VictorJuiz/thesis huggingface dataset:
Regulation of sovereign wealth funds

This thesis analyses the motivations, behaviours and outcomes of Sovereign Wealth Funds (SWFs), and the regulations pertaining to them. The motivation for examining these issues includes the growing role of SWFs as large investors in a wide range of global asset classes, their continued resistance to transparency, and the perceived lack of any unified regulatory framework to cover their activities. We consider the evolving attitudes amongst regulators, SWF officials, and independent analysts and commentators to the current and evolving regulatory environment for SWFs. Regulatory approaches include both mandatory and voluntary measures. Following a review of both the academic literature and other available materials on SWFs, we consider what type of regulation would seem both appropriate and proportionate for SWFs, and we evaluate the significance of the fact that although SWFs operate within frameworks similar to other alternative investment funds, their culture is inherently different.
We conducted fourty-three in-depth interviews, and compared and contrasted the various opinions regarding the current and evolving operation and regulation of SWFs. We followed these up with two country case studies, for Russia and China respectively. For these, we set out the background to their respective SWFs, and discuss the current and evolving state of their investment strategies and of the regulatory environments in which they operate. We consider in particular the extent to which SWFs may be pursuing geopolitical agendas, and on the other hand the degree to which they may be potential contributors to the public good, for example as a stabilising factor during global financial crises. We thus consider the impact on global markets of their investments – and the implications of the degree of transparency and accountability within which they tend to operate; and we explore the case for additional regulation of these entities.
We conclude, firstly, that greater visibility and control of SWFs would be desirable; and secondly, that a range of regulatory approaches and policies might prove appropriate in dealing with what are often rather different SWFs, often reflecting the outlook of their parent state. Thus, the Norwegian SWFs (Government Pension Fund Norway, and the Oil Fund) reflect the transparency favoured by that state; the Russian National Wealth Fund reflects the preference for secrecy inherent in the Russian state; while the activities of the China Investment Corporation match the breadth and high profile favoured by the Chinese state, albeit restricted by the controlling tendencies of the Chinese government.

Advisor: Michie, J
Mathematical modelling of mitotic controls

The mitotic cell cycle is fundamental to eukaryotic life. In mitosis, replicated chromosomes are segregated to form two new nuclei. This is essential to ensure the maintenance of chromosome number between parent and daughter cells. In higher eukaryotes, numerous cytological changes occur to facilitate the separation of the genetic material: the nuclear envelope breaks down, the mitotic spindle assembles, and the cell rounds-up. There is a well-conserved control network that regulates these processes to bring about the entry into mitosis, the separation of the genetic material, and the reversal of these processes during mitotic exit. To build a coherent model of these regulatory networks requires us to write the biochemical reactions in mathematical form.
The work in this Thesis pertains to three fundamental switches: entry into mitosis, the metaphase-to-anaphase transition, and exit from mitosis. I present three studies from a systems-level perspective. The first investigates a novel bistable mechanism controlling mitotic entry/exit in vitro using purified proteins. Dephosphorylation of Greatwall kinase by the phosphatase PP2A-B55 creates a double negative feedback loop that gives a bistable system response with respect to cyclin-dependent kinase 1 (Cdk1) activity. The second looks at hysteresis between mitotic entry and mitotic exit in HeLa cells. Hysteresis persists when either of the regulatory loops of Cdk1 or its counter-acting phosphatase PP2A-B55 is removed, but is diminished when they are both removed. Finally, the regulation of separase in the metaphase-to-anaphase transition is analysed. Separase that is liberated from securin inhibition is isomerised by Pin1 into a conformation that can bind to cyclin B1. This binding peaks after separase has cleaved cohesin and initiated anaphase.

Keywords: Cdk1
Greatwall
PP2A-B55
Separase
Advisor: Novak, B
Cyclic nucleotide signalling in cardiac myocytes from the mdx model of Duchenne muscular dystrophy

Background and Aims: Duchenne muscular dystrophy (DMD), the most frequent muscular dystrophy, is caused by mutations in the dystrophin gene resulting in the absence of dystrophin. Loss of cardiac dystrophin eventually leads to dilated cardiomyopathy and congestive heart failure in at least 20% of patients. Previous studies have shown that inhibition of enzymes that degrade cGMP improves cardiac contractility, energy metabolism and cardiac myocyte integrity in the DMD mouse model mdx. The aim of this project is to explore whether defective cGMP and cAMP signalling is a feature of mdx cardiac myocytes and whether this may play a role in the pathogenesis of the cardiomyopathy associated with dystrophin deficiency.
Methods: Live-cell fluorescent imaging of Fluoresence Resonance Energy Transfer (FRET) has been used to investigate real-time changes in cAMP and cGMP in specific subcellular compartments of neonatal and adult isolated cardiomyocytes. The IonOptix contractility and force transducer system were used to explore the contractile performance and force generation upon contraction in mdx adult cardiomyocytes.
Results: cAMP and cGMP regulation and compartmentalisation seem to be significantly altered in mdx mice cardiomyocytes. The data suggest that the activity of several isoforms of phosphodiesterase and the ability to generate cGMP and cAMP in specific subcellular compartments is altered in neonatal cardiomyocytes (NCM) from the mdx model, indicating that not only the cGMP pathway might underpin the cardiomyopathy associated with DMD but disruption of cAMP signalling may also play a role. Analysis of cyclic nucleotide signalling in adult mdx cardiac myocytes indicated significantly higher levels of oxidised sGC and PDE mRNA levels. Additionally, adult mdx cardiomyocytes presented lower nNOS expression in the PM and in the ER. Basal levels of cyclic nucleotides significantly changed with age, suggesting that compensatory mechanisms may develop with age. Furthermore, mdx cardiomyocytes showed significantly impaired force of contraction which was abolished upon IBMX treatment suggesting that altered PDE activity might underpin defects in contractility.
Conclusions: In summary, the data presented in this thesis supports the hypothesis that defective cyclic nucleotides signalling might play a role in the cardiomyopathy associated with DMD in the mdx.

Advisor: Zaccolo, M
Molecular regulation and function of Gata2 in the programming of haemogenic endothelium

Haematopoietic stem cells (HSCs) maintain the vertebrate blood system throughout life. Exploiting their clinical potential requires a thorough understanding of the natural origins of the HSCs. They first arise from the haemogenic endothelium (HE), located in the main embryonic artery, the dorsal aorta. Our understanding of the genetic mechanisms underlying HE specification remains incomplete, but one of the crucial transcription factors is Gata2.
We found that a conserved enhancer of zebrafish gata2a gene (i4 enhancer) is active in vivo specifically in endothelial cells, including the HE. To unravel the function of gata2a in specifying the HSCs, we have targeted the i4 enhancer with CRISPR/Cas9, generating the first reported genomic deletion of an endogenous cis-regulatory region in zebrafish. Deletion of the i4 enhancer leads to a decrease in endothelial gata2a expression and a concomitant transient decrease in the number of HSCs. This is marked by an early decrease in the expression of gata2b, a gata2a paralogue previously shown to be required for the initiation of the haematopoietic programme. Our results suggest non-redundant roles of both zebrafish gata2 paralogues in programming of HSCs, providing insights into different roles of GATA2 throughout the programming of HSCs.
We also confirmed the previously reported loss of HSCs upon MO-mediated knockdown of lmo4a, associated with increased gata2a expression in HE. We validated the increase in gata2a levels in TALEN-generated lmo4a mutants. To identify the links between lmo4a, gata2a and the HE programming, we have profiled the transcriptome of lmo4a-deficient endothelial cells, including the HE. Our results suggest that Lmo4a may be a global regulator of the transcriptional programming of the HE. Moreover, Wnt signalling pathway may regulate gata2a downstream of lmo4a. This provides novel insights into the gene regulatory network orchestrating the generation of HSCs in the embryo.

Keywords: ATAC-seq
Embryonic development
Haematopoietic stem cells
Haematopoiesis
Zebrafish
CRISPR/Cas9
Advisor: Monteiro, R
Patient, R
Theory of optical transitions in pi-conjugated polymers

Conjugated Polymers have attracted a great deal of research interest in recent years due to their optoelectronic properties which makes them suitable for applications in organic light-emitting devices (OLEDs) and organic photovoltaics. Their properties are strongly dependent on the electron-electron and electron-nuclear interactions as well as the disorder which is present in almost all systems at finite temperatures.
In this thesis the optical properties of electronically neutral conjugated polymers will be investigated. The results obtained are general and applicable to a wide range of parameters. In order to compare these to experiment the optical properties of poly( paraphenylene), poly(para-phenylene vinylene), and derivatives have been calculated. In these polymers the primary photoexcitations are Frenkel excitons which can be described by the Frenkel-Holstein Hamiltonian, which explicitly takes into account the exciton-nuclear coupling. Disorder can be introduced into this model both as diagonal and off-diagonal disorder within the Hamiltonian.
First the optical transitions in ordered, linear conjugated polymers are investigated. It is found that the length of the polymer has a direct spectroscopic signature in the emission spectrum. When off-diagonal disorder is introduced the excitons localise on portions of the chain and the length of these portions, the conjugation length, then shows a clear emission signature. As such, a disordered polymer can be described theoretically as a chain of shorter segments, which define chromophores in a polymer context.
Following from these calculations the role of conformation was investigated and effects were observed that greatly determine the optical properties of non-linear polymers. Most notable the Herzberg-Teller effect, which renders symmetrically forbidden transitions weakly allowed and greatly affects the absorption and emission spectra. The signatures observed in these spectra allow the determination of the (coarse grained) conformation of the polymer, something that has been difficult to measure directly.

Keywords: Frenkel-Holstein Model
Spectroscopy
Conjugated Polymers
Advisor: Barford, W
Aspects of work in quantum thermodynamics

Landauer’s principle states that it costs at least kBT ln 2 of work to reset one bit in the presence of a heat bath at temperature T. The bound of kBT ln 2 is achieved in the unphysical infinite-time limit. Here we consider two different finite-time protocols - one with discretised time and the second in the continuous limit. We prove analytically that the discrete time protocol enables one to reset a bit with a work cost close to kBT ln 2 in a finite time. We construct an explicit protocol that achieves this, which involves thermalising and changing the system’s Hamiltonian so as to avoid quantum coherences. Using concepts and techniques pertaining to single-shot statistical mechanics, we furthermore prove that the heat dissipated is exponentially close to the minimal amount possible not just on average, but guaranteed with high confidence in every run. Moreover we exploit the protocol to design a quantum heat engine that works near the Carnot efficiency in finite time. We further contrast this to a continuous time version of the protocol which is substantially less energy sufficient. We also consider the fluctuations in the work cost, and calculate how their magnitude is suppressed by a factor depending on the length of the protocol.
We demonstrate with an experiment how molecules are a natural test-bed for probing fundamental quantum thermodynamics. Single-molecule spectroscopy has undergone transformative change in the past decade with the advent of techniques permitting individual molecules to be distinguished and probed. By considering the time-resolved emission spectrum of organic molecules as arising from quantum jumps between states, we demonstrate that the quantum Jarzynski equality is satisfied in this set-up. This relates the heat dissipated into the environment to the free energy difference between the initial and final state. We demonstrate also how utilizing the quantum Jarzynski equality allows for the detection of energy shifts within a molecule, beyond the relative shift.

Keywords: Landauer
Fluctuation Relations
Single Shot
Jarzynski
Advisor: Vedral, V
ERAP1 inhibitor development

ERAP1 has been associated with a set of immune-mediated diseases, including ankylosing spondylitis. Currently, there is no selective and potent ERAP1 inhibitor available that would allow in-depth research of its functions and roles in diseases. Therefore, the aim of this work is to apply fragment-based drug design approach for the development of such inhibitor.
A set of 12 structurally diverse hits was identified as a result of a screen containing 1200+ fragments using orthogonal ERAP1 activity assays. These hits can be used as a basis for development of a larger lead inhibitor, which requires structural information about their binding mode to ERAP1. Three different approaches have been tried in order to obtain such information about the binding mode. Unfortunately, ERAP1 crystallisation trials did not succeed, the potential reason being heterogeneity of the protein samples due to presence of several glycoforms. A set of 31 analogues of an IRAP inhibitor, which has been shown to inhibit ERAP1 activity, was synthesised and screened providing valuable structure-activity relationship information. Taken together, the screening campaign has resulted in a novel ERAP1 inhibitor with a single digit micromolar potency against ERAP1.

Advisor: Oppermann, U
Brennan, P
Complex phase space representation of plasma waves: theory and applications

This thesis presents results on the description of plasma waves in terms of wavepackets. The wave field is decomposed into a distribution of wavepackets in a space of position, wavevector, time, and frequency. A complex structure joining each pair of Fourier conjugate variables into a single complex coordinate allows the efficient derivation of equations of motion for the phase space distribution by exploiting its analytic properties. The Wick symbol calculus, a mathematical tool generalizing many convenient properties of the Fourier transform to a local setting, is used to derive new exact phase space equations which maintain full information on the phase of the waves and include effects nonlocal in phase space such as harmonic generation. A general purpose asymptotic expansion of the Wick symbol product formula is used to treat dispersion, refraction, photon acceleration, and ponderomotive forces. Examples studied include the nonlinear Schrödinger equation, mode conversion, and the Vlasov equation. The structure of partially coherent wave fields is understood in terms of zeros in the phase space distribution caused by dislocations in its complex phase which are shown to be correlated with the field entropy. Simulations of plasma heating by crossing electron beams are understood by representing the resulting plasma waves in phase space. The local coherence properties of the beam driven Langmuir waves are studied numerically.

Keywords: Waves
Plasma
Wavepackets
Advisor: Norreys, P
The role of the state in the construction of 'human trafficking' in the UK

The way in which the concept 'human trafficking' has been constructed in the UK (in the words and actions of law enforcement bodies, state-funded NGOs and courts, for example) has changed significantly since the early 2000s. Yet legal and policy definitions of trafficking have remained largely consistent. This is surprising if we expect the state, through instruments like legislation and policy statements, to authoritatively define particular concepts and categories in a way that then shapes how others think and act. This did not happen - at least not straightforwardly - in the case of trafficking. What, then, was the state's contribution to the construction of ‘human trafficking’ in the UK?
To answer that question, this thesis explores the three most significant state interventions relating to trafficking: a 2007 policy statement, a 2009 set of administrative rules and a 2015 piece of legislation. Each had different characteristics and was used in a different way. I argue that the state used these instruments not to authoritatively define 'human trafficking' but to shape already existing or incipient ideas and assumptions about trafficking. The state collated, codified and legitimised certain configurations of ideas and assumptions through the three instruments discussed.
To place the state's activities in context, the thesis also investigates how the state first came to recognise 'human trafficking' as an issue and what influence the concepts and categories shaped by the state went on to have. The former is addressed through identifying the ideas and assumptions that fed into the state’s early efforts and tracing their historical development. The latter is addressed through examining the ways in which actors who are engaged in implementing the concepts and categories shaped by the state have had to adapt their ideas and practices in order to do so.

Advisor: Pirie, F
Hippo tumour suppressor and Hedgehog pathway crosstalk at the primary cilia

Inappropriate activation of the Hedgehog signalling pathway is implicated in broad range of cancers, particularly basal cell carcinoma and medulloblastoma. Recent attempts to target Hedgehog signalling clinically have yielded mixed patient responses, highlighting the need for further study into Hedgehog pathway regulation. Vertebrate Hedgehog signalling occurs within, and is dependent on, the primary cilia. The function of a critical negative regulator of Hedgehog signalling, Suppressor of Fused (Sufu), is regulated by post-translational modification within its intrinsically disordered region, spanning amino acids 279-360. Sufu has previously been shown to be stabilised by phosphorylation at Ser342/Ser346 and Ser352, where S342 phosphorylated Sufu appears to localise to the cilium tip. Here, S342 of Sufu was identified as a potential substrate of the Large Tumour Suppressor (LATS) kinases, LATS1 and LATS2, of the Hippo pathway. This project aimed to determine whether Sufu is regulated by LATS1/2 phosphorylation. LATS1/2 were found to interact with and phosphorylate Sufu at S342. This phosphorylation did not appear to affect the levels of Sufu or of its S352 phosphorylated form, indicating that LATS1/2 does not regulate Sufu stability. Immunofluorescent staining of endogenous Sufu confirmed that Sufu localises to the primary cilium and accumulates at the cilium tip. Reduction of LATS1/2 lead to removal of Sufu from primary cilia, suggesting that S342 phosphorylation of Sufu promotes the ciliary localisation of Sufu. Additionally, S352 phosphorylated Sufu localises to the basal body of primary cilia, confirming that Nek2A phosphorylation of Sufu inhibits its entry into the cilium. Comparison of the mRNA expression of two well-known Hedgehog target genes, GLI1 and PTCH1, between wild type and LATS1/2-/- MEFs revealed that loss of LATS1/2 phosphorylation diminishes the repressive activity of Sufu on Hedgehog target gene transcription in response to Hedgehog pathway activation. Thus, LATS1/2 phosphorylation of Sufu at S342 appears to maintain its ability to repress Hedgehog target gene transcription. This adds to the growing body of literature showing that the Hippo and Hedgehog signalling pathways interact and coordinate to regulate cell proliferation. The data presented here unveils a novel role for LATS1/2 in restricting Hedgehog signalling via Sufu, and highlights the importance of LATS1/2 as tumour suppressors. This may identify LATS1/2 as potential targets in the treatment of Hedgehog signalling-dependent tumorigenesis.

Keywords: Primary Cilia
Hippo pathway
Hedgehog signalling pathway
Advisor: O'Neill, E
D'Angiolella, V
On the use of transport and optimal control methods for Monte Carlo simulation

This thesis explores ideas from transport theory and optimal control to develop novel Monte Carlo methods to perform efficient statistical computation.
The first project considers the problem of constructing a transport map between two given probability measures. In the Bayesian formalism, this approach is natural when one introduces a curve of probability measures connecting the prior to posterior by tempering the likelihood function. The main idea is to move samples from the prior using an ordinary differential equation (ODE), constructed by solving the Liouville partial differential equation (PDE) which governs the time evolution of measures along the curve. In this work, we first study the regularity solutions of Liouville equation should satisfy to guarantee validity of this construction. We place an emphasis on understanding these issues as it explains the difficulties associated with solutions that have been previously reported. After ensuring that the flow transport problem is well-defined, we give a constructive solution. However, this result is only formal as the representation is given in terms of integrals which are intractable. For computational tractability, we proposed a novel approximation of the PDE which yields an ODE whose drift depends on the full conditional distributions of the intermediate distributions. Even when the ODE is time-discretized and the full conditional distributions are approximated numerically, the resulting distribution of mapped samples can be evaluated and used as a proposal within Markov chain Monte Carlo and sequential Monte Carlo (SMC) schemes. We then illustrate experimentally that the resulting algorithm can outperform state-of-the-art SMC methods at a fixed computational complexity.
The second project aims to exploit ideas from optimal control to design more efficient SMC methods. The key idea is to control the proposal distribution induced by a time-discretized Langevin dynamics so as to minimize the Kullback-Leibler divergence of the extended target distribution from the proposal. The optimal value functions of the resulting optimal control problem can then be approximated using algorithms developed in the approximate dynamic programming (ADP) literature. We introduce a novel iterative scheme to perform ADP, provide a theoretical analysis of the proposed algorithm and demonstrate that the latter can provide significant gains over state-of-the-art methods at a fixed computational complexity.

Keywords: Monte Carlo
Markov chain Monte Carlo
Normalizing constants
Sequential Monte Carlo
Optimal control
Annealed importance sampling
Mass transport
Reinforcement learning
Approximate dynamic programming
Advisor: Doucet, A