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Linking obesity with breast cancer: effect of fat tissue microenvironment on tumour growth and invasion
No full textAbstract not currently available
Investigating the role of Ajuba LIM domain protein in Pancreatic Ductal Adenocarcinoma
Get PDFThe relationship between a cell and its microenvironment is complex, dynamic and bidirectional. In cancer, an altered extracellular matrix (ECM) composition promotes tumour development through the modification of activities such as cellular proliferation, metabolism, mobility and survival. In pancreatic ductal adenocarcinoma (PDAC), the high matrix rigidity results in large tumours and leads to increased invasiveness. The ECM stiffness is sensed by cells through mechanosensing proteins and transduced by mechanotransduction actors into a cellular response. YAP/TAZ, several LIM domain proteins and a plethora of other proteins are involved in mechanotransduction pathways. Using polyacrylamide hydrogels of tuneable stiffnesses, I showed that cell morphology, proliferation, mRNA expression, transcription factors activities and cellular metabolism are modified by stiffness in a pancreatic KPC-derived mouse cell line (KRasG12D and p53R172H) named PDACA. The combination of polyacrylamide hydrogel stiffness and the use of RNA sequencing technology allowed me to identify Ajuba, a LIM protein, as a mechanosensitive protein. Ajuba was shown to be a versatile scaffold protein involved in many cellular activities such as adhesion, cell migration, invasion, and proliferation in many cancer types. However, in PDAC, the role of Ajuba is mostly unexplored. Our study shows that Ajuba localises at mature focal adhesions in PDACA cells. Interestingly, the downregulation of Ajuba induces a decrease in cellmatrix adhesion and an increase in cell invasion. However, no modification of focal adhesion formation, focal adhesion turnover or cellular migration was found. Finally, using a combination of polyacrylamide hydrogel stiffness and the use of RNA sequencing technology, I also showed that the downregulation of Ajuba modifies both mRNA expression and transcription factor activities. Collectively our results indicate that Ajuba is both a mechanosensitive and a mechanotransducer in PDAC
Wireless PBFT consensus blockchain networks
Get PDFAs wireless networks evolve towards increasingly heterogeneous environments with a growing number of mobile users, ensuring security and privacy becomes paramount. Blockchain technology, renowned for its decentralization and security features, presents a promising solution to these challenges. Practical Byzantine Fault Tolerant (PBFT), a voting-based consensus blockchain, is suitable for the wireless network because it is not computationally intensive, as most mobile devices are computationally limited due to the battery size and processing limitations. Moreover, PBFT can provide the essential byzantine fault tolerance to provide resistance to network failure and malicious attacks. This thesis investigates the application of PBFT consensus mechanisms to wireless networks, specifically focusing on IEEE 802.11 protocols, base station-enabled architectures and a hybrid network solution.
The performance of the wireless PBFT network using the IEEE 802.11 broadcast scheme under unsaturated conditions is investigated. Through a Markov model, the throughput, transmission success probability, and transaction confirmation delay of such a network are derived. View change is a mechanism incorporated to provide liveness to the PBFT, but frequent view change can undermine the overall performance of the PBFT network by delaying the consensus. The view change delay is introduced and derived in reference to the transaction confirmation delay. The impacts of channel contention from the non-PBFT nodes on the performance of the wireless PBFT network are further investigated. Channel contention impairs the transmission success probability and increases the chance of view change. The findings highlight a critical minimum transmission success probability required for effective PBFT consensus, proposing optimal configurations of the packet arrival rate and contention window size to balance success probability and network performance.
Furthermore, this thesis proposes an innovative PBFT framework leveraging base stations for inter-node communication. This approach reduces communication complexity and node transmit power while enhancing scalability and consensus success probability. The uplink and downlink communication between the base station and nodes are modelled based on the signal-to-interference-plusnoise ratio (SINR) threshold, which measures the strength of the wanted signal compared to the unwanted interference and noise. A good SINR is essential for reliable data transmission speed and integrity. A novel ‘timeout’ mechanism is incorporated to mitigate communication overheads. The performance is evaluated by metrics including consensus success probability, communication complexity, view change delay, view change occurrence probability, average transmit power, consensus delay and consensus throughput. The proposed framework demonstrates improvements in consensus success probability and throughput and reduced consensus delays compared to traditional PBFT implementations. A special case with f deterministic Byzantine nodes is also presented. The optimal configuration for achieving the target consensus success probability to provide analytical guidance for deploying wireless PBFT networks is analysed and demonstrated with numerical results.
To mitigate the influence of the poor wireless connection, which results in increased view changes and reduced consensus success probability, a hybrid PBFT network integrating a private and a public cloud is introduced. The security performance of the hybrid network is assessed in the presence of crashes and malicious attacks with decentralised and centralised coordination modes. This hybrid approach shows enhanced security capabilities compared to conventional PBFT, particularly when the private cloud is secure.
Overall, this thesis provides a comprehensive analysis of PBFT’s application in wireless networks, offering practical insights and solutions to improve security, efficiency, and scalability in future wireless and IoT environments
Investigating the role of 70 bp repeats and VSGs in formation of DNA double strand breaks in Trypanosoma brucei bloodstream expression sites
Get PDFTrypanosoma brucei are protozoan parasites, which evade the immune system by antigenic variation with the use of a variant surface glycoprotein (VSG). A double strand DNA break (DSB) has been proposed as the first step in VSG switching and it has previously been demonstrated that when DNA breaks arise in the active expression site, this leads to accumulation of RNA-DNA hybrids, R-loops, however, there is still uncertainty of how and where the double stranded breaks form. Mapping of DNA breaks in the expression site by BLISS has implicated two key features in the formation of the breaks: the VSG 3’ end where the break is found and in the 70 bp repeats. This project aimed to examine the relative contribution of both the VSG 3’ end and the 70 bp repeats to the formation of a DNA break and VSG switching. To address this, bloodstream form T. brucei cell lines with alterations in the active bloodstream expression site (BES) were generated using CRISPR/Cas9. Two regions of 70 bp repeats were successfully removed and a distinct VSG sequence (VSG121) was relocated to two other locations within the active BES. In addition, a plasmid containing the VSG of the active expression site in this cell line (VSG221) was successfully generated. To confirm alterations to the active BES PCR screening, VSG immunofluorescence, and Oxford Nanopore sequencing were performed. It was identified by Oxford Nanopore sequencing that when the large section of 70 bp repeats was removed, the smaller section of 70 bp repeats expanded. In future work, these cell lines will allow for investigation of R-loops and double strand breaks by comparison of DRIP-seq and INDUCE-seq/BLISS data with the natural organisation of the active BES and so, give an insight into whether the 70 bp repeats and/or VSG sequence drive R-loop and DNA DSB formation and if they are necessary for break formation linked to VSG switching
Human T cell responses to bone regenerating biomaterials
Get PDFEnhanced bone healing and bone provision are fundamental therapeutic orthoplastic strategies for complex fracture management, and for post-oncological or traumatic composite wounds with critical bone loss. Such surgery remains highly challenging and potentially morbid, such that synthetic bone provision would have particular appeal. It could also be indicated to enhance prosthetic fitment after blast injury, and for restoration after digit or limb loss or congenital absence.
Regenerative medicine aims to improve the body’s inherent regenerative capacity after injury, or to replace damaged or lost tissues with fully functional, engineered ones, to address unmet clinical need. Bone requires both scaffold and cellular therapy options. Bioengineered tissues come in many forms, with allogenic mesenchymal stem cell (MSC) based biomaterials achieving successful osteogenesis in vitro, and in animal models in vivo.
Despite these advances, the T cell immune reactivity of a human host towards bone biomaterials remains unknown yet may present a critical barrier to the clinical translation of these promising therapies. Ethical investigation has been precluded through lack of a human in vitro model. Here, a novel, human, multicellular, in vitro, T cell response model was established. Host responses to osseoreconstructive fibronectin and laminin MSC biomaterials were defined across their differentiation into osteoblasts, for the first time. Subsequent, T cell responses to engineered immunomodulation of the allogenic biomaterial were examined.
These data demonstrate successful in vitro T cell modelling. MSC biomaterials triggered human T cell activation responses that increased with osteogenic differentiation. These responses were mixed encompassing regulatory, Thelper (Th) 1 and Th17 associated responses that were detectable by 5 days in vitro. Furthermore, manipulation of the biomaterial glycoprotein did not change the surface activation marker expression of T cells but revealed differences in the cytokine response. Less osteogenic differentiation of MSCs occurred on laminin biomaterials, highlighting the importance of fibronectin for functional presentation of bone morphogenic protein 2 (BMP-2) to guide successful osteogenesis. Finally, manipulation of the immune microenvironment, towards pro-inflammation, appeared to reduce the viability of the allogenic MSCs within the biomaterial, which may have consequences for biomaterial engraftment, longevity and function in vivo
Economic inferences using language models
Get PDFI consider how causal and predictive economic inference problems can be solved using textual data. In doing so, I particularly investigate opportunities created by recent advances in natural language modelling, which appear to remain underexplored as an econometric methodology—a gap this thesis aims to help fill. Through this lens, I revisit three economic inference problems: estimation of the dynamic causal effects of monetary policy, forecasting of macroeconomic aggregates, and predicting financial risk premia. Re-examining the dynamic causal effects of UK monetary policy, I find that orthogonalising conventional instrumental variables with respect to large language model-extracted information appears to help resolve longstanding puzzles within empirical monetary economics. Examining the incremental value of the text of the Federal Reserve System’s ‘Beige Book’ for forecasting US macroeconomic aggregates, I find apparent improvements in forecast accuracy, but also show how the inclusion of language model-generated predictors can make bias-free forecast evaluation challenging. Considering an investor’s inference problem, I make a formal connection between microeconomic theory regarding rankings of information structures and the practical choice of which words or tokens should be prioritised in financial language modelling. Taken together, these findings underscore that language models are a powerful addition to the econometric instrumentarium available to researchers and practitioners. Whilst there are pitfalls to avoid, there can be little doubt that language models will become essential tools for drawing economic inferences
Restricted and repetitive behaviours in autistic women: a mixed methods approach
Get PDFAbstract available at each chapter
Guideline directed medical therapy for secondary prevention after coronary artery bypass grafting
Get PDFAtherosclerotic cardiovascular disease, and specifically coronary artery disease is a major cause of mortality and morbidity in the Unites States. A large proportion of patients with atherosclerotic cardiovascular disease receive coronary artery bypass grafting. However, despite this surgical intervention, patients are at continued risk for progression of atherosclerosis, both in their native coronary arteries as well as the conduits used for the coronary artery bypass surgery. Patients also have other cardiovascular risk factors, specifically diabetes, obesity, and many have poly-vascular disease. The American Heart Association has recommendations for pharmacotherapy in these patients, which is termed as guideline directed medical therapy for secondary prevention of cardiovascular disease.
The US Department of Veteran Affairs is the single largest unified healthcare system in the United States and supports the healthcare needs of approximately 9 million US Veterans. These people are older, more frail, and have more cardiovascular risk factors than the average US population. All these conditions put them at higher risk for recurrent cardiovascular events after receiving coronary artery bypass surgery.
Therefore, the overarching aim of my PhD was to study the use of guideline directed medical therapy and factors associated with non-use among US Veterans. To achieve this aim, six papers were completed and included in this thesis. The broad synopsis of the thesis is that guideline directed medical therapy does improve cardiovascular outcomes. However, the present use of these therapies among US Veterans is suboptimal; additionally, some reasons for non-use were identified. Therefore, in conclusion, more work needs to be done to ensure improved use of these life-saving therapies.
Links to the articles.
Manuscripts included in this thesis:
Deo SV, Al-Kindi S, Motairek I, McAllister D, Shah ASV, Elgudin YE, Gorodeski EZ, Virani S, Petrie MC, Rajagopalan S, Sattar N. Impact of Residential Social Deprivation on Prediction of Heart Failure in Patients With Type 2 Diabetes: External Validation and Recalibration of the WATCH DM Score Using Real World Data. Circ Cardiovasc Qual Outcomes. 2024 Mar;17(3):e010166. doi: 10.1161/CIRCOUTCOMES.123.010166. Epub 2024 Feb 8. PMID: 38328913; PMCID: PMC11093755.
Deo SV, Althouse A, Al-Kindi S, McAllister DA, Orkaby A, Elgudin YE, Fremes S, Chu D, Visseren FLJ, Pell JP, Sattar N. Validating the SMART2 Score in a Racially Diverse High-Risk Nationwide Cohort of Patients Receiving Coronary Artery Bypass Grafting. J Am Heart Assoc. 2023 Nov 7;12(21):e030757. doi: 10.1161/JAHA.123.030757. Epub 2023 Oct 27. PMID: 37889195; PMCID: PMC10727407.
Deo SV, McAllister D, LaForest S, Altarabsheh S, Elgudin YE, Dunlay S, Singh S, Parikh S, Sattar N, Pell JP. Disparities in PCSK9 Initiation Among US Veterans with Peripheral Arterial Disease or Cerebrovascular Disease. Am J Cardiovasc Drugs. 2023 May;23(3):311-321. doi: 10.1007/s40256-023-00576-7. Epub 2023 Mar 22. PMID: 36947397.
Deo S, Ueda P, Sheikh AM, Altarabsheh S, Elgudin Y, Rubelowsky J, Cmolik B,
Hawkins N, McAllister D, Ruel M, Sattar N, Pell J. Lipid Lowering in "Very High Risk" Patients Undergoing Coronary Artery Bypass Surgery and Its Projected Reduction in Risk for Recurrent Vascular Events: A Monte Carlo Stepwise Simulation Approach. J Cardiovasc Pharmacol. 2023 Feb 1;81(2):120-128. doi:10.1097/FJC.0000000000001374. PMID: 36315474.
Deo SV, McAllister DA, Al-Kindi S, Elgudin Y, Chu D, Pell J, Sattar N.
Trends in Prescriptions of Cardioprotective Diabetic Agents After Coronary
Artery Bypass Grafting Among U.S. Veterans. Diabetes Care. 2022 Dec
1;45(12):3054-3057. doi: 10.2337/dc22-0570. PMID: 36256925.
Deo SV, Marsia S, McAllister DA, Elgudin Y, Sattar N, Pell JP. The time-varying cardiovascular benefits of glucagon-like peptide-1 receptor agonist therapy in patients with type 2 diabetes mellitus: Evidence from large multinational trials. Diabetes Obes Metab. 2022 Aug;24(8):1607-1616. doi: 10.1111/dom.14738. Epub 2022 May 23. PMID: 35491516; PMCID: PMC9540124
and other selected manuscripts published during the PhD period
Digital Twins for offshore wind turbines: physics-based model updating for improved operations and maintenance
No full textAbstract not currently available
Crown Estate devolution: assessing the process, substance and rationale
Get PDFThis main goal of this thesis is to set out and analyse the process that led to the devolution of responsibility for the management of the Crown Estate to the Scottish Ministers, evaluating the strengths of that process with a view to determining whether it proceeded in a cohesive and logically consistent manner. This consideration of the process is accompanied by detailed scrutiny of aspects of the legislation that resulted out of that reform, arriving at a determination of whether the legislation is conducive to the resolution of the various issues that led to the consistent calls for reform.
The thesis begins with a literature review that sets out the relevant academic writing and official publications concerning the Crown Estate in Scotland. This offers a foundation on which to proceed with analysing the strengths of the devolution of the Crown Estate. Also detailed is an example of dissatisfaction with the manner in which the Crown Estate Commissioners carried out their functions, focussing on their statutory duty to maximise revenues.
The second chapter focusses on the political backdrop against which the reform of the Scottish elements of the Crown Estate took place, also providing insight into the politically divisive debates that were taking place in the Scottish Parliament and elsewhere, and whether the extent of this divisiveness hampered reform. The view can be taken that the Crown Estate is a particularly useful issue through which to analyse the transfer of power between legal and political institutions in the United Kingdom. The reasons for this are numerous: for example, the way in which management of the Crown Estate is governed and carried out has profound implications for the achievement of public policy goals in Scotland.
Chapter three deals with the legislation that resulted out of this process, the Scottish Crown Estate Act 2019. The process that was engaged in during that Bill’s passage through the Scottish Parliament is found to be encouraging in terms of its rigorous Committee stages, under which a very wide variety of relevant stakeholders were consulted on how they believed long-term management of the assets should be guided. The chapter then analyses in detail the Bill at various stages, taking a specific interest in the economic and social duties placed on Crown Estate managers, as well as the provisions concerning further devolution to local authorities and community bodies.
The thesis then adopts a theoretical perspective in Chapter 4 by seeking to ascertain whether a certain conception of property theory can be identified at each stage of reform. By this, it is possible to demonstrate the extent to which the Crown Estate in Scotland exemplifies an expansion in the obligations owed by property owners towards society, particularly by reference to the manner in which the new legislation broadened the duties of Crown Estate managers.
The thesis concludes by taking the view that the initial reservation of management functions relating to the Crown Estate along with the continued reservation during the first decade of the Scottish Parliament were borne out of a desire to preserve the integrity of the United Kingdom. The Crown Estate, due to its proximity to the monarchy, is embedded with both emotional and practical relationships with the Union, and as such the Crown Estate is an understated focal point of any such devolution. The view is then taken that the Crown Estate demonstrates a divergence in policy between Scotland and the UK, with the former placing a greater emphasis on the extent of the obligations owed by property owners to wider society
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