Congenital Myasthenic Syndromes (CMS) are a group of rare genetic disorders affecting the neuromuscular junction structure and function. They are characterised by the presence of fatigable muscle weakness, but the age of onset, presenting symptoms and distribution of weakness differ depending on the genotype and specific mutations affected. The severity of CMS is highly variable amongst individuals, fluctuating and worsening with physical effort, which makes assessments challenging. Currently, there are no validated outcome measures for use in CMS, with most clinicians using outcome measures validated in Myasthenia Gravis and other neuromuscular conditions. The need to establish robust natural history data and validated outcome measures in this rare condition will be increasingly important with emerging novel treatments already in development. This study looks to answer whether there is a relationship between an instrumented six-minute walking test (6MWT) and community physical activity levels through the u…
The Wnt signalling pathway is a fundamental cell-to-cell communication system that plays a pivotal role in orchestrating diverse developmental processes across metazoans. There are thirteen subfamilies of Wnt ligands, seven of which are represented in the model organism Drosophila melanogaster. Similar expression of some Drosophila Wnt genes has been observed in several tissues, which suggests they may play overlapping roles, however, loss of certain Wnt genes such as Wnt6 appear to affect only certain tissues. This could suggest that Wnt ligands act in a combinatorial manner in Wnt signalling landscapes in different tissues, despite functional differences at the molecular level. Despite significant advances in our understanding of the Wnt pathway, the functional specificity of these diverse Wnt ligands remains enigmatic. This thesis aimed to address this knowledge gap, using the following different approaches. Sequences of the seven Drosophila Wnt ligands were compared to each other and protein structures …
The Spindle Assembly Checkpoint (SAC) is a cell signalling system that regulates cell division. SAC ensures the correct separation of chromosomes during mitosis. Defects in SAC can result in genome instability, increasing the risk of cancer development and making it a potential therapeutic target for cancer treatment. The commercial compounds Reversine (an Aurora kinase B and Mps1 inhibitor) and Apcin (an APC/C inhibitor) have been established to be cytotoxic to cancer. This thesis aimed to confirm the efficacy of these compounds and to test the cytotoxicity of three novel small molecules that interfere with cell cycle progression in cancer cells, ultimately inducing apoptosis (cell death). MTT and clonogenic assays were the techniques selected to test the cytotoxicity of the compounds in a cancer cell line panel. The cancer cell lines tested includes (b) Hormone responding breast cancer, MCF7 (c) Triple-Negative Hormone Resistant breast cancer, MDA-MB 231 (d) Ovarian cancer, SKOV3 (e) Cervical cancer, HeLa.…
Quality of life, symptoms, and experiences of patients with an elevated body mass index undergoing catheter ablation for atrial fibrillation Background Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice. Previous studies have demonstrated that AF may result in high symptom burden and a reduced quality of life (QoL). Rhythm control in the form of catheter ablation has become an established treatment option for AF. Certain risk factors are associated with the development and progression of AF, notably, an elevated body mass index (BMI). Emerging evidence suggests that risk factor modification in the management of AF is an important component of the patient pathway. The relationship between AF ablation, QoL, symptoms and BMI is poorly understood. We need to understand this further to provide more effective and targeted care. Previous studies concerning the influence of a raised BMI on QoL and symptoms after ablation have been contradictory. Qualitative research in this area has b…
This research analyses the memories of characters from 38 scripts, whose films were released in cinemas during the 2015-2017 film season and received state funding. By analysing the dialogues and flashback scenes that express the memories of the fictional characters in these works, the following questions were answered: What aspects of memory are brought to light? What idea of society, what social and civic values, what power relations are conveyed by these works? These questions can be answered by analysing memory, since memory reflects a collective vision of present values. The words and themes that scriptwriters assign to their characters to recall the past represent what is saved from oblivion, what is most important for the present. The research is framed within the Digital Humanities. The original contribution of my research can be seen in three different aspects: in the choice to focus the analysis exclusively on screenplays, studied as autonomous literary texts, in the choice to analyse me…
Important security constellations within the state, suggest that at the local level the state is no longer a referent object of security but rather one stakeholder among many. My thesis challenges the assumption of a fixed hierarchy between stakeholders in the security landscape at the local level. By exploring interorganisational collaboration in the security context I illustrate that this is feasible, in a way that allows a new way of seeing non-state actors as the whole, and the state as a component part. I have used an interdisciplinary approach to open up a new viewpoint and appropriately conceptualise security at the local level. The context within which security collaborations exist at the local level are often underexplored, and my insights contribute to the Security debate, and the Interorganisational Collaboration (IOC) debate. My research philosophy reflects a constructivist ontology and an interpretivist epistemology, which focuses on understanding how people perceive the world. I used a qualitati…
Introduction Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease of unknown aetiology in childhood. JIA is an umbrella term for arthritis of unknown origin, lasting for >6 weeks and with onset at <16 years of age. JIA negatively affects physical and mental health and well-being through direct pathology and the secondary impact on lifestyle. Moreover, JIA exerts a long-term impact on social and occupational opportunities and quality of life. Despite several medical interventions available for treating JIA (1,2), studies on the impact of lifestyle interventions remain limited (3). Nevertheless, evidence from other clinical groups concerning lifestyle management (4) strongly suggests the potential benefits of lifestyle management in the context of JIA. Considering the long-term impact of the disease, and the impact on lifestyle, there is a need to develop a broader range of behavioural interventions, alongside drug therapies, to support healthier lifestyle in children and young peopl…
Intention and trajectory prediction are key factors in the autonomy stack of self-driving vehicles. They help to avoid potential collisions and plan safe paths.This thesis presents a comprehensive investigation into the enhancement of intention and trajectory prediction in Autonomous Vehicles (AV) through a multi-faceted approach involving enhancing all the autonomy stack's blocks that proceed Prediction, namely, data, detection, and prediction. Firstly, we introduced ROAD-Waymo, an extensive dataset that significantly augments the (US) Waymo Open dataset with a wealth of annotations, enabling the development and benchmarking of algorithms for agent, action, location, and event detection in road scenes. This dataset addresses the need for holistic scene understanding beyond mere object detection, providing a robust platform for domain adaptation and advanced perception in AV systems, aiming to provide high-level understanding to models trained on it. Secondly, we improved object detections under challengin…
Breast and colorectal cancers present significant challenges for the UK healthcare system, placing a substantial burden on the National Health Service (NHS). Early detection is crucial for improving survival rates and reducing healthcare strain, especially as metastasis, the primary cause of mortality in these cancers, remains poorly understood. Protein glycosylation, a post-translational modification of carbohydrate structures, is a significant contributor to cancer progression and metastasis. Small extracellular vesicles (sEVs) have emerged as key players in cancer development and metastasis, facilitating intercellular communication through bioactive cargo transfer. Despite mounting evidence, the importance of sEV glycosylation in cancer and metastasis is often overlooked. Liquid biopsies, including sEV biomarker analysis, offer promising non-invasive diagnostic approaches. Given the prevalence of glycoproteins among blood cancer biomarkers, exploring the glycosylation of sEVs as biomarker targets could rev…
The perception of clinical breathlessness is a complex experience, modulated by physical and psychological factors. Distinguishable types of breathlessness arising from different peripheral mechanisms have been delineated, experimental models of these specific types have been developed and advances have been made in multidimensional assessments. However, current knowledge about cerebral mechanisms of breathlessness is lacking. Functional brain imaging studies have identified involvement of certain cortical structures but interpretations of these data are limited by various assumptions. Aim:The primary purpose of this thesis was to interrogate the validity of the conclusions drawn by recent brain imaging studies and to draw further inferences about cerebral mechanisms of dyspnoea from neurological patients undergoing deep brain stimulation (DBS) for relief of other symptoms. Focusing on experimentally induced ‘air hunger’ (the most unpleasant form of clinical breathlessness) two primary working hypotheses wer…