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Using theoretical physics to address complex dynamical problems in turbulence, geosciences and biology
No full textReal-world systems are generally nonlinear, exhibiting complexity across a range of physical and temporal scales. In this thesis I tackle a series of real-world problems and questions which span the breadth of these different scales, from the microbiological to interplanetary. This is possible when each system is viewed from the perspective of theoretical physics as being reducible to the level of a dynamical system. Early on in my research, I realised that these approaches could be applied across many fields and chose to work in three of them. Turbulence remains one of the greatest challenges remaining in classical physics, and arises in our first dynamical system, the Navier-Stokes equations (NSEs). I investigate higher-dimensional versions of these equations using Direct Numerical Simulation studies to search for evidence of critical phenomena, using chaos as a measure. Using this together with a closure-approximated model, I investigate how increasing spatial dimensions appears to lead to a reduction in chaos, which might tentatively suggest a critical dimension of six for these equations. From the problem of turbulence, I turn to a related problem in ensemble numerical weather prediction, the signal-to-noise paradox. The paradox is that current ensemble systems seem to predict reality better than they predict themselves. By applying ergodic theory to ensemble forecasting, I show that using the ensemble mean as our best forecast of observations amounts to interpreting it as the most likely phase-space trajectory, which relies on the ergodic theorem. I argue that this fails in certain cases due to evidence of multi-modality, which can break the ergodic theorem, creating the paradox. Moving up a scale, the next problem I address is the practical challenge of contamination when trying to detect microbiology in Earth's upper atmosphere. Leveraging advances in aerospace technology, such as CubeSats and rocket-borne samplers, this research proposes a new technique called relative-velocity sampling, for capturing large particles in the understudied mesosphere and lower thermosphere. This technique reduces the contamination challenge to a simple one-dimensional dynamical system, obeying the NSEs. My ultimate problem lies on the largest scales where I apply the theory of island biogeography to interplanetary scales for planetary protection. This theory models population dynamics for inter-island populations and has been suggested as applicable to interplanetary systems. This is used to show that although such an equilibrium theory generally breaks down when applied to interplanetary scales, the mean-time to extinction resulting from the combined effects of growth and death rates can be quantified. This is used to challenge the probabilistic model of planetary protection and suggest how the mean-time to extinction can instead be used to assess colonisation risk. The broader applicability of island biogeography to considering biotic transfer at the interplanetary scale is considered. This thesis concludes with a synthesis of the problems tackled, illustrating the capability of theoretical physics to advance understanding in different fields underpinned by dynamical systems, and the role of interdisciplinary research
Using serious leisure theory to explore the experiences of people walking the Camino
Get PDFThis study aims to investigate the differences in flow experiences between individuals walking alone and those walking with companions along the Camino de Santiago in Spain. The researcher conducted fieldwork in Arzúa, Spain, collecting both questionnaires and implementing interviews directly along the pilgrimage route. A mixed-methods approach was used, dividing participants into two groups: those walking alone and those walking with companions. Quantitative data were collected using the Flow State Questionnaire, with ANOVA and U-tests employed to determine if there were significant differences in flow experiences between the two groups. Semi structured interviews served as the primary source for qualitative data, which were subsequently coded and categorized to reduce single-method bias and to enhance cross validation. Results showed that solo walkers experienced higher flow across all nine dimensions compared to those walking with companions. However, statistically significant differences emerged specifically in the dimensions of “transformation of time,” “action-awareness merging,” “autotelic experience,” and “feedback.” Qualitative data further highlighted that walking alone allowed individuals to concentrate more fully on the act of walking, enriching their overall experience. The study also found that religious factors influence flow on the Camino, with Catholics having higher flow experiences levels compared to non-Catholics or those without religious affiliations. Additionally, from the perspective of serious leisure theory, long distance hiking on the Camino can indeed be categorized as a form of serious leisure, enhancing both the sense of achievement and the personal growth of participants
Sexual offending in adults with intellectual disabilities: A systematic review evaluating risk assessment measures for sexual offending in adults with intellectual disabilities; &, An interpretative phenomenological analysis on the experiences of families of adults with an intellectual disability charged with sexual offence
Get PDFThis thesis portfolio is submitted in fulfilment of the requirements for the Doctorate in
Clinical Psychology. The portfolio comprises two studies that explore aspects of
sexual offending in adults with intellectual disabilities (ID).
The first study is a systematic review evaluating the predictive validity of risk
assessment measures for sexual offending in adults with ID. A systematic search
across five electronic databases identified nine eligible studies, which were critically
appraised and synthesised following PRISMA guidelines. Findings revealed
considerable variability in predictive performance across tools. Structured
Professional Judgement (SPJ) tools, particularly those specifically developed for ID
populations, demonstrated superior predictive validity for sexual recidivism
compared to general actuarial measures. However, methodological limitations
across studies, including inconsistent definitions of recidivism and ID, should be
noted. The implications for clinical practice and future research are discussed, with
particular emphasis on the need for validated, ID-specific risk assessment measures.
The second study is an empirical investigation using Interpretative
Phenomenological Analysis (IPA) to explore the lived experiences of family members
of adults with ID who have been charged with a sexual offence. Semi-structured
interviews were conducted with five participants (three mothers and two brothers) to
explore the experiences and impacts of the offence. The analysis identified four
Group Experiential Themes: ‘Sense-making’, ‘Weight of Carer's Identity’, ‘Living in
Fear’, and ‘Navigating the System’. Participants described complex processes of
reconciling prior perceptions of their relative, heightened caregiving burdens,
experiences of stigma and hypervigilance, and significant challenges accessing
adequate systemic support. The findings contribute to an under-researched
population and underscore the need for trauma-informed, family-inclusive services.
Together, the two studies provide a novel contribution to understanding both risk
prediction in ID sexual offending populations and the broader systemic effects on
families. Recommendations for clinical practice and future research are outlined
Investigating relationships between long-lived macrophages, microbes, and immune cell composition in the intestine
No full textIn most organs, long-lived macrophages (mϕ) are tissue resident and have non-redundant tissue specific roles. The functions of recently identified Tim-4+ long-lived gut mϕ are currently unknown. To gain an understanding of their role, a depletion model using a novel Tim4-Cre iDTR transgenic mouse line was used to selectively deplete Tim-4+ mϕ. This approach allowed us to assess the effects of depleting long-lived intestinal mϕ on other intestinal immune cell populations. Conversely, the role played by microbes in shaping the functions of long-lived intestinal mϕ was investigated through transcriptional analyses of long-lived intestinal mϕ isolated from specific-pathogen-free, germ-free and ex-germ-free mice. Results from our depletion model demonstrate that steady-state intestinal immune cell composition in adulthood is not regulated by long-lived intestinal mϕ. Results from our transcriptional analyses suggest that long-lived intestinal mϕ gene expression is largely determined during development, independently of microbial influence. Mϕ from germ-free and ex-germ-free mice displayed few differences in gene expression compared with those from specific-pathogen-free mice. Of the few genes that were differentially expressed, most were involved in defence responses to bacterium and epithelial cell proliferation, suggesting that the presence of microbiota during development suppresses expression of genes involved in these mϕ functions. Further, genes responsible for wound healing were upregulated in mϕ from specific-pathogen-free mice, suggesting that their homeostatic properties are reliant on exposure to commensal bacteria during development. Finally, our results confirm previous findings that CD163 is a useful marker in identifying subpopulations of long-lived intestinal mϕ with differing functions, linked to their different intestinal niches
A 'new' frontier: extractive pasts, presents, and futures in Kabwe, Zambia
No full textThe history of Kabwe, Zambia is a history of a succession of frontiers. With the opening of the Broken Hill mine in 1904, Kabwe became a resource frontier for desired minerals. However, following the nationalisation of the Zambian mining industry, the mine began to operate at a loss. As a result, the mine was closed, and the area transformed into a waste frontier characterised by abandoned infrastructure and a mineral tailings heap known as the Black Mountain. Today, reprocessing operations have commenced in the area to reclaim the mineral waste and transform Kabwe into a waste-based commodity frontier. The material vestiges of the mine are one potential pathway to a better future in Kabwe, as envisioned by some residents. Another vision for a better future in Kabwe involves the remediation of lead poisoning. A class action lawsuit has been filed on behalf of residents against Anglo American South Africa, a former owner of the mine, to account for the toxic legacy of lead pollution. The lawsuit is one of many remediation efforts to mitigate lead poisoning in Kabwe. Although class action lawsuits are increasingly used to address environmental harm, I consider how what is valued in a legal context renders slow violence legally unintelligible. Building on a rich anthropological history in Zambia, this research explores the different, and often conflicting, strategies of frontier and future making out of an extractive past in Kabwe. Based on participant observation, interviews, focus groups, document analysis, and archival research, I evaluate cycles of extraction and remediation. This research is an important part of understanding extractive industry and the green transition as it contributes to a growing body of scholarship in anthropology, and social science broadly, providing critical perspectives on sustainability discourses. With mining communities, like Kabwe, at the centre of these developments, it is important to understand community concerns about livelihoods, toxicity, and futurity in the face of environmental, economic, and social change
Optic disc pallor and brain health
Get PDFBACKGROUND:
There is a growing need for accurate and cost-effective biomarkers for neurological disorders. Brain imaging is not suited to mass screening, owing to its cost and complexity of operation. The retina offers a promising and accessible alternative as it is directly connected to the brain via the optic nerve and shares its blood supply, embryological origins, and structural features.
Changes in the brain are often reflected in the retina. One such change observed in multiple neurological disorders is thinning of the retinal nerve fibre layer (RNFL), which is measured using Optical Coherence Tomography (OCT), reflecting loss of nerve tissue in the brain. However, OCT is not universally accessible and may be challenging to use with certain populations, such as frail individuals or those with movement disorders. An alternative approach still utilising the retina involves assessing the paleness of the optic disc in colour fundus photographs, based on the premise that a pale disc indicates RNFL degeneration or loss. Fundus photographs are the most widely available retinal imaging modality and routinely captured during high-street eye examinations and other standard clinical settings.
OBJECTIVE:
In this thesis I aim to develop a method for quantifying optic disc pallor in fundus images, and to investigate optic disc pallor and in conditions affecting the health of the brain.
METHODS:
I developed software to measure optic disc pallor using a combination of image processing techniques and deep learning segmentation networks. Validation was performed by comparing pallor measurements to peripapillary RNFL thickness from the same eyes and by assessing how pallor values aligned with clinically diagnosed pallor in an external dataset. I applied the software to three clinical datasets using linear, logistic, and linear mixed-effects models to investigate associations between pallor measurements and clinical features, including MRI-detected lesions, cerebral small vessel disease (cSVD) ratings, stroke type, and Parkinson’s disease (PD) status and duration. I also manually reviewed 1,485 images from an aggregated dataset and used these labels to create two methods for automated quality control.
RESULTS:
The resulting software can process an image in under one second. In clinical research, I found that disc pallor was associated with MRI-visible enlarged perivascular spaces (indicative of underlying cSVD), lacunar stroke, cSVD ratings, and PD status and disease duration.
CONCLUSION:
Optic disc pallor, measured in colour fundus photographs, reveals insights into neurological dysfunction. Future investigation is warranted to see if pallor could be an imaged-derived biomarker of disease or whether it holds predictive value in addition to conventional risk factors used clinically
Forgiveness as a hermeneutical key to the Gospel of Matthew: an exegetical Investigation of the ἀφίημι logia in the Matthean Gospel
No full textForgiveness as a Hermeneutical Key to the Gospel of Matthew: An Exegetical Investigation of the ἀφίημι logia in the Matthean Gospel
It is argued in this thesis that the concept of forgiveness when expressed by the verb ἀφίημι in the Gospel of Matthew does not constitute a homogeneous theme but rather one which is multifaceted. This idea is not sufficiently emphasized by scholars. Additionally, the notion of forgiveness is employed by the evangelist as a theological template with which other important themes concerning the mission of Jesus, such as sin, revelation, judgment, christology, eschatology, and the consideration of the social location of the Matthean community, are revealed. This explains the reason why forgiveness can be construed as a hermeneutical key to the Gospel of Matthew. This implies that a better grasp of the concept of forgiveness could foster a much deeper understanding of the central message of the gospel.
Furthermore, the present study also shows that divine and interpersonal forgiveness can certainly be distinguished to an extent but, more fundamentally, they cannot be separated. Both divine and human are dialectically connected to one another when read through the lens of the ἀφίημι logia, especially in Matt 6:12 and 18:35. Divine and human forgiveness are intertwined for Matthew (Matt 6:14-15).
Moreover, it has been demonstrated in this study that the Matthean treatment of forgiveness provides new meaning for the concept relative to that of the Hebrew Bible, thus effectuating a revolution in the manner in which forgiveness is obtained which is radically different from that in the Jewish worldview of the first century. The specificity of Matthew, however, is that even though divine forgiveness is possible without the Temple (Matt 9:2a) and its attendant paraphernalia, it is conditioned by human forgiveness (Matt 6:14-15).
The methodology employed throughout this investigation is that of a careful reading of the ἀφίημι logia, complemented by synchronic and diachronic approaches, bearing in mind that no method is absolute or is sufficient in isolation. These approaches integrate the textual, intra-textual, inter-textual, linguistic, semantic, grammatical, structural, redactive, literary and theological methods, depending on the nature of the pericope or ἀφίημι logion at stake. These ἀφίημι logia under consideration were: Matt 1:21; 6:9-13; 6:14-15; 9:1-8; 12:22-32; 18:15-35
Molecular analysis of germ cell specification
No full textThe first step to ensure successful sexual reproduction and species survival is the correct differentiation of primordial germ cells (PGCs). PGCs are the first cells in the germline, and their
correct specification is essential for the eventual production of gametes (eggs and sperm).
Murine PGCs arise as a small population in the post-implantation epiblast in response to external signals, including BMP4 and WNT. However, what governs the first steps in the decision
of cells to enter the germline remains unknown. Here we use single cell omics (scRNA-seq
and scATAC-seq) to characterise the progressive alterations in gene expression and chromatin
readout at short time intervals during in vitro germline specification. Our results establish
distinct trajectories for the specification of early somatic and germline cells during pluripotent
cell differentiation. Epiblast-like cells (EpiLCs) do not contain cells predisposed for germline
differentiation. Rather, two populations emerge after 48h of exposure to external signals:
cells expressing early PGC markers (i.e Prdm1, Ap2y, Esrrb) and cells expressing mesoderm
markers (i.e T, Mixl1, Wnt3a). These populations are mutually exclusive, as germline markers
are expressed in different cells than mesoderm markers. Moreover, commitment of cells to
these fates is asynchronous, as cells expressing PGC markers appear before cells expressing
somatic markers. We propose novel regulators of both WNT and Epithelial-to-Mesenchymal
transition (EMT) which might play a key role in the earliest steps of the decision between
germline and the somatic fate. Moreover, we assess the germline differentiation potential of
cells lacking all three TET enzymes and we show that TET triple knockout cells are unable to
commit to the somatic fate but instead enter the germline and at an enhanced and accelerated
rate. These data establish the order with which cells commit to the germline and to the soma
and suggest that germline entry might be enhanced in cells unable to commit to the somatic
fate
Exploring the structure-function relationship of CHIP mutants associated with cognitive impairment and dementia
No full textThe C-terminus of Hsc70-Interacting Protein (CHIP) has important neuroprotective roles in the protein quality control network as both a co-chaperone and as a chaperone-independent E3 ubiquitin ligase. These functions are intrinsically linked to its structure with the N-terminal TPR domains facilitating its binding to chaperones, Hsp70 and Hsp90; the C-terminal U-box domain possessing intrinsic E3 ligase activity and a central charged domain that allows for protein homodimerization. Loss of function point mutations across all domains of the protein are causative for Spinocerebellar Ataxia Recessive Type 16 (SCAR16) and dominant Spinocerebellar Ataxia Type 48 (SCA48). These multisystemic neurodegenerative diseases result in degeneration of the cerebellum, causing poor coordination and gait instability, as well as cognitive impairment with many patients developing early-onset dementia.
Molecular dynamic simulations of disease-causing point mutations suggested that those localized to the central charged domain of the protein would be highly destabilising for the protein homodimer. Structural analysis of four patient-derived CHIP mutations (R154C, L165F, C199F and M211I) and a recently described ‘monomer’ mutation (L165R) was then performed through Native and Semi-Native immunoblotting. This revealed that contrary to the in silico predictions, all mutant proteins were capable of forming dimeric complexes, although the L165R mutant maintained a greater proportion of monomeric protein in comparison to the others. Hydrogen-Deuterium exchange (HDX) mass spectrometry revealed that the L165R mutation resulted in dramatically increased flexibility of the charged domain which explained its reduced propensity to form higher order structures. Additionally, in all mutant proteins there was disruption to the hydrophobic Hsp90 binding pocket of the TPR domain. These structural changes only led to reduced U-box-dependent ubiquitination activity for L165R CHIP in assays using p53 and IRF-1 as substrates.
Stable, isogenic, undifferentiated SH-SY5Y cell lines that express wildtype or mutant (L165F, L165R or R154C) CHIP were then generated using the Flp-In system. Quantitative label-free proteomics was performed to compare the steady-state cellular proteome of mutant CHIP expressing cells to those expressing wildtype CHIP. This revealed that in cells expressing mutant CHIP, there was an upregulation of membrane proteins and in particular mitochondrial membrane proteins with a structural tethering role in intracellular membrane contact sites. Concurrently, there was downregulation of some cytoskeletal and focal adhesion proteins involved in organelle trafficking and maintaining the structural integrity of the cell. Immunofluorescence experiments identified that expressing mutated CHIP in the cell model resulted in increased fragmentation of mitochondria. This had a functional consequence on mitochondrial-linked respiration in a metabolomics assay, with reduced basal and maximal ATP-linked respiration in cells expressing mutant CHIP, accompanied by an increased rate of glycolysis.
Taken together these findings show that although patient mutations in the charged domain of CHIP did not significantly alter the dimerization or E3 ligase activity of the protein in vitro, the co-chaperone function may be disrupted through altered affinity for Hsp90. Commonly dysregulated pathways amongst cells expressing mutated CHIP suggests that dysregulated organelle trafficking and mitochondrial bioenergetics may underlie the disease spectrum in patients with SCAR16 and SCA48
Ontogeny and functions of foetal mast cells
No full textMast cells (MCs) are a lineage of myeloid innate immune effectors
evolutionarily conserved across species. They are present in the foetus, and
already contain intracellular granules filled with effector molecules (e.g.
heparin and proteases), suggesting that they are functionally mature. Although
MCs are currently thought to be dispensable, we challenge this paradigm and
hypothesise that MCs have critical developmental roles. They may do so by
safeguarding healthy pregnancy to term and/or ensuring survival during preand
postnatal stages. In this thesis, I address this gap in knowledge regarding
MC phenotype and function in three main aims:
Aim 1. To characterise foetal MCs in the extraembryonic compartment and
barrier tissues
Aim 2. To assess the utility of “enhanced MC-Cre” mouse models in targeting
foetal MCs.
Aim 3. To investigate whether foetal MC targeting affects pre- and postnatal
development and survival
I began by examining tissues involved in foetal development and pregnancy
for the presence of MCs. Specifically, I focused on the extraembryonic
compartment (umbilical cord, foetal membrane, amniotic fluid and placenta)
and the foetal barrier tissues (skin, gut and lung). I confirmed that foetal MCs
are present in the barrier tissues, and identified their previously unreported
presence in the extraembryonic compartment (excluding the placenta).
Extraembryonic MCs express integrin α4β7, CD16/32, CD200R and CX3CR1,
with expression levels varying between tissues and developmental stages.
Preliminary data from genetic fate mapping models suggests that
extraembryonic MCs are predominantly derived from erythro-myeloid
progenitors from the yolk sac, with some contribution from haematopoietic
stem cells (HSCs).
I used three conventional “MC-Cre” models in a complementary manner to
comprehensively address the role of MCs in foetal development and survival.
To improve the limited efficiency of existing conventional “MC-Cre” models, we
crossed them with a Cre amplification strain to create “enhanced MC-Cre”
models. We anticipated that this strategy would enable more complete
targeting of foetal MCs, and lead to a more penetrant phenotype. However,
surprisingly, I found that only one of the three “enhanced MC-Cre” models
demonstrated substantial genetic labelling and deletion specifically in foetal
MCs within the extraembryonic and barrier tissues.
When foetal MCs are targeted, I observed increased intrauterine death in
some litters. However, this effect only occurred sporadically and was not
genotype-specific, suggesting it may not be MC-mediated. My focus then
shifted to investigating the role of MCs in postnatal development, revealing that
MC-targeted pups (in our Cpa3-Cre-based models) had significantly reduced
survival, with death occurring within the first day of life. I further examined for
potential skin defects, which indicated a transient ‘outside-in’ barrier defect
prior to birth, followed by an ‘inside-out’ barrier defect in (some) newborn MCtargeted
mice. However, the overall findings between the models are
inconsistent, making it unclear if the skin is indeed defective. Interestingly,
preliminary data suggest that MC-targeted pups may experience defects in
lung function, as evidenced by a higher occurrence of laboured breathing
shortly after birth.
In conclusion, this project generated novel findings that question prior
assumptions about the role of MCs and suggest that they may have important
function(s) during foetal and neonatal life. Specifically, my findings implicate
foetal MCs in the maturation of the epidermal barrier and/or lung, highlighting
the need for further work into the underlying mechanisms, and potential
defects in other organs
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