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Epistemic metaphysics
Get PDFMetaphysical proposals are strongly influenced by epistemic considerations. Our capacity to know, explain or perceive influences theories about what is fundamental, exists or is true. These kinds of connections are pervasive as, for example, Fine (2012) and Schaffer (2009) base their metaphysics on explanation, Benacerraf (1973) and Peacocke (1999) base their metaphysics on our ability to know metaphysical truths, and Lewis (1986) and Jackson (1994) base their metaphysics on compatibility with contemporary physics. In each case, pertinent epistemic factors are used to motivate – provide reasons to accept or reject – particular metaphysical theories. This thesis examines significant epistemic factors, their connected metaphysical theories and the nature of the motivating connection exhibited between them to develop a novel approach to metaphysics: called ‘Epistemic Metaphysics’.
To do this, in four papers, arguments are constructed in specific areas of metaphysics where epistemic considerations play central roles. Among others, topics covered include explanation, realism, normativity, laws, chance, dependence, empirical adequacy, and ontology. Then, by drawing inspiration from this wide array of philosophical arguments, a fine-grained account of the epistemic constraints on metaphysical inquiry can be composed; one that properly respects the intricacies of functional philosophical debate and provides general guidelines that are appropriate in any piecemeal application. Identifying the epistemic factors already employed in metaphysical arguments makes it possible to systematise the motivating connections into a set of general metaphysical maxims that constrain metaphysical theory choice: a framework for an explicitly epistemic approach to metaphysics
The effect of inflammatory cytokines on steroidogenesis in colon cancer cells
Get PDFColorectal cancer (CRC) is the third most prevalent cancer worldwide and has a high incidence and mortality rate. It is known that oestrogens impact CRC incidence and prognosis. Sulfated oestrogens, primarily oestrone sulfate (E1S), are taken into cells via organic anion transporting polypeptides (OATPs). Steroid sulfatase (STS) then desulfates this into oestrone (E1). E1 can be reduced by 17β-hydroxysteroid dehydrogenases (HSD17Bs) to form biologically active oestradiol (E2). Our group previously showed that STS activity and HSD17Bs expression are altered in CRC to favour E2 synthesis. However, what regulates STS activity, HSD17Bs and OATPs expression in CRC is poorly understood. My hypothesis is that inflammatory cytokines drive these changes in E2 synthesis. In this thesis, the Cancer Genome Atlas (TCGA) human colorectal adenocarcinoma RNA-Seq dataset (n = 433, normal=51 and CRC=382) was analysed to generate Kaplan–Meier survival curves and correlation graphs comparing normal and CRC tissue expression of TNFα, HSD17Bs, OATPs, and STS. How inflammatory cytokines impacted oestrogen uptake, enzyme activity and cell proliferation were further assessed through radiolabelled enzyme activity assays, LC-MS/MS, and proliferation assays. In CRC tissue, results demonstrated positive correlations between TNFα and STS (*P=0.036), HSD17B4 (**P=0.0045), HSD17B12 (*P=0.016), OATP2B1 (***P<0.0001), OATP3A1 (***P<0.0001), OATP3A1 (***P<0.0001), and OATP1C1 (***P<0.0001). In CRC cell lines, treatment with TNFα significantly increased STS activity as measured via the conversion of H-E1S to H-E1. An increase in STS activity was associated with an increase in CRC cell proliferation. HCT116 and Colo205 cells displayed the greatest proliferative responses compared to LoVo and SW620 cells. For HSD17Bs, TNFα treatment decreased HSD17B2 and HSD17B4 expression and increased HSD17B7 and HSD17B12 expression, suggesting greater E2 synthesis. TNFα also significantly upregulated OATP2B1 expression in HCT116 and Colo205 cells. E1S uptake significantly increased in HCT116 and SW620 cells. Finally, CRC oestrogen metabolism, measured by LC-MS/MS, showed that TNFα reduced E2 loss in CRC cell lines and reduced E1 synthesis from E2. Taken together, these data show that TNFα significantly increases STS activity, alters HSD17B expression, and upregulates oestrogen uptake in CRC cells. This suggests that TNFα is an important regulator of oestrogen metabolism in CRC
An exploration of religion and desistance from crime
Get PDFReligious involvement is considered to provide an opportunity for a ‘second chance’ for individuals with offending histories, however, there has been limited research conducted in the area of religious involvement in this population. This thesis aimed to contribute to the literature base by exploring the impact of religion, and specifically the conversion to Christianity, on individuals with forensic histories. Chapter 1 provides an introduction to the literature regarding the broader context of religion and crime. Chapter 2 presents a systematic review of the literature investigating whether involvement in religious programmes or practices impacts on recidivism rates, or on other factors which are associated with crime. The findings suggest that involvement in religious programmes and practices can reduce reoffending rates following release from prison. Chapter 3 presents an empirical study exploring the lived experiences of individuals with offending histories who had converted to Christianity, in order to gain insight into the role that religious beliefs play in their lives. Participants described their lives before they became Christians and spoke of the positive impact their new faith has on their lives, as well as the struggles they experience. Chapter 4 examines the psychometric properties of the Brief Religious Coping Scale (Brief-RCOPE; Pargament et al., 1998) in relation to religious coping in cultures and populations outside of the United States. The main findings are summarised in Chapter 5, alongside recommendations for practice and suggestions for further research
Wax hardening in melt emulsification
Get PDFWax-in-water emulsions can be defined as a mixture made up of one or more waxes in water. Although wax and water are immiscible materials, wax-in-water emulsions can be stabilised by using surface-active agents such as surfactants (these can be either ionic or non-ionic or a combination of both) to reduce the interfacial tension between droplets and to prevent instability scenarios such coalescence, creaming, flocculation, aggregation, etc occurring within the emulsion. Wax emulsions as they are commonly known are generally used in a wide range of applications, from personal care to coatings to surface care applications to cosmetics, etc. As versatile as they are, wax emulsions are most effective and desirable when they are stable and have a long shelf life.
This body of work employed the use of a non-ionic surfactant (Tween 20) and a Fatty Alcohol (Stearyl Alcohol or 1-Octadecanol as the wax); various compositions of these two in the presence of water were explored while evaluating how the different compositions influenced the Rheology and the particle size distribution. It was found that the compositions with lower surfactant amounts had a more polydisperse particle size distribution and consequently, reduced viscosity over time as a result of the effective packing of droplets that accompanies polydispersity. This research explores potential scenarios resulting from the use of high surfactant concentrations and the surpassing of Critical Micelle Concentration. These scenarios include micellar phase transition at ambient temperatures, the release of surfactant molecules from micelles during aging leading to the formation of new phases, and the development of lamellar phases under heat exposure
Client experience of compassion focused therapy (CFT) & compassion following therapy
Get PDFMeta synthesis abstract:
Introduction: This meta-ethnography aimed to synthesise the existing literature surrounding participant experiences of Compassion-Focused Therapy (CFT) interventions. This was to address a gap in the literature and bring together the emerging qualitative studies concerned with CFT.
Method: A combination of a systematic literature search and additional search strategies was used to identify the existing qualitative studies. Four databases were searched covering a range of healthcare disciplines. A meta-ethnography was conducted according to the 7 stages outlined by Noblit and Hare (1988) and these are outlined along with details about how this was carried out by the researcher.
Results: 3 overarching themes and 7 subthemes were identified. These related to ‘psychological safeness’, CFT active ingredients’ and ‘processes of change’. Within the themes, the role of the therapist, the group experience, resonance of the model, practice of skills and barriers to compassion are explored. Participants recognised the changes they experienced during CFT and their implications for their future.
Discussion: The results are discussed in the context of the broader processes of change literature and the common experiences of individuals who have experienced CFT. The results have particular implications also for the broader therapy literature around group processes. Potential limitations are also discussed.
Empirical abstract:
Introduction: This IPA aimed at addressing a gap in the literature surrounding long-term follow up and client experience of compassion following CFT.
Method: Participants were recruited from a pool of participants from a previous study. All participants had completed a 12-month CFT intervention and were identified as having experienced attachment and relational trauma. Seven IPA stages were followed alongside reflexivity and credibility checks including consultation with the wider research team during the development of themes and research supervision.
Results: 3 overarching themes and 7 subthemes were identified. These included participants experience of initial therapeutic ‘epiphanies’, steps taken to integrate ideas and their experiences of compassion post therapy. The transformative impact of compassion on their decision making post therapy and their key relationships are also highlighted. A sense that compassion is a work in progress is also identified.
Discussion: The concept of epiphanies are discussed in the context of the broader behaviour change literature as well as the idea of compassion being likened to a journey. The contribution of these findings to the CFT literature base is highlighted as prior follow-up study was scarce and short in duration. Potential limitations are discussed as well as the clinical implications for services supporting adults with attachment and relational trauma
Intergovernmental relations and the dynamics of local revenue mobilisation in a decentralised Indonesia
Get PDFThis thesis investigates how local revenue mobilisation is affected by the institutional arrangements governing decentralisation through a case study of Indonesian local government. It establishes the expectations and scope of local autonomy in the country through analysis of the rules and regulations affecting decentralisation and intergovernmental relations. It then examines specifically the impact of the devolution of revenue-raising powers on local own-source revenue in the 2011-2013 period as an example of increased local autonomy. Lastly, through interviews of central officials and local officials in two individual municipal case studies, the study reveals the factors and considerations which shape the use of new revenue-raising powers alongside other existing sources of local revenue such as intergovernmental transfers.
The findings show evidence of the impact of devolution of property tax on local revenue mobilisation in Indonesia and how contextual and institutional factors affect the local revenue mobilisation process. Changes in the institutional arrangements governing decentralisation in Indonesia from the year 1999 to 2015 provided local governments with an increased autonomy over policy making and financial resources, yet those changes still left a room for central control in the name of maintaining the unitary state and promoting the centrally-led development planning agenda. Within these institutional arrangements, the devolution of property tax in the 2011-2013 period increased the proportion of own-source revenues and average local own-source revenues per capita in the municipalities implementing the reform, despite an increase of central transfers in the same period. Evidence from the interviews showed that despite the positive effect of devolution on revenue mobilisation the rules regarding the allocation and use of central transfers have lessened the impact of that below its maximum potential. Local revenue mobilisation is conditioned by the extent of mismatch between activities driven by local preferences and activities promoted by central policy makers.
The findings of this thesis contribute to the literature by showing that in this case study of Indonesia, the devolution of revenue-raising powers increased local revenue mobilisation although this increase was limited by the rules governing intergovernmental transfers and central-local relations in decision making processes. In particular, central control over human resources reduced the impact of devolution of property tax, which show that local revenue mobilisation is also lessened by the lack of autonomy municipalities work under in decision making concerning human resources. The thesis also shows a nuanced picture about local autonomy in Indonesia, where there is room for local decision makers to influence central government’s decisions regarding the use of central transfers. The results from this study provide support for a more detailed analysis in institutional arrangements governing decentralisation in future studies to better understand the scope of local autonomy which can affect decentralisation outcomes
Investigating the Effect of Perhexiline and FPER-1 in pulmonary Arterial Hypertension
Get PDFPulmonay arterial hypertension (PAH) is a vascular remodelling disease whereby proliferation of pulmonary artery smooth muscle cells (PASMCs) is increased. The pathophysiology of the disease is not fully understood, but there is a growing body of evidence in the literature that supports the notion that PAH PASMCs exhibit a similar metabolic phenotype to that of cancer cells. Previous studies have shown that PAH PASMCs reprogram their energy metabolism to utilise glycolysis over oxidative phosphorylation for ATP production due to a reduction in pyruvate dehydrogenase (PDH) activity. In the present study, we hypothesised that by increasing PDH activity, perhexiline and the novel fluorinated perhexiline (FPER-1), both carnitine palmitoyltransferase 1 (CPT1) inhibitors, would restore PDH flux and hence increase oxidative phosphorylation, and attenuate PASMCs proliferation. Utilising cultured PASMCs from healthy and PAH patient donors, we showed that perhexiline and FPER-1 effectively attenuates the increased rate of proliferation of PASMCs from PAH donors, whilst maintaining cell viability. We futher propose a novel mechanism of action of perhexiline/FPER-1 in PAH PASMCs whereby both perhexiline and FPER-1 reduces PAH PASMC proliferation by suppressing the activation of the AKT pathway (reduced phosphorylation of AKTser473) and activating PDH (dephosphorylation of PDH-E1α ser293). Our findings demonstrate that both perhexiline and FPER-1 show promise as a novel therapeutic agent for reversing the increased PASMC proliferation apparent in PAH, but additional studies regarding the safety of FPER-1 as a therapy are required
Sensory gating and EEG oscillatory markers in the context of cognitive reserve in healthy ageing
Get PDFThe number of older adults (> 65 years) developing a neurological or neuropsychiatric disease will rise as the population aged over 80 years old grows. Ageing has diverse impacts on cognitive function, significantly affecting daily life in older adults. Cognitive Reserve (CR), the brain's ability to resist age-related changes, is thought to be built up over a person's lifetime through various intellectual, educational, and social activities. Measuring CR consistently proves challenging due to varied approaches and tools used throughout the literature.
Studies utilising electroencephalography (EEG) and magnetoencephalography (MEG) for non-invasive brain measurement demonstrate that high CR individuals exhibit increased connectivity and amplified event-related potentials (ERPs) or oscillatory amplitudes. However, establishing causal relationships between MEG or EEG measures and CR remains challenging due to methodological variations and participant heterogeneity.
We investigated inhibitory EEG measures using sensory gating (SG). A paired stimulus click paradigm was applied to measure the P50, N100 and P200. Our study found an age-related decline in neuropsychological function and CR but not in SG among healthy older adults (n = 27). Significant relationships were observed between P200 and verbal as well as visual long-term memory (both p < .05), and N100 with inhibitory memory (p < .001). No other neuropsychological measures correlated with SG.
Auditory Steady-State Responses (ASSR) are electrophysiological evoked oscillatory responses entrained to the frequency and phase of temporally modulated tones. These responses are often deficient in disorders of consciousness, such as schizophrenia. Three blocks of tones were presented: 2.5 Hz and 40 Hz, 2.5 Hz and 80 Hz, and 2.5 Hz and 40 Hz. Results revealed associations between verbal fluency and lower ASSR power responses (n = 14, p = .039), independent of age or other neuropsychological assessments.
Alpha frequency is thought to represent inhibiting irrelevant sensory pathways, and the peak frequency can be calculated over a short period of EEG recording time (~4 minutes). Older participants had significantly lower peak alpha results than the younger participants (p = .023), and age significantly predicted the peak alpha frequency (PAF) (p = .017). The PAF was also significantly predicted by IQ (p = .017) and a digit span task (p = .039), but this was not seen when age was controlled for, implying that this relationship isn’t robust. Similar predictors were found for SG measures as well as PAF.
Results from each chapter contribute to the overall understanding of the relationships between SG, neural measures, and CR in healthy older adults. Our chosen EEG responses all demonstrated associations with inhibition measures. These findings provide insights into the neural underpinnings of sensory processing and inhibitory functions, contributing to our understanding of their potential impact on overall cognitive functioning in the ageing population. Limitations of methodological chapters are discussed with recommendations for future research.
Emphasising clinical significance, the thesis suggests using an EEG setup with fewer electrodes and a passive listening task for faster, less burdensome assessments. This approach allows for a faster setup, reducing burden on patients. The findings suggest that measuring cognitive vulnerability, especially in older adults, is crucial in clinical settings, offering support before major healthcare events such as planned major surgery
Limit shapes in one dimensional free fermion systems
Get PDFIn this thesis we study rare fluctuations in one dimensional free fermion systems which take the form of space-time disturbances known as limit shapes. Limit shapes have a long, rich history, but substantially less has been said on what happens when limit shapes meet. The expectation is that they should combine to create some new shape. This work deals with finding a rigorous way to find and characterise these \textit{limit shape
transitions}. We are able to make considerable progress by mapping the free fermions to a class of models known as Coulomb gas models which can be readily solved. These Coulomb gas models exhibit phase transitions that we show correspond to transitions in the underlying limit shapes. As an extension, we are able to classify the limit shapes we find in an industrial way and better understand their fluctuations. Further, we present simple physical arguments that suggest that our results will be valid even in the strongly interacting regime, i.e. when the fermions are no longer free
The effect of perceptual noise on the Eriksen flanker effect: insights from Bayesian parameter estimation & model comparison
Get PDFDecades of research using the Eriksen Flanker Task have provided valuable insight into the mechanisms of visual attention. However, this body of work has largely overlooked a critical aspect of our visual experience – the dynamic and noisy nature of our visual environments. This thesis aims to address this gap in the literature by exploring how adding noise to the stimuli influences attentional focusing in the flanker task. To reach this aim, we present three novel flanker tasks, two of which explore noise in the motion domain while the final study explores noise in the color domain. Furthermore, by comparing these results to a standard task, we explore differences in flanker suppression across noisy and standard, noise-free conditions. Within this field, there is also debate as to whether increases in attentional selectivity, or the suppression of flankers, proceeds as a gradual or discrete process. To test these differing views, two computational models have been proposed which realize the two viewpoints, namely the Shrinking Spotlight Model (SSP) of White et al. (2011) implementing the former and the Dual-Stage Two-Phase Model of Hübner et al. (2010) implementing the latter. Using the rarely used Bayesian approach, we fit both models to the data, and through a combination of average performance analyses, distributional analyses and model simulation, we can explain how noise influences the flanker effect and how this is accounted for under each theoretical framework. Firstly, we find that noise does indeed influence the flanker effect, in that adding noise to the stimuli impedes flanker suppression. Secondly, by independently manipulating the noise level in targets and flankers, we find solid evidence that the adverse effect of noise stems mainly from adding noise to the target. Finally, and in contrast to previous research using the standard paradigm, we find decisive evidence that a discrete improvement model (DSTP) best accounts for flanker suppression under noisy conditions. Our distributional analyses allow us to ascertain that the superiority of DSTP can be localized mainly to its ability to better model data patterns indicative of considerably poor flanker suppression, particularly observed in high noise conditions. Combining our data analyses with the predictions of both models, we propose a theory of flanker suppression under noisy conditions, in which the extent of flanker interference is primarily determined by the saliency of the target: the less salient the target, the greater the flanker interference
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