VictorJuiz/thesis huggingface dataset:
Brain mechanisms underlying fatigue and its impact on the motivation to exert effort

Fatigue, a feeling of tiredness or exhaustion, increases with effortful exertion and impacts motivation and performance. While healthy people typically recover during periods of rest, persistent forms of fatigue are a debilitating symptom in many medical conditions and in particular in Parkinson’s disease (PD). To date, the neural and computational mechanisms in the brain that underlie fatigue and its impact on the willingness to exert effort are still poorly understood. Using physical effort-based decision-making paradigms and trial-by-trial self-report ratings in combination with a novel computational model, functional Magnetic Resonance Imaging and pharmacological manipulation, this thesis addresses the following outstanding research questions: How are brain systems implicated in effort-based decision-making impacted by momentary levels of fatigue in healthy individuals (Chapter 2)? Do people prioritise effort or reward information before option selection and are these preferences associated with fatigue and motivation to exert effort (Chapter 3)? How does fatigue develop as a function of effort, rest and rewards (Chapter 4), and what are the specific effects of dopaminergic medication in PD patients (Chapter 5)? Finally, how closely linked are dynamic changes in fatigue ratings and in the motivation to exert effort (Chapter 6)?
Together, the findings suggest that levels of fatigue fluctuate on a moment-to-moment basis as a function of the recent history of effortful exertion and rest, with underlying recoverable and unrecoverable components, impacting people’s sensitivity to efforts and the subjective value of exerting effort to obtain rewards. Separate frontal sub-regions signalled recoverable and unrecoverable fatigue states, while current fatigue levels were integrated with value in the ventral striatum and the frontal pole. Dopaminergic medication affected self-reported fatigue, playing a differential role in recovery. In addition to these insights, the studies demonstrate that the paradigms and the computational model developed here may provide new approaches for the assessment and quantification of pathological forms of fatigue and associated deficits in motivation and might thereby help identify potential avenues for prevention and treatment.

Keywords: frontal lobe
fatigue
reward
magnetic resonance imaging
decision-making
choice behaviour
exertion
dopamine
ventral striatum
psychopharmacology
computational modelling
Parkinson's disease
effort
motivation
Advisor: Apps, M
Husain, M
Molecular diagnosis of infectious disease and cancer via synthetic biological methods

Synthetic biology is an emerging field that unveils a new dimension to biology, where the disciplines of engineering and biological sciences are brought together to program novel biological entities or re-wire existing ones. The ultimate goal is to achieve de novo engineering of biological systems to address the most pressing societal issues ranging from environmental and industrial to healthcare while accelerating the progress of fundamental biological research to answer important questions about life. However, the complications, instability and insecurity of a genetic network have hindered the translation of synthetic biological technologies into real-world applications. This thesis aims to contribute partly to these challenges and seeks to address two of the most urgent global health threats at the moment, the COVID-19 pandemic and cancer.
To support the testing strategy for COVID-19, I begin by re-purposing a traditional cell-free enzymatic reaction, RT-LAMP to detect multiple targets on the SARS-CoV-2 RNA genome. Reported here are proof-of-concept experiments to demonstrate the diagnostic sensitivity and specificity of this method and highlight the practicality of using RT-LAMP as a rapid diagnostic test for COVID-19. To refine the testing method, I introduce a molecular switch that reduces the false positive likelihood by preventing self- and off-target amplification. In particular, the adoption of molecular switch has seen a drop of the false positive rate from 60 % to 0 % in a RT-LAMP experiment with 20 replicates. Through a large-scale clinical validation, this optimised RT-LAMP is shown to provide COVID-19 diagnosis within a short turn-around time at point-of-care setting.
To design a diagnostic for colorectal cancer, I first develop a bacterial whole-cell biosensor by expressing a specific single-domain antibody on the outer membrane of Escherichia coli BL21 to confer binding specificity to a cancer biomarker, carcinoembryonic antigen. I then demonstrate the diagnostic sensitivity of the whole-cell biosensor in a biological agglutination assay format. To transform the whole-cell biosensor into a potential in vivo diagnostic and therapeutic agent, I adopt two different top-down approaches to generate synthetic biological chasses, SimCell and minicell, which are non-replicable, non-growing and metabolically active. These chasses allow the housing and actuation of synthetic circuits without any interference from the host genome, which can thus be exploited for a wide range of healthcare-related applications.
Overall, the research on the cell-free system and genome-less chassis described herein provides a genetically stable and secure system to help synthetic biology reach its translational potential.

Keywords: biosensor
synthetic biology
RT-LAMP
cancer
microbiology
diagnostic
therapeutic
Advisor: Huang, W
Papachristodoulou, A
Lung measurement and quantification of lung heterogeneity using the inspired sinewave test

The lung is a complex organ. The most familiar and significant lung disease, chronic obstructive pulmonary disease (COPD), can be severely debilitating. Additionally, acute lung injury in the critically ill can be life-threatening. Lung diseases are known to be correlated with the heterogeneity of the lung (ventilation mismatch and perfusion mismatch). Currently, there is no “standard” method for assessing lung heterogeneity. Many lung function tests and computational methods have been proposed to diagnose and monitor lung heterogeneity. The Inspired Sinewave Test (IST) is a non-invasive and practical test to investigate lung pathophysiology.
To investigate the usability of the IST, we compare the IST results to similar lung function tests (current “standard” tests). A mathematical lung simulation is developed to enable the IST to quantify lung heterogeneity. This simulation is proved to work with the IST by testing with simulated data and sensitivity analysis. The resulting validated process is implemented in thirteen pigs (pre-injury and post-injury) and 104 human volunteers (healthy and COPD patients, including different phenotypes). The IST lung heterogeneity measurement is compared to CT scan results.
The IST results show that it is potentially a suitable device for bedside monitoring in mechanically ventilated patients. Additionally, by using the lung simulation, lung heterogeneity can be quantified by the IST using 60 s and 180 s period tracer gas. The ventilation and perfusion heterogeneity in injured animals are found to be higher than in non-injured animals. There is no clear distinction between healthy subjects and patients with COPD in the COPD human data set. The multiple alveolar compartments lung simulation is proposed to boost the COPD prediction accuracy using only IST data.
The results in this thesis suggest the translation of the IST into human medicine as a tool for detection and prevention of lung injury. Future investigations are proposed, which could potentially improve the works in this thesis.

Keywords: Lung diseases
Inspired Sinewave Test
Lung heterogeneity
Advisor: Farmery, A
Payne, S
Phan, P
Co-evolution of bats and viruses and how it has shaped host biology

Although the general link between bats and viral diseases is clear, tracing outbreaks to their bat origins can be difficult. It is believed that the lack of symptoms in bats may be caused by their long co-evolution with viruses, their immunological traits, or evolutionary adjustments arising from endogenized viral genes.
Our work confirmed that, despite a small genome size, bats have a comparable diversity of endogenous retroviruses (ERVs) to other mammals. Some of these ERVs are suffi- ciently preserved to be expressed, with potential effects for host biology. We detected an unusual diversity of complex retroviruses, which are generally rare in endogenous form, and a novel class of recombinant retrovirus with an alpharetrovirus-like envelope which has not previously been seen in mammalian genomes.
In parallel we studied Toll-like receptors (TLRs) in bats, a class of innate immunity recep- tors. Although highly conserved in vertebrates, the viral and bacterial ligand recognition properties of TLRs can have subtle variations between species, which may have driven the evolutionary pathways of interactions with infectious diseases. We found that bat species differ between each other with respect to the array of TLR genes and discuss these in the context of a broader mammalian profile.
In addition, we studied the mammalian ACE2 receptor, which is an entry receptor for SARS viruses. With coronaviruses which can change tropism quickly, the host range can at least partially be predicted with knowledge of the receptor specificity. We analysed the ACE2 SARS binding region of several vertebrates and discovered that it can vary even between related species e.g. bats.
Collectively these results strengthen the unique position the Chiroptera order has in regards to its relationship with viruses, both exogenous and endogenous and confirm the special role of bats among other mammals as virus reservoirs.

Keywords: ERV
endogenous viruses
immunology
bats
syncytin
evolution
EVE
Advisor: Katzourakis, A
Smith, A
How to design, optimise and implement a fibre-tip Fabry-Pérot cavity for quantum networks of atoms and photons

One of the most exciting prospects of quantum physics today is to simulate large quantum systems, intractable by classical computation, by connecting many smaller systems together. A cavity-based quantum network of atoms and photons constitutes one such approach, where each cavity interfaces between stationary atomic qubits in a node and photonic qubits travelling along optical fibre channels. For this scheme to work well, the cavity-based interface must be faithful and well-controlled.
In this thesis, we construct a fibre-tip Fabry-Pérot cavity by aligning two optical fibre-tips against each other, where each has a concave, mirror-coated surface. Three properties make it highly suitable for interfacing: a small mode volume for strong atom-photon coupling, directly fibre-coupled cavity light, and optical access for trapped atoms. For the latter, we design a scheme that allows for a 2D reconfigurable array of atoms, held in the cavity mode by holographically-generated optical tweezers. Our particular design will allow us to move atoms independently of one another.
We find the atom-cavity system parameters for optimal single photon generation, absorption and remote state transfer using V-STIRAP (vacuum-stimulated emission by Raman adiabatic passage). Using master equations and the Nelder-Mead algorithm, we optimise both the parameters and V-STIRAP pulse shapes to do this.
We assemble the first fibre cavity formed of two single-mode fibres in ultra-high vacuum. Aligning two single-mode fibres is particularly demanding; we overcome this with an assembly method that gives permanent sub-micron alignment precision, unlike other similar cavities that need realigning using a translation stage. We fully characterise the cavity's parameters, then test it by probabilistically loading atoms from a magneto-optical trap, measuring the Purcell-enhanced fluorescence from the cavity.
Altogether, our advances facilitate deterministically controlled, strongly-coupled and networked quantum systems.

Keywords: atomic physics
fibre Fabry-Pérot cavities
cavity quantum electrodynamics
quantum optics
quantum networks
Advisor: Kuhn, A
The use of iPSC-derived neurons to investigate the role of clusterin trafficking in Alzheimer’s disease

Clusterin’s role in neurodegeneration and Alzheimer’s disease (AD) remains unclear. Clusterin (CLU) protein expression and trafficking are altered in response to stress; the treatment of rodent neurons with beta-amyloid (Aβ) increases intracellular retention and reduces secretion of clusterin proteins. CLU knockdown in rodent neurons provides protection against Aβ-induced toxicity including cell death indicating clusterin may mediate Aβ toxicity.
Although traditionally referred to as a highly glycosylated and secreted protein, clusterin can also be found intracellularly. However, the biogenesis, structure, and functional importance of these intracellular proteins remains debated.
In this thesis, CRISPR/Cas9 genome engineering was used to remove exon 2 from CLU, since this exon contains the endoplasmic reticulum (ER) signal peptide required for the generation of glycosylated, secreted clusterin proteins. This generated heterozygous and homozygous exon 2 knockout (KO) iPSC lines. These were then differentiated into neurons and treated with Aβ to compare cellular and genetic responses of KO and control cells.
The data demonstrated that heterozygous KO neurons responded similarly to control neurons when treated with Aβ, displaying both cell death and neurite retraction indicating no altered sensitivity. Furthermore, Aβ treatment, and not neuronal genotype, was identified as the largest contributor to gene expression changes measured by RNA-Seq. In contrast, homozygous exon 2 KO was sufficient to generate intracellular, non-glycosylated clusterin proteins, and prevent secretion. This manifested as reduced sensitivity to Aβ: neurons displayed cell death but no evidence of neurite damage indicating exon 2 KO provides partial protection to iPSC-neurons.

Keywords: CRISPR/Cas9
neurons
APOJ
Clusterin (CLU)
iPSC
Alzheimer's disease (AD)
Advisor: Buckley, N
Lovestone, S
Metabolic flux analysis in Euglena gracilis

In this study, 13C metabolic flux analysis and flux balance analysis are used to investigate the metabolic phenotypes of Euglena gracilis grown on glucose, acetate, ethanol and pyruvate. A set of metabolic flux maps of E. gracilis are presented. These flux maps emphasise the limited contribution of plastidic metabolic processes and the oxidative pentose phosphate pathway in heterotrophic metabolism of E. gracilis. Comparison of the flux maps of wild-type and aplastidic E. gracilis on glucose reveals that disruption of chloroplast increases demand for the cofactors required for cell maintenance, resulting in higher fluxes through the central pathways of carbohydrate oxidation and a decrease in carbon conversion efficiency in aplastidic cells. Moreover, flux maps of E. gracilis on different respiratory substrates emphasise the importance of the glyoxylate shunt and malate dehydrogenase in supporting anaplerosis when grown on acetate and ethanol, but not on pyruvate in which the precursor for gluconeogenesis is mainly provided by pyruvate carboxylase. The flux maps reported in this study reveal the impact of chloroplast disruption on the metabolic phenotype of Euglena and provide new insights into the metabolism of substrates differing in carbon composition and chemical redox potential.

Keywords: flux balance analysis
metabolic flux analysis
Euglena gracilis
carbon metabolism
Advisor: Kruger, N
Ratcliffe, R
O'Neill, E
Enter Xiuhquilitl: indigo in the Spanish Empire, c.1550-1700

Over the course of the sixteenth century, the burgeoning globalising forces of exploration and discovery transformed the indigo trade in Asia and the Americas, the histories of blue, and woad producing regions in Europe. Around 1560, the Spanish Crown found indigo-producing plants grew wild in parts of New Spain, and across the Captaincy General of Guatemala; settlers turned with enthusiasm to the new industry, and by 1600 indigo ranked third on the list of exports from the Spanish colonies – after bullion, and cochineal, contending for its place with cattle hides. Previous studies of colonial Mesoamerican indigo have concentrated on eighteenth century production methods and the problematic of indigenous labour, rarely following the blue dye past the port of Seville, to the dyer’s vat or the artist’s studio. Processes of reception, accommodation (sometimes rejection), and commodification, the initial development of manufacturing techniques and the diffusion of these new practices, have been left unexamined. This thesis seeks to address some of these, neglected chapters in the history of indigo, constructing a narrative that integrates the experiences of producers and consumers, considering the materiality of indigo (in its raw, and multiple finished forms). Drawing on selected case studies from across the Empire, I examine the production, trade, and consumption of New World indigo over the course of two centuries – between 1550 and 1750 – focusing on the individuals and groups, connections and interactions that determined its path from an unfamiliar, exotic dye, to a commodity circulated globally.

Keywords: Atlantic trade
Indigo
colonial Latin America
natural dyes
merchant networks -Iberian Atlantic
early modern Spain
Yucatan
Guatemala
Advisor: Roper, L
Elliott, J
Laser engineering of defects in diamond for quantum technologies

Colour centre defects in diamond are promising candidates for many quantum technologies because they act as isolated two level systems in the solid-state that can be controlled and read-out through photonics [1][2][3]. Realisation of these technologies requires the placement of many highly coherent centres in a regular array with high positional accuracy and high fabrication yield [4]. Previous fabrication techniques have lacked the ability to produce high yields with high positional accuracy without causing irreparable damage to the lattice which reduced the quality of the spin and optical properties [5]. Ultra-fast laser writing has been shown to produce highly coherent nitrogen vacancy (NV) colour centres within the diamond lattice with positional accuracies of order hundreds of nanometers and a stochastic yield. In this case, the yield and positional accuracy is held back by the need to thermally anneal the diamond within a furnace to convert laser generated defects into colour centres; a fabrication step in which there is little to no control over individual site [6]. In this thesis, the ultra-fast pulsed laser writing technique is broached in detail from both a theoretical and experimental standpoint. The theory behind the highly non-linear light-matter interactions is studied and a hypothesis is developed for the energy transfer between photo-excited carriers and the lattice via the non-radiative recombination of self-trapped multi-excitonic states [7]. In addition, this thesis presents an expansion on the laser writing of colour centres through broaching the generation of different colour centres that have some preferential properties over the NV [8], and the development of a new engineering technique involving a local laser anneal [9]. The yield of generated centres is increased from stochastic to deterministic by replacing the global thermal anneal with the local laser anneal in combination with a fluorescence feedback mechanism. In addition, the use of the laser to locally anneal generated centres leads to a factor of five improvement in the positional accuracy due to the highly non-linear interaction of the laser with the material. These results culminate in a key step forward in the development of a large scale quantum device and improved understanding of the highly dynamical processes that occur upon femtosecond laser interaction with a wide bandgap material.

Keywords: femtosecond lasers
NV centres
quantum technologies
colour centres
laser processing
Advisor: Smith, J
Booth, M
Speaking to voters: explaining variations in the class-based support for social democratic parties through language complexity

What explains variations in the class-based support for social democratic parties? Demand-size explanations have focused on the size and turnout of the working class, while supply-side explanations have focused on strategic policy maneuvering by parties. However, with both approaches, unexplained variation in the class-based support for social democratic parties remained. I introduce a novel argument, which I call the “language recognition thesis”. The language used by politicians can be considered a way of symbolic representation used to appeal to voters. I test out this thesis in Great Britain, focusing specifically on whether and how language complexity in parliamentary debates influences class-based support for the social democratic Labour Party.
In preparing my variables, I draw on techniques from linguistics, sociology and computer science, using a linguistic formula and applying it to 1.8 million parliamentary speeches from the UK House of Commons, as well as distilling debate topics from these speeches using the machine learning technique Latent Dirichlet Allocation (LDA). After the data preparation, I use a two-step research strategy to investigate the proposed mechanism.
First, using a multilevel logistic regression, I investigate the relationship and its strength, through the use of the speech transcripts from the UK Parliament, which span a period of over thirty years, as well as thirty years of survey data.
Second, using a survey experiment, I attempt to provide evidence in support of my proposed mechanism, by subjecting participants to UK parliamentary speeches of varying complexity on a topic closely related to social class: welfare benefits.
The results show that when the language use across parties becomes more complex, people are more likely to rely on their class identity to determine what party they support. Working class individuals are more likely to support social democratic parties under these conditions, while members of higher classes are less likely to support these parties under the same conditions. Furthermore, people are more likely to support politicians who use less complex language. These findings provide important insights for the literature on class voting, social democratic party politics and political communications.

Keywords: Parliament
social democratic parties
UK politics
Labour Party
experimental research
symbolic representation
Topic Modeling
text analysis
Natural Language Processing (NLP)
political communications
Advisor: Dilling, M