VictorJuiz/thesis huggingface dataset:
The role of the sigma subunit of Adaptor Protein-2, AP2σ2, in the regulation of calcium homeostasis

The calcium sensing receptor (CaSR), a G-protein coupled receptor (GPCR), and its downstream signalling pathways are essential for calcium homeostasis. Loss- or gain-of-function (LOF and GOF, respectively) mutations in components of these pathways result in disorders of calcium homeostasis including Familial hypocalciuric hypercalcaemia (FHH) and Autosomal dominant hypocalcaemia (ADH). FHH type 3 (FHH3) is due to LOF mutations in the σ2 subunit (AP2σ2) of adaptor protein-2 (AP-2). The FHH3-associated AP2σ2 mutations identified to date affect the Arg15 residue and comprise heterozygous Arg15Cys, Arg15Leu, and Arg15His mutations. AP-2 is a ubiquitously expressed heterotetrameric protein, with a central role in clathrin-mediated endocytosis of transmembrane proteins, such as GPCRs.
This thesis demonstrates that AP2σ2 mutations account for &Tilde;7% of all FHH mutations, only affect the Arg15 residue and show evidence of mutation bias, with only AP2σ2 Arg15Cys, Arg15Leu, and Arg15His mutations identified. Additionally, the study has identified de novo AP2σ2 mutations and revealed that FHH3 probands may present with a broader phenotype not seen in FHH1. The heterozygous missense AP2σ2 mutation was demonstrated to have no effect on the stability of the AP-2 complex in vivo. This thesis revealed that gain-of-function AP2σ2 mutations are unlikely to be a cause of ADH, which is due to GOF mutations in CaSR in &GT;70% of cases.
The CaSR activates its downstream signalling pathways, including the mitogen-activated protein kinase (MAPK) pathway, through coupling with its associated G-proteins. The AP2σ2 mutations resulted in loss of activating phosphorylation events in the MAPK pathway suggesting a role for AP2σ2 in CaSR signalling. Additionally, the AP2σ2 Arg15Cys, Arg15His and Arg15Leu mutations were revealed to exert differential effects on the Gαq/11 and MAPK signalling pathways, suggesting mutation-bias signalling.
Clathrin-mediated endocytosis is crucial for embryological development. This thesis has demonstrated that mice homozygous for an Ap2s1 splice site mutation, predicted to produce a functional knock-out, were lethal before embryonic day 12.5 (E12.5), suggesting AP2σ2 is essential for cell viability in the developing embryo.
Thus, the work of this thesis has further elucidated the role of AP2σ2 in the biological pathways of CaSR signalling and clathrin-mediated endocytosis, and in the molecular pathology of disorders of calcium homeostasis.

Keywords: adaptor protein 2 sigma 2
GPCRs
familial hypocalciuric hypercalcaemia
calcium homeostasis
MAPK signalling
Advisor: Thakker, R
Cox, R
Mathematical studies of morphology in early life palaeobiology

The overarching topic of this thesis is the mathematical study of morphology, applied to palaeobiology, more specifically the palaeobiology of early life. The first part of this thesis concerns the study of growth in the enigmatic late Ediacaran macrobiota (579-541 Ma). A new framework is presented for quantitative comparison of the ontogeny of dickinsoniomorphs and rangeomorphs, and this setup is applied to the iconic Ediacaran taxa Dickinsonia costata and Charnia masoni. The methodology, based on measurements of branch/segment lengths at different stages of ontogeny, reveals an intricate, complex system of growth in both taxa. The segments of Dickinsonia grow in two stages of growth, a first phase of rapid growth and a second phase of slower inflation. After around 50 segments are present on each side of the axis, the rate of insertion starts to decrease while the growth of the organism continues. I speculate that this switch might reflect a change from somatic to reproductive growth. Interestingly, a very similar mode of growth is found in the first order branches of Charnia masoni, which also grow in two distinct phases, and potentially can be seen to halt their insertion after around 18-20 branches are present on each side of the organism, while the organism continues to grow. In contrast, the second order branches do not follow this pattern but continue to be added. These modes of growth are reconstructed in a computer model. This model can be extended to other Ediacaran life forms, effectively generating a "morphospace" of rangeomorphs and dickinsoniomorphs.
The second part of this thesis focuses on the biological or abiological origin of the iconic trace fossil Paleodictyon, shaped like a hexagonal mesh. This ichnogenus occasionally displays incredible regularity, as well as a very high connectivity, a very broad environmental tolerance and a temporal range from the Cambrian until the present day. Despite extensive research on modern patterns, no organism has yet been identified as creator. These facts cast doubt on the biogenic interpretation of Paleodictyon. I propose the hypothesis that some of these patterns are created abiotically by regular hexagonal standing Faraday waves resulting from events such as earthquakes. This hypothesis is put to the test by means of experiments and computer modelling of the wave. In particular, a hexagonal pattern very similar to the most regular specimens of Paleodictyon could be formed in experiments and preserved on the surface of a calcium carbonate paste.

Advisor: Brasier, M
Politics of transparency: contested spaces of corporate responsibility, science and regulation in shale gas projects of the UK and the US

This thesis presents a political geography of transparency, regulation and resource making in shale gas projects in the United Kingdom (UK) and the United States (US). The emergence of shale gas as a politically and economically desirable resource occupied national political aspirations, most notably in the US and to some extent in the UK, for reasons of energy security and economic development. Although shale gas has become a globally desirable resource, this thesis shows that the resource is not same everywhere. Following knowledge making practices in distinct regulatory regimes of the UK and the US, I trace how making of shale gas resource is subjected to contestation in a range of technical fields, such as law, economics, geosciences and environmental impact assessment. The study is based on in-depth analysis of technical and policy documents, and interviews with a wide range of actors (i.e. regulators, gas companies, investors, scientists, landowners), and field visits in the US (New York, Pennsylvania and Texas) and the UK (Lancashire, Litchfield and London). Drawing on theoretical insights from the Science and Technology Studies (STS), legal and resource geographies, I empirically showed that both regulatory practices and resource materialities matter in encapsulating making of shale gas projects in different national contexts. Documenting how information production and its contestation is entangled with assemblages of materials and technologies, as well as regulatory, geoscientific and market interventions in the context of the UK and the US, this thesis offers an alternative account of the geography of transparency and regulation regarding the development of shale gas policies. The political viability of shale projects depends on how these informational spaces are generated, contested and transformed in nationally specific scientific practices and regulatory regimes.

Advisor: Barry, A
Clark, G
Probabilistic modelling of functional modes in the human brain

It is well established that it is possible to observe spontaneous, highly structured fluctuations in human brain activity from functional magnetic resonance imaging (fMRI) data when the subject is 'at rest'. This activity can be decomposed into groups of spatially distributed brain regions that are consistently temporally co- activated, and this thesis is concerned with developing new methods to identify these functional modes.
We introduce a probabilistic model that allows us to infer functional modes without making restrictive assumptions about the spatio-temporal interactions between them, and furthermore, the model also accounts for the variability of these modes over subjects. Both of these facets of the model represent advances compared to current mode-identification techniques. We use a computationally efficient variational Bayesian approach to make inferences from this model, and this allows us to draw upon the enormous amount of information available from the types of large-scale fMRI data collection initiatives that are becoming the norm.
We demonstrate, using data from over 450 subjects collected as part of the Human Connectome Project, that we can reliably infer a set of modes that captures an enormous degree of spatial variability over subjects and that makes a novel set of predictions about the temporal relationships that modes have with one another. Finally, we highlight the importance of functional registration and bring to light a surprising link between temporal non-stationarities and the fMRI global signal.

Advisor: Smith, S
Woolrich, M
Role of Tal1 in murine blood vessel development

Detailed knowledge about the mechanisms involved in vascular establishment, differentiation and growth is essential to develop new therapies to treat blood vessel formation related conditions like cancer and blinding eye diseases. Although research has investigated the cellular mechanisms of vessel growth in great detail, a clear understanding of the integration of extracellular signals into the transcriptional programme regulating blood vessel formation still remains elusive.
In this thesis the role of the transcription factor Tal1 as a regulator of blood vessel formation and differentiation is investigated. Tal1 is a master regulator of embryonic haematopoiesis, adult megakaryopoiesis, and erythrocyte maturation. Tal1 depleted mice die at gestational day E9.5 due to a complete lack of blood. However, several lines of evidence also suggest an important function of Tal1 in blood vessel development.
I chose an inducible, endothelial-specific knock-out strategy to investigate the effects of Tal1 depletion in mice with a focus on vascular development. A distinct time window during embryogenesis, in which Tal1 is required for the proper formation of the primitive intra-embryonic vascular network and the dorsal aorta, was identified. In contrast, I demonstrate that there is no requirement of Tal1 for postnatal sprouting angiogenesis or blood vessel homeostasis. This suggests an important role in vasculogenesis rather than angiogenesis and is in line with recent findings which attribute the proper differentiation of endothelial cells to Tal1.
In addition, I have generated and characterised transgenic mouse lines in which Cre recombinase activity is controlled by a Dll4 promoter/enhancer construct. Thereby, Cre expression is specifically directed to the arterial endothelium. I believe that this model can be of great interest for angiogenesis research in general and especially for the understanding of induction and maintenance of arterial-venous identity.

Advisor: De Val, S
Building mounds: Viking-late Norse settlement in the North Atlantic c. AD800-1200

The subject of this study is Viking-Late Norse settlement (c. AD800-1200) in the North Atlantic, focusing on Orkney and on longhouse complexes constructed on mounds. For the first time these mound settlements are investigated as a group and as deliberately constructed mounds. Settlement mounds in Orkney are also closely associated with nearly 40 Skaill ON skáli ('hall') place-names, which place-names linked the sites with the social and economic networks of Orkney's peripatetic leaders. This association is examined more closely. The analysis also demonstrates that constructing settlements on mounds required particular building techniques, which relied heavily on the use of midden-type material.
Those techniques are examined using new and freshly analysed material from published and grey literature-published excavations and surveys of sites from the Viking-Late Norse period in Orkney and elsewhere. Three core data-sets were established to provide the evidential basis: the first, also drawing on site-visits, looking broadly at mound landscapes and skáli-areas in Orkney; the second at the building techniques and materials used on settlement mounds; and the third, also requiring site-visits, at all the skáli place-name sites. The possible origins of settlement mound living in the settlers' Scandinavian homelands are investigated, then the extent to which mound living was also followed in Shetland, Caithness and the Western Isles, and finally in previously unoccupied lands, using Iceland as a case study.
The mound-sites, their archaeology, mound architecture, place-names and landscape setting are also analysed in a new theoretical framework to reach fresh understandings of Viking-Late Norse settlement in Orkney. The analysis thus considers the wider cultural significance of constructing and living on settlement mounds, and what that communicated about Viking-Late Norse society. The thesis argues that Viking-Late Norse groups chose prominently-placed sites for their visual dominance and commanding views, but also that the rebuilding of mound structures in one spot, and building out and up of the mound itself using midden material, set strong cultural messages about stability, continuity and association with the surrounding landscape. The mounds were complex features of culturally meaningful architecture.

Keywords: Settlement mounds
Midden
Orkney
Viking settlement
Advisor: Griffiths, D
At the frontier of precision QCD in the LHC Era

This thesis discusses recent advances in precision calculations of quantum chromodynamics and their application to the Large Hadron Collider (LHC) physics program and beyond.
The first half of the thesis is dedicated to the study of vector boson fusion Higgs (VBF) production; fully differential at the next-to-next-to-leading order level (NNLO), and inclusively at next-to-next-to-next-to-leading order (N3LO). Both calculations are performed in the structure function approximation, where the VBF process is treated as a double deep inelastic scattering. For the differential calculation a new subtraction method, "projection-to-Born", is introduced and applied. We study VBF production in a number of scenarios relevant for the LHC and for Future Circular Colliders (FCC). We find NNLO corrections after typical cuts of 5 − 6% while differential distributions show corrections of up to 10 − 12% for some standard observables. For the inclusive calculation we find N3LO corrections at the order of 1 − 2‰.
The second half of the thesis presents recent results on the matching of fixed order calculations with parton showers. We first present the POsitive Weight Hardest Emission Generator (POWHEG) method for matching next-to-leading order (NLO) calculations with parton showers. We then proceed to apply it to the case of vector boson fusion ZZjj production and discuss the results for scenarios relevant for the LHC and a possible FCC. In order to present the matching of a NNLO calculation with a parton shower, we next discuss the Multi-Scale Improved NLO (MiNLO) procedure. By applying a reweighting procedure to MiNLO improved Drell-Yan production, we obtain a generator which is NNLO accurate when integrated over all radiation while providing a fully exclusive description of the final state phase space. We compare the calculation to dedicated next-to-next-to-leading logarithm resummations and find very good agreement. The generator is also found to be in good agreement with 7 and 8 TeV LHC data.

Keywords: Higgs
Perturbative Calculations
Precision QCD
Advisor: Zanderighi, G
Teper, M
The future of indigenous protected areas in Australia

An Indigenous Protected Areas (IPA) is an area of land and/or water that an Aboriginal or Torres Strait Islander group has decided to voluntarily declare and manage through a mixture of legal and other effective mean in line with the International Union for the Conservation of Nature’s (IUCN) protected area (PA) guidelines. The Australian Government’s IPA program supports the declaration and management of IPAs. Currently, there are 72 IPAs covering over 65 million hectares, making up more than 44 per cent of the national PA network. IPAs represent the first time a PA has been established with the informed consent of Aboriginal and Torres Strait Islander peoples. The IPA concept and program have been in effect for 20 years; however, despite national and international recognition as an approach that surpasses the constraints of collaborative forms of conservation, the Government have not made a commitment to continue funding IPAs post-2018.
To date, there is limited critical analysis of the IPA concept and program. This thesis aims to fill this gap in the literature by utilising an original analytical framework – addressing the role of Indigenous recognition, the role of language, bureaucracy, territoriality, accounting and accountability, and asymmetrical relations of power – to investigate the form and function of the IPA concept and program, against principles of the established 'fortress' (Brockington et al., 2008a) and emerging rights-based paradigms for conservation. The analysis highlights that the concept and program reinforce a number of the principles of both paradigms. Nonetheless, the concept and program have in some respect evolved beyond the principles by further grounding the IPA concept and program in Aboriginal and Torres Strait Islanders peoples’ conception of their relationship to country. The future of IPAs is not only in the guarantee of long-term funding but also in how they continue to evolve and adapt.

Keywords: Australia
rights-based paradigm
Indigenous Protected Area (IPA)
Indigenous peoples
fortress paradigm
co-management
conservation
Advisor: Thornton, T
Towards the development of a universal influenza vaccine: investigating viral-vectored vaccine-induced heterosubtypic immune responses to influenza A

Influenza A viruses pose a continual threat to global society and are responsible for considerable morbidity and mortality on an annual basis. Existing seasonal vaccines must be regularly reformulated to match circulating strains and do not protect against pandemic viruses. A universal influenza vaccine capable of protecting against both seasonal and pandemic strains is a major goal of vaccine developers. In recent years there has been considerable interest in broadly neutralising antibodies that target the stem region of haemagglutinin (HA). Work in this thesis reports the design and production of several tools designed to measure anti-stem responses, namely, two recombinant chimeric HA proteins and a phage display library. In addition the development of three novel viral-vectored vaccines aimed at inducing anti-stem responses and the investigation of their immunogenicity is described. This thesis also examines the cellular events associated with the development of antibody responses in response to viral-vectored vaccination and reports on the immunogenicity of multivalent, multi-antigen viral-vectored vaccination against influenza in work towards the development of a universal influenza A vaccine.

Advisor: Gilbert, S
Lambe, T
Creation and study of matter in extreme conditions by high-intensity free-electron laser radiation

The recent development of free-electron lasers operating at XUV and X-ray wavelengths are proving vital for the exploration of matter in extreme conditions. The ultra-short pulse length and high peak brightness these light sources provide, combined with a tunable X-ray wavelength range, makes them ideally suited both for creating high energy density samples and for their subsequent study. In this thesis I describe the work done on the XUV free-electron laser FLASH in Hamburg, aimed at creating homogeneous samples of warm dense matter through the process of volumetric XUV photo-absorption, and the theoretical work undertaken to understand the process of high-intensity laser-matter interactions. As a first step, we have successfully demonstrated intensities above 1017 Wcm−2 at a wavelength of 13.5 nm, by focusing the FEL beam to micron and sub-micron spot sizes by means of a multilayer-coated off-axis parabolic mirror. Using these record high intensities, we have demonstrated for the first time saturable absorption in the XUV. The effect was observed in aluminium and magnesium samples and is due to the bleaching of a core-state absorption channel by the intense radiation field. This result has major implications for the creation of homogeneous high energy density systems, as a saturable absorption channel allows for a more homogeneous heating mechanism than previously thought possible. Further, we have conducted soft X-ray emission spectroscopy measurements which have delivered a wealth of information on the highly photo-excited system under irradiation, immediately after the excitation pulse, yet before the system evolves into the warm dense matter state. Such strongly photo-excited samples have also been studied theoretically, by means of density functional theory coupled to molecular dynamics calculations, yielding detailed electronic structure information. The use of emission spectroscopy as a probe for solid-density and finite-temperature systems is discussed in light of these results. Theoretical efforts have further been made in the study of the free-free absorption of aluminium as the system evolves from the solid state to warm dense matter. We predict an absorption peak in temperature as the system heats and forms a dense plasma. The physical significance of this effect is discussed in terms of intense light-matter interactions on both femtosecond and picosecond time-scales.

Keywords: opacity
laser
plasma
matter in extreme conditions
free-electron
intense radiation
spectroscopy
electronic structure
X-ray
high energy-density
Advisor: Wark, J