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Regression models for extreme values with random function covariates
No full textA fundamental principle of statistics of extremes is that any realistic quantification of risk requires extrapolating into a distribution's tail—often beyond the observed extremes in a dataset. Yet, as modern technology advances, an increasing amount of data is recorded continuously or intermittently, and hence the question arises: how to take advantage of such data in an extreme value framework? Motivated by this question, this thesis develops a class of novel statistical methods that can be used for marginal and joint distributions to learn how the extreme values may change according to a functional covariate. The first contribution consists of a functional regression model for the tail index that can be used for assessing how the magnitude of the extremes can change according to a random function. Another contribution of this thesis is the development of a nonparametric regression model that can be regarded as a functional covariate regression method, designed for situations where there is a need to assess how the extremal dependence of a random vector can change according to a functional explanatory variable. Such development is based on modelling a family of angular measures indexed by a random function. The performance of the proposed methodologies is assessed via numerical studies, and financial data is used to illustrate their application
Decoding enhancer grammar using regressive evolution
No full textThe PAX6 gene encodes a transcription factor expressed in the developing eye, brain, spinal cord and pancreas. Deletions downstream of PAX6 disrupt its expression and cause abnormal eye development, indicating that non- coding sequences are essential for the complex expression pattern of PAX6. Multiple-species sequence alignments identify non-coding conserved elements of tens to thousands of base-pairs. Many such elements drive consistent, tissue-specific and PAX6-overlapping expression in transgenic reporter assays and are described as tissue-specific ‘enhancers’.
It is hypothesised that enhancers together drive the complex expression pattern of PAX6, implying that variants within conserved enhancers may alter PAX6 expression in specific tissues. However, only one pathogenic PAX6 enhancer variant with loss of tissue-specific expression has been reported to date. Identification of other putative deleterious variants above the background of neutral variants is hampered by a lack of understanding of the rules of enhancer sequence features, or ‘grammar’.
In this thesis I explore whether evolutionary analysis can identify sequences important for PAX6 enhancer grammar. It has been reported that moles have an accelerated rate of evolution, or loss of conservation, in their PAX6 eye enhancers, a feature that correlates with regressed eye development in these mammals. These mole-associated enhancer variants could uncover features in PAX6 enhancers that are important for activity.
I used reporter assays to investigate whether accelerated evolution in mole PAX6 enhancers alters their activity during eye development. First, I investigated differences using a luciferase reporter assay in eye-related cell- lines. The distal Cre21/HS3 PAX6 enhancer was active in the RPE1 cell line, but reporter expression was variable between mole and non-mole species alike. Other PAX6 eye enhancers were inactive across cell lines. I therefore utilised live imaging of enhancer-linked fluorescent reporters in zebrafish embryos to survey enhancer activity across a range of cell-types and developmental stages. I found that the PAX6 enhancer with the most accelerated evolution – the neuro-retinal enhancer (NRE) from naked mole- rat (Heterocephalus glaber) - remained active across zebrafish retinal development. I concluded that this enhancer retains tissue-specific activity in early retinal development despite its accelerated evolution.
I then employed a dual-enhancer-reporter design to directly compare activity of the naked mole-rat and human NRE in single zebrafish embryos. A surprising observation of loss of enhancer function was found to result from genome mis-integration, as identified by long-read sequencing. Recommendations are made for future study of potential loss-of-function variants.
A second, distal PAX6 enhancer – SIMO – was investigated in the dual reporter assay, given that a pathogenic variant in this enhancer was previously reported to disrupt lens expression. The naked mole-rat SIMO sequence carries a variant adjacent to that mutation, but this did not disrupt lens expression in dual-reporter zebrafish lines. I further investigated this difference using an in vitro binding assay.
In a final exploratory chapter, I move from considering enhancers as individual conserved elements to studying their combined effect on gene expression. I utilised the deep conservation of PAX6 enhancers in the compacted genome of Fugu (Takifugu rubripes) and assayed the consistency of the expression pattern driven by the Fugu pax6b regulatory region across independent zebrafish lines. I demonstrate the potential for this assay to compare the effect of regulatory region rearrangements on the pattern of gene expression
Caste and political competition in a village panchayat in Western India
Get PDFIn 1992, India, the world’s largest and most diverse democracy, decentralised power beyond the
national and state governments to a third tier of local governments. As the most intimate and
important form of government for the vast majority of citizens, the third tier paradoxically remains
at the margins of politics, policymaking, and political analysis. Scholarship has variously captured
the deficits of adequate devolution, substantive representation, and democratic functioning;
consequently, envisaging little scope for political competition and enterprise. This study’s primary
contribution is towards substantiating the thriving political life of India’s grassroots governments.
Drawing on 12 months of village ethnography, this thesis presents a contextualised, differentiated,
and relational analysis of the politics of a gram panchayat (village council) in the Marathwada region
of Maharashtra state in western India. I find that the village continues to be ‘home’ despite
significant migration due to sluggish urban growth and accommodation of poor in-migrant
workforce on the one hand and greater rural welfare policies and changing village society on the
other. This fuels residents’ and migrants’ interest and investment in village panchayati politics. I
explore the evolution and substance of power dynamics in the panchayat along the most
prominent cleavage of caste in the study village, which I call Laturwadi. Taking a longue durée
approach to village governance structures, I find the advance of panchayati raj radical, not
disappointing: from centuries-long feudal rule by hereditary village officers until independence to
multi-panel competition in modern panchayats since 1962 when Maharashtra decentralised power.
In that, the political capacity of reserved office-bearers (women and low castes), the source of most
popular and scholarly pessimism over panchayati raj, has shown significant improvements over
time and intergenerational experience. This owes as much to the provision of reservations as to
the larger advances in social, political, and economic freedoms in post-independence India. A
bottom-up analysis of political competition in India then suggests greater scope for inclusion and
contestation in local governments compared to the higher tiers, signifying a transformatory
potential for the larger polity itself. In focussing on the politics of caste, this thesis provides insights
into the mechanisms of mobilising caste in politics, including political selection by panels, use of
caste conflict and violence for polarisation, and construction of inter-caste rhetoric as a routine
means to rationalise and socialise one’s (caste) ranks into partisan logics. These mechanisms
demonstrate both the political inequalities of castes and the politicisation of inequality. However,
caste, even if the primary cleavage in Laturwadi, is neither the only one nor a solely political one.
An examination of the material manifestations of caste politics reveals the contentions over use
and distribution of development funds in the village. Such caste–class politicisation also holds the
potential for the realignment of permanent ‘communal majorities’ to dynamic ‘political majorities’
as Ambedkar (1945, 1955) had envisaged. I thus submit that not only is village politics competitive
in itself but also holds the potential for creative enterprise in the face of limited devolution and for
transformation of the larger polity by politicising the historical discontents of power and generating
new, inventive, and ambitious leaders. Their political enterprise covers not only the representation
of their castes and development of the village, but also politicisation and counteraction of the
inequalities that mark their lives and relations in the polity
Characterization of meromorphic tensor categories and TT̅ deformations of CFT's using perturbative OPE's of extended operators in holomorphic-topological field theories
Get PDFThis work, at the frontier between physics and mathematics, is set in the realm of quantum field theories. Posing as a more fundamental framework that subtends classical physics, as well as a viable playground to combine gravitational physics, particle physics and more string-theoretic considerations, quantum field theories have naturally been thoroughly studied in the hope of understanding fundamental physical interactions. Moreover, mathematicians have also started paying increasing attention to quantum field theories as parallels started to be drawn between physical objects and abstract mathematical structures, leading to a mutual enrichment of both disciplines.
Of particular interest to mathematicians is the study of algebras generated by local and extended operators in various types of quantum field theories, whose properties are dictated by the physical constraints and symmetries of the theory. Indeed, physical interactions between fields of a quantum field theory are in direct correspondence with mathematical data like products and co-products of algebras generated by said fields.
In this work, we shall study more closely a particular type of theories called holomorphic quantum field theories. More specifically, we will describe operator product expansions of extended operators as constrained by the framework of holomorphic QFTs for two different types of theories of different dimensionalities, and study their possible applications. On the one hand, we will make use of interactions between surface operators in four-dimensional holomorphic Chern-Simons theory to realize a well-known type of integrable deformations of 2d curved-space conformal field theories in a novel way. On the other hand, we will study operator product expansions of line operators in the holomorphic-topological twist of 3d N=2 supersymmetric theories, and thereby investigate the product structure of meromorphic tensor categories, of which these line operators are expected to be objects. Going further, we will endeavor to interpret our results under the prism of Koszul duality, and thusly determine explicitly the algebraic structure of the Koszul duals to the operator algebras of well-known quantum field theories. Finally we will slightly generalize our considerations beyond the scope of physical QFT's, and reframe them into the description of a new "shifted'' type of Lie bialgebra structure that borrows a lot of its essence from the Yangian
Conserving power: the elusiveness of trust and justice in biodiversity conservation practice within Nepal and beyond
No full textThis thesis analyses the internal workings of biodiversity conservation organisations, contextualised through a case study of conservation practice in Nepal. It builds on increasing recognition that conservation organisations demand study because they are the ‘frontline’ of conservation’s mission to tackle biodiversity decline and safeguard social justice for actors living in biodiverse areas. Attention to inner workings is justified because, despite progressive shifts in policy and increased efforts by conservationists themselves to improve conservation from ‘the inside’, injustices and distrust in the sector remain pervasive. I explore the contention that many organisations may struggle to address social conflicts because of the taken-for-granted assumptions, norms, and managerial ontologies that have become hardwired into organisational culture, and simultaneously because there is a lack of attention to the wider political-economic, social-cultural ambit and even the changing natures and non-human assemblages they operate within. This, I show, places conservation in a crisis of (ir)relevance.
My first original contribution in this thesis is a conceptual one. Critical scholars embedded in organisations have proven effective in revealing the internal barriers and micro-political reasons why the trust of Indigenous Peoples and Local Communities and resolving their justice concerns is so elusive to attain by conservation. While this scholarship is insightful, the presence of such organisational ethnographers is still not sufficiently mainstreamed in conservation organisations to help catalyse a sea change in practices that would engender trust and address perceptions of injustice. I undertake a systematic review, whereby I reveal why there is hesitancy in undertaking and hosting organisational ethnographic research, with key reasons including the challenges in balancing the usefulness of ethnography for organisations while maintaining a critical stance, conservationists worrying about ethnographers’ presence and their ability to compromise funding, and ethnographers’ weaker power positions which encourages covert approaches. To facilitate uptake of organisational ethnography more widely in the future, I provide ethical and methodological reflections for social scientists and conservationists alike.
For my second original contribution, based on a critical review I show how trust-building efforts by conservationists have often sought engagement with communities paternalistically, incentivising them to work within dominant conservation or scientific paradigms. I argue that critical inquiry into these trust-building efforts has gone largely unattended by the academy and hence trust-building has been long taken-for-granted as a positive action. This has, therefore, masked the underpinning colonial relations in conservation’s efforts at partnering and improving cooperation with marginalised groups. To move beyond an instrumental framing of trust-building, I provide a conceptual model based upon a political ecology of trust that highlights the interdependencies between trust, justice, and power.
In my case study in Nepal, there has been a poor track record between the State and conservation organisations’ interactions with Indigenous peoples and local communities. Although social justice issues in community forestry are well-studied, including the barriers faced by professionals working in the sector, the species and area-based biodiversity conservation sector has not received the same scrutiny. Motivated to undertake an empathetic yet critical study of Global South conservation, I draw on 17 months of multi-sited ethnographic field work in a Nepali quasi-governmental conservation organisation, the National Trust for Nature Conservation (NTNC), between its office headquarters in the capital, Kathmandu, and outposts in villages in the Himalayas and Terai plains.
Situating my analysis in the historical and contemporary social politics of the organisation and these regions, and working alongside conservationists, I demonstrate how socially just conservation practice is impeded by Nepali societal structures and contradictory Northern donor prerogatives. Centring power whilst not condemning conservationists through a deterministic lens, through a theoretical-empirical offering, I demonstrate conservation’s relational, compromised, and negotiated pursuits for authority in Himalayan Conservation Areas in the context of rising local government influence under the federal constitution, making a case for the concept of ‘everyday territoriality’. In my final original contribution, I centre the inner workings of the NTNC and show how forwarding just practice is limited by the injustices that conservationists themselves experience, underpinned by organisational culture, unequal labour along gender, seniority-based, urban-field, and ethnic-caste lines, the dominance of pragmatism, and positivist disciplinary leanings.
If Global North conservation donors and agencies are to support the South in achieving just conservation practice, it must recognise how local social structures and inner workings strongly impact the capacity and running of organisations in the South. Further, the incoherences within Northern institutions, their contradictory relationship with justice, characterised by progressive policy on the one hand and reluctance to cede power and trust the South on the other—what I term ‘Imperial Pretendings’—must also be addressed. Nepali conservation in performing according to universalisms inherent contradictions is struggling to adapt to changing natures such as forest growth and increasing wildlife numbers, political change and the co-constitutive changes in society these developments render. As such it both struggles to have its public authority legitimised and loses relevance in the eyes of Indigenous People and Local Communities. Organisational ethnographies — such as that offered in this thesis — can help identify contradictions, performativity, the danger of inertia in organisations so they can thus adapt and reflect accordingly, allowing alternative practices and diverse conservation cosmologies and transformations to emerge.RESTRICTED ACCES
Modelling the influence of a growing hydrogen economy on the atmosphere
No full textMitigation of global warming requires a shift in how energy is produced. Hydrogen energy
has been proposed as an important component of the future energy landscape by many
governments. Hydrogen occupies a unique position when compared to other routes of
energy production, as it is able to store excess energy produced by renewables at peak
times. This role is crucial, as renewable energy production is not consistent, and instead
peaks and troughs at times not always aligned to demand. Hydrogen is therefore able to aid
this drawback of renewable energy by providing a method of storage when production
outweighs demand. However, hydrogen can leak from the system, leading to increased
concentrations of hydrogen in the atmosphere. Understanding the atmospheric life cycle of
hydrogen, and the implications of leakage to the atmosphere, in regard to how it interacts
with other chemical species, is therefore critical in understanding the overall environmental
impact of hydrogen technologies.
This thesis used an atmospheric chemistry transport model, the United Kingdom Chemistry
and Aerosols model (UKCA) to explore the behaviour of hydrogen in the atmosphere.
Through its reaction with hydroxyl, additional hydrogen leads to increases in the mixing
ratios or lifetimes, or both of several species, most crucially methane and ozone. These are
both radiatively active and so changes have a global warming effect. This causes hydrogen to
have an indirect global warming effect, despite not being radiatively active itself.
Using UKCA, the Global Warming Potential (GWP) of hydrogen has been calculated under a
variety of scenarios. The GWP of a gas is a measure of its time-integrated radiative effect
compared to carbon dioxide (CO₂). These experiments, as part of a multi-model intercomparison
were used by researchers at the Centre for International Climate and
Environmental Research (CICERO) to find a GWP for hydrogen, over a 100-year time horizon,
of 11.8 ± 2.8.
This thesis demonstrates that the GWP of hydrogen can be used to improve the assessment
of the environmental impact of switching to hydrogen technologies, compared to fossil fuels,
by including the impact of hydrogen emissions, as well as the avoided emissions of other
species. This comparison (using a 100-year time horizon) demonstrates that the impact of
leaked hydrogen (at a rate of 3.4%) contributes less than 5% of the total CO₂ equivalent
emissions created by the respective technologies for grey hydrogen (3%), blue hydrogen
with carbon capture and storage (3%), and blue hydrogen with carbon capture and storage
and flue gas treatment (4%). For blue hydrogen powered by renewables, this contribution
rises to over 10%, indicating that leakage becomes progressively more important (as a
percentage of the total) as production gets greener. For green hydrogen production in
transportation, the contribution of direct hydrogen leakage to the total CO₂ equivalent
emissions depends on the production route chosen. For the routes assessed in this thesis,
hydrogen leakage represented between 5% and 65% of the total CO₂ equivalent emissions at
3.4% leakage rates.
Hydrogen is also able to influence the concentration of other species in the model. Increased
atmospheric hydrogen is associated with increased carbon monoxide in the troposphere of
the model. Carbon monoxide is an air pollutant, but the impacts on air quality due to
hydrogen through this route were shown to be small.
This thesis then demonstrated the influence of hydrogen on the chemical reactions which
produce and destroy ozone in the atmosphere. The GWP of hydrogen under different
background atmospheres of nitrogen oxides (NOₓ) was calculated, by adjusting the NOₓ
anthropogenic emissions by factors spanning various future scenarios. There was a small
decrease in hydrogen tropospheric GWP modelled under decreasing anthropogenic
emissions of NOₓ, but when considering the uncertainty surrounding this metric, this
decrease is insignificant.
Finally, a configuration of hydrogen within UKCA with emissions and deposition was
developed, using the pre-existing deposition scheme for hydrogen in UKCA for an alternative
version of the model which had a form of interactive hydrogen. This was then calibrated to
measurements of hydrogen from the National Oceanic and Atmospheric Administration
measurement network. This configuration of UKCA was also used to simulate hydrogen in a
quasi-pre-industrial atmosphere and demonstrated that the mixing ratio of near-surface
hydrogen in the pre-industrial atmosphere was 346 ppb, compared to 540 ppb in the
present-day. This was in good agreement with published polar firn air measurements, and
provides further evidence that the model can simulate atmospheric hydrogen adequately. In
a simulation of hydrogen with doubled anthropogenic hydrogen emissions, a sensible
estimate based on likely increases in hydrogen demand by 2050, modelled hydrogen mixing
ratios in the first model level increased from 540 to 623 ppb.
There are very few human actions which sit in harmony with our planet. Understanding the
limitations of each action we take is vital to reaching a safe and equitable future.
Overestimating the benefits of the solutions we choose to implement will be costly, and
instead we must try to best quantify the full effects of each technology. This thesis sits
within this branch of climate research, and has demonstrated that while hydrogen is a useful
tool in the energy sector, regulation of leakage is paramount to maximising the benefits for
global temperatures
Mining high-speed data streams using sketches
Get PDFIn our increasingly connected society, enormous amounts of data are constantly flowing through networks and online platforms. Monitoring this data in real time is crucial for detecting trends, identifying threats, and maintaining smooth system operation. However, traditional methods that attempt to track detailed information about every item or flow are often too slow and require too much memory to keep pace with the speed and scale of modern data streams. This thesis presents a series of compact and efficient approximate data structures, known as sketches, that accurately and rapidly summarize traffic information in large-scale streaming environments.
The first design, P-Sketch, is specifically developed to identify items that persist over extended periods, such as recurring network threats or consistently popular products on online platforms. It introduces the concept of arrival continuity, which distinguishes persistent items by assessing the consistency of their appearances. By integrating item frequency with temporal consistency, P-Sketch achieves higher detection accuracy and more efficient memory usage compared to existing methods.
Building on this idea, Stable-Sketch enhances the measurement framework by introducing a stability metric that quantifies how frequently the tracked items in each bucket change over time. By combining this bucket stability information with individual item statistics, Stable-Sketch can more effectively distinguish between items that are consistently significant and those that appear suddenly. When determining whether to replace an item in a bucket, the sketch takes into account both the item's properties and the stability of the bucket, making it less likely to evict items that are frequent and stored in stable buckets. This design allows Stable-Sketch to accurately perform tasks such as heavy hitter identification, heavy changer detection, and persistent item tracking, while maintaining high processing speed and memory efficiency.
Pontus further refines the measurement approach by achieving both high memory efficiency and strong detection accuracy for tracking persistent items in high-speed data streams. Unlike earlier methods that either require extra memory to monitor multiple features or risk losing important persistent items due to frequent hash collisions, Pontus introduces two compact flags for each bucket: one to prevent duplicate counting within a time window and another to protect against unnecessary reductions in persistence caused by hash collisions. By combining these flags with a probabilistic strategy that favors keeping persistent items, Pontus minimizes wrong replacements and helps ensure that persistent items are not inadvertently replaced by less important ones. As a result, Pontus delivers higher detection accuracy and faster processing speeds than previous solutions, even when operating under tight memory constraints, and is well suited for deployment on resource-limited platforms such as programmable switches.
Finally, Pallas is specifically designed for use on modern programmable network devices that handle network traffic at extremely high speeds. In contrast to earlier methods that require frequent coordination between the data plane and control plane to reset tracking flags at the start of each time window, Pallas operates entirely within the data plane. This approach removes delays associated with inter-plane communication and enables accurate tracking of persistent items, even in high-throughput network environments. As a result, Pallas delivers both high detection accuracy and efficient real-time performance when deployed on hardware switches.
Collectively, these sketches offer a practical and robust toolkit for analyzing high-speed data in both streaming and network environments. They achieve an effective balance of memory efficiency, processing speed, and accuracy. The innovations presented in this work have the potential to greatly enhance data management and responsiveness in areas such as cybersecurity, e-commerce, and real-time analytics, offering valuable benefits to both academic research and industrial applications
Machine learning-driven Gait analysis for at-home health assessment of older adults
Get PDFThis doctoral thesis investigates the feasibility of monitoring the health of older adults
in an at-home setting using Computer Vision-powered gait assessment. This chal-
lenge holds significant real-world value, as such a system could provide high-quality,
personalized insights into the progression of an older adult’s health—whether they are
recovering from injury, experiencing age-related neurological decline, or adjusting to
new medications that may affect their risk of injury. The data and analyses generated
by a gait monitoring system could enable precision care comparable to that avail-
able in residential care facilities, without the associated loss of autonomy or financial
burden.
The thesis presents four principal contributions to advance this field of research. The
first is the development of a custom data pre-processing pipeline, dataset, and model
that achieves state-of-the-art performance in gait abnormality detection, despite a set
of self-imposed recording and processing constraints designed to reflect the realities
of at-home assessment technologies.
The second contribution is a systematic review of smart-home health monitoring
research across disciplines. A meta-review of existing literature reviews is used to
identify ten common barriers to adoption, which are then synthesized into a scoring
metric. This metric is applied across studies to highlight the critical importance of
multidisciplinarity and to identify persistent research gaps in the domain and how to
address them.
Third, traditional supervised gait assessment is extended to the more realistic chal-
lenge of semi-supervised gait abnormality detection. Novel feature importance met-
rics are proposed to describe gait abnormalities using only data from individuals’ typ-
ical gait patterns. These metrics are shown to produce meaningful and interpretable
outputs that align with descriptions provided by healthcare professionals specializing
in older adult care.
Finally, this thesis presents an in-home live study using a prototype vision-based gait
monitoring system. Informed by insights from the previous contributions, co-design
interviews with healthcare professionals, and public involvement workshops with older
adults, the prototype was deployed in the homes of 10 participants. Despite technical
and practical limitations, the system was able to collect consistent, high-quality gait
data sufficient for building meaningful gait profiles of the participants
Search for light long-lived neutral particles from Higgs boson decays via vector-boson-fusion production with the ATLAS detector
No full textIn the context of dark sector searches performed by the ATLAS Collaboration at
the Large Hadron Collider (LHC), a search is reported for long-lived dark photons
with masses between 0.017 GeV and 15 GeV resulting from exotic decays of Higgs
bosons produced via vector boson fusion (VBF). Events that contain displaced
collimated Standard Model fermions reconstructed in the calorimeter or muon
spectrometer are probed. This search uses the full LHC Run-2 (2015-2018) data
sample collected in proton-proton collisions at √s = 13 TeV, corresponding to
an integrated luminosity of 139 fb⁻¹. Dominant backgrounds from Standard
Model processes and non-collision sources are estimated by using data-driven
techniques. The observed event yields in the signal regions are consistent with
the expected background. Upper limits on the branching fraction of the Higgs
boson to dark photons are reported as a function of the dark photon mean proper
decay length, and of the dark photon mass and the effective coupling between
the Standard Model and the potential dark sector. This search is combined
with previous ATLAS searches obtained in the gluon-gluon fusion (ggF) and Wassociated
(WH) production modes. A branching fraction above 10% is excluded
at 95% CL for a 125 GeV Higgs boson decaying into two dark photons for dark
photon mean proper decay lengths between 173 and 1296 mm and mass of 10
GeV
Modelling sex differences in metabolic dysfunction-associated steatotic liver disease using stem cell-derived liver tissue
Get PDFLiver disease claims around 2 million lives annually, with liver cirrhosis and hepatocellular carcinoma being the most common causes of death. The most prevalent factors when developing cirrhosis are extensive alcohol use, chronic hepatitis and metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is an umbrella term for a variety of different disorders with ranging severity of liver inflammation and fibrosis. Such disorders include a fatty liver (steatosis) which is associated with F0/F1 stage fibrosis. In a fraction of patients, MASLD develops into inflammatory disease, termed metabolic dysfunction-associated steatohepatitis (MASH). This is associated with moderate fibrosis (F2) in the early stages. MASH then progresses in subset of patients (F3 fibrosis) and may culminate in cirrhosis (F4 fibrosis) and hepatocellular carcinoma. MASLD is a metabolic disorder, highly influenced by other diseases such as type II diabetes (T2D), cardiovascular disease and obesity. Despite current MASLD prevalence being over 30%, there is currently only one drug available, with many candidate drugs failing in the late phases of clinical trials. This highlights the need for a better understanding of the disease in order to improve drug development and medical intervention. Liver homeostasis is influenced by a number of factors, including sex hormones, in particular testosterone and estrogen. Men are twice as likely to die from liver disease or develop MASLD than women. However, women post-menopause have the same risk as men, suggesting that the metabolic age influences the MASLD establishment and disease progression. Clinical and animal studies demonstrated that balanced concentrations of estrogen and testosterone in healthy individuals reduce the risk of impaired glucose and fat metabolism. Therefore, hormone replacement therapy (HRT) could be a viable therapy. Indeed, HRT has been shown to reduce the development of T2D in men and women. However, it is not a suitable treatment option for all patients and has risks associated with its long term usage. My research project focused on developing a better understanding of sex hormone signalling in metabolic liver disease. I employed human pluripotent stem cells (PSCs) as a renewable resource to generate male and female liver tissue. Stem cell derived liver tissue was composed of hepatocytes, endothelial and stellate cells which are important in health and disease. I hypothesised that in vitro engineered liver tissue could effectively model sex hormone signalling in MASLD. Following biochemical confirmation of metabolic dysfunction, two transcriptomic approaches (NanoString and single nuclei RNA-sequencing) were employed to better understand the protective roles played by sex hormone signalling in disease development. Those results were benchmarked against RNA-sequencing from a human patient database, SteatoSITE, encompassing a full spectrum of MASLD and MASH in humans. The protective mechanisms of testosterone and estrogen exposure were uncovered at a gene expression level. Although gene expression differences were observed between sexes, the pathways important for prevention against late-stage MASH were similar between male and female liver spheres. In conclusion, the novel findings of my thesis identified new patterns of gene regulation in human metabolic liver disease, with several candidate targets already druggable. Moving beyond these studies, the platform described in my study could be used to model other liver diseases, and to develop new biomarkers and precision medicines of the future
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