VictorJuiz/thesis huggingface dataset:
Molecular architecture of SAS-5 enables construction of a daughter centriole

In dividing cells, centrioles are duplicated once per cell cycle in a semi-conservative manner. A daughter centriole forms perpendicularly to the mother in a process templated by cartwheel-like structures. Cartwheels are found in centrioles of most eukaryotes, and are regarded as the key factor in establishing the nine-fold symmetry of centrioles. Cartwheels comprise the self-oligomerising protein SAS-6, recruitment of which to the mother centriole is mediated by direct binding to protein SAS-5 (also known as Ana2 or STIL). Although SAS-5 is an essential protein for centriole duplication, depletion of which completely terminates centrosome-dependent cell division, its exact role in this process has remained obscure. Using X-ray crystallography and a range of biophysical techniques, we have determined the molecular architecture of SAS-5. We show that SAS-5 forms a complex oligomeric structure, mediated by two self-associating domains: a trimeric coiled coil and a novel globular dimeric Implico domain. Disruption of either domain leads to centriole duplication failure in worm embryos, indicating that large SAS-5 assemblies are necessary for function. We propose that SAS-5 provides multivalent attachment sites that are critical for promoting assembly of SAS-6 into a cartwheel, and thus centriole formation.

Keywords: protein structure
biophysics
X-ray crystallography
structural biology
biochemistry
centrioles
Advisor: Vakonakis, I
Deane, C
Human trafficking, human rights and the right to be free from slavery, servitude and forced labour

The thesis engages with a dynamic discourse on the human rights approach to human trafficking. Building on the traditional doctrine of human rights, the thesis demonstrates that human trafficking is not a human rights violation, save for a state involvement in it, either directly or through a failure to observe its positive obligations imposed by the existent human rights. In situations that do engage human rights law, the thesis defends an argument that conceptually, human trafficking falls within a domain of the right to be free from slavery, servitude and forced labour. This argument is grounded in both a doctrinal and a conceptual analysis. In particular, the thesis conducts a unique conceptual and legal analysis of Article 4 of the European Convention of Human Rights offering an original interpretation of the concept of exploitation in the context of practices associated with trafficking and 'modern slavery'. This type of inquiry is missing in the existent scholarship. The thesis also conducts a detailed analysis of the jurisprudence of the European Court of Human Rights on positive obligations to protect vulnerable individuals arising out of 'absolute' rights. In addition to providing a complete analysis and classification of these positive obligations, the thesis draws attention to the important difference between the scope of the right and the scope of state responsibility in situations of private infringements of 'absolute' rights. Accordingly, the thesis demonstrates that whereas the prohibition contained in these rights is absolute for the state, positive obligations in situations of their infringements by private individuals are of a limited scope. The analysis of the jurisprudence of the Strasbourg Court is supplemented by a comprehensive discussion of the obligations established in the trafficking-specific instruments. The thesis explains how victim protection provisions contained in these instruments may inform human rights obligations, yet, it demonstrates that these do not represent such obligations on their own. This analysis provides a roadmap for practitioners and activists when arguing cases before the Strasbourg Court and domestically. In addition to this practical dimension, the thesis intends to provide an important contribution to the scholarship on human rights law, and on human trafficking specifically.

Advisor: Lazarus, L
States' prescriptive jurisdiction and the 'police powers doctrine'

States' ability to promote the 'public interest', and to pursue their social, environmental, economic and fiscal objectives in light of widening and deepening international economic regulation has generated significant discussion. This dissertation critically examines the 'police powers doctrine' developed in arbitral practice and academic discussion concerning international law on investment protection. It considers whether police powers can be reconciled with the 'traditional' approach to States' regulatory authority in general international law, the rules governing prescriptive jurisdiction.
Three main issues are considered: (i) how general international law governs States' ability to create and apply laws within their territory; (ii) the origins of the police powers doctrine and how it has featured in arbitral practice on investment protection; and (iii) whether police powers can be doctrinally and conceptually reconciled with the general international law governing States’ prescriptive jurisdiction.
It is demonstrated that police powers suffers from critical flaws when considered from both legal validity and coherence perspectives. The dissertation’s central argument however is that police powers is more broadly irreconcilable with the general international law governing States’ prescriptive jurisdiction. It is shown that police powers represents a significant departure from the extant law on States' prescriptive jurisdiction in three respects: (i) it changes the nature of States' authority to create and apply laws within their territory from one of residual plenary freedom to one based on conditional authorisation; (ii) it shifts from an approach based on legality to one based on 'legitimacy'; and (iii) it shifts the focus away from the legal content and consequences of States' assumed obligations, with corresponding consequences for auto-limitation as the basis of obligation in the protection of foreign investment.

Keywords: customary international law
jurisdiction
sources
public interest
regulation
police power
Advisor: Tzanakopoulos, A
Peptidomimetic foldamers of β-secondary structural elements

Foldamers have the potential to be the synthetic equivalent of Nature's macromolecules; man-made oligomers that use a range of non-covalent interactions to fold into well defined structures.
Chapter 1 introduces the challenges laid down by Gellman to chemists in creating foldamers; i) to design new polymers that reliably display interesting folding properties; ii) to be able to include novel and unnatural functional groups; and iii) make them easy to synthesise. Each of the foldamers made in this thesis will be evaluated against these challenges.
Chapter 2 develops a mimic of the linear β-strand, based on alternating pyridyl/urea units, with the conformation enforced by dipolar repulsion. Conformational bias is demonstrated in the solution phase by computational and NMR studies, and in the solid phase by X-ray crystallography. The concept is extended to the inclusion of hydrophilic residues and conformation is maintained in a polar protic solvent.
Chapter 3 describes the design and synthesis of a three- and four-stranded β-sheet mimic templated by the diphenylacetylene motif. The folding is enforced by a hydrogen bonding network demonstrated via extensive solution phase studies and X-ray crystallography.
Chapter 4 explores the scope of this new architecture. The meander is successfully elongated to seven strands, and the structure shown to be amenable to the inclusion of D-amino acids and hydrophilic residues. The foldamer is therefore shown to meet all of Gellman's criteria.
Chapter 5 uses the diphenylacetylene motif to study the factors involved in the formation of β-sheets, specifically the effect of side-chain identity on hydrogen bond strength. The difference in strengths is shown to be minimal, suggesting that β-sheet propensity is due to the energy changes in forming the extended conformation rather than forces between strands.

Advisor: Thompson, S
Hamilton, A
Securing the internet of things: decentralised security for wireless networks of embedded systems

The phrase 'Internet of Things' refers to the pervasive instrumentation of physical objects with sensors and actuators, and the connection of those sensors and actuators to the Internet. These sensors and actuators are generally based on similar hardware as, and have similar capabilities to, wireless sensor network nodes. However, they operate in a completely different network environment: wireless sensor network nodes all generally belong to a single entity, whereas Internet of Things endpoints can belong to different, even competing, ones. This difference has profound implications for the design of security mechanisms in these environments. Wireless sensor network security is generally focused on defence against attack by external parties. On the Internet of Things, such an insider/outsider distinction is impossible; every entity is both an endpoint for legitimate communications, and a possible source of attack. We argue that that under such conditions, the centralised models that underpin current networking standards and protocols for embedded systems are simply not appropriate, because they require such an insider/outsider distinction.
This thesis serves as an exposition in the design of decentralised security mechanisms, applied both to applications, which must perform access control, and networks, which must guarantee communications security. It contains three main contributions. The first is a threat model for Internet of Things networks. The second is BottleCap, a capability-based access control module, and an exemplar of decentralised security architecture at the application layer. The third is StarfishNet, a network-layer protocol for Internet of Things wireless networks, and a similar exemplar of decentralised security architecture at the network layer. Both are evaluated with microbenchmarks on prototype implementations; StarfishNet's association protocol is additionally validated using formal verification in the protocol verification tool Tamarin.

Advisor: Martin, A
Nitrogen-status sensing in Arabidopsis

Plant nitrogen use efficiency (NUE) is important in agriculture because it significantly influences yield and fertiliser requirements. Many factors influence NUE; these include nitrogen availability, internal nitrogen-status, nitrogen uptake and assimilation rates as well as carbon status. Previous attempts to improve NUE by targeting the main nitrogen uptake or assimilation machinery (e.g. over-expression of nitrate reductase or glutamine synthetase) have had mixed results. This is because these enzymes are strictly controlled by multiple feedback mechanisms relating to internal and external nitrogen-status. Arguably, a better approach to manipulating NUE would be to identify and supress these feedback signals either alone, or in conjunction with over-expression of the uptake and assimilation machinery. This could enhance exploitation of nitrogen resources leading to increased growth.
Internal nitrogen-status signalling is poorly understood. However, it is known that amino acids, when exogenously supplied, inhibit the uptake of nitrate. The mechanism for this inhibition has not been identified, but it is likely the result of sensing of internal nitrogen status, the amino acids representing a signal of nitrogen sufficiency, in turn leading to reduced expression and activity of the nitrogen uptake and assimilation machinery. In this thesis I conducted a reverse-genetic screen based on the response of candidate amino acid transporter knock-out mutants to exogenous alanine. In wild-type Arabidopsis, exogenous alanine caused inhibition of vegetative growth, which is accompanied by a reduction in nitrate uptake and transcripts encoding nitrate transporters. In the reverse-genetic growth screen, I identified four mutants with vegetative growth that was insensitive to exogenous alanine. Further characterisation of these mutants revealed that nitrogen uptake was not inhibited and this was accompanied by a lack of repression of nitrate transporter transcripts. Based on this evidence, I concluded that these amino acid transporter mutants were perturbed in nitrogen-status signalling. However, the origin of this signalling perturbation remains unclear. I formulated two hypotheses to explain how four amino acid transporter mutants could have the same signalling phenotype. The first suggested that the four alanine-insensitive transporters could form a functional complex, which is part of the nitrogen-status signalling pathway. The second suggested that the loss-of-function of the amino acid transporter perturbs metabolite levels, in a common way in each mutant, producing a metabolic signature which is sensed downstream of the transporter by an unknown mechanism. The latter hypothesis was tested by extensive metabolite profiling and I could find no evidence in support of the hypothesis. Preliminary investigations were made of the functional-complex hypothesis but technical problems prevented significant progress.

Keywords: plant science nitroge metabolism nitrogen-status sensing
Advisor: Sweetlove, L
Up-down asymmetric tokamaks

Bulk toroidal rotation has proven capable of stabilising both dangerous MHD modes and turbulence. This has allowed existing tokamaks to generate extra fusion power at a fixed size and magnetic field. However, most methods of inducing the plasma to spin do not appear to scale well to larger devices such as ITER or a future power plant. In this thesis, we explore a notable exception: up-down asymmetry in the tokamak magnetic equilibrium. When tokamak flux surfaces are not mirror symmetric about the midplane, turbulence can transport momentum from one surface to the next, creating spontaneous rotation that is "intrinsic" to the geometry. We seek to maximise this intrinsic rotation by finding optimal up-down asymmetric flux surface shapes.
First, we use the ideal MHD model to show that low order external shaping (e.g. elongation) is best for creating up-down asymmetric flux surfaces throughout the device. Then, we calculate realistic up-down asymmetric equilibria for input into nonlinear gyrokinetic turbulence analysis. Analytic gyrokinetics shows that, in the limit of fast shaping effects, a poloidal tilt of the flux surface shaping has little effect on turbulent transport. Since up-down symmetric surfaces do not transport momentum, this invariance to tilt implies that devices with mirror symmetry about any line in the poloidal plane will drive minimal rotation. Accordingly, further analytic investigation suggests that non-mirror symmetric flux surfaces with envelopes created by the beating of fast shaping effects may create significantly stronger momentum transport.
Guided by these analytic results, we carry out local nonlinear gyrokinetic simulations of non-mirror symmetric flux surfaces created with the lowest possible shaping effects. First, we consider tilted elliptical flux surfaces with a Shafranov shift and find little increase in the momentum transport when the effect of the pressure profile on the equilibrium is included. We then simulate flux surfaces with independently-tilted elongation and triangularity. These two-mode configurations show a 60% increase over configurations with just elongation or triangularity. A rough analytic estimate indicates that the optimal two-mode configuration can drive rotation with an on-axis Alfven Mach number of 1.5% in an ITER-like machine.

Keywords: Gyrokinetics
Intrinsic rotation
Advisor: Diaz, F
Molecular mechanisms of immune regulation by the receptors CD5 and CD6

T cells are adaptive immune cells that are essential for initiating and regulating immune responses. T cell activation is triggered by stimulation of the T cell receptor. However, sustained T cell activation requires the function of a variety of coreceptors, among them CD5 and CD6. Both receptors have been shown to have activating and inhibitory functions and modulation of CD6 function is dependent on engagement by its ligand CD166. Costimulatory signalling by CD6 involves a phosphorylation-dependent interaction between the C-terminal Y662 residue and the adaptor protein SLP-76. However, the CD6 cytoplasmic region is one of the longest in the immune system and contains phosphorylated residues which suggests that additional signalling molecules can be recruited.
I identified an interaction of CD5 and CD6 with the cytoskeleton via ezrin, radixin and moesin. This interaction has an activating function on Jurkat cell activation and may play a role in receptor localisation.
I also identified the adapter protein GADS as a binding partner of the CD6 Y629 residue and found evidence for bivalent binding of the GADS/SLP-76 complex to the CD6 C terminus. Costimulation by CD6 is dependent on the recruitment of this complex and mutant CD6 that cannot recruit it does not provide costimulation and may even be inhibitory in the absence of its ligand. These results suggest a model in which costimulation by CD6 depends on cooperative binding of the GADS/SLP-76 complex to two C-terminal phosphotyrosine residues in the CD6 cytoplasmic region. Binding of this complex to CD6 may enhance long-term signalling by keeping GADS/SLP-76 at the membrane or it may provide an alternative signalling pathway that enhances TCR signalling.

Keywords: CD6
TCR signalling
CD5
Advisor: Brown, M
Barclay, N
Models for prebiotically-relevant self-reproducing systems

Autocatalysis is central to the propagation of living systems and is widely agreed to have played a central role in the emergence of life on earth. Chemical systems which self-reproduce like living cells can offer insight into the transition from chemistry to biology. Self-reproducing micelles and vesicles, or physical autocatalysts, are an important class of autocatalytic chemical systems that have used to model the first living systems for several decades.
The study of physical autocatalysis has been restricted to a limited set of reactions, and hindered by experimental difficulties precluding full characterisation. Together these limitations pose both conceptual and technical barriers to a deeper understanding of this important class of prebiotic system. This thesis addresses both limitations in turn.
Chapter 1 introduces the concept of physical autocatalysis and argues for its importance in the field of prebiotic chemistry. A survey of chemical models of physical autocatalysis is presented and the present work is placed into context.
Chapter 2 describes the development of the first examples of physical autocatalysis driven by irreversible bond-forming reactions. Steps towards the development of asymmetric variations and systems of self-reproducing vesicles are discussed.
Chapter 3 describes the application of interferometric scattering microscopy to physical autocatalysis, allowing for the first time the observation of micellar self-reproduction on the single particle level.
Chapter 4 discusses the limitations of this work and argues that the results described in Chapters 2 and 3 respectively address major conceptual and technical barriers to the study of physical autocatalysis, with recommendations for future work.

Keywords: interferometric scattering microscopy
physical autocatalysis
Advisor: Fletcher, S
Wallace, M
Lipschitz geometry and rough paths

Motivated by building a Lipschitz structure on the reachability set of a set of rough differential equations, we study first Lipschitz maps in full detail and in many aspects: we show embedding properties of Lipschitz spaces, study algebraic properties, local versus global behaviour of Lipschitz maps, give a version of the inverse function and the constant rank theorems and analyse flows of Lipschitz vector fields. Along the way, we give quantitative estimates, which is, after all, one of the main strengths of the Lipschitz geometry. Second, we combine our observations on the local properties of rough paths and Lipschitz maps to give a rather flexible structure on manifolds that allow the definition of rough paths on them and explain how the same process can be used to define a notion of coloured paths on manifolds, assuming that one can build a suitable functorial rule. Finally, we make use of those remarks to derive a quantitative condition that endow orbits of vector fields with the structure of a Lipschitz manifold and show, that under this condition, the space of solutions of rough differential equations driven by rough paths is the same as the one we obtain by driving the RDEs with smooth paths.

Keywords: Rough Paths
Advisor: Lyons, T
Multi-parametric MRI techniques for the non-invasive assessment of patients with liver disease

Liver disease is a major worldwide health problem with high prevalence and poor patient outcomes. In the last decade, efforts to improve liver disease severity assessment have led to the development of many non-invasive methods, including magnetic resonance (MR) techniques.
The overarching aim of this thesis was to examine a multi-parametric MR technique in the evaluation of different aspects of liver disease. The MR protocol included T1 and T2&ast; mapping techniques which were used to compute the iron corrected T1 (cT1) and the liver inflammation and fibrosis (LIF) score as measures of liver inflammation and fibrosis.
In healthy volunteers, it was found that premenopausal women had a higher median liver cT1 (784ms) compared to postmenopausal women (741ms; p=0.038) or age matched men (742ms; p=0.005). Furthermore, blood volume was identified as the most significant physiological determinant of liver cT1 and a correction algorithm was developed to compute the "volume adjusted and iron corrected T1" (vacT1), which removes the confounding effect of liver congestion and improves the performance of the test as a biomarker of liver fibrosis.
Against histology, liver cT1 was strongly associated with liver collagen proportionate area, particularly in patients with viral hepatitis (r=0.80; p&LT;0.0001). Furthermore, liver cT1 / LIF had an excellent diagnostic accuracy for the assessment of multiple aspects of non-alcoholic fatty liver disease (NAFLD) with an area under the receiver operating curve of 0.89 for the identification of significant NAFLD.
In the evaluation of portal hypertension, liver cT1 (r=0.49; p=0.038) was associated with the hepatic vein pressure gradient (HVPG), and spleen cT1 was identified as a new biomarker of portal pressure (r=0.66; p&LT;0.0001 vs HVPG). Furthermore, liver cT1 / LIF was shown to be useful in predicting clinical outcomes, with a negative predictive value of 100% for a LIF&LT;2.
Overall, this thesis demonstrated multi-parametric MR to be a robust technique that can assess the whole spectrum of liver disease.

Keywords: liver related end points
collagen proportionate area
MRI
liver fibrosis
non-alcoholic fatty liver disease
portal hypertension
Advisor: Neubauer, S
Barnes, E