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The role of the cingulate cortex in depression in dementia with Lewy bodies
Get PDFPhD ThesisDementia with Lewy bodies (DLB) is a significant cause of dementia in the older population with a core set of clinical symptoms that help to distinguish DLB from other forms of dementia such as Alzheimer’s disease (AD). The core symptoms of DLB include fluctuating cognition, recurrent complex visual hallucinations and parkinsonism. Additionally, depression is experienced in around half of DLB patients and is associated with faster rate of cognitive decline, higher mortality rates and a poor response to treatment. The subgenual anterior cingulate cortex (sgACC) is integral in mood regulation, displaying structural, functional and metabolic abnormalities in depression, and shows early and extensive pathological changes in DLB. However, little is known about how any pathological or neurochemical changes in sgACC contribute to the aetiology of depression in DLB.
Post-mortem tissue from cingulate cortex subregions was used to quantify neuropathological lesions in DLB cases with and without depression, and cognitively normal controls. Neurochemical analysis was performed to assess disease and depression specific changes in the sgACC in GABAergic, glutamatergic and monoaminergic transmission. Synaptic changes were assessed using confocal and stimulated emission depletion (STED) microscopy.
Neuropathological burden in cingulate subregions showed disease, but not depression specific changes in DLB. Abnormalities in GABAergic and glutamatergic neurotransmission were observed in DLB cases with depression, showing greater dysregulation compared to DLB cases without depression. Dopaminergic deficits were observed in sgACC in DLB cases, with a greater reduction in DLB cases with depression, whereas no major changes in serotonergic or noradrenergic neurotransmission were observed in DLB.
The results demonstrate that neurodegenerative neuropathological changes within the cingulate cortex do not appear to influence the development of depression in DLB. An imbalance in GABAergic/glutamatergic transmission within the sgACC was greater in DLB cases with depression, which may suggest greater dysregulation in excitation and inhibition, possibly contributing to the development of depression in DLB. This work also demonstrates the major role of dopaminergic neurotransmission in the aetiology of depression in DLB. Overall, this work indicates that treatment of depressive symptoms in DLB could benefit from modulation of dopaminergic, glutamatergic, or GABAergic transmission.The Alzheimer’s Societ
Designing for Disconnection : long-distance Family Relationships in a South Korean Context
Get PDFPhD ThesisThis PhD thesis aims to understand communication in long-distance relationships (LDRs)
in the context of South Korean culture and define the value of disconnection in
communication. I have situated this work within the South Korean context due to the
prioritisation of the family unit in Korean culture and the additional demands this can
cause for family members. I have conducted a design-led, experience-centred research to
develop a rich understanding of the communication practices and the value of
disconnection to support healthy family relationships between South Korean international
students in the UK and their parents in their home country.
I have done this through three interrelated research steps. Firstly, I ran two exploratory
studies consisting of in-depth diaries and extended interviews. These provided a rich
understanding of LDRs between Korean students and their parents, the challenges they
face, and the communication strategies they use to maintain those relationships. The
studies surfaced many students feel a duty to always be in contact with their parents and
are trying to find ways to respectfully disconnect so that they can focus on their academic
performance and adjusting to life in the UK. I then designed an experiential prototype,
Silent Knock, to explore how technology might be designed to support it. Lastly, the
system was deployed with geographically separated families between the UK and South
Korea, exploring its role in reducing the communication pressure that the students feel
while reassuring their parents that they are still thinking of them. I identified that intended
disconnection may have a positive impact on alleviating communicational tensions
between individuals and developing new channels for healthy LDRs.
This research makes four significant research contributions: (i) it provides a rich account
of the lived experiences of South Korean family, highlighting a series of tensions in their
LDRs. (ii) it presents a concept of Respectful Disconnection, which supports intended
disconnection (or limitation) in communication to form healthy patterns of LDRs within a
South Korean context. (iii) it proposes disconnection as an important component when
designing future relationship-based technology, with Silent Knock as an implementation
example. (iv) it details the sketching interviewing method, Sketching Dialogue, which
was used in the extended interview study, to support participant’s engagement in the
research, especially participants from more reserved cultures
Figure-ground processing in the auditory cortex of the macaque monkey
Get PDFPh. D. Thesis.Natural sensory scenes are often very complex, with a multitude of overlapping
objects in space and time. In order to direct behaviour, a critical aspect of everyday
perception is the segregation and grouping of relevant features from those scenes,
known as figure-ground segregation. The neurobiological basis of auditory figureground processing is poorly understood. To gain insights into different aspects of this
process, I have investigated the behavioural, systemic and neuronal mechanisms the
brain uses to segregate and group temporally coherent elements from a complex
acoustic scene in macaque monkeys.
This thesis presents the result of this research in five chapters: Chapter 1
reviews the fundamental basics of auditory scene analysis and the auditory system.
Chapter 2, 3 and 4 present experimental work and cover figure detection behaviour
(Chapter 2), systemic organisation of figure-ground analysis (Chapter 3) and the
underlying neuronal mechanisms (Chapter 4). Finally, Chapter 5 discusses and
interprets the results in the context of previous research.
In summary, this work establishes that macaques are an excellent animal
model for auditory scene analysis and provides new evidence of the cortical response
mechanisms during auditory figure-ground segregation. I show that macaques have
not only similar detection performance to humans but that the areal organisation
measured with fMRI is comparable. Furthermore, I demonstrate robust effects on
neuronal firing rates in response to auditory figures across the cortical hierarchy.
Lastly, this thesis establishes neuronal differences in figure processing between
anterior and posterior auditory cortical fields
An analysis of human movement accelerometery data for stroke rehabilitation assessment
Get PDFPh. D. Thesis.Human Activity Recognition (HAR) is concerned with the automated inference of what a
person is doing at any given time. Recently, small unobtrusive wrist-worn accelerometer
sensors have become affordable. Since these sensors are worn by the user, data can be
collected, and inference performed, no matter where the user may be. This makes for a
more flexible activity recognition method compared to other modalities such as in-home
video analysis, lab-based observation, etc. This thesis is concerned with both recognizing
subjects activities as well as recovery levels from movement-related disorders such as
stroke.
In order to perform activity recognition or to assess the degree to which a subject
is affected by a movement-related disease (such as stroke), we need to create predictive
models. These models output either the inferred activity (e.g. running or walking) in a
classification model, or else the inferred disease recovery level using either classification
or regression (e.g. inferred Chedoke Arm and Hand Activity Inventory Score for stroke
rehabilitation assessment). These models use preprocessed data as inputs, a review of
preprocessing methods for accelerometer data is given.
In this thesis, we provide a systematic exploration of deep learning models for HAR,
testing the feasibility of recurrent neural network models for this task. We also discuss
modelling recovery levels from stroke based on the number of occurrences of events
(based on mixture model components) on each side of the body. We also apply a MultiInstance Learning model to model stroke rehabilitation using accelerometer data, which
has both visualization advantages and the potential to also be applicable to other diseases
Applications of next generation sequencing for the assessment of microbiological safety of fresh produce
Get PDFPh. D. ThesisFresh produce, which is often minimally processed and consumed raw, is increasingly recognised as a route of contamination leading to foodborne illness. This study focussed on the potential of next generation sequencing (NGS) to detect and characterise foodborne pathogens and elucidate the microbiome and potential influences on the survival and transmission of human pathogens within the fresh produce supply-chain.
Initial research assessed the ability of several NGS methodologies to screen the microbiome of fresh produce and identify the limit of detection of bacterial and viral pathogens, using a mock sample set created with known levels of contamination. The limit of detection of human pathogens was found to be dependent upon enrichment method, sequencing approach and bioinformatics analysis utilised. The most sensitive approach tested involved sequence preparation using ribosomal depletion followed by RNAseq and analysis of the microbiome using Kraken; yielding a limit of detection of 105 colony forming units / plaque forming units (CFU/PFU) per extraction. Subsequent in silico work showed the differing read lengths obtained from the MiSeq, HiSeq and NovaSeq has no influence on the limit of detection of human pathogens within a mock community.
Methodological work was applied to study the microbiome associated with commercial fresh produce samples to identify species that may confer a positive or negative effect on the survival of human pathogens. Sequences were also screened for antimicrobial resistance (AMR) associated genes. Data revealed the microbiome to be dominated by potential spoilage organisms and plant pathogens. Four unique AMR-associated genes, with over 80% identity and coverage, were found (CRP, H-NS, MexF, MexB). Nine taxa, including Pectobacterium and Dickeya - soft rot causing bacteria previously linked in the literature to survival of Salmonella on fresh produce - were found to be positively correlated with the microbiological detection of Enterobacteriaceae and Listeria species. Pseudonocardia was the only taxon detected in a large proportion of samples that was inversely correlated with detection of Enterobacteriaceae.
A collection of 48 strains of Listeria monocytogenes originating from the fresh produce supply chain was subject to a combination of phenotypic and genotypic methods to characterise the resistome, virulome, and biofilm forming ability. The genes present and phylogenetic identity of these isolates was then compared to those of 80 isolates from meat
and clinical origin, to identify signatures of fresh produce contaminating L. monocytogenes. Phenotypic screens revealed no evidence of AMR within L. monocytogenes isolated from UK fresh produce. All isolates of L. monocytogenes tested were capable of forming biofilms and displayed an increased propensity for biofilm formation in nutrient broth than in brain heart infusion broth (suggesting that biofilm formation may be induced by stress). Whole genome sequencing data from fresh produce isolates, meat isolates and clinical isolates were indistinguishable based on phylogeny, resistome and virulome. When screened using genome wide association study (GWAS) many potential genes of interest were highlighted
The role of β₂ integrins on dendritic cells in tolerogenic and autoimmune environments
Get PDFPh. D. Thesis.The human immune system reacts swiftly to pathogens while remaining oblivious to
self, an important concept termed self-tolerance. Dendritic cells (DCs) are pivotal in
this process, as they mediate both initiation of adaptive immune responses as well as
induction of tolerance. Recently, evidence has been accumulating that β₂ integrins,
heterodimeric adhesion receptors that can assume an active conformation in
response to stimulation through various receptors, may have both pro-inflammatory
and immunoregulatory roles on DCs. In this thesis, I investigated the hypothesis that
dysregulation of β₂ integrin signalling on DCs can contribute to aberrant inflammatory
responses, such as in the autoimmune disease rheumatoid arthritis (RA).
To test this hypothesis, I first developed and optimised a multi-colour flow cytometry
panel to measure both expression (‘total’ β₂ integrin) and expression of the active
conformation (‘active’ β₂ integrin) of three β₂ integrin subunits: CD11a, CD11b and
the pairing subunit CD18. As conformational state of integrins is highly important for
the functionality, this provided important proof of concept that simultaneous staining
for both ‘total’ and activation-specific epitopes is possible.
Then I utilised mature and tolerogenic monocyte-derived DCs (Mo-DCs) as a model
system to explore the role of β₂ integrins in circumstances of immune activation and
tolerance. I found that tolerogenic Mo-DCs expressed significantly more active
CD11a, while expressing significantly less active CD11b compared to mature MoDCs. Furthermore, treating mature Mo-DCs with a CD11b-blocking antibody
significantly decreased their T cell stimulatory ability, suggesting that CD11b might
have pro-inflammatory roles on DCs.
Lastly, I compared total and active β₂ integrin expression on DCs and monocyte
populations in RA patients and healthy controls. While no differences in β₂ integrin
expression were observed in peripheral blood (PB), comparing synovial fluid (SF) to
PB of active RA patients showed that expression of total and active CD11a was
significantly reduced in SF, while CD11b was significantly increased.
To conclude, I found that CD11a and CD11b might play opposing roles on DCs in
both tolerogenic and autoimmune environments. From my findings, it could be
concluded that CD11a has immunoregulatory roles on DCs, while CD11b is proinflammatory
Assessing treatment technologies for reducing antibiotic resistant gene abundance and diversity in domestic wastewater treatment effluents
Get PDFPhD ThesisAntibiotic resistance is natural, but the wide use of antibiotics in anthropogenic activities has accelerated the rate of evolution and dissemination of antimicrobial resistance (AMR) strains around the world. One location of interest relative to AMR is domestic wastewater treatment plants (WWTPs). WWTPs are very effective at reducing the discharge of water contaminants and pathogens to the environment, and AMR levels are generally lower in places where wastewater is treated. However, understanding the relative value of different treatment options is less clear, which is central to this work. Here, four full-scale biological wastewater treatment technologies (trickling filter, granular activated sludge, activated sludge, and membrane bioreactor) were compared in their relative ability to reduce antibiotic resistance genes (ARGs) in treated effluents. Further, two advanced oxidation processes (AOPs; i.e., ozonation and hydrogen peroxide coupled with UV) and different combinations, and also a Fenton-like system using Fe-bearing clay minerals were assessed as additional steps to biological treatment. Data based on quantitative polymerase chain reaction (qPCR) and high-throughput qPCR showed that all biological options effectively reduced ARG abundance and diversity in final effluents, and enrichment of ARGs was not evident. The efficacy of each WWTP at reducing ARGs and overall bacterial loads was highly related to the treatment technology applied, with secondary treatment contributing > 0.73 to the total ARG removal in all WWTPs, while, membrane bioreactor was the most effective technology achieving up to a log removal of 6.1. Ozonation (3 g/m3) as an additional step to an activated sludge system showed potential to reduce further abundances and diversities of ARGs by 1.25 log unit, achieving a total removal of 3.61. Using propidium monoazide (PMA)-qPCR to differentiate viable vs non-viable cell carriage of ARGs, we showed that ARGs were often carried in non-viable cells, which has implications to downstream gene exchange related to AMR spread. Finally, removal rates up to log 2.94 of target ARGs achieved by using iron-bearing clay minerals, which shows promise as an alternate to AOPs for ARG reduction in WWTPs. With a few AOP exceptions, all treatment technologies removed ARGs from domestic wastewater, although the membrane bioreactor was the most effective overall.Engineering and Physical Sciences Research Council (EPSRC) and Thames Water (TW
The Mediterranean diet and multiple sclerosis: a case-control study in The Republic of Cyprus
Get PDFM. D. ThesisBackground: It has been suggested that dietary habits are associated with multiple sclerosis.
Some eating patterns have been considered protective while others harmful.
Objectives: A case–control study was used to examine the association between multiple
sclerosis and the Mediterranean diet, food groups and individual foods.
Methods: A total of 127 multiple sclerosis cases and 718 controls from across The Republic
of Cyprus completed a self-reported questionnaire which included lifestyle and food
questions. A 9-unit Mediterranean diet score (MDS) was calculated. Logistic regression was
used to assess associations. An age-matched analysis of 119 cases and 119 controls was
evaluated using conditional regression.
Results: In the logistic regression analysis adjusted for age, a higher MDS (OR=0.96, 95%
CI: 0.93-1.00, p: 0.04) was inversely associated with being a multiple sclerosis case.
Significant inverse associations were found in the following groups: vegetables (OR=0.83,
95% CI: 0.70-0.98, p: 0.03) alcohol (OR=0.87, 95% CI: 0.80-0.95, p: 0.001) legumes
(OR=0.78, 95% CI: 0.64-0.95, p: 0.01) non-refined cereals (OR=0.81, 95% CI: 0.66-0.98, p:
0.03) while significant associations were found with dairy products (OR=1.24, 95% CI: 1.05-
1.46, p: 0.01). Similar results were seen in the age-matched conditional regression analysis.
Conclusions: There was found to be a statistically significant association between a
Mediterranean type diet and multiple sclerosis. There was an inverse association of being a
multiple sclerosis case, with an increase in the MDS. Certain food groups and individual
foods may also be associated with an increased or decreased association of being a multiple
sclerosis case. This study may have significant effects on health planning in The Republic of
Cyprus. When interpreting the results, there is always the possibility of reverse causality. That
is, the disease itself, or the diagnosis of the disease, may lead to a change in eating habits. It is
recommended that a Mediterranean type diet type be considered as a prevention measure to
investigate in future intervention studies
Development of high force dense linear generators for wave energy converters
Get PDFPhD ThesisThe main concern of this thesis is the development of force dense linear generators for a Direct Drive Wave Energy Converter. Linear machines for direct drive power take-off systems are required to deliver very high force in order to harness the significant amount of power from the low velocity oscillation of an ocean wave. Therefore, the linear Vernier Hybrid Machine is investigated for its simple design structure and high force density at low speed, due primarily to the inherent magnetic gearing. Attention is focused on improving the performance of the existing linear Vernier Hybrid Machine and developing new variant topologies with higher force density.
An improved E-core stator design, optimised permanent magnet dimensions and new segmented translator structure have been proposed which improve the machine performance in terms of mass and magnet utilisation. The implementation of a pole shifting method is shown to provide a significant reduction in the cogging force. Two cylindrical variants with three-dimensional flux paths are also developed from the improved E-core Vernier Hybrid Machine, which further improves the force with similar magnet mass and current density. Furthermore, a new combination of Halbach magnets arrays and Consequent Pole topology are employed in the flat E-core structure, known later as Halbach Consequent Pole Vernier Hybrid Machine, which significantly improves the flux density by reducing the inherent pole-to-pole leakage and thus further improve the force density and power factor of the machine. A cylindrical variant of the flat Halbach Consequent Pole topology has been designed and analysed to prove the performance improvement of the cylindrical versions compared to the flat.
The flat Halbach Consequent Pole and two small scale cylindrical variants of the E-core Vernier Hybrid Machines have been built and tested in the laboratory. The flat prototype is built from laminated steel and both the cylindrical machines are made of Soft Magnetic Composites to allow the three-dimensional flux path. All the experimental results are shown to provide good agreement with the static and dynamic generator performance predictions.
Finally, this thesis compares the performance of three flat and three cylindrical Vernier Hybrid Machine topologies for various axial lengths and air-gap diameters and investigate the feasibility of using them for a wave energy devic
Improving participation in environmental decision-making using Bayesian Belief Networks
Get PDFPhD ThesisParticipation is increasingly recommended to improve democratic processes; however, in
practice it is often perceived as an empty and frustrating process (Arnstein, 1969, p. 216). In
participatory environmental decision making (PEDM) extractive methods of data collection
focus on accuracy of data rather than democratic values and prioritise expert knowledge over
public views. As a result, participants become disillusioned and negative feelings develop into
active opposition (Wolsink, 2007), causing delays, spiralling costs, and conflict (Haggett,
2008). Previous studies claim that features of advanced statistical modelling, such as Bayesian
Belief Networks (BBNs), could aid participation. Using an exploratory case study, a proposed
tidal energy scheme in the UK’s Solway Firth, Solway Energy Gateway (SEG), this study
investigates how features of BBNs could be harnessed to improve PEDM. A Participatory
Action Research (PAR) inspired framework of phases of action and reflection was used to
collect and analyse qualitative data from a diverse sample of stakeholders. BBNs were coproduced
and co-analysed with the participants over five cycles of engagement. The capacity
for BBNs to improve PEDM was evaluated against criteria derived from theoretical ideals of
deliberative democracy, procedural environmental justice, and science and technology
studies. BBNs were found to partly contribute to the fulfilment of the criteria. Working
through the logical structure of the BBNs helped the participants broaden their thoughts and
generate knowledge. However, the complexity of BBNs caused anxiety and consultation
fatigue. Knowledge was lost as BBNs were built, reducing the ability to communicate
knowledge and facilitate learning between participants. BBNs highlighted opposing views,
emphasising existing hostilities. There is capacity for BBNs to aid in the scoping phase of
PEDM. Further research is needed to explore this proposition and how BBNs could be used in
combination with other modelling tools to implement a more comprehensive solution to the
challenges associated with PEDM