http://theses.ncl.ac.uk/jspui/handle/10443/5256 2026-04-20T19:34:09Z 2026-04-20T19:34:09Z Lu, Huiwen http://theses.ncl.ac.uk/jspui/handle/10443/6734 2026-04-15T11:31:28Z 2025-01-01T00:00:00Z

Title: Identifying the mechanism behind mitochondrial changes in the cholinergic neurons of the pedunculopontine nucleus in patients with Parkinson’s disease Authors: Lu, Huiwen Abstract: n Parkinson’s disease (PD), patients often exhibit higher levels of somatic mitochondrial DNA (mtDNA) damage, particularly large-scale deletions, in their brains. This damage is associated with neuronal loss and has been seen in multiple neuronal types including nigral dopaminergic of the substantia nigra (SN) and cholinergic neurons in the Pedunculopontine Nucleus (PPN). Unlike dopaminergic neurons, PPN cholinergic neurons tend to maintain wild-type mtDNA levels by increasing mtDNA copy number (mtCN) in response to mtDNA deletions. This study employed ultra-deep sequencing to analyse single cholinergic neurons isolated in an unbiased fashion from postmortem PPN tissue of PD and controls, examining both the mtDNA deletions, and point mutations across various parameters. Comparative analysis of mtDNA deletions was also conducted with nigral dopaminergic neurons to elucidate compensatory response to mtDNA damage. Additionally, singleneuron qRT-PCR was used to quantify the expression of three nuclear genes involved in mitochondria biogenesis, maintenance and mitophagy. Our findings confirm significantly higher levels of large mtDNA deletions in PD patients compared to aged controls, with deletions ranging from 5-140bp (small) to >1,400bp (large). The distribution of large deletions suggests that replication errors are the primary mechanism underlying their generation, aligning with patterns observed in POLG patients and aged controls. Conversely, the low prevalence of small deletions suggests that oxidative damage is not a major contributor of mtDNA damage in these neurons. Point mutation levels did not differ significantly between groups across various parameters assessed. At the transcriptional level, PINK1 expression was upregulated in PD neurons, whereas no significant changes were observed in TFAM or PGC1α expression. These findings suggest that the mitophagy pathway plays a prominent role in regulatory response to mitochondrial changes in PD. Description: PhD Thesis

2025-01-01T00:00:00Z Alias, Siti Hazlina http://theses.ncl.ac.uk/jspui/handle/10443/6726 2026-04-10T08:52:21Z 2025-01-01T00:00:00Z

Title: Religiosity, Thought Action Fusion, and Obsessive-Compulsive Disorder in the UK and Malaysia Authors: Alias, Siti Hazlina Abstract: Over decades, many authors have suggested that religiosity is related to obsessive symptoms and cognitive model of OCD (Steketee, Quay, &White, 1991; Shafran, Thordarson, & Rachman, 1996; Shafran, Watkins, & Charman, 1996; Abramowitz, Huppert, Cohen, Tolin, & Cahill, 2002; Yorulmaz, et al., 2009; Williams, et al., 2013) but the relationship is unclear and the evidence to date is weak. The lack of scales to adequately assess religiosity/spirituality among individuals may have affected the findings to date. Therefore, the present study primarily aimed to investigate the relationship between religiosity, Thought Action Fusion (TAF), and OCD among two multicultural samples, namely 1) in the United Kingdom and 2) Malaysia. For the purpose of the main study, a multidimensional measure of religiosity/spirituality was developed in order to be used for a range of religions and cultures. The existing definitions of religiosity and spirituality in academic literature have yet to achieve universal consensus, as they are influenced by various disciplinary viewpoints and research environments. Additionally, discrepancies in the conceptualization and measurement of these constructs may diminish the significance of studies in this field. In response to this challenge, the Newcastle Spirituality and Religiosity Scale (NSRS) was developed as a multidimensional instrument that can be applied across different religious traditions, non religious groups, and cultural contexts. This scale consists of eighty-two items, organized into eight dimensions: Religious Behavior, Non-Theistic Spirituality, Theistic Spirituality, Intrinsic Religiosity, Personal Extrinsic Religiosity, Social- Family Extrinsic Religiosity, Religious Fundamentalism, and Quest. In the beginning, multiple steps were conducted in the development of 82 items of the Newcastle Religiosity and Spirituality Scale (NSRS). Results of Exploratory Factor Analysis (EFA) showed consistencies in terms of factor structures in both samples, with a few differences in the factor structure. The NSRS subscales showed excellent internal consistency and validity in both samples. A previous study has investigated the internal consistency and construct validity of the Newcastle Spirituality and Religiosity Scale (NSRS) through Exploratory Factor Analysis (EFA). Nonetheless, the absence of studies confirming the scale's reliability and validity, coupled with varying results, has prompted significant inquiries in both the United Kingdom and Malaysia. Consequently, the present study aims to further examine the psychometric properties of both the original and Short Versions of the NSRS. The initial phase concentrates on the convergent and divergent reliability of the NSRS-Short Version, utilizing a sample of 130 participants from Malaysia. The findings revealed consistent results that affirm the convergent and divergent validity of the NSRS SV. Although some unexpected and noteworthy outcomes were noted, the majority of the subscales exhibited correlations that met expectations, indicating strong convergent and divergent validity. The second phase evaluated the test-retest reliability among a sample of 130 individuals in Malaysia over four weeks, employing Pearson correlation and Intraclass Correlation. The results, derived from Pearson correlation and the Intraclass Correlation Coefficient (ICC), demonstrated a high degree of reliability. In the final phase, Confirmatory Factor Analysis (CFA) was utilized to assess the original version of the NSRS with a sample of 564 individuals from the United Kingdom. The CFA was based on three models developed from the EFA findings from the previous study (Alias, Freeston, & Rosenkranz, 2012): (a) Model 1 - an eight correlated factor model, (b) Model 2 - a seven correlated factor model based on the UK sample identified in EFA, and (c) Model 3 - a seven correlated factor model based on the Malaysian sample identified in EFA. It is crucial to acknowledge that the samples in this study differed in ethnicity, religion, cultural dimensions, and other characteristics. However, none of the models assessed achieved an optimal goodness of fit, highlighting the need for further investigation. This is especially crucial in heterogeneous samples that encompass particular religious or non-religious demographics. Although the optimal models for the samples were not identified and some discrepancies among the models were noted, the findings from the CFA indicated that the eight factors of the scale exhibited an adequate goodness of fit following the requisite modifications. Additionally, the findings consistently supported the factor structures and the removal of certain items, which aligned with the shortened version of the NSRS. Next, the relationship between the key components of the main study (i.e., religiosity/spirituality variables, Thought Action Fusion (TAF), and OCD) was investigated among 493 participants in the UK and 581 participants in Malaysia. In both samples, participants were recruited through both paper and pencil and Internet-based methods. Five measures were used in the studies, namely the Obsessive-Compulsive Inventory- Revised (OCI-SV), the Depression Anxiety Stress Scale (DASS-21), the Student Thought-Action Fusion Questionnaire (STAF-Q), the Vancouver Index of Acculturation Revised (VIA-R), and the new religiosity measure, Newcastle Religiosity and Spirituality Scale (NSRS). Further, Thought Action Fusion (TAF) variables were examined as a mediator in understanding how religiosity/spirituality relates to OC symptoms. Next, the role of Religious Fundamentalism as a moderator was examined in the indirect effect relationship. The studies in the UK and Malaysia found several consistent findings with a few inconsistent findings. First, there were positive correlations between TAF and OCD in both samples. Second, religiosity/spirituality was indirectly related to OC symptoms through TAF Likelihood in both studies, but in opposite directions (i.e., positive direction in the UK study and negative direction in the Malaysian study). Third, results of the conditional indirect effect showed that Religious Fundamentalism did moderate the indirect effect of religiosity/spirituality on OC symptoms in both samples. This finding also suggests that Religious Fundamentalism may potentially be a protective factor against the development of obsessions by the direction of the direct and indirect effects of religiosity/spirituality on obsessions through TAF Likelihood in the Malaysian sample. The consistent findings across the two samples may be due to the similarities, such as age group, young, educated, and with a modern outlook, while the differing findings are perhaps understandable considering different sample characteristics, religions, and cultures. In terms of the cognitive model of OCD, the present results provide some support for theoretical proposals and empirical findings that suggest TAF Likelihood is related to OCD in the expected direction (i.e., higher TAF with higher OCD) in both studies. Although future studies are needed to replicate this finding in different samples, there is some support that some aspects of the cognitive model of OCD may be universal in both Western and non-Western countries. In sum, although subsequent studies are required in order to increase our understanding of cognitive models of OCD and vulnerability factors in OCD, these studies can contribute to a 6better understanding of religiosity, thought-action fusion, and OCD. There are also implications for cognitive therapy that addresses beliefs and appraisals of thoughts across countries and cultures. Description: PhD Thesis

2025-01-01T00:00:00Z Kindred, Nathan Shaun http://theses.ncl.ac.uk/jspui/handle/10443/6704 2026-03-27T09:48:53Z 2025-01-01T00:00:00Z

Title: Interactive effects of ageing processes and early life stress on brain structure: a neuroimaging informatics approach Authors: Kindred, Nathan Shaun Abstract: Though it is well established that ageing and early-life stress can cause changes in brain structure, there is less agreement on both region-specific changes and how interactions between ageing and early-life stress may impact on brain structure. Investigations in humans often rely on cross-sectional studies, and are confounded by a number of drawbacks and biases. These issues can be mitigated through the use of model animals, such as rhesus macaques. However, processing macaque MRI data comes with a number of issues, precluding the use of human MRI processing pipelines. Therefore, this project first involved the creation of a novel processing pipeline for macaque MRI data. The outputs of the AutoMacq pipeline had a low error-rate and high levels of reliability. As the majority of previous studies focus on brain changes in late adulthood, this project focused on the under-researched period of early to mid-adulthood. Using a longitudinal approach, significant decreases, in both cortical thickness and grey matter volume, with ageing were identified, primarily within the frontal, temporal and parietal lobes. Early weaning was utilised as a measure of early life stress. In an age- matched cross-sectional dataset, subjects weaned before 12 months showed significantly lower cortical thickness in regions of the temporal lobe, compared to those weaned after 12 months. Significant interactions between weaning and ageing were found for grey matter volume in one area of the occipital lobe, as well for cortical thickness in regions of parietal and occipital lobes. Brain areas across the whole brain appeared sensitive to ageing, whereas regions specifically involved in visual processing seemed most affected by early weaning. Overall, this project resulted in the creation of a novel macaque MRI processing pipeline, and provided new knowledge on the impacts of ageing and early-life stress on brain structure during early to mid-adulthood. Description: Ph. D. Thesis

2025-01-01T00:00:00Z Howladar, Mohammed http://theses.ncl.ac.uk/jspui/handle/10443/6699 2026-03-05T15:22:49Z 2025-01-01T00:00:00Z

Title: The Role of Tumour Microenvironmental Signals in TP53-dependent Therapeutic Strategies for Chronic Lymphocytic Leukaemia (CLL) Authors: Howladar, Mohammed Abstract: Chronic lymphocytic leukaemia (CLL) is a haematologic malignancy of B cells that shows a highly heterogeneous clinical course, with approximately 90% of patient CLL samples being wild type for the TP53 tumour suppressor gene at diagnosis. CLL accounts for approximately 1000 deaths annually in the United Kingdom alone, highlighting the need to unravel the molecular mechanisms that could be used to produce more effective treatment options. Since TP53 disruption by either mutation and/or deletion occurs in only 10-15% of CLL cases, targeting MDM2 to activate TP53 in a non-genotoxic manner is a potential treatment strategy for wild type TP53 CLL. In this study, the combination of WIP1 inhibitor (GSK2830371) with RG7388 was investigated to potentiate the stabilization and pro-apoptotic effects of wild type TP53 at lower concentrations. The potential effect of the microenvironment on the response to MDM2 and WIP1 inhibitors was modelled ex-vivo, including the stimulation of CLL cells with CD40 ligand (CD40L), IL-4 and B cell receptor (BCR) signalling with anti-IgM treatment. The results identified that WIP1 inhibitor potentiated the effect of the MDM2-p53 binding antagonist (RG7388) in wild type TP53 haematological cell lines and non-proliferative CLL cells. The stabilization activity of TP53 was confirmed by the induction of downstream target genes. Furthermore, ex-vivo combined CD40L/IL-4 stimulation showed the proliferative CLL cells became more sensitive to RG7388 as a single agent treatment. The WIP1 inhibitor potentiated the effect of RG7388 and increased the expression of TP53 dependent pro-apoptotic genes. Both immobilized anti-IgM antibody and IL-4 signalling induced proliferation and cell survival signals, which was associated with the ex-vivo primary CLL cells becoming less sensitive to RG7388, and under these conditions the combination with WIP1 inhibitor also did not significantly potentiate the TP53 stabilization by RG7388. However, in the presence of IL-4 the expression of TP53 downstream target genes showed a transcriptional induction of the TP53-dependent pro-apoptotic gene (PUMA) and negative regulator of TP53 (MDM2). In summary, the WIP1 inhibitor (GSK2830371) significantly potentiated the effect of non-genotoxic small molecule MDM2 inhibitor (RG7388) in functional TP53 CLL cells. Modelling the ex-vivo microenvironment with CD40L, IL-4 and BCR activation with anti-IgM antibody was found to reduce the sensitivity of the CLL cells to both single agent RG7388 and when in combination with GSK2830371. This highlighting the importance of the in-vivo microenvironment and the need to develop combination strategies that overcome its limiting effect on the response to p53-dependent therapies. Description: Ph. D. Thesis.

2025-01-01T00:00:00Z