurotransmitters and neuropeptides and on receptor binding in post-mortem tissue. To perform these investigations (i) a sensitive radioimmunoassay which is specific for substance P and has low cross-reactivity with other similar peptides and (ii) a common extraction medium for the concomitant extraction of catecholamines, indoleamines, substance P and TRH from CNS tissue were developed. The main findings were: There were significant correlations between the levels of 5HT, TRH and α2-adrenoceptor binding and both subject age and the PMI. In Parkinson's disease compared with control subjects: (i) the levels of noradrenaline were significantly reduced in the thoracic ventral region of the spinal cord,(ii) dopamine levels were higher in the thoracic ventral and dorsal spinal cord,(iii) in the lumbar spinal cord 5HT levels were significantly reduced in the dorsal horn with an increase in the ratio of 5HIAA/5HT, (iv) noradrenaline levels were reduced in both dorsal and ventral horns of the lumbar spinal cord and (v) there were no differences between the levels of substance P and TRH in any spinal cord region. There were no measurable 5HT1A or 5HT2 binding sites in the human spinal cord under the conditions used. However, specific α2-adrenoceptor binding was defined in terms of binding affinity and number of receptors in the spinal cord