VictorJuiz/thesis huggingface dataset:
Junctional modulation of sympathetic transmission

This project involved the study of mechanisms which modulate autonomic transmission within the sympathetic nervous system using the mouse vas deferens as a model tissue. Data was collected using contraction studies, electrophysiological techniques with sharp microelectrodes, and fluorescent calcium imaging of both smooth muscle cells and nerve terminal varicosities. An additional series of experiments was conducted using the PC12 cell line, derived from a phaeochromocytoma of the rat adrenal medulla, for flow cytometry experiments using fluorescence-activated cell sorting.
During the course of this project a novel technique for studying the activity of the norepinephrine transporter within a whole organ preparation was developed using the neurotransmitter uptake assay. The uptake of this assay within the nerve terminals of the vas deferens was abolished by desipramine whilst its rate of washout was increased by amphetamine. However, some non-neuronal, peri-nuclear staining which could not be prevented by a range of pharmacological means was also observed. This new technique was then used in other work exploring putative NET regulation by cannabinoids.
The modulatory effects of two pharmacological groups were assessed: testosterone and cannabinoids. Testosterone was found to have a rapid, non-genomic effect inhibiting neurotransmission within the vas deferens. This was a postjunctional effect which appeared to involve modulation of the opening of L-type calcium channels on the smooth muscle cells.
For the studies of cannabinoids, two broad areas of research were conducted. First the effects of Δ9-tetrahydrocannabinol were investigated with regard to the pre-junctional release of neurotransmitters and the effect of THC on calcium dynamics within individual nerve terminal varicosities. Secondly, a surprising novel effect upon the norepinephrine transporter was identified and examined. This inhibitory effect was revealed initially by contraction experiments demonstrating a decrease in the rate of uptake of noradrenaline from the junction.
This work demonstrates that there are still novel modes of regulation of sympathetic transmission to be uncovered. The ongoing challenge is to establish their role within physiology and pathophysiology.

Keywords: cannabinoids
autonomic
calcium
testosterone
neurotransmission
sympathetic
Advisor: Brain, K
Forecasting with large datasets

This thesis analyzes estimation methods and testing procedures for handling large data series. The first chapter introduces the use of the adaptive elastic net, and the penalized regression methods nested within it, for estimating sparse vector autoregressions. That chapter shows that under suitable conditions on the data generating process this estimation method satisfies an oracle property. Furthermore, it is shown that the bootstrap can be used to accurately conduct inference on the estimated parameters. These properties are used to show that structural VAR analysis can also be validly conducted, allowing for accurate measures of policy response. The strength of these estimation methods is demonstrated in a numerical study and on U.S. macroeconomic data. The second chapter continues in a similar vein, using the elastic net to estimate sparse vector autoregressions of realized variances to construct volatility forecasts. It is shown that the use of volatility spillovers estimated by the elastic net delivers substantial improvements in forecast ability, and can be used to indicate systemic risk among a group of assets. The model is estimated on realized variances of equities of U.S. financial institutions, where it is shown that the estimated parameters translate into two novel indicators of systemic risk. The third chapter discusses the use of the bootstrap as an alternative to asymptotic Wald-type tests. It is shown that the bootstrap is particularly useful in situations with many restrictions, such as tests of equal conditional predictive ability that make use of many orthogonal variables, or `test functions'. The testing procedure is analyzed in a Monte Carlo study and is used to test the relevance of real variables in forecasting U.S. inflation.

Advisor: Sheppard, K
A comparison of discrete and continuum models of cardiac electrophysiology

When modelling tissue-level cardiac electrophysiology, a continuum approximation to the discrete cell-level equations, known as the bidomain equations, is often used to maintain computational tractability. The bidomain equations are derived from the discrete equations using a mathematical technique known as homogenisation. As part of this derivation conductivity tensors are specified for use in the continuum model. Analysing the derivation of the bidomain equations allows us to investigate how microstructure, in particular gap junctions that electrically connect cells, affect tissue-level conductivity properties and model solutions.
We perform two distinct but related strands of investigation in this thesis. In the first, we consider the effect of including gap junctions on the results of both discrete and continuum simulations, and identify when the continuum model fails to be a good approximation to the discrete model. Secondly, we perform a comprehensive study into how cell-level microstructure properties, such as cell shape, impact the homogenised conductivities to be used in a tissue-level continuum model. This will allow us to predict how the onset of a disease or a change in cellular microstructure will affect the propagation of action potentials.
To do this, we first derive a modified version of the bidomain equations that explicitly takes gap junctions into account. We then derive analytic solutions for the homogenised conductivity tensors on a simplified two-dimensional geometry and find that diseased gap junctions have a large impact on the results of homogenisation. On this same geometry we compare the results of discrete and continuum simulations and find a significant discrepancy between model conduction velocities when we introduce gap junctions with lower coupling strength, or when we consider elongated cells. From this, we conclude that the bidomain equations are less likely to give an accurate representation of the underlying discrete system when modelling diseased states whose symptoms include reduced gap junction coupling or an increase in myocyte length.
We then use a more realistic two-dimensional geometry and numerically approximate the homogenised conductivity tensors on this geometry. We discover that the packing of cells has a substantial effect on conduction, with a brick-wall geometry particularly beneficial for fast propagation, and that gap junctions also have a large effect on conduction. Finally, we consider a three-dimensional cellular geometry and show that the effect of changing gap junction properties is different when compared to two dimensions, and discover that the anisotropy ratios of the tissue are highly sensitive to changes in gap junction parameters.
Overall, we conclude that gap junctions and cell structure have a large effect on discrete and continuum model results, and on homogenised conductivity calculations in tissue-level cardiac electrophysiology.

Keywords: Bidomain
Advisor: Whiteley, J
Pathmanathan, P
Image analysis of cardiac computed tomography towards regional functional analysis

Global assessment of myocardial function is widely performed by estimating ejection fraction (EF), but many common cardiac diseases initially affect the myocardium on a regional, rather than global, basis. Computed tomography (CT), most commonly applied to assess the coronary arteries, is a prime candidate for such regional analysis. This doctoral thesis makes steps towards regional CT functional analysis with two clinical and two technical contributions.
The first clinical contribution focuses on evaluating the feasibility and utility of functional analysis with currently available CT technology. Our study found that CT strain analysis could identify regional wall motion abnormalities in cardiomyopathy that are not otherwise detected using conventional metrics of myocardial function such as EF.
In order for cine CT of the heart to become routine clinical practice, improvements need to be made to the image acquisition protocol. The second clinical contribution focus on making these improvements with results pointing to the possibility of one millisievert range cine CT images with high (>50 milliseconds) temporal resolutions.
Moving to technical considerations, a key concern has been how to better characterise the myocardium in CT. To address this, the first technical contribution examines the use of feature-based attribute vectors, which were found to improve image registration towards deriving more reliable motion estimations.
The second technical contribution focus on developing a pipeline tailored towards CT strain analysis. Noting that CT naturally provides information in 3D, a 3D hyperelastic biomechanical model fitting method was evaluated. Analysis of an infarction model demonstrated that regional myocardial strain can be estimated in the 3D space and areas of infarction can be detected.
By considering both technical and clinical perspectives, these advances will contribute to the the field of regional cardiac functional analysis towards improving patient care.

Advisor: Noble, JA
The acceptability and efficacy of a brief universal preventive parenting intervention for child behavioural and emotional disorders

This thesis investigates the acceptability and efficacy of a brief universal preventive parenting intervention for child behavioural and emotional difficulties. The methodology included a systematic review, a literature review, a pilot randomised controlled trial and focus group discussions. The systematic review aimed to show whether behavioural and emotional difficulties are a significant problem in Greece. Greek children appeared to display high scores on, and prevalence of behavioural problems, compared to children from other countries. The results suggested that, based on parental reports, Greece seems to have a high prevalence in child behavioural and emotional difficulties. The literature review explored the effectiveness of universally delivered Triple P preventive interventions and identified research gaps. There was also insufficient evidence on the effectiveness of brief universal Triple P programmes to draw any definitive conclusions. No randomised trial had examined the short-term and long-term effectiveness of the Triple P brief universal interventions (Seminar Series). The pilot randomised trial explored the efficacy of the Triple P Seminar Series for the reduction of child behavioural and emotional difficulties. 124 parents were randomly allocated to receive three seminars on positive parenting, while parents in the control group received information on child development. There was a significant reduction in behavioural problems over time (primary outcome), and a reduction in parenting dysfunctional difficulties in the short-term. Parents gave positive feedback on the intervention indicating that overall it was acceptable, feasible, culturally relevant, and useful. Preliminary moderator analyses indicated that there were no moderator variables affecting the relation between group allocation and change in child disruptive scores. Preliminary mediator analyses suggested that a reduction in dysfunctional practices partially explained improvements in children’s disruptive behaviours over time. Lastly, 46 parents of the intervention group shared their personal experiences regarding the Seminar Series during six focus groups. The facilitators of positive parenting were relevant to what they did before, during, and after their practices, while barriers included child, parent and external factors. The final conclusions after triangulation and the implications of this thesis for practice and further research were discussed.
Clonal dynamics of TEL-AML1+ childhood ALL: an in vivo model

ETV6–RUNX1 gene fusion is an early or initiating genetic lesion of Childhood Acute Lymphoblastic Leukaemia, followed, in disease progression, by a modest number of recurrent or "driver" copy number alterations. Among patients diagnosed with this particular cytogenetic subtype of ALL cure rate reaches over 80% . However, treatment protocols are extremely demanding, and the molecular mechanisms driving drug-resistance and relapse in the remaining 10% of patient are still unknown. Recently a genetic signature of subclones arranged in a complex non-linear or branching architecture has been identified in this leukaemia, pioneering similar observations in many other cancer types. At present, most reports of this intratumor diversity represent static, in-depth snapshots of clonal diversity of tumours at a given time. "Real-time" longitudinal and spatial analysis of subclonal evolutionary dynamics is required to understand the functional characteristics of individual subclones. Such approach also promises to reveal the overall clinical relevance of this phenomenon.
This project therefore aims to understand whether genetically distinct subclones are also functionally different, particularly with respect to chemoresistance.
A mouse model that allows for the independent exposure of the same tumour to treatment multiple times, and the tracking of clonal dynamics by mean of a selected pool of genetic markers was established. While the analysis is still ongoing, preliminary data confirm that tumours generated from the same inoculum are highly similar in their genetic makeup across recipients, that multiple clones within a tumour can survive chemotherapy, but sensitivity of clones equally represented within the bulk can vary, and unexpectedly that spatially segregated subclones can be identified in this model of liquid cancer. The complete analysis of the collected samples by mFISH as well as by single cell whole genome sequencing will provide unprecedented insight into the impact of cytotoxic treatment on intratumour genetic heterogeneity, and might reveal novel mechanisms of chemoresistance and relapse.
Additionally, a lentiviral overexpression system was designed to endogenously manipulate clonal interactions through the restored expression of TEL and PAX5 in primary cells from patients, and evaluate their impact on clonal relationships and hierarchies and to validate the results obtained from the first part of the study. Lentiviral vectors for TEL and PAX5 second hit overexpression were produced and tested by Western blot and qPCR. The TEL vectors were adopted in a preliminary in vivo experiment, showing no effect on overall engraftment ability.

Advisor: Enver, T
Jacobsen, S
Electrochemical detection of thiol containing molecules

This thesis presents the experimental work with the main aim of developing new electrochemical based methods for detecting thiol-containing molecules, specifically homocysteine, glutathione, and cysteine, with little to no sample treatment in an aqueous system. The first chapter introduces the principles and techniques of electrochemistry. The second chapter gives a brief introduction to the importance of thiol containing molecules in biological systems; thus, the need for its analytical determination and quantification.
This thesis reports a suitable electrochemical methodology to selectively detect thiols using a combination of different ortho-quinone derived mediators and carbon electrode materials. The methodology exploits two ortho-quinone reaction pathways with a thiol molecule, electrocatalytic and 1,4-Michael addition reaction. Proof-of-concept was carried out in buffered systems then realized in synthetic and real biological sample; where ultimately, quantitative performance in 'real world' sample was shown to be analogous to a commercially available enzyme test.
Finally, screen-printed electrodes are employed in the presented study to show the prospect for a point-of-care system. The compact design, such as having a three-electrode system printed onto a single strip, allows versatility and easy utilization. These electrochemical chips are ideal and advantageous for high throughput applications.
Overall, the development of a quick, easy, and cheap methodology for thiol determination discussed in this thesis makes a significant contribution to the clinical and biomedical community as an alternative and simpler diagnostic pathway.

Advisor: Compton, R
Ultra-low emittance lattice design for advanced synchrotron light sources

Storage ring based synchrotron light sources deliver high brightness radiation generated by high quality electron beam. The electron beam emittance plays an importance role in controlling the brightness and coherence of the radiation output. An extensive design effort is required to optimse the lattice to improve the beam emittance and machine performance. This thesis reports a series of investigations into lattice tuning, modification and full upgrade to improve the machine performance of third generation light sources, using the Diamond storage ring lattice as a model.
In the first part of this thesis, the optics functions of the existing lattice are optimised in order to reduce the natural beam emittance. A reduction of 27% is achieved and verified experimentally, although the effects of strong insertion devices (IDs) reduce this improvement. A second study was carried out with the aim of replacing one of the existing double bend achromat (DBA)cell with one and two double-double bend achromat (DDBA) cells providing additional straight sections for IDs. It was proven that the addition of one DDBA cell can be implemented without significant deterioration of the performance of the machine. The case with two DDBA cells however provides a beam lifetime which is only half of the value in the existing machine. A third study was carried out to consider a full lattice upgrade using multibend achromat (MBA) cells aiming for ultra-low emittance.
The last part of this thesis concentrates on the study of an improved beam injection scheme employing a pulsed multipole kicker (PM). The aim is to achieve an eficient beam injection while producing a lower perturbation to the stored beam during the injection. Based on particle tracking, the beam injection performance of the scheme is optimised for the existing Diamond and for the one DDBA lattice. The effects of the PM on the stored beam is proven to be negligible. The compatibility of the existing injection system with the new injection scheme is evaluated. Such scheme provides a feasible alternative to the existing injection scheme that could reduce the perturbation during the beam injection during Top-up injection.
The gatherer and the grindstone: towards a methodological toolkit for grindstone analysis in southern Africa

Although grindstones – that is, pairs of stone implements used to grind, pound, pulverise or otherwise process intermediate materials – have been intensively studied by archaeologists in other parts of the world, in southern Africa to date they have received little attention. Despite a near-ubiquitous presence on Middle and Later Stone Age archaeological sites, their primary function in archaeological reconstructions has been as proxies for other behaviours. These include behavioural modernity; gender; particular plant types, such as geophytes/underground storage organs.
This doctoral thesis interrogates grindstones with a view not only to establishing specific (rather than proxy) uses in the southern African archaeological record,but also as a means to explore the gathered side of hunter-gatherer lifeways, which have also historically been neglected. It does this by developing a methodological toolkit for grindstone analysis in southern Africa.
Comparison of archaeological and historical literature from the southern African Grassland Biome and elsewhere suggests a tension between archaeological accounts which posit geophyte and mineral pigment grinding as a primary purpose for grindstones and ethnohistorical accounts suggesting that grass-processing was a staple of hunter-gatherer life. Finally, a corpus of putative grindstones from the site of Ha Makotoko in western Lesotho is typologically assessed and analysed for plant starches and phytoliths. It emerges that at this site, and in contrast to received wisdom, geophyte grinding was not extensive but by contrast, grass seed processing was practised. This belies models suggesting that C4 grass seeds were unlikely to have contributed to hunter-gatherer diets, and questions interpretations of grass 'bedding' as well as the distinction between 'forager' and 'farmer'. Most importantly, this thesis validates the idea that grindstone study is worthwhile, and should be integrated into wider lithic study in southern Africa as a matter of course.

Keywords: hunter-gatherers
Archaeobotany
lithic technology
southern Africa
Advisor: Mitchell, P
Essays on the implementation of monetary policy

Chapter 1 builds a two-bank bargaining model of the overnight interbank market in which, due to the commitment of the central bank to its interest rate target, bargaining between banks impacts loan sizes rather than interest rates (the converse of existing models). As a result, policy changes have a different impact to what is posited by existing models.
The model is applied to a market where the commitment of the central bank is well documented (Australia). With reasonable parameter values, the model replicates five stylised facts of the Australian market. Moreover, the stylised facts are replicated without recourse to any asymmetries.
Chapter 2 extends the two-bank model to incorporate a large number of heterogeneous banks. This model is able to replicate the asymmetric shape of banks' end-of-day central bank deposit distributions (despite symmetric initial distributions); a novel contribution to the literature. Moreover, after inputting recent changes in Australian central bank policy, this model produces percentage changes in interbank trading volumes that closely align with the data.
Central banks typically supply more overnight deposits than banks desire to hold (in aggregate), but this aggregate is typically small relative to interbank lending. With commitment, this is not required for the central bank to achieve its interest rate target (the typical explanation in the literature). So, to explain this phenomenon, Chapter 3 builds a DSGE model that incorporates commitment and the results from the previous chapters.
Due to asymmetric information, there may be stigma associated with borrowing from the central bank's overnight lending facility, which is costly. But while the central bank can reduce use of its lending facility, by increasing aggregate deposits, the resulting fall in interbank lending is also costly; because the interbank market helps banks monitor their counterparties. Therefore, low but positive aggregate deposits can be explained as the welfare-optimising point in the trade-off between stigma and monitoring costs (a novel contribution to the literature).

Keywords: Stigma
Interbank Market
Monetary Policy
Bargaining
Commitment
Australia
Central Bank
Advisor: Ellison, M