VictorJuiz/thesis huggingface dataset:
The legal regulation of gene drive technologies 

Gene drive technologies purport to provide a panacea and yet in doing so present unprecedented risks that threaten to change, potentially irreversibly, the way in which we live in the world. Gene drive technologies raise questions about what ends societies ought to seek for their citizens, how they are constituted and how those ends might be attained. Despite this, current discussions surrounding gene drive technologies and their regulation focus almost exclusively on the technical implications.
Drawing on the work of sociologists and STS scholars, this thesis argues that lawyers ought to think critically about the ways in which they go about developing their understandings of new technologies as regulatory objects. Lawyers need to evaluate and scrutinize the knowledge claims with which they are presented, and work to identify those extending beyond the required technical expertise, if the regulatory frames they build are to bear fidelity to the realities of the technology.
This thesis draws out the regulatory disconnection generated by the current regulation of gene drive technologies through the existing European Union GMO regime. It then goes on to describe the ways in which regulatory reconnection might be achieved by constructing broader frames through which we describe gene drive technologies as a regulatory object. In thinking about how lawyers might go about broadening the frames that they build, this thesis takes examples from Public Health Law scholarship and legislation.
In response to both the normative and epistemic lacunae highlighted above, this thesis develops an account of why and how ethical enquiry ought to play a significant role in informing our descriptions of gene drive technologies as regulatory objects. Furthermore, this thesis argues that ethical enquiry is capable of articulating questions to which technical experts must provide answers if we are to develop fuller understandings of the technologies we regulate. In this way, ethical enquiry can help lawyers bridge both the normative and epistemic gaps that they are so often faced with in the regulation of emerging technologies.

Keywords: ethics
regulation
risk
administrative law
uncertainty
emerging technologies
Advisor: Herring, J
Fisher, E
The clinical features, microbiology, and genomics of neonatal sepsis in a children’s hospital in Vietnam

Sepsis is a common and deadly condition affecting the neonatal population. I aimed to understand the causes and outcomes of neonatal sepsis at Children’s Hospital 1 in Ho Chi Minh City, Vietnam. A retrospective study from 2013 to 2016 found that Acinetobacter spp., Escherichia coli, Klebsiella spp., Pseudomonas spp., coagulase-negative staphylococci (CoNS), Staphylococcus aureus, and Streptococcus pneumoniae were the most common organisms. These organisms were resistant to a wide variety of antimicrobials, which may impact on the efficacy of antimicrobial therapy. I next conducted a prospective study of sepsis in 524 neonates with 69 deaths from January 2017 to June 2018. This group had a mortality of 13.2%; sclerema, leukopenia <4,000/mm3, thrombocytopenia <100,000/mm3, base excess < –20 mEq/L, lactate >4 mmol/L, and hyperglycaemia >180 mg/dL, were associated with death. The major organisms (from 405 isolates) included Klebsiella spp. (6.9%), Escherichia coli (6.7%), Acinetobacter spp. (4.0%), Enterobacter spp. (3.5%), CoNS (57.3%), Staphylococcus aureus (4.4%), and Streptococcus spp. (2.5%). These organisms were highly resistant to all non-carbapenem antimicrobials. The genomics of 15 Acinetobacter baumannii identified sequence type ST570 within genomic complex 2 in 80% of isolates and found the blaOXA-23, blaMBL, blaADC, blaA2, mphE, msrE, and armA AMR genes. A common transposon, carrying blaOXA-23 was associated with widespread carbapenem resistance. In this location, neonatal sepsis was associated with high mortality, complicated clinical features and caused by caused by differing MDR bacteria.

Keywords: neonatal
genomics
sepsis
clinical features
microbiology
Vietnam
Advisor: Boinett, C
Baker, S
Robust frameworks for the observability and lie symmetries of structural dynamical systems

System identification is an important technique in reconstructing and estimating dynamic states, unknown parameters and unmeasured inputs of dynamical systems using measured input-output signals, and in minimizing the gaps between real engineering systems and their mathematical models. Whether a system for a given setup of sensors can be, in theory, successfully identified is associated with its observability properties.
This thesis is overall devoted to two research directions: 1) developing efficient observability algorithms for handling large and complex dynamical systems and 2) incorporating unmeasured or unknown inputs into robust observability computation and tool. The research is motivated by the need to relax the computational limitation of the existing observability methods that is associated with their high physical memory requirements when used for large and complex real systems, as for example large civil infrastructures encountered in Structural Health Monitoring (SHM). Moreover robust observability computation with the consideration of unmeasured inputs is needed to account for joint state-parameter-input identification problems which have gained increasing attention in recent years.
In particular, two efficient and robust algorithms are proposed to test observability properties in Chapter 2 and Chapter 3. The first algorithm applies to large linear systems with unknown parameters, based on the efficient implementation of the Observability Rank Condition (ORC) method. The second algorithm applies to rational nonlinear systems with unmeasured inputs, based on the extended use of the extended Observability Rank Condition (EORC-DF) and a power series-based computational framework.
In Chapter 4, computational frameworks are developed for Lie symmetries of nonlinear systems with unmeasured inputs. The obtained Lie symmetries can provide an alternative path to approach the observability properties of a system for a given setup of sensors. More importantly, Lie symmetries imply the mathematical relationship between the true solutions of the system’s states, parameters and unmeasured inputs and their other possible solutions.
Finally in Chapter 5, the application of observability and Lie symmetry analyses is illustrated through a complex, nonlinear and non-smooth mechanical model. The model is successfully reduced and identified using suitably chosen identification methods.

Keywords: Observability/Identifiability
System Identification
Structural Health Monitoring
Lie Symmetries
Advisor: Chatzis, M
Williams, M
Cohort study to assess the quality and methodological conduct of clinical trials

Clinical trials should be based on well-constructed study protocols. In practice, however, trial protocols are variable in their content and quality. This thesis examined the design and planned methodological conduct of contemporary clinical trials using a cohort of clinical trial protocols. The DPhil candidate was granted access to 259 clinical trial protocols approved by the United Kingdom National Research Ethics Service in 2012. The cohort included non-randomized clinical trials as well as randomized controlled trials (RCTs) and there was no restriction by intervention, funding source or medical specialty. There were five broad findings. First, clinical trial protocols were variable in the quality of reporting of multiple methodological items, including items that have been associated with bias. Second, the majority of trial protocols included patient reported outcome measures (PROMs) but few discussed the validity of the PROM, the strategy for dealing with missing data and the sample size calculation. Third, the primary and secondary outcomes in the trial protocols were compared to the trial registry entry if available. In this analysis, agreement in the reporting of outcomes in the trial protocol and trial registry was modest. Notably, pharmacologic trials and multicentre trials were less likely to have discrepancies between the protocol and registry as compared to non-pharmacologic and single centre trials, respectively. Fourth, multi-arm trials made up just 8% of all clinical trial protocols. Methodological items that were important for multi-arm trials were also omitted in trial protocols. Finally, phase I trials were generally safe but recommended strategies for the identification of starting doses and the administration of the novel agents were infrequently followed. Also, phase I trials with serious adverse events were not disseminated. Taken together, this thesis has provided insight into different methodological issues in the design, conduct and dissemination of clinical trials.

Keywords: phase 1 trials
clinical trials
trial registration
multi-arm trials
Advisor: Altman, D
Hopewell, S
Multiscale molecular dynamics to investigate sodium ion channel oligomerisation

Electrical signalling is key to a vast number of biological processes within the nervous system. For this to occur, specific types of transmembrane proteins, named voltage-gated ion channels, are utilised. In voltage-gated sodium (Nav) channels, recent advances in structural biology are beginning to solve structures in complex with so-called “auxiliary” β subunits. These transmembrane proteins are multifunctional and interact with the main α subunit of the Nav channel, in addition to having a cell adhesion function through their extracellular immunoglobulin (Ig) domain. In Nav1.5, β3 has been found to cross-link subunits within the membrane, as well as form trimers and higher order oligomers.
In this thesis, both atomistic and coarse grained (CG) molecular dynamics (MD) simulations are performed to gain an insight into the behaviour of the α subunit, the α - β subunit relationship, and β subunit dynamics in isolation.
Firstly, atomistic simulations are used to investigate a splice variant of Nav1.5. Two single point mutations that were responsible for a shift in voltage-gating characteristics were investigated and found to most likely disrupt gating through interruption of voltage-sensing arginine residues.
Secondly, a large number of simulations are performed to explore Nav β1 and β3 subunit behaviour in a simple membrane composition. Results showed large differences between β1 and β3, with the latter exhibiting increased fluctuations in Ig domain orientation. These differences are attributed to key charged residues that influence Ig domain interaction with the membrane surface. Protein - lipid interactions suggest that a conserved glutamic acid residue is important in transmembrane domain location, rather than being involved in observed oligomerisation.
Finally, the use of CG simulations examines the dependency of both α and β subunit clustering with various lipids in a complex membrane composition. Protein clustering of both subunits was primarily mediated by glycosphingolipids present in the upper leaflet. The β subunit orientations adopted three states, one of which agreed well with an atomistic trimer model of the β3 Ig domain. Large-scale simulations explored a large (≈ 2 million particle) system within which multiple protein binding events occurred. Conformations present between α and β subunits agreed with experimental results from atomic force microscopy and increase our understanding of Nav subunit interaction.
Overall, the in silico multiscale approach adopted in this thesis aims to characterise Nav channel subunit behaviour in a variety of contexts. These simulations demonstrate the predictive power of MD in characterising channel function away from the pore, as well as informing potential future strategies against various channelopathies.

Keywords: ion channels
molecular dynamics
voltage-gated ion channels
Advisor: Biggin, P
McGrady, J
Predictive decision-making during exploration and social interaction in frontal cortex

In this thesis, I investigated computational and neural mechanisms underlying adaptive decision-making in social and non-social contexts. I focused on the exploration/ exploitation dilemma, during which one has to choose between exploiting the familiar option with relatively known value or exploring the option with relatively uncertain value which might lead to a better outcome in the future (reviewed in Chapter 1). Switching between exploration and exploitation was dependent on external factors such as the number of future choice opportunities (i.e. time horizon) and internal factors such as the belief estimates about the accuracy of a predictor (‘accuracy’) and the subjective uncertainty in the accuracy estimate (‘uncertainty’) (Chapter 2). I used functional magnetic resonance imaging to investigate the neural correlates of accuracy, uncertainty and their modulation during exploration and exploitation (Chapter 3). Medial and lateral frontal areas were active during exploratory decisions, while ventromedial prefrontal cortex had a unique role in representing multiple decision variables depending on the current behavioural mode. Tracking one’s beliefs is not only important when selecting between predictors, but also when evaluating one’s confidence in the predictor. When we estimate our confidence we take into account the identity of the predictor -- whether it is another social agent or a non-social stimulus that provides information, as well as the experience that we have with the agent or stimulus; people expressed more confidence for social compared to nonsocial predictors. The difference between social and non-social confidence judgments covaried with activity in right posterior temporoparietal junction (Chapter 4). Not only are the estimates we form shaped by the social or non-social identity of the predictors; in addition, whether we learn through direct experience of another person’s actions or vicarious observation of such actions influences how loyal or opportunistic we estimate these other people to be (Chapter 5).

Keywords: decision-making
computational modelling
Advisor: Wittmann, M
Rushworth, M
Aggregation of a heterogeneous population of solar panels: verification and control

The ever-growing presence of renewable energy sources has started a radical transformation of power grids worldwide. Their dynamical characteristics, the connections via power electronics, and their geographically distributed locations render their connection to the power grid substantially different from the traditional synchronous machines. Household solar panels are a striking example of this transition: their distribution is extremely sparse, and individual devices have a negligible contribution to the global electricity network; however, the presence of a large population of such devices influences the power grid in ways yet to be fully understood.
In the first part of this thesis we test the behaviour of a variety of solar devices, in order to develop models representing the aggregated, heterogeneous population that is connected to the power network. We then present a model of the power grid whose parameters depend on the amount of solar devices connected to the grid. In particular we focus on the network frequency, and we study how features of the PV population affect the overall frequency signal.
We investigate the frequency response after a generation loss contingency at varying levels of renewable penetration. We aim at identifying scenarios that lead to significant frequency deviations which activate a load shedding procedure. Simulations of critical circumstances are useful to highlight potential issues, yet are often not sufficient to guarantee the reliability of a complex, stochastic system as the power grid. In the second part of this dissertation we introduce formal methods, a suite of techniques to model complex systems as mathematical entities and to outline tight requirements about such systems. In particular we rely on the formal abstraction technique, which translates a stochastic system into a Markov model. By means of model checking, we assess the satisfaction of given requirements and we provide a formal guarantee of correctness.
Our formal tests must specify a significant number of parameters as we consider various populations of solar devices. The perfect tuning of such parameters is a cumbersome, handmade responsibility. Finally, we automate this task proposing a parameter synthesis framework which automatically returns the values of parameters that satisfy the predefined requirements.

Keywords: control theory
renewables
solar panels
abstraction
formal verification
population model
Advisor: Abate, A
What makes a 'machi' a real 'machi': an exploration of the problem of ritual healing efficacy

This ethnography examines ritual healing transformations in the Mapuche context from the perspective of the phenomenology of the body. It seeks to explore how people know who is a ‘real’ machi or a Mapuche shaman. A real machi can both know or see illness and misfortune and treat them, and make ‘spirits from the past’ present so they can provide a message to a community of people.
Machi can see illness and misfortune through divinatory techniques. These techniques produce changes in bodily and affective experience which are not mediated by reconfigurations of symbolic meaning. In turn, somatic and affective transformations may be therapeutic by enhancing the experience of trans-individual connection through the creation of shared bodily experience, and promoting awareness and volition, predisposing a person to new dispositions to everyday experience. Moreover, healing bodily transformations provide the experiential ground from which the reflexive understanding of a situation is elaborated and possible courses of action are explored.
Machi experience küymin or ritual trance, through which a group of people can receive a direct message from ‘spirits from the past’. Thus, machi embody the ancestors, so they can provide explanations of illness and misfortune and moral guidance for future action. In addition, machi’s embodiment of the past is fundamental to the transmission of cultural practices and the circulation of feelings of belonging to a community.

Keywords: mapuche
medical efficacy
ritual healing
Advisor: Hsu, E
Apartheid’s African soldiers: a history of black Namibian and Angolan members of South Africa’s former security forces, 1975 to the present

In this study, I examine the history of black Namibian and Angolan soldiers who fought in apartheid South Africa’s security forces during the Namibian war of independence and the Angolan post-independence civil war from 1975 until 1989. I ask how and why these soldiers got involved in South Africa’s security forces, and what the legacies of that involvement have been, in particular for the individual soldiers and their families. Based primarily on black former soldiers’ own accounts, I argue that their experiences deeply disrupt dominant narratives of heroic struggles of ‘national liberation’ against colonial occupation.
While scholars have remained almost entirely silent on the histories of African soldiers of colonial and settler armies during the period of decolonisation, nationalist narratives have either ignored or denounced them as ‘mercenaries’ and ‘collaborators’. I complicate such portrayals by highlighting the limits and divisions of the wars of ‘national liberation’ in Namibia and Angola. More specifically, I trace the long history of different forms of ‘collaboration’ during colonial conquest and occupation, and examine black soldiers’ complex motivations for joining and remaining in South Africa’s security forces.
Both during and after the war, many black soldiers repeatedly crossed boundaries between countries, liberation movements, and military units. I show how these soldiers’ trajectories not only impacted the particular military cultures of the units they fought in, but their post-war claims of citizenship and belonging. Their history therefore provides new insight into the local, regional, and transnational dynamics of southern Africa’s wars of decolonisation and liberation, which have shaped the region’s political and military history to this day.

Advisor: Alexander, J
Development of a beam position monitor for co-propagating electron and proton beams

Novel acceleration technologies promise a large improvement in particle accelerator performance, but pose a number of technical challenges due to the use of several beams and the beam parameters involved. To exploit these new technologies, these technical challenges need to be addressed. Innovative beam instrumentation is to be devised, to allow these acceleration experiments to become operational accelerators.
The AWAKE experiment at CERN aims to develop proton beam-driven plasma wakefield acceleration, with the aim of producing high brightness and high energy particle beams for particle physics research. At AWAKE, plasma wakefields are excited by means of a 400 GeV proton beam driver, and used to accelerate an electron witness beam. The plasma is formed by ionising a Rubidium gas with a terawatt laser pulse. The laser, electron and proton beams co-propagate in the same beampipe for metres before entering the plasma. The electron beam diagnostic is obfuscated by the presence of the more intense proton beam. Consequently, the electron beam position cannot be measured in the presence of the proton beam. To drive the acceleration efficiently, a precise positioning of the three beams is crucial. Therefore, a technique to measure the electron beam position in the presence of the stronger proton beam has to be studied.
This work addresses the beam position measurement when more than one beam is present in the beampipe. For the case of AWAKE, a technique to measure the electron-beam position exploiting the bunch-length difference with the proton beam is described. It is shown that the electron-position measurement can be carried out, provided that the detection frequency is sufficiently high. In the second part, a novel beam-position-measurement device, capable of working in the required frequency regime, is developed. Such a device is based on the emission of Cherenkov Diffraction Radiation from dielectric inserts in the beampipe. Electromagnetic simulations of the device are shown, together with the results of experimental tests on a prototype. Further developments to produce an operational instrument are discussed. The potential applications of this technology are not only in plasma-acceleration schemes, but also in any accelerator that uses short bunches, e.g. Free Electron Lasers.

Keywords: RF
AWAKE
Cherenkov-diffraction
Instrumentation
plasma-wakefield
Accelerator-physics
Advisor: Burrows, P
Wendt, M
Krupa, M