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Cholestasis-Induced Cognitive Decline: Neurological Mechanisms and Therapeutic Implications
Get PDFPh. D. ThesisCognitive dysfunction occurs during the cholestatic liver disease Primary biliary
Cholangitis (PBC). Patients experience with short-term memory and concentration deficit,
termed ‘brain fog’. This can be debilitating and severely affect quality of life, with no
beneficial treatments (Newton, Hollingsworth et al. 2008)
In this thesis, using the murine Bile Duct Ligation (BDL) model and in vitro modelling with
human neuronal cells, I investigated the effects of cholestasis on the blood-brain barrier
(BBB) and resultant changes within the brain. This study focussed on the hippocampus
due to its crucial role in learning and memory. Changes to BBB could be observed from
day 6, including astrocyte detachment, and permeability using MRI. By day 10 mice had
visual spatial memory deficits, neuroinflammation was seen within the hippocampus, and
changes were observed in gamma frequency oscillations. Interestingly, neurons in the
hippocampus possessed features of senescence in cholestatic mice (telomere associated
DNA damage, and P21+ RNA), highlighting parallels in pathology between the liver (where
senescence is known to occur during cholestasis) and the brain. This effect was mirrored
during in vitro studies, where neurons treated with PBC patient serum (to simulate
pathological exposure to bile acids) also displayed increased sen-B-gal, a feature of
senescence.
In another strand, I examined the ability of both approved (ursodeoxycholic acid,
Obeticholic Acid) and experimental (Bezafibrate) therapies to modify cognitive processes.
Only Obeticholic Acid provides a potential therapeutic due to its in vivo and in vitro effects.
Strikingly, OCA improve cognition and reduces neuronal senescence in BDL mice and in
vitro when neurons are pre-treated before serum treatments.
Therefore, the data presented in this thesis implicates senescence as a key pathological
feature of cholestatic disease not just in the liver but also in brain where it has been
previously linked to poor cognition (Baker, Wijshake et al. 2011, Fielder, Tweedy et al.
2020). Further investigation of early intervention with OCA may prove beneficial to
patients experiencing cognitive deficit
The Intersection of Entrepreneurial Identity and Ethnic Identity: An Interpretative Phenomenological Analysis of Black African Migrant Entrepreneurs in the UK
Get PDFPh. D. ThesisRecently, entrepreneurship research is beginning to identify how identity shapes the
practice and discourse of entrepreneurship. This burgeoning stream of research
explores how multiple dimensions of identity intersect, to create and reproduce
inequality in entrepreneurship. This study builds on such area of research to explore
the role of identity in entrepreneurship. In particular, it explores the intersection of
entrepreneurial identity and ethnic identity among black African migrants practising
entrepreneurship in Britain. The research focuses on the question: ‘how do black
African migrant entrepreneurs balance, negotiate and experience their (potentially
disparate) identities as ‘entrepreneurs’ and ‘ethnic minorities’ within their lives?’
Qualitative data was elicited by phenomenologically exploring the narratives of the
lived experiences of participants. The analysis is based on the different ways black
migrant entrepreneurs perceive, interpret and make sense of their identity in
entrepreneurship. Research findings show the pervasiveness of whiteness in
entrepreneurship. The entrepreneurial space in Britain structurally excludes black
ethnic identity. Structural forces that create and sustain inequality in the labour market
are also at play in entrepreneurship. Entrepreneurship is a site of identity negotiation.
To navigate this entrepreneurial space, they employed different dramaturgical
performances and enacted certain identity work such as hard work and different
masking strategies, in their attempt to be seen as legitimate entrepreneurial actors.
Ethnicity plays different roles in entrepreneurship. It is perceived as a source of
advantage for exploring ethnic and co-ethnic markets and as a source of disadvantage
for accessing mainstream markets in the host country. Findings show the gendered
nature of identity work, as black female migrant entrepreneurs tend to compensate
more for their identity in entrepreneurship. This research contributes to the study of
migrant entrepreneurship by showing how intersectional identities influence
entrepreneurial venturing and activities.Newcastle University Overseas Research Scholarshi
The influence of sirtuin-controlled circadian rhythmicity anddiet on lifespan in the honey bee, Apis mellifera
Get PDFPhD ThesisThis thesis explores the role of sirtuin controlled circadian rhythmicity and diet on honey bee
longevity. By manipulating the circadian period of newly emerged honey bees and using
qPCR to measure the expression of metabolic and circadian genes, we attempt to understand
the effect of non-24 h circadian periods on longevity. We found evidence that altering the
circadian period to 20 h or 28 h resulted in reduced longevity and a 1.6-fold increase in
mortality, disruption to circadian clockwork and observed that this effect was not additive
with that of a high-EAA diet, suggesting a potential shared pathway (Chapter 3).
Rapamycin is an inhibitor of the mTOR pathway and has been shown to extend lifespan
across species. We investigate the effect of rapamycin on longevity and appetite in the honey
bee. We also observe the effects of rapamycin in combination with high-EAA diets. We found
no evidence of any life extending effects and in some cases a reduction in longevity as well as
polyphagic behaviour common in metabolic diseases (Chapter 4).
Methylation plays an important role in sirtuin controlled mediation of lifespan, however the
study of methylation in insects is time consuming and costly due to low global methylation
levels. In this study we aim to test the viability and suitability of common methods of
measuring global and site-specific methylation changes. We determine that methylation levels
were too low to effectively measure with generic ELISA-kits in the honey bee and this also
made site specific analysis for circadian genes challenging (Chapter 5).
In the final chapter we analyse the effect of methionine on longevity and behaviour in the
honey bees. By varying the dietary methionine content and analysing key metabolic genes
FOXO and Sir2 we attempt to determine the mechanisms controlling these effects. We found
that a high methionine diet reduced lifespan, appetite and lead to upregulation of FOXO but
not Sir2 (Chapter 6)
Molecular understanding of fungal cell wall metabolism by gut Bacteroides
Get PDFPh. D. Thesis.The human gut is populated with a vast community of microbes, the microbiota.
The Bacteroidetes play a prominent role in the breakdown of complex
carbohydrates. Fungi are also normal members of the gut microbiota. Fungal cell
wall proteins are extensively mannosylated, forming a highly branched matrix of
mannan. Previous data from our lab show that the common gut bacterium,
Bacteroides thetaiotaomicron (Bt) degrades cell wall mannan from S. cerevisiae
via a selfish mechanism. Bt does this by releasing large oligosaccharides at the
cell surface, which are transported into the periplasmic space to be further
depolymerised.
Firstly, the degradation of mannan from a common human pathogen, Candida
albicans was investigated. Here, novel enzymes from the Glycoside Hydrolase
130 family, which target β-1,2-mannosidic linkages found in C. albicans mannan,
have been biochemically characterised. Bt was genetically manipulated to
examine its ability to utilise mannan from C. albicans. This work demonstrated that
degradation of C. albicans mannan in Bt requires an additional regulatory
mechanism.
Secondly, I discovered that another gut Bacteroides, B. salyersiae (Bs), degrades
yeast α-mannan in a mechanism contrasting to the ‘selfish’ strategy. Unlike Bt, Bs
releases a range of smaller manno-oligosaccharides into the extracellular milieu,
which are utilised as ‘public goods’ by other members of the gut microbiota.
Biochemical characterisation of this alternative mechanism revealed that proteins
orchestrating mannan breakdown contain signals, targeting them for the
Bacteroidetes specific type 9 secretion system (T9SS). Our analysis revealed that
Bs directs at least 109 proteins of diverse functions to the T9SS, implicating its
role in a plethora of metabolic processes. This is the first description of T9SS in a
human gut Bacteroides. This work demonstrates that members of the microbiota
have developed multiple strategies for utilisation of the same carbon to survive in
a highly populated human gut
Innovative big data integrationand analysis techniques for urban hazard management
Get PDFPhD ThesisModern early warning systems (EWS) require sophisticated knowledge of natural hazards,
the urban context and underlying risk factors to enable dynamic and timely
decision making (e.g., hazard detection, hazard preparedness). Landslides are a common
form of natural hazard with a global impact and are closely linked to a variety of
other hazards. EWS for landslide prediction and detection relies on scienti c methods
and models which require input from the time-series data, such as the earth observation
(EO) and ancillary data. Such data sets are produced by a variety of remote sensing
satellites and Internet of Things sensors which are deployed in landslide-prone areas.
Besides, social media-based time-series data has played a signi cant role in modern
disaster management. The emergence of social media has led to the possibility of the
general public contributing to the monitoring of natural hazard by reporting incidents
related to hazard events. To this end, the data integration and analysis of potential
time-series data sources in EWS applications have become a challenge due to the complexity
and high variety of data sources. Moreover, sophisticated domain knowledge of
natural hazards and risk management are also required to enable dynamic and timely
decision making about serious hazards. In this thesis, a comprehensive set of algorithmic
techniques for managing high varieties of time series data from heterogeneous
data sources is investigated. A novel ontology, namely Landslip Ontology, is proposed
to provide a knowledge base that establishes the relationship between landslide hazard
and EO and ancillary data sources to support data integration for EWS applications.
Moreover, an ontology-based data integration and analytics system that includes human
in the loop of hazard information acquisition from social media is proposed to
establish a deeper and more accurate situational awareness of hazard events. Finally,
the system is extended to enable an interaction between natural hazard EWS and
electrical grid EWS to contribute to electrical grid network monitoring and support
decision-making for electrical grid infrastructure management
Use of Serial Block Face-Scanning Electron Microscopy to Study the Ultrastructure of Vertebrate and Invertebrate Biology
Get PDFPhD ThesisThe development of Serial Block Face Scanning Electron Microscopy (SBF-SEM)
allows for acquisition of serially sectioned, imaged data of ultrastructure at high
resolution. In this project, optimisation of both SBF-SEM methodology and 3-D image
segmentation analysis was applied to the ultrastructural examination of two types of
biological tissues, each requiring a different experimental approach. The first project
was a connectomic based study, to determine the relationship between the neurons
that synapse upon the Lobula Giant Movement Detector 2 (LGMD 2) neuron, within
the optic lobe of the locust. A substantial portion of the LGMD 2 neuron was
reconstructed along with the afferent neurons, enabling the discovery of retinotopic
mapping from the photoreceptors of the eye onto the LGMD 2 neuron. A sub-class of
afferent neurons was also found, most likely vital in the process of signal integration
across the large LGMD 2 neuron. For the second project, two types of skeletal
muscle (psoas and soleus) obtained from fetal and adult guinea pigs were analysed
to assess tissue-specific changes in mitochondrial morphology with muscle
maturation. Distinct mitochondrial shapes were found across both muscles and age
groups and a classification system was developed. It was found that, in both
muscles, by late fetal gestation the mitochondrial network is well developed and akin
to that found in the adult. Quantitative and qualitative differences in mitochondria
morphology and complexity were found between the two muscles in the adult group.
These differences are likely to be related to functional specialisation. All data
collected during the experiments have also been made available online on Zenodo,
roughly 240GB, which can be used for further studies. Overall SBF-SEM was proven
to be a robust method of gaining new insights into the ultrastructure in both models
and has wide ranging capabilities for a variety of experimental objectives
Retrieval Analysis of Total, Unicompartmental and Patellofemoral Knee Prostheses
Get PDFPhD ThesisKnee replacement is an effective intervention in reducing pain and increasing the function of
a debilitated knee. However, the rise in revision knee procedures calls for better understanding
of the working of different knee designs in vivo.
This thesis investigated 84 retrieved knee prostheses which included 22 Total Knee
Replacement (TKR), 38 Unicompartmental Knee Replacement (UKR) and 24 Patellofemoral
Knee Replacement (PKR) protheses. Roughness analysis of the metal component and semiquantitative damage scoring of the polyethylene (PE) components was undertaken for: TKR
designs with 3 different types of PE inserts (Conventional PE (CPE), Crosslinked PE (XLPE),
Antioxidant doped PE (AOXPE)); 2 UKR designs (fixed and mobile bearings); and 2 PKR
designs (Cobalt-chromium (CoCr) and Oxidised Zirconium (OxZr)).
The femoral components of all the 3 TKR designs were observed to have significantly
roughened in vivo, however, the damage score of CPE, XLPE, AOXPE were not significantly
different (p = 0.57). Only the femoral component of the fixed UKRs significantly roughened
in vivo (p = 0.00), however, the PE inserts of mobile UKRs had significantly higher damage
score (p = 0.04). In PKRs, both CoCr and OxZr trochlear components significantly roughened
in vivo, however, there was no statistical difference observed between them. Two OxZr
trochlear components had undergone substantial abrasion and scratch damage.
With AOXPE being introduced relatively recently, understanding in vivo surface changes and
comparison with XLPE and CPE inserts gives valuable insights about its performance. Few
roughness studies have investigated in vivo surface changes of UKRs; therefore, this study
adds to the limited literature available. This is the first report on the in vivo surface changes of
retrieved PKRs
Cyanobacterial biocomposites for in situ treatment of domestic wastewater
Get PDFPh. D. Thesis.Centralised water treatment infrastructure is increasingly being put under strain due to
population growth. In situ treatment (i.e. a distributed treatment network) may minimise or even
negate the need for centralised infrastructure. Cyanobacteria grown in open-ponds and
photobioreactors are used for wastewater treatment; however these cultivation systems struggle
with batch consistency and have a high capital cost. Biocomposites (biomass immobilised on a
solid substrate within a semi-porous matrix) theoretically support increased active biomass
within a more compact space and prevent cell wash-out, thereby increasing bioremediation
efficiency. Wild-type Synechococcus elongatus (strains PCC 7942 and CCAP 1479/1A) and a
novel engineered strain (SBG363; designed to overproduce and excrete sucrose) were trialled
as potential bioremediation biocomposites. Commercial latex-based binders (AURO 320 and
321) were used for biocoatings formulation, and applied to a selection of natural and synthetic
textiles to form textile-based biocomposites. Biomass growth was increased by up to 800%,
retaining up to 97% of biomass after 72 hours. Sucrose output from S. elongatus SGB363 was
unaffected. Wild-type immobilised biomass supported up to 80% greater CO2 sequestration
over a 20-day period than its suspension culture control. However, after three and six days of
immobilisation there were no significant differences in total protein content, CO2 removal, or
orthophosphate uptake per cell between immobilised and suspension treatments. Whole
transcriptome sequencing (RNA-Seq) was attempted to determine the genetic response of S.
elongatus surviving within a biocoating. However, immobilised samples had very low RNA
integrity number equivalents that prevented differential gene expression analysis. This research
shows that cyanobacteria textile biocomposites are a promising solution for process
intensification in the wastewater treatment industry, and addresses concerns regarding
environmental safeguarding. Metabolically active biocomposites can be used for de-centralised
wastewater treatment applications thereby alleviating problems associated with Victorian era
infrastructure without creating an additional environmental burden.Enviresearch Foundatio
Dietary nitrate in vascular and brain health
Get PDFPhD ThesisNitric oxide (NO) is a highly reactive molecule that is essential for several biological processes,
including the regulation of vascular resistance, neurotransmission and muscular energetics.
Sufficient NO production is crucial for the maintenance of a healthy vascular system. With
ageing, NO synthesis from arginine, catalysed by NO synthase (NOS), is reduced, which may
contribute to increased blood pressure (BP), endothelial dysfunction (ED) and impaired brain
function. Dietary nitrate (NO3-) is an important source of NO production via a non-enzymatic
pathway involving the progressive conversion of NO3- into nitrite (NO2-) by the action of oral
bacteria, and then to NO in low pH and hypoxic environments (i.e., stomach and arterial-tocapillary
circulation). Whilst several clinical studies have assessed the effect of supplemental
dietary NO3- intake (often supplied as beetroot juice (BJ)) on vascular and cognitive functions,
there is a significant gap in the literature concerning the effects of longer-term intervention,
especially in older people. This PhD investigated the effects of BJ supplementation in adult
population, including healthy younger and older overweight and obese adult population who is
at a higher risk of physiological dysfunctions, including cardiovascular disease and cognitive
impairment.
I conducted a systematic review of observational studies to assess NO3- intake by adults. The
review included 55 articles and found that the median daily NO3- intakes were similar in both
healthy and patient populations and below the safe upper intake of daily NO3- intake (3.7 mg/kg
body weight). Then, I performed a meta-analysis of 18 randomised control trials (RCT) to
examine the effect of NO3- or NO2- supplementation on cognitive function and cerebral blood
flow (CBF). This meta-analysis revealed no overall effect of NO3- or NO2- supplementation on
cognitive function or CBF. This meta-analysis helped to inform the design of the subsequent
feasibility study.
Next, I conducted a small pilot study to examine the validity and reliability of NO2- salivary
strips (against reference standard laboratory measures) with and without the use of mouthwash.
This study showed that these strips have a high level of reproducibility and repeatability in
detecting changes in salivary NO2-. The study also indicated that the strips can be used to
monitor NO3- intake in long-term dietary NO3- interventions.
The final phase of this project provided evidence of the acceptability and feasibility of an
intervention testing the effects of prolonged consumption of incremental doses of NO3- in
overweight and obese older participants. The findings of this study showed that cognitive
function and CBF were not affected by long-term BJ supplementation. However, there was a
non-significant trend towards on systolic BP (SBP) reduction with lower BJ doses.Umm Al-Qura University and the ministry of
higher education in Saudi Arabi
Tribological evaluation of total shoulder arthroplasty implants : advanced in vitro wear testing and retrieval analysis
Get PDFPhD ThesisThe glenohumeral joint is subject to dynamic and cyclic loading and motion during
activities of daily life (ADLs), which can promote the wear of the articulating surfaces
of shoulder joint replacements. The adverse reaction to the generated wear debris can
influence the long-term survival of the implant and is considered an issue of
contemporary concern.
Therefore, it is important to be able to measure the wear and surface characteristics of
anatomical and reversed total shoulder replacements in order to understand the
complex wear mechanisms that occurs in vivo and predict their performance. To date,
there is no consensus in the literature regarding the methods to test the in vitro wear of
shoulder replacements. Hence, the aim of this research was to develop a novel protocol
based on the loading and motion of relevant ADLs. This protocol subjects the shoulder
prosthesis to cyclic loading and intermittent motion in a multi-station shoulder wear
simulator.
After five million cycles, the polymeric volumetric wear was 58.8 mm3 for reverse
shoulder components against metallic glenospheres. The three-dimensional surface
roughness (Sa) values of the polyethylene humeral components fell from 692 ± 132 nm
to 42 ± 29 nm. Comparison with an earlier wear tests revealed a non-statically
significant difference in wear, suggesting that the addition of intermittent loading is
unnecessary. This could help those wear testing shoulder implants in future. When an
anatomic shoulder design consisting of a PyroCarbon humeral heads (ceramic-like
alternative bearing material) and a polyethylene glenoid inserts were tested, the
polyethylene wear was 90.6 mm3
. The surface roughness of the polyethylene
components fell from 296 ± 28 nm to 32 ± 8 nm. Interestingly, PyroCarbon components
did not exhibit a measurable loss in mass or change in the surface roughness.
Explant analysis can give key insights into how artificial joints have performed in the
body. Therefore, and for the first time, the surface characteristics of retrieved metal–
on–polyethylene reverse shoulder prostheses were assessed. From a heterogeneous
cohort of thirteen explants with a mean time in vivo of 16 ± 11 months, results indicated
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no correlation between the surface roughness and duration of implantation. However,
tantalisingly among the metallic components available, low surface roughness values
were found (ρ = 0.032) when the bearing material was inverted and used as a humeral
component. If shown to be true in larger explant studies, this could suggest that such
inverted materials could be associated with a superior tribological performance
compared with a conventional arrangement.
Predominant surface damage modes observed on most of the conventional reverse total
shoulder arthroplasty implants during the analysis of the surface topography were
similar to those obtained from the in vitro wear test, and consistent with previous
observations on retrieved components; the similitude between these results helped to
validate the Newcastle Shoulder Wear Simulator.
The collection of results and findings obtained in this research at Newcastle University
may help others who test artificial shoulder joints to validate the design of their
simulators, improve mathematical wear model predictions, optimize the selection of
bearing materials, and contribute to the ongoing efforts to produce the first international
standard for in vitro wear testing of shoulder prosthesesNational Council of Science and Technology (CONACYT) of México and The
Institute of Innovation and Technology Transfer (I2T2) of Nuevo Leó