VictorJuiz/thesis huggingface dataset:
TDP-43 based biomarker development in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is a devastating neurodegenerative disease which is clinically and aetiologically heterogenous. However, TDP-43 neuropathology is a unifying hallmark found in 97% of ALS cases. Understanding the common pathological pathways downstream of TDP-43 dysregulation is essential for the development of novel drug targets, and the development of a TDP-43 based biomarker for clinical translation would have profound implications for early diagnosis and monitoring of disease progression.

The work presented in the first part of this thesis addresses the need to develop TDP-43 as a unifying disease-specific biomarker. Mass spectrometry was used to detect TDP-43 from insoluble protein fractions extracted from ALS post mortem tissue with TDP-43 pathology which led to the discovery of ALS disease-specific TDP-43 peptides. These peptides were then validated in an independent targeted proteomic experiment which, for the first time, allowed the quantification of disease-relevant peptides. This enabled the measurement of an ALS-specific TDP-43 peptide signal that reflects sites of pathological truncation and an increased C-terminal TDP-43 protein ratio. This now provides a platform with which to investigate ALS biofluids with the aim to ultimately develop a disease-specific TDP-43 in vivo assay for patient stratification.

In the second part of the thesis I describe the use of affinity-enrichment mass spectrometry to investigate the human wild-type and M337V mutant TDP-43 interactome in a low expression (BAC)-transgenic mouse motor neuron model. I demonstrate that the C-terminal mutation of TDP-43 disrupts specific protein-protein interactions associated with human wild-type TDP-43. In response to oxidative stress, wild-type TDP-43 interactions shift towards proteins that are relevant to cellular stress pathways, while mutant TDP-43 is bound to proteins that are independently linked to pathways known to drive ALS pathogenesis. The key interactions that were disrupted by the M337V mutation involve proteins that are important for stress granule formation and extracellular vesicle secretion. Furthermore, I was able to demonstrate correlative phenotypic abnormalities in stress granule assembly and exosome secretion in motor neurons from the human TDP-43 (BAC)-transgenic mouse model and also in human iPSC-derived motor neurons with the same TDP-43 M337V mutation.

In conclusion, work in this thesis provides significant novel data to support the further development of TDP-43 as an in vivo biomarker in ALS. Analysis of the TDP-43 interactome in a physiologically relevant mouse model has defined core cellular pathways matched to relevant phenotypes which will be important for the identification of pathways relevant for drug target development.

Keywords: neurodegeneration
biomarker
interactome
amyotrophic lateral sclerosis
motor neurone disease
proteomics
TDP-43
Advisor: Turner, M
Talbot, K
Gray, E
Maritime infrastructure in the eastern Mediterranean: a context-based approach to continuity and innovation in nautical technology (c. 1400-700 B.C.)

The present thesis offers a comprehensive study of ships and nautical technology in the Eastern Mediterranean of the Late Bronze and Early Iron Age periods (c.1400-700 B.C.). Previous synoptic works on the subject typically cover either a single region or period all the while focusing exclusively on the technical aspect of ship depictions. The aim of this thesis seeks to address these limitations in a twofold manner. First, by charting trans-regional trends and patterns from a longue durée perspective, integrating all available representational, textual and shipwreck evidence for Cyprus, the Levant and the Aegean as well as the scatter of additional sources from elsewhere in the broader Eastern Mediterranean region. Second, by approaching ship representations as cultural artefacts, providing a historically situated, context-based analysis that integrates the technical aspects with socioeconomic practices, cultural significance and attitudes. The work includes a detailed catalogue of over 350 ship representations, a third of which consist of new finds which do not feature in previous compilations. In addition to technical description, each individual entry provides detailed information on the medium, archaeological context, visual impact and use of the artefact. Roughly 40% of the corpus was furthermore either drawn or re-drawn to offer high resolution images. An important aim of this structuring was to provide readers with a means to consult, examine and assess individual representations independently of my own analysis and conclusions. The thesis identifies distinct Levantine, Aegean and Cypriot nautical traditions, each comprised of a set of technical, artistic and consumption habits peculiar to the region while also exhibiting a unique pattern in terms of external influences. An effort is made to identify specific vessel types and post terminals as well as to provide a historical trajectory for landmark technological improvements, their potential source of origin, chronology, and long-term historical impact.

Keywords: maritime infrastructure
Aegean
Eastern Mediterranean
nautical technology
Early Iron Age
maritime archaeology
Cyprus
ship iconography
Late Bronze Age transition
Late Bronze Age
Levant
Advisor: Lemos, I
Statebuilding from the bottom up: foreign interveners, local governance, and stabilisation

This thesis interrogates an increasingly prevalent narrative regarding international statebuilding interventions. A growing policy consensus, as well as an incipient body of academic literature, contends that “bottom-up statebuilding” presents a viable alternative to the international community’s traditional liberal statebuilding models, focused on top-down approaches and national-level institutions and actors. In practice, bottom-up statebuilding interventions often take the form of localised civilian “stabilisation” programmes that, it is hoped, will serve as the building blocks of effective subnational governance structures.
Yet the concept of bottom-up statebuilding remains under-theorised, and its outcomes under-examined. Further, the mechanisms through which foreign donors’ local stabilisation programmes will actually lead to durable, “better” statebuilding outcomes are largely unspecified.
This study aims to empirically examine the underlying processes and outcomes of bottom-up statebuilding interventions. Its central research question asks: Under what conditions have donor-backed civilian stabilisation programmes advanced effective and durable decentralised local governance structures in the midst of conflict, thereby successfully promoting bottom-up statebuilding?
To undertake this evaluation, this thesis conducts a structured, focused comparison of three civilian stabilisation programmes. For reasons of comparability and maturity, all were based in Afghanistan between 2009 and 2014; each explicitly aimed to improve local government functions. The evaluative framework assesses each programme upon whether it bolstered capacity, accountability, authority and autonomy at subnational levels of government, and whether these effects endured beyond the lifetime of the programme.
The emergent theory is that bottom-up statebuilding programmes in Afghanistan were more likely to achieve effective, durable local governance when, first, the programme enjoyed a strong partnership with its host government ministerial counterpart, and second, when the programme achieved “local embeddedness” within Afghan vertical and local political economy. The thesis demonstrates that bottom-up statebuilding interventions are far from the panacea sometimes imagined; yet it also contributes a fine-grained picture of how and why one bottom-up initiative did achieve modest success in the otherwise bleak Afghan context. The thesis concludes by considering broader implications for the exogenous statebuilding literature, including the primacy of national actors’ agency in affecting outcomes, and the flaws of service delivery and capacity building as two twin orthodoxies of the donor-backed statebuilding interventions.

Keywords: stabilisation
subnational governance
Statebuilding
International peacebuilding missions
Afghanistan
local governance
Advisor: Caplan, R
Sleep in the intensive care unit:  limiting elements of noise in the critical care environment (SILENCE)

Introduction
Sound levels in the intensive care unit (ICU) are persistently higher than World Health Organisation recommendations. This can lead to poor patient experiences including limited sleep, increased risk of delirium during admission, and prolonged recovery. Staff too can be affected. High noise levels are a distractor, can reduce concentration, and impair effective delivery of care.
This thesis explores the working environment of the ICU and proposes practical interventions for reducing sound levels.
Methods
The mixed methods approach incorporates an exploratory sequential design with an embedded convergent parallel design. Findings from secondary analysis of interviews with ICU patients and relatives, staff focus group discussion, ethnography, and sound levels were amalgamated to build a rich sonic picture of the ICU.
These findings generated materials for the accelerated experience-based co-design (AEBCD) trigger film and subsequent discussion with staff and patients.
The AEBCD process facilitated a complex noise reduction intervention focussed on quantitative measures of sound, which were explained by qualitative analyses of ethnography and interviews.
Teaching materials were developed in line with adult education theory. The electronic interface (visual display of sound) was designed using agile methodology with a focus on user-centred experience.
Results
Staff were motivated to reduce sound levels but were unaware how to do this, or how to assess change. This DPhil has identified opportunities for noise reduction strategies. Experiential learning in combination with online modules increased staff knowledge of how high sound levels can affect patients in their care.
High-fidelity sound level monitoring identified elevated levels occurring at handover, and throughout the day are generated mostly close to patients’ heads.
Conclusions
It is feasible to reduce sound levels in the ICU. Maintaining long-term support for change in the clinical environment requires an understanding of the social and cultural influences that will facilitate or hinder sustained improvement, and multi-disciplinary involvement at all stages.

Keywords: AEBCD
patient involvement
ITU
intensive care
environmental monitoring
graphic design
electronic monitoring
qualitative research methods
adult teaching theory
ICU
sound levels
mixed methods
Advisor: Young, JD
Hinton, L
Suboptimality and efficiency in human decision-making

A good decision in isolation may be a bad decision in other conditions. Existing normative theories have been used to benchmark human performance. This is a compelling feature as they provide an understanding of how our decision unfolds in an orderly and rational way. These theories often assumed that decisions are made independent of contexts. However, decisions we have to make in the real-world depends on the context in which they occur. In the past few decades, psychologists and economists notably reveal that human decisions deviate from normative principles when the decisions are made in a context, and protest against one another about whether humans are suboptimal under different considerations of suboptimality. The goal of this thesis is to take these “suboptimal” decisions as a tool to understand what contributes to these suboptimalities. In this thesis, I refine these normative models to show that under reasonable assumptions, biases by decision context can be optimal; and (ii) describe a model embodying an efficiency principle that captures these biases by context across an unusually wide range of settings. In particular, I will focus on how a system that maximises computational efficiency with respect to behavioural needs and environmental statistics can explain: i) why do humans discard useful information during summary judgements, ii) take into account irrelevant information in perceptual judgement tasks, cognitive control, and value-based judgement tasks, and lastly iii) which efficient algorithm can approximate human performance in a trinary choice task.

Keywords: decision making
efficient coding
gain control
suboptimality
adaptive gain
Advisor: Summerfield, C
Pre-supernova neutrinos at Super-Kamiokande with gadolinium

Supernova detection is a major objective of the Super-Kamiokande (SK) ex- periment. In the next stage of SK (SK-Gd), gadolinium (Gd) sulfate will be added to the detector, which will improve the ability of the detector to iden- tify neutrons. A core-collapse supernova will be preceded by an increasing flux of neutrinos and anti-neutrinos, from thermal and weak nuclear pro- cesses in the star, over a timescale of hours; some of which may be detected at SK-Gd. This could provide an early warning of an imminent core-collapse supernova, hours earlier than the detection of the neutrinos from core col- lapse. Electron anti-neutrino detection will rely on inverse beta decay events below the usual analysis energy threshold of SK, so Gd loading is vital to reduce backgrounds while maximising detection effciency. Assuming normal neutrino mass ordering, more than 200 events could be detected in the final 12 hours before core collapse for a 15-25 solar mass star at around 200 pc, which is representative of the nearest red supergiant to Earth, alpha Ori (Betel- geuse). At a statistical false alarm rate of 1 per century, detection could be up to 10 hours before core collapse, and a pre-supernova star could be de- tected by SK-Gd up to 600 pc away. A pre-supernova alert could be provided to the astrophysics community following gadolinium loading.

Keywords: supernova
neutrino
Super-Kamiokande
Advisor: Wark, D
Vagins, M
Impact of per-cycle changes in spatial and temporal pattern of dose and biokinetics in neuroblastoma patients receiving 177Lu-DOTATATE

Recently, there has been a growth in using post-treatment dosimetry after the first treatment cycle to plan the prescription for subsequent administrations to achieve an acceptable safe dose to kidneys and therapeutic dose to tumour. This level of personalisation recognises inter-patient variability in the uptake and clearance of 177Lu-DOTATATE by the kidneys and tumours. Increasingly, studies are showing additional variation in pharmacokinetics between cycles in an individual patient which may be particularly relevant in NETs cases in paediatric cases like NBL. The central goals for this work were to characterise variability in the spatial and temporal patterns of renal and tumour biokinetics and dose during a four cycle course of 177Lu-DOTATATE and investigate relationships between these variabilities and patient response.
To accomplish this, an open-source software platform was written to facilitate calculation of per cycle pharmacokinetics of organs at risk and lesions using published clinical protocols. Subsequently, we applied these protocols on a single pretherapy Ga68-DOTATATE PET/CT and intra-therapy longitudinal SPECT/CT image sets acquired in six children with NBL after each cycle to understand the temporal change in physical dose and effective half life over a course of treatment in two anatomical and one functional region. The kinetics of radiobiological dose in the tumour was explored using parameters derived from in-vitro experiments.
The effective half life of 177Lu-DOTATATE in the tumour showed the greatest variation between cycles. Overall, the temporal and spatial variability in renal and tumour pharmacokinetics and dose showed no clear relationship with response in this small cohort. This thesis is a significant step towards further understanding intra-cycle variability during a course of treatment which may impact dosimetry based treatment planning aimed at delivering a set dose per cycle.

Keywords: lutetium
personalised
dosimetry
radionuclide
Advisor: Falzone, N
Vallis, K
Investigation of the DNA uptake machinery in naturally competent bacteria

Natural transformation is a mode of horizontal gene transfer in bacteria which involves uptake of naked DNA from the environment. The acquired DNA can be incorporated into the bacterial genome and confer useful traits, such as antibiotic resistance and increased virulence. The mechanistic details of how specialised transport proteins allow passage of DNA trough the cell envelope remain elusive.
The membrane protein ComEC forms a channel for DNA transport into the cytoplasm but the molecular details of its structure and function are unknown. An extensive expression screen identified ComEC from Moorella thermoacetica as a candidate for structural and biochemical analysis. Low resolution structural data suggest that the two extramembranous domains of ComEC are located on the same side of the membrane and that they interact.
Biophysical and biochemical studies of the C-terminal soluble domain of ComEC showed that it has manganese(II)-dependent nuclease activity. It was shown that the nuclease activity of the C-terminal domain is required for efficient transformation in B. subtilis. It is likely that the C-terminal domain degrades the non-transforming strand during DNA uptake.
Attempts at isolating DNA uptake complexes for biochemical and structural analysis from competent Bacillus subtilis cells revealed that the competence machinery components are present at very low levels. No native DNA uptake complexes could be isolated.
ComFA is a cytoplasmic membrane-associated ATPase which is thought to power DNA uptake through the ComEC channel. A thermophilic homologue of ComFA was expressed, purified and shown to bind both single- and double-stranded DNA. ComFA was also shown to have ATPase activity. A unique N-terminal extension domain was identified in the thermophilic ComFA, but its function remains unknown.
Together these data contribute to our understanding of DNA uptake across the cytoplasmic membrane.

Keywords: Bacillus subtilis
Bacteria
Membrane protein
Horizontal gene transfer
Metalloenzyme
Natural transformation
DNA transport across membranes
Advisor: Berks, B
Lea, S
Ecology of palm populations and communities in a fragmented tropical landscape

Dramatic declines in the global forested area in recent decades have been particularly severe in tropical areas. Tropical forests have been heavily impacted by a range of human activities including conversion to agriculture, hunting, and timber extraction. Deforestation has led to extensive habitat fragmentation, and most tropical forests are now embedded in human-modified landscapes comprising a mosaic of land-cover types. The consequences of these changes for biodiversity and species interactions are an area of active research interest.
In this thesis, I assess whether remnants of rainforest conserve species and interactions within a fragmented tropical landscape in tropical Mexico, and compare data from fragments with data from nearby protected and continuous rainforests. I focus on palms (Arecaceae), an ecologically and economically important plant family of tropical and subtropical regions, and investigate responses to fragmentation at the population and community level, as well as interactions with mutualists (pollinators) and antagonists (pathogens and herbivores).
I found evidence that management practices within fragments affects palm populations: palm abundances were lower in unprotected forest fragments than in those protected from human activities such as wood and timber extraction, extraction of plants and hunting and poaching. Community composition did not differ significantly between these protected and unprotected fragments. Edge effects were also apparent in forest fragments: changes in palm abundances and palm diversity were most pronounced within 100 m of the forest edge, and these edge effects were similar in both protected and unprotected fragments.
For one focal palm species, Geonoma interrupta, pollination and fruit production, and the likely consequences for demography, were investigated in detail. Reproductive success was significantly lower in fragments than in continuous forest. Native bees were the most frequent visitors and likely pollen vectors. Experimental exclusion of natural enemies in a field significantly increased seedling survival of two palm species. However, the effect of excluding enemies did not differ significantly between the forest edge and interior of a fragmented forest.
The results presented in this thesis should be valuable in informing conservation and management strategies to conserve viable populations of rainforest palms. They show that the full effects of habitat fragmentation on palm distributions, diversity and abundance are best understood by taking into account biotic interactions and human management practices.

Keywords: tropics
plant-animal interactions
palms
fragmentation
Advisor: Lewis, O
Gripenberg, S
On dynamics of fluidic jet switching and shear layer instabilities

Active flow control systems pave the way for increased cycle efficiency and reduced operational costs of next-generation jet engines. An active fluidic switching device is here proposed as the technological building block required for such a system. A novel switching mechanism based on acoustic excitation of natural flow instabilities is developed for that purpose and, what's more, investigated experimentally, numerically and analytically. The novel actuation mechanism outperforms the current state of the art and thus offers great potential to be used in future aerospace applications. Unlike conventional actuators, acoustic excitation is shown to achieve the balancing act between high bandwidth, sufficient control authority and cost effectiveness.
A proof of concept study using low-frequency excitation and low subsonic flow velocities reveals that the excitation and amplification of the natural shear layer instability results in detachment, switching and reattachment of the flow in a Coanda based fluidic device. The switching mechanism is explained by an enhanced roll-up of vortical structures on the unattached side of the jet causing an asymmetry in entrainment that ultimately leads to a pressure drop sufficient to counteract the attachment force. The detailed analysis of the switching mechanism then allows the development of a second device that operates up to sonic conditions using ultrasound. However, the switching mechanism of the second device is found to rely on the excitation of a different flow instability; namely, the jet preferred mode as well as the first subharmonic of the natural shear layer instability. This can be attributed to a change in the shear layer characteristics as the Reynolds number increases.
In addition, ambiguous data obtained from both Large-Eddy Simulation and Particle Image Velocimetry suggest a fundamental different relationship between the natural shear layer instability and the jet preferred mode with respect to the currently accepted point of view. This is investigated separately by means of the downstream development of the shear layer characteristics of an excited round jet subject to different initial conditions.

Keywords: Active flow control
Free shear layer
Fluidics
Flow instabilities
Advisor: Bacic, M