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Characterising the prostate stem cell niche and its architecture in benign prostatic tissue
Full text linkM. D. Thesis.Prostate cancer is the most common cancer among males in the UK with 1 in 8 men being
diagnosed with the disease during their lifetimes. Despite its high prevalence and
incidence, a lot about the disease process is still unknown. To understand the changes
that occur in a malignant state, it is important to understand normal physiology and
homeostatic mechanisms. It then becomes easier to pinpoint and understand what exactly
goes wrong. Understanding the role of stem cells could also help in understanding
castration-resistant prostate cancer as there could be cells that exhibit similar
characteristics driving the tumour process at that point.
Key among the factors in maintaining a normal physiological state is the existence of
prostate stem cells and prostate stem cell niches. There was a debate about the location
of these cells – and whether they were basal or luminal. Previous work done also
conclusively pointed towards a basal location although there was also evidence to say that
luminal stem cells existed. Further work done in the lab previously, also confirmed these
findings in addition to saying that these cells were clustered at the juxta-urethral prostatic
ducts. There has also been research that has pointed to the existence of stem cells by
discovering two cell types that did not fit into traditional classifications of prostate cells.
This study attempts to characterise the location of the stem cells and the stem cell niche
within the larger context of prostate tissue. By using immunohistochemical methods to
characterise each type of cell based on cell type-specific markers such as Prostate
Specific Antigen and Uroplakin 1b, the aim is to paint a picture of the architecture of the
stem cell niche and the surrounding microenvironment.
Some positive findings from this study could only add to the evidence that there exist
certain areas of the prostate tissue which do not fall under traditional categorisations of
prostate epithelium or urothelium. There also exist areas of overlap between prostate and
urothelium which could point towards an important overlap in their origin stories – this
needs to be studied further. However, for various reasons, the methods of study need to
be optimised further for better results.
In conclusion, this project adds to evidence of a potential basal location for stem cells as
well as talking about the various limitations with the methodologies used. In addition, there
is also potential for future studies with regard to more structural as well as functional
aspects of the niche including evaluating the role of stem-like cells in castration resistant
prostate cancer
Citizen participation, collective action and digital media: Seeking spatial justice in Manizales, Colombia
Full text linkPh. D. Thesis.This thesis explores the possibilities and limitations of citizen participation and
collective action for spatial justice across the online and offline spaces of the
everyday. It uses the case study of Manizales, Colombia; a city that proclaims itself
as innovative, socially inclusive and participatory. Two hypotheses informed the
research design. One, that despite city’s efforts on digital innovation, local
government in Manizales had yet to use the collaborative potential of digital media,
in order to improve participatory and collaborative processes of city-making. And
two, that there are significant differences in the perceptions from local government
and social collectives, about the transforming potential of collective action and digital
media uses for inclusion and participation. Consequently, the research questions
explore the relationships between governmental initiatives and the everyday life of
socio-territorial movements seeking spatial justice, as well as the ways in which
citizens mobilise, the local roles of digital media in collective action, and the
implications of the findings to transform debates about spatial justice in Manizales
and beyond.
Drawing on five months of place-based participant observation in Manizales, a year
and a half of netnographic exercises (online participant observation), complemented
by interviews and perception exercises, the thesis provides an empirical analysis that
is grounded in the everyday processes of city-making, from the formal protocols to
the informal and alternative. Three socio-territorial movements in the city served as
the sub-cases of study, which included several individuals and collectives that
became crucial participants in this research.
Overall, this thesis highlights the importance of understanding local socio-political
contexts in relation to processes and efforts around digital innovation for participation
and collective action. Additionally, it argues that the expansion of urban planning, as
a practice that embraces and makes the most of the chaos of participation – both
online and offline, requires recognition and integration of city-making practices
outside of hegemonic structures of power. Moreover, the findings reveal a case of
urban contestation as an exercise of transgressive, rather than insurgent citizenship,
which can enrich current debates about the Right to the City and practical
approaches towards data and spatial justice in the city.Research Excellency Academy, School of Architecture
Planning and Landscape at Newcastle Universit
Negotiating eldercare in Chinese middle-class families : a case study of Tianjin, China
Full text linkPhD ThesisThis study investigates changing views and practices of eldercare in Chinese middle-class families. It aims to understand the context in which shifting expectations, dynamics and various forms of family practices influence the lives of older people. The thesis concludes by making suggestions for policymakers, planners, and the market to provide appropriate support and options for the rising number of middle-class families.
This thesis begins by exploring the fusion of two phenomena: the rising middle-class and increasing percentage of older people in China driven by increased longevity and the one child policy. The interaction of these is producing new dilemmas for families providing elder care and new strategies. Fieldwork took place in the urban region of Tianjin, China, to collect narratives of participants’ eldercare practices, their life stories and later life plans. After six-months fieldwork, a total of ten families were interviewed, including: seven families with three generations (grandparents, older parents and one-child) and three families without the oldest generation (older parents, one-child). Their family stories are analysed in three chapters (6,7,8) that discuss those families who are self-reliant; those who buy in support for the grandparents and finally those whose older parent generation are the oldest in the family who reflect on their own preferred ageing trajectory. The key findings are that in middle-class families, the grandparent generation have little need to rely on their adult children financially but can use their own good pensions. Older generations were able to use their wealth and housing assets to benefit younger generations and through that to promote familial support. Families had different interpretations of filial obligations but shared common values. For example, grandparents are happiest to age in the community with regular visits from their children. With only one child to rely on, older parents are very reluctant to burden their children and look to reciprocity in their family practices. The research revealed that while these middle-class households have stronger economic conditions, they still expect to care for the grandparent generation but, with many calls on family resources of time, need to navigate buy in support particularly when there is frailty in the very old. In the past co-residence would have supported filial piety but new living arrangements of living close by or ‘living with’ on a rotational or short-term basis are options embraced by middle class families. The research exposes the fragility of market based elder care support and the thesis concludes by making recommendations for building more robust services
Multi-objective torque control of switched reluctance machine
Full text linkPhD ThesisThe recent growing interest in Switched Reluctance Drives (SRD) is due to the electrification
of many products in industries including electric/hybrid electric vehicles, more-electric
aircrafts, white-goods, and healthcare, in which the Switched Reluctance Machine (SRM) has
potential prospects in satisfying the respective requirements of these applications. Its main
merits are robust structure, suitability for harsh environments, fault-tolerance, low cost, and
ability to operate over a wide speed range. Nevertheless, the SRM has limitations such as large
torque ripple, high acoustic noise, and low torque density. This research focuses on the torque
control of the SRD with the objectives of achieving zero torque error, minimal torque ripple,
high reliability and robustness, and lower size, weight, and cost of implementation.
Direct Torque Control and Direct Instantaneous Torque Control are the most common methods
used to obtain desired torque characteristics including optimal torque density and minimized
torque ripple in SRD. However, these torque control methods, compared to conventional
hysteresis current control, require the use of power devices with a higher rating of about 150%
to achieve the desired superior performance. These requirements add extra cost, conduction
loss, and stress on the drive’s semiconductors and machine winding. To overcome these
drawbacks, a simple and intuitive torque control method based on a novel adaptive quasi sliding mode control is developed in this study. The proposed torque control approach is
designed considering the findings of an investigation performed in this thesis of the existing
widely used control techniques for SRD based on information flow complexity.
A test rig comprising a magnet assisted SRM driven by an asymmetric converter is constructed
to validate the proposed torque control method and to compare its performance with that of
direct instantaneous torque control, and current hysteresis control methods. The simulation and
experimental results show that the proposed torque control reduces the torque ripple over a
wide speed range without demanding a high current and/or a high switching frequency. In
addition, It has been shown that the proposed method is superior to current hysteresis control
method in the sensorless operation of the machine. Furthermore, the sensorless performance of
the proposed method is investigated with the lower component count R-Dump converter. The
simulation results have also demonstrated the excellent controller response using the standard
R-Dump converter and also with its novel version developed in this thesis that needs only one
current sensor
The Road to Recovery : understanding and improving the process of rebuilding seismic resistant schools in Nepal.
Full text linkPhD ThesisMany schools in Nepal were damaged or destroyed in the 2015 Gorkha earthquake,
highlighting major vulnerabilities in Nepal’s school infrastructure. Schools are particularly
important within communities, providing education, and often acting as a centre for aid
distribution and shelter following disasters. Therefore, it is vital that when these facilities are
reconstructed, they have an improved resilience to enable them to resist future earthquake
events. Since the 2015 earthquake, school reconstruction programmes have been initiated
and there are examples of good school reconstruction both within Kathmandu and in some of
Nepal’s more remote areas. However, there are a wide range of challenges affecting this
process, and evidence that knowledge transfer between stakeholders is limited, meaning that
practices to reduce challenges are not being utilised in all projects, impeding successful and
efficient construction.
This thesis presents data collected within two fieldwork visits to Nepal. These took the form
of a pilot study to identify key challenges, and understand the broader context, followed by a
phase two study, building on the pilot study findings, understanding the challenges in more
detail, and identifying good practice to overcome or mitigate the challenges. Across the two
visits, 20 interviews were conducted, with stakeholders at both a case-specific school level,
and a high-level with broad involvement across multiple projects, in addition to other
complementary research activities such as meeting with engineering professors, visiting case specific schools, and visiting earthquake affected communities to explore broader resilience
efforts. Six key challenges that affect the school reconstruction process have been identified:
1) accessibility and transportation, 2) skill and availability of labour, 3) quality and availability
of materials, 4) suitability and availability of land, 5) community involvement, and 6)
government processes. Of these, accessibility and transportation was the most frequently
reported challenge, and had the greatest perceived impact, of 0.75 on a scale of zero to one.
It was also found that different challenges were perceived differently by different stakeholder
groups, and the impact varies relative to the contexts in which they occur. Good practices
have also been identified, specific to the contexts in which they were implemented, and would
be applicable, including: 1) training of labour, 2) training for SMCs, to better manage projects,
3) planning projects around the monsoon, for projects that are only accessible via seasonal
roads, and 4) accounting for higher transportation costs to harder to reach sites.
Based on these findings, a decision-making framework has been created, to help stakeholders
identify practices to improve project delivery, specific to the individual project context. The
process of producing this framework, and subsequent validation, conducted via an online
questionnaire with nine stakeholders, are also presented. Five out of nine participants
reported that most or all of the good practice recommended would have been suitable for the
projects they considered, and eight out of nine reporting that the framework would be
valuable for either themselves or less experienced stakeholders, if implemented within a
project. A range of benefits of implementing the framework were reported, including: 1)
better managing and planning projects, 2) bringing additional benefits to the school and
community, 3) increasing the quality of construction, and 4) reducing delays. Utilising this
framework within projects would therefore work to improve the resilience of Nepal’s school
infrastructure and assist in efforts to build back better and safer following the 2015
earthquake or future earthquake events
Evaluation of a shorter 12h acetylcysteine regimen & development of a simpler acetylcysteine (SNAP) protocol for the treatment of paracetamol poisoning
Full text linkPhD ThesisParacetamol is the commonest drug involved in hospital admissions with poisoning
in the UK. Acetylcysteine (NAC) is the antidote of choice for treatment of
paracetamol overdose, but the original 3-bag NAC regimen, designed in
Edinburgh, is associated with infusion-related adverse reactions related to high
peak plasma acetylcysteine concentrations from the high loading infusion of
600mg/kg/h. The Scottish and Newcastle Antiemetic Pre-treatment (SNAP) study
has shown that a simpler 12 h regimen (SNAP) consisting of a reduced loading
infusion rate of 50mg/kg/h, causes significantly fewer adverse reactions (1). The
SNAP regimen was implemented in 3 UK hospitals with the approval of their local
medicines management committees with prospective audit of clinical outcomes.
In this thesis, I have compared the efficacy in preventing hepatotoxicity of a 12h
(‘SNAP’) regimen with the conventional 21 h NAC regimen used to treat
paracetamol poisoning, including in patients at high risk of developing
hepatotoxicity. Secondly, I have developed and validated a simple clinical decision
rule for safe discharge of patients at the end of the 12h NAC treatment. Thirdly, I
have developed a simpler 12 h NAC (‘SNAP’) protocol and care pathway to
facilitate implementation in clinical practice.
The major findings and conclusions of the thesis are: i) development of
hepatotoxicity (peak ALT >1000) and hepatic synthetic dysfunction (INR greater
than 2) in patients treated with the SNAP regimen were not significantly different
compared to the conventional regimen both in high-risk and low-risk patients
(14.6% SNAP vs 15.2% standard, 95% CI, - 8.2 to 9.8), and (3.2% SNAP vs 2.6%
standard, 95% CI, - 0.7 to 1.8), respectively; ii) paracetamol-aminotransferase
multiplication product (APAP×AT) >1500 mg L-1× IU L-1 h is a predictor of
hepatotoxicity in patients treated with NAC and an important confounding variable,
particularly in patients presenting late (P=0.001); iii) The SNAP regimen can
interfere with coagulation activity with a median INR increase of 0.3 from baseline,
even in the absence of liver injury, indicating that re-measurement of the INR at
least 24 h post exposure if there is no other evidence of hepatic injury can avoid
unnecessary additional treatment with NAC; iv) a simple clinical decision rule
(paracetamol <10 and ALT≤ ULN, and ALT not doubled or more than doubled from
admission value) accurately predicted patients who were eligible to discharge
safely after a shorter 12 h SNAP regimen with 100% positively predictive value,
which can be used to facilitate earlier discharge of low-risk patients.Princess Norah bint Abdurahman University, Riyadh,
Saudi Arabia, the Saudi Ministry of Education and the Saudi Cultural Bureau in
Londo
Trans Forms: Gender-Variant Subjectivity and First-Person Narration
Full text linkPh. D. ThesisMy thesis argues for the ‘gender-variant’ narrator as a key figure in contemporary Anglophone literature. I examine first-person narratives from the past five decades in a range of genres (memoir, literary fiction, science fiction, historical fiction) that explore gender identities that are other than binary or fixed. The purposes and impacts of these narratives vary according to their different engagement with feminist, queer and trans theory and activism. These differences can be ultimately read in the formal choices (uses of temporality, pronouns, metaphors, focalisation, description, etc.) of the texts representing gender-variant narrators. Throughout the thesis, I establish a methodology at the intersection of studies of narrative form and studies of trans and non-binary gender identity. In Chapter One, I develop two key concepts as part of this methodology: trans-inhabitation and re-narration. Trans-inhabitation builds on theorisations of gender as space in trans, queer and feminist theory and on narratological understandings of metaphor: it designates an inhabitation of gender categories that is successive, multiple and/or in between, and I argue that gender-variant narrators trans-inhabit genders and texts. Re-narration designates the way in which narratives of gender variance exist in tension with canonical plots of transition, disrupting them and reconfiguring them. In Chapters Two to Six, I test this methodology on a range of contemporary texts with gender-variant narrators. My conclusion summarises what has emerged from these readings in relation to the politically and textually resonant concepts of ‘visibility’ and ‘voice’ and argues for an examination of metaphors of time and space that does not only apply to gender in an abstract manner but considers the geographical realities of borders, homes and inhabitations.S.Y. Killingley Memorial Trus
Mechanisms of pulmonary inflammation in ageing and chronic lung disease
Full text linkPh. D. Thesis.The human respiratory tract is exposed to copious antigen over the course of the lifespan by virtue of its free communication with the external environment through the process of ventilation. The host immune system must therefore distinguish innocuous inhaled antigen in the respiratory tract from antigen potentially associated with infection, produce an inflammatory response with minimal collateral host damage if required, and allow a return to homeostasis once infection is cleared. Inadequacies of these processes can result in a predisposition to respiratory illnesses. Respiratory diseases are leading causes of morbidity and mortality worldwide. It is notable that the burden of respiratory disease disproportionately falls upon older adults, and disorders of inflammation arising with ageing may contribute to this disparity.
The work in this thesis describes a viable platform for the assessment of pulmonary inflammation that could be adapted to facilitate experimental medicine studies characterising inflammation in advanced age or early phase trials of immunomodulatory drugs that might alter the course and resolution of inflammation. This thesis also describes a method to identify candidate immunomodulatory drugs using connectivity maps and puts forward Del-1 as a target for drugs that enhance the resolution of inflammation.
In considering the role of inflammation in chronic lung disease, this thesis also presents an exploration of the mechanisms of inflammation in chronic hypersensitivity pneumonitis, using a systems biology approach to implicate tissue-resident memory T lymphocytes in the pathogenesis of the disease. This opens up the possibility of IL-15 signalling as a potential target for treatment of the disease where few treatments are currently proven to be effective.NIHR Newcastle BRC, the MRC SHIELD AMR Research Consortium and the Medical Research Foundation National PhD Training Programme in Antimicrobial Resistance Researc
Developing novel therapeutic strategies for the treatment of TET2-mutated acute myeloid leukaemia
Full text linkPh. D. Thesis.Acute myeloid leukaemia (AML) is a clinically heterogeneous disease driven by somatic
mutations and chromosomal abnormalities. TET2 mutations occur in 7%-23% of AML, with
approximately 75% monoallelic and 25% biallelic mutations. TET2 encodes a protein involved
in regulating DNA demethylation and TET2-mutated AML has a significantly lower event-free
survival and higher relapse rate compared to disease with wild-type TET2. As such, there is an
urgent clinical need to develop novel methods to treat patients with TET2-mutated AML.
Hypomethylating agents such as azacytidine that inhibits DNA methylation are now established
as a therapeutic strategy for AML. This study evolved from an index patient with biallelic
TET2-mutated AML, that was chemoresistant to anthracycline and cytarabine, but acutely
sensitive to azacytidine monotherapy resulting in long-term morphological remission with
overall survival of 850 days. The primary focus of my research is to interrogate the role of TET2
mutant allele dosage in determining AML cell response to azacytidine. Using an isogenic cell
model system, we demonstrated that biallelic TET2 mutation leads to complete loss of TET2
protein and acquisition of a hypermethylated phenotype. Of note, TET2 mutant allele dosage
significantly affected the azacytidine sensitivity of cells. TET2 biallelic mutants were
hypersensitive to azacytidine with significantly lower proliferation in liquid media (P<0.0001)
and cloning efficiency (P=0.0056) compared to their isogenic TET2 monoallelic mutants.
RNA-sequencing identified ABCB1, a major azacytidine efflux transporter, to be
downregulated in cells with TET2 biallelic mutation. Inhibition of ABCB1 using selective
inhibitors (Tariquidar and Verapamil) increased sensitivity to azacytidine. Also, azacytidine
resistant AML cell clones were developed through long-term exposure of TET2 mutated cells
to azacytidine. ABCB1 is upregulated in resistant clones compared to the azacytidine sensitive
cells and inhibition of ABCB1 re-sensitised the resistant clones to azacytidine. In addition, gene
ontology analysis identified ribosomal pathway components to be downregulated in TET2
biallelic mutated cells compared to their isogenic TET2 monoallelic mutated counterparts. As
such, the findings of this investigation suggest the potential involvement of multiple genes and
pathways in sensitizing TET2 null cells to azacytidine. Finally, using ten different AML cell
lines, we demonstrated that there was significant correlation between TET2 protein expression
and azacytidine IC90 (R2=0.77, P=0.0008) and IC50 (R2=0.88, P<0.0001). Together, our
findings argue in favour of using azacytidine for the treatment of TET2 biallelic mutated AML
and highlights the importance of TET2 mutant allele dosage in developing precision medicine
in AML.Newcastle University Overseas Research Scholarship
(NUORS), Funds for Women Graduates (FFWG), Bloodwis
Learning Logical Rules from Knowledge Graphs
Full text linkPh.D. (Integrated) ThesisExpressing and extracting regularities in multi-relational data, where data points are interrelated
and heterogeneous, requires well-designed knowledge representation. Knowledge Graphs (KGs),
as a graph-based representation of multi-relational data, have seen a rapidly growing presence in
industry and academia, where many real-world applications and academic research are either
enabled or augmented through the incorporation of KGs. However, due to the way KGs are
constructed, they are inherently noisy and incomplete. In this thesis, we focus on developing
logic-based graph reasoning systems that utilize logical rules to infer missing facts for the
completion of KGs. Unlike most rule learners that primarily mine abstract rules that contain
no constants, we are particularly interested in learning instantiated rules that contain constants
due to their ability to represent meaningful patterns and correlations that can not be expressed
by abstract rules. The inclusion of instantiated rules often leads to exponential growth in the
search space. Therefore, it is necessary to develop optimization strategies to balance between
scalability and expressivity. To such an end, we propose GPFL, a probabilistic rule learning
system optimized to mine instantiated rules through the implementation of a novel two-stage
rule generation mechanism. Through experiments, we demonstrate that GPFL not only performs
competitively on knowledge graph completion but is also much more efficient then existing
methods at mining instantiated rules. With GPFL, we also reveal overfitting instantiated rules
and provide detailed analyses about their impact on system performance. Then, we propose RHF,
a generic framework for constructing rule hierarchies from a given set of rules. We demonstrate
through experiments that with RHF and the hierarchical pruning techniques enabled by it,
significant reductions in runtime and rule size are observed due to the pruning of unpromising
rules. Eventually, to test the practicability of rule learning systems, we develop Ranta, a novel
drug repurposing system that relies on logical rules as features to make interpretable inferences.
Ranta outperforms existing methods by a large margin in predictive performance and can make
reasonable repurposing suggestions with interpretable evidence