VictorJuiz/thesis huggingface dataset:
Methods development for structural biology

Two research questions are investigated here: the first, major, section addresses the problem of uneven distributions of dose (absorbed energy per unit mass) in crystals used for macromolecular crystallography (MX), and the second presents the develop- ment of a high-throughput metalloprotein characterisation technique, HT microPIXE.
In MX, the advent of X-ray microbeam data collection has led to uneven distributions of dose within the crystal volume becoming increasingly common. In these cases, the rotation method creates a highly damaged central region of crystal that stays within the beam throughout exposure, and less damaged outer regions, which are introduced during rotation. This thesis presents a new software program, raddose-3d, which performs a full 3D simulation of the profile of absorbed energy (the dose state) within a crystal during X-ray exposure. In order to utilise this time resolved, 3D picture of the dose state of the crystal, a new metric – Diffraction Weighted Dose – is proposed. This metric is then experimentally validated, and is found to summarise the dose state into a single dose value, which reflects the damage state of the crystal. Simulations are performed using raddose-3d and Diffraction Weighted Dose to compare possible dose spreading strategies, and generalised recommendations for MX experimentalists are offered.
Uniquely identifying the species and stoichiometry of bound metals in protein sam- ples is a significant challenge for biophysical characterisation. Low throughput mi- crobeam Proton Induced X-ray Emission (microPIXE) provides an unambiguous anal- ysis of these properties, but has a limited throughput of &Tilde;10 samples per day. As a consequence, its applicability has been restricted to niche cases. This thesis presents significant progress, including proof of principle experiments, on developing sample preparation methods, data acquisition systems, and data analysis protocols to increase this throughput by an order of magnitude, opening up major new applications for the technique.

Advisor: Garman, E
The clinical applications of working memory training

Working memory is involved in a variety of cognitive tasks, with working memory capacity predicting an individual's ability to process information and focus attention on taskrelated information. Subsequently, recent research has investigated whether working memory capacity can be improved through training and whether improvements generalise to other cognitive, behavioural or emotional domains. This training is typically adaptive in nature, changing in difficulty according to participant ability, and can be completed in the participant’s home on a computer, giving it the potential to be an easily accessible intervention for a range of clinical populations.
The first paper presents a systematic review evaluating the effectiveness of computerised working memory training for individuals with neurodevelopmental disorders, which are often associated with working memory difficulties. The review found that to date, working memory training has been investigated in four neurodevelopmental disorders: attention deficit/hyperactivity disorder; autism spectrum disorder; intellectual disability and specific learning disorder. The findings indicate that although training appears to produce short-term improvements in the working memory capacity, this does not reliably generalise to other cognitive processes or disorder-specific symptoms.
The second paper presents a randomised controlled trial investigating the effects of working memory training for reducing worry in high-worriers. Working memory capacity limitations, and subsequent difficulties in attentional control, are believed to be central to the maintenance of worry. Participants were randomly assigned to complete 15 days of nonadaptive working memory training using a 1-back task, or adaptive working memory training using a n-back task. Training led to improvements in working memory capacity and worry symptoms post-training and at four-week follow-up, with improvements on the adaptive training task significantly correlating with improvements in working memory capacity and worry. These findings are discussed in terms of implications for clinical practice and future research, together with the limitations of the study.

Keywords: Worry
Working memory training
Neurodevelopmental disorders
Advisor: Murphy, D
Investigating the mechanism of non-catalytic tyrosine-phosphorylated receptor triggering

Non-catalytic tyrosine-phosphorylated receptors (NTRs) are a large group of leukocyte receptors that bind to surface-associated ligands and include both activating and inhibitory members. They contain, or associate with adaptor molecules which contain, tyrosine residues within conserved cytoplasmic motifs that are phosphorylated and dephosphorylated by extrinsic kinases and phosphatases respectively. The mechanism by which NTR-ligand engagement leads to sustained phosphorylation of receptor tyrosinebased motifs and initiation of downstream signalling (termed "receptor triggering"), is as yet unknown.
Our hypothesis is that the NTRs signal using the kinetic-segregation (KS) model. The model proposes that large inhibitory phosphatases, but not inner leaflet-bound activating kinases, are segregated in a size-dependent manner from engaged receptors upon ligand binding. This favours kinase activity and drives sustained receptor phosphorylation.
To systematically test whether predictions of the KS model hold for all NTRs, we have developed an artificial generic ligand system in which biophysical and biochemical properties of NTR-ligand interactions can be manipulated. These include NTR-ligand dimensions, ligand densities and valency. Our system exploits the interaction between a Strep-Tag II, which is attached to the ectodomain of the NTR, and StrepTactin protein. We first demonstrate that representative NTRs, both activating and inhibitory, can be triggered through ligation of this Strep-Tag II. In agreement with a key KS model prediction, we next show that only ligation by surface-associated ligand leads to triggering, whilst ligation by soluble ligand does not. Additionally, by altering ligand valency and mobility, we provide evidence that receptor clustering can enhance activation. Also in agreement with the KS model, we show that elongation of the artificial ligand dramatically affects activation of a representative NTR. Finally, we provide evidence to suggest that increased receptor clustering may be able to compensate for ligand elongation-mediated defects in NTR signalling.
The flexibility of this system will allow us to analyse other NTRs, test further predictions of the model, and investigate the role of other properties of NTR signalling.

Keywords: StrepTactin
Non-catalytic tyrosine-phosphorylated receptor
Strep-Tag II
Advisor: Goyette, J
van der Merwe, P
Correlation methods in the statistical analysis of financial trading data

This thesis considers problems associated with the statistical analysis of correlation in financial trading data. Sources of data are identified and their characteristics are described. Nowadays most financial transactions are carried out electronically on automated exchanges or electronic communication networks and active participants in the market re- quire sophisticated computing infrastructure to compete effectively. These data are shown to present novel statistical challenges both in retrospectively analysing the vast stores of accumulated historical data and also in online processing of high-bandwidth multiple data streams arriving on millisecond time-scales. We show that computational speed dictates the range of statistical tools that are available for high-speed calculation.
The measurement and interpretation of correlation is a dominant concern in the analysis of high-frequency financial data. We compare and develop methods for assessing volatility, cross-asset correlation and lead-lag effects. For volatility estimation we consider a class of estimates that can accommodate noisy irregularly spaced data. We derive explicit expressions for the variance of these estimators and show how the estimators can be modified to obtain infill consistency. We then consider the problem of covariance estimation and develop a new estimator, demonstrating its superior performance. We explore the problems of quantifying lead-lag relationships and show that our new covariance estimator provides a sharper estimate of lead-lag delay. We then develop a method of exploring lead-lag structure in depth and demonstrate how to obtain a maximum likelihood estimator of the delay structure. The final chapter briefly describes ongoing research questions relating to the design of hedging strategies at times of market disruption.

Keywords: Trading Latency
Latency
Asynchronous correlation
High Frequency Trading
Big data
Correlation
High-Frequency Covariance Estimates With Noisy
Financial data
Asynchronous Financial Data
Statistical Learning
Machine Leaning
Correlation methods in the statistical analysis of financial trading data
Lagged correlation
Volatility
Advisor: Clifford, P
Infrared spectroelectrochemical study of E. coli NiFe hydrogenase 1

This thesis investigates the catalytic mechanism of NiFe hydrogenases. The specific enzyme studied in this work, E. coli Hyd-1, is an efficient catalyst for H2 oxidation even in the presence of O2. A method for studying the chemistry of the active site of this enzyme, under catalytic conditions, is developed. The combination of IR spectroscopy with protein film electrochemistry in situ is demonstrated. This was achieved by adsorbing the hydrogenase on a high surface area carbon nanoparticle electrode; and by the design of a spectroelectrochemical flow cell that provides efficient mass transport conditions.
A complete redox characterisation of the active site for a hydrogenase immobilised on a carbon electrode is described for the first time. The study of the effect of pH on the distribution of redox states demonstrates the existence of a pH equilibrium between the Ni-C and the Ni-L states. It is shown that the active site responds to the pH of the external solution, and that the increase in pH acts as a driving force that removes the proton further away from the active site. Studies under electrocatalytic conditions provides direct evidence of intermediates of the catalytic cycle. The role of Ni-SI, Ni-R, and Ni-C is confirmed. Furthermore, Ni-L is detected under turnover conditions and therefore shown to be an important intermediate in the cycle. The detection of different protonation states of Ni-L and Ni-R is proposed to provide information on the transport of the protons as they start to move away from the active site.
In the investigation of O2 inhibition, Ni-B (detected spectroscopically) is directly related to the loss in activity upon the attack of O2 for the first time. Also, the formation of solely Ni-B from the reaction with O2 (no other O2-damaged species are detected) provides further evidence on the ability of O2-tolerant hydrogenases of having an effective mechanism for dealing with O2 tolerance. A thorough study on the interaction of CO with Hyd-1 proves unequivocally that this O2-tolerant hydrogenase does bind CO, and that CO does inhibit its catalytic activity (both H2 and H+ reduction). This helps clarify how CO interacts with O2-tolerant hydrogenases.
Overall, the work in this thesis contributed to the understanding of key mechanistic aspects in O2-tolerant hydrogenases. The technique for combining protein film electrochemistry with IR spectroscopy in situ shall provide valuable opportunities for providing new insight into the mechanisms of hydrogenases and other metalloenzymes that bind small molecules.

Keywords: hydrogenase
in situ spectroelectrochemistry
protein film electrochemistry
H2 activation
Advisor: Vincent, K
Welfare politics in East Asia: an analysis of welfare legislation patterns in South Korea, Japan and Taiwan

The project mainly seeks to explain the structural logic behind the welfare expansion trend in three developed East Asian democracies—Korea, Japan, and Taiwan—since 1990. The major finding of the research is that the dispersed power structure (e.g. coalition, minority, divided governments) was a hitherto unnoticed significant political factor behind the transformation of fragmented, indirect, and weak welfare benefits into universal, direct, and generous ones.
Unlike the conventional approach using welfare expenditure data in analysing welfare politics, the project examined possible relations between the changes in power structure and the legislative activities of major political actors using the whole universe of bills—roughly 50,000 in total—in three nations during the past two decades. Among others, the research focused on how dimensions such as the number, the success ratio, or the primary political sponsors have changed along with the different levels of power dispersion/concentration applying regression analyses. Moreover, the key analysis includes both orthodox and unorthodox social policies and applies multiple methods (e.g. social network analysis, media content analysis, or theory-informed narratives) to verify/triangulate/fine-tune findings from the legislation patterns.
The result suggests that when bargaining among a number of parties/politicians prevailed, welfare policy tended to be premised on the lowest common denominator—the median voters such as consumers, women, labourers who often were unorganized and not geographically concentrated. As a result, the dispersed power structure went hand in hand with a loose but broad issue coalition—for specific welfare expansions–among academia, civil society, bureaucrats, and politicians irrespective of their ideology. In contrast, the concentrated power structure has seen radical turns to zero-sum political or ideological issues such as the constitutional reform in Japan or military measures toward North Korea/Mainland China in South Korea/Taiwan. This, in turn, marginalized welfare-related issues.

Advisor: Seeleib-Kaiser, M
Neary, I
Individual pains and social gains: the personal and social consequences of collective dysphoric rituals

This thesis presents the results of a multi-method exploration of the effects of collective dysphoric rituals on self-identification, group affiliation, and prosocial behaviour. Findings are presented from a worldwide sample of martial artists, student participants in artificial ritual experiments, and observers and performers of Shinto firewalking festivals in Japan. The thesis tests recent predictions of the Modes of Religiosity theory in regards to the psychological processes that underpin shared dysphoric rituals and various costly signalling theories concerning the group orientated consequences of participating in extreme ritual events. The results from the studies raise questions with the broader generalisability of recent findings linking collective dysphoric rituals and inclusive self- identification and urge for a more nuanced appraisal of associations with prosocial behaviour. Furthermore, the role of subjective positive assessment of dysphoric experiences is shown to be a topic that has been unduly overlooked and preliminary evidence is provided for a potential relationship with identity fusion. Methodologically the thesis presents a series of novel artificial ritual studies that offer initial evidence in support of shared dysphoria’s ability to enhance cooperation and promote positive ingroup association.

Keywords: Ritual
Extreme Ritual
Dysphoria
Advisor: Whitehouse, H
Stem cell culture on 3D-scaffolds for cardiac regenerative medicine and in vitro studies

Most life years lost due to death and disability in the Western world arise from non-communicable diseases, such as cancer and cardiovascular disease. Myocardial infarction (MI) and heart failure (HF) still have a particular poor prognosis, despite the development of improved pharmacological therapy and surgical interventions. No cure, other than heart transplant, is available for patients with HF. As a result, further research into new treatment strategies is paramount. Many potential avenues have been suggested, but this thesis aimed to work towards using stem cells and tissue engineering strategies as tool for in vitro testing and in vivo therapy.
In the first place, the thesis aimed to develop a humanised Langendorff perfused heart as an in vitro testbed. The decellularised rat heart was chosen as biomaterial, because it allows perfusion, and cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPS) as cell source. Given the size of the constructs and to enable biomimetic mechano-electrical stimulation of the organoids, which may aid in the differentiation and maturation of the cardiomyocytes, a bioreactor was constructed for culturing the recellularised hearts. Finally, the feasibility and performance of culturing decellularised hearts seeded with iPS-CMs in the bioreactor under biomimetic conditions was assessed. The performance of this technique was currently insufficient for it to be used as an in vitro model of the heart. Hence, further improvements in bioreactor design and cell culture technique are required.
Secondly, the therapeutic benefit of a cell-loaded collagen scaffold was investigated in a rat ischaemia-reperfusion myocardial infarction (MI) model. A bilayer collagen scaffold was designed for this purpose and biocompatibility demonstrated both in vivo and in vitro. Cardiosphere-derived stem cells were used as cell source, given their potential to form cardiomyocytes and blood vessel structures, and their therapeutic benefit post-MI. In the present study, the cells were pre-conditioned with hypoxia, as this increased stemness and pro-angiogenic factor secretion, before implantation post-MI. However, a twelve week study using magnetic resonance imaging to study cardiac function failed to show significant improvements in function post-MI.
In summary, this thesis contributed to the development of technology for both in vitro and in vivo cardiac tissue engineering. However, further investigation and optimisation will be required before this technology can be applied in practice.

Keywords: tissue engineering
regenerative medicine
heart
stem cells
Advisor: Carr, C
Tyler, D
'With no direction home': refugee resistance against repatriation in Africa's Great Lakes region since 1994

Why do refugees in Africa's Great Lakes Region refuse to repatriate? This thesis offers a detailed examination of this question through a comparative study of Rwandan and Congolese refugee communities across three countries: Uganda, Rwanda, and the Democratic Republic of Congo. The policies of international agencies and local governments are assessed against the lived experiences, responses, and perceptions of refugees through first-hand research, undertaken in eighteen sites across the region during extensive fieldwork conducted between 2009 and 2013. The pervasiveness and intensity of reactions amongst refugees against repatriation is forceful and striking. Conversely, it is aggressively promoted and implemented by international actors, home, and host states.
The thesis examines the interactions that occur as refugees seek to remain 'in exile', whilst international actors and regional states seek to coerce them to repatriate, and investigates the mechanisms that underpin this stalemate. The principal chapters of this thesis address the themes of (i) acculturation, de facto integration, and de jure segregation; (ii) conceptualisations of rights secured through refugee status; (iii) information concerning homelands and its diffusion in exile; and (iv) experiences of return. It is shown that refugee communities are adept at articulating past and present grievances, and are critically aware of their human rights in the context of their exile. The international protection of exile is perceived as a pseudo-citizenship that secures more rights than those accorded citizens in their states of origin. These communities maintain a wealth of information concerning their homelands, the diffusion of this knowledge being determined by connections between sites of exile, shaping it into accepted and collective communal narratives. This collective consciousness of status selectively reinforces refugees' resolve against repatriation. When repatriation is forced or frustrated, its experience is integrated into communal narratives of persecution, generating further grievance and reifying resistance to return.

Advisor: Anderson, D
Confidential enquiry into child deaths in two contrasting settings in Africa

Background: There is evidence that in-facility death reviews can lead to reductions in hospital-based maternal and perinatal mortality, but there are no studies of child death reviews in sub-Saharan Africa. The aim was to adapt the UK confidential enquiry (CE) methodology to the context in sub-Saharan Africa, to evaluate its implementation and impact.
Methods: The CE process was adapted in consultation with health workers and researchers in Mali and Uganda, and was piloted in five sites in each country from 2011 to 2014. Village Health Teams reported all deaths within their area to fieldworkers, who then attempted to interview the family and any health workers involved. Cases were summarised and discussed by a multidisciplinary panel, who determined the most likely cause of death, identified avoidable factors and made recommendations to avoid similar deaths. The process was evaluated both by measuring quantitative indicators (number of child deaths per year in the study areas) and by qualitative observation and interviews.
Results: It was usually possible to interview the families of children who had died (over 75% in all sites) although interviewing health workers and finding medical records often proved difficult. Nevertheless, in almost all cases, review meetings were able to assign a cause of death, identify avoidable factors, and make recommendations, many of which were implemented. Between the first and second years of the CE, estimated child mortality declined by -27.0% (95% CI -40.2% to -11.4%), compared to -4.4% at the national level in Uganda, and by -18.2% (95% CI -30.2% to -4.3%) compared to -3.9% at the national level in Mali.
Conclusion: It was feasible to implement a community-based CE into child deaths in Mali and Uganda. This was associated with a faster reduction in under-five mortality in most study sites than at the national level.

Advisor: Mant, D
Harnden, A