VictorJuiz/thesis huggingface dataset:
The role of ATF4 in hypoxia-induced cell death in cancer

Cancer cells survive the harsh oxygen and nutrient deprivation of the tumour microenvironment through the selection of apoptosis-resistant and glycolytic clones (Cairns et al., 2011; Graeber et al., 1996). In particular, the integrated stress response (ISR) has been shown to be pivotal in cancer cell survival in vivo and the resistance of cancer cells to therapy (Harding et al., 2003). In recent years, it has become apparent that increased autophagy is one mechanism by which the ISR can confer resistance to stress (Kroemer et al., 2010).
ATF4 is a major transcriptional effector of the integrated stress response in severe hypoxia (<0.01% O₂). ATF4 is a well-established regulator of genes involved in oxidative stress, amino acid synthesis and uptake, lipid metabolism, protein folding, metastasis, and angiogenesis. Recent work has demonstrated an important role of ATF4 in promoting resistance to severe hypoxia through the transcriptional upregulation of MAP1LC3B and ATG5, essential components of the autophagy machinery (Rouschop et al., 2009b; Rzyski et al., 2010).
In this work, the author describes several novel ATF4 target genes, and examines their role in the regulation of autophagy and the resistance of cancer cells to severe hypoxia. In the first part of this thesis, the author shows that three BH3-only members of the BCL-2 family of proteins--HRK, PUMA, and NOXA--are upregulated in response to severe hypoxia in an ATF4-dependent manner. In particular, the author shows that the poorly described BH3-only protein HRK is a direct target of transcriptional activation by ATF4, and that HRK induces autophagy in severe hypoxia, thereby providing the first evidence that the integrated stress response can transcriptionally trigger the autophagy process. In contrast to the previously described role of HRK in apoptosis, this thesis demonstrates that HRK can play a pro-survival role in the context of breast cancer cells.
In the latter part of this thesis, the author identifies the essential autophagy gene ULK1 as an ISR target. The author shows that ULK1 expression in severe hypoxia is transcriptionally upregulated through direct activation by ATF4. The author identifies ULK1 as a crucial regulator of autophagy and mitophagy in both normoxia and severe hypoxia and shows that ULK1 plays a pivotal role in cancer cell survival. Furthermore, it is shown that human breast cancer patients with high levels of ULK1 relapse earlier than those with low levels of ULK1, thereby identifying ULK1 as a potential target for cancer therapy.

Keywords: integrated stress response
ULK1
unfolded protein response
HRK
hypoxia
ATF4
Advisor: Harris, A
Mathematical approaches to modelling healing of full thickness circular skin wounds

Wound healing is a complex process, in which a sequence of interrelated events at both the cell and tissue levels interact and contribute to the reduction in wound size. For diabetic patients, many of these processes are compromised, so that wound healing slows down and in some cases halts. In this thesis we develop a series of increasingly detailed mathematical models to describe and investigate healing of full thickness skin wounds.
We begin by developing a time-dependent ordinary differential equation model. This phenomenological model focusses on the main processes contributing to closure of a full thickness wound: proliferation in the epidermis and growth and contraction in the dermis. Model simulations suggest that the relative contributions of growth and contraction to healing of the dermis are altered in diabetic wounds.
We investigate further the balance between growth and contraction by developing a more detailed, spatially-resolved model using continuum mechanics. Due to the initial large retraction of the wound edge upon injury, we adopt a non-linear elastic framework. Morphoelasticity theory is applied, with the total deformation of the material decomposed into an addition of mass and an elastic response. We use the model to investigate how interactions between growth and stress influence dermal wound healing. The model reveals that contraction alone generates unrealistically high tension in the dermal tissue and, hence, volumetric growth must contribute to healing. We show that, in the simplified case of homogeneous growth, the tissue must grow anisotropically in order to reduce the size of the wound and we postulate mechanosensitive growth laws consistent with this result. After closure the surrounding tissue remodels, returning to its residually stressed state. We identify the steady state growth profile associated with this remodelled state. The model is used to predict the outcome of rewounding experiments as a method of quantifying the amount of stress in the tissue and the application of pressure treatments to control tissue synthesis.
The thesis concludes with an extension to the spatially-resolved mechanical model to account for the effects of the biochemical environment. Partial differential equations describing the dynamics of fibroblasts and a regulating growth factor are coupled to equations for the tissue mechanics, described in the morphoelastic framework. By accounting for biomechanical and biochemical stimuli the model allows us to formulate mechanistic laws for growth and contraction. We explore how disruption of mechanical and chemical feedback can lead to abnormal wound healing and use the model to identify specific treatments for normalising healing in these cases.

Keywords: finite elasticity
epidermis
contraction
dermis
growth
wound healing
Advisor: Byrne, H
Maini, P
Moulton, D
Exploring and exploiting selectivity in Rhodium-catalysed hydroacylation reactions

Chapter 1 is an overview of the key developments in rhodium-catalysed hydroacylation. The main focus of this chapter is the use of various chelation strategies for the stabilisation of key rhodium-acyl intermediates. In addition, the more recent emergence of regioselective hydroacylation processes has been highlighted.
Chapter 2 discloses the branched-selective intermolecular hydroacylation of 1,3-dienes and S-chelating aldehydes to afford synthetically useful 1,5-dione products. The evaluation of a number of different phosphine ligands for this process identifies a correlation between ligand bite angle and reaction regioselectivity.
Chapter 3 discusses the development of a linear-selective hydroacylation process for previously challenging alkyne substrates. This, in combination with a complementary branched-selective process, provides a ligand-controlled regioselectivity switch between the branched and linear pathways.
Finally, Chapter 4 details efforts towards the development of multicomponent, tandem processes through exploitation of our synthetically useful branched hydroacylation adducts.

Keywords: selectivity
hydroacylation
catalysis
regioselectivity
rhodium
Advisor: Willis, M
The missile design bureaux and Soviet manned space policy, 1953-1970

The Soviet manned space programme is one of the most impressive and mysterious legacies of the Soviet Union. Evidence that has come to light since 1989 throws considerable doubt on earlier Western understanding of the Soviet space effort. One of the more puzzling aspects of the new data is the claim that the Chief Designers of several missile design bureaux played a pivotal role in the making of Soviet manned space policy. This claim contradicts much of what was thought to be known about the Soviet space programme, their research and development system, and Soviet politics generally.
This dissertation is an empirical study that seeks to answer four interrelated questions. 1. What major manned space projects did the Soviet Union engage in during the 1960s, and how were these projects authorised? 2. Did the Chief Designers play an influential role in the promotion, selection, approval, and implementation of these projects? 3. What were the overall objectives and purposes of the Soviet manned space programme? 4. What does the example of Soviet space policy tell us about the Soviet political system?
The examination of institutions, individuals, and the policymaking process has led to the following conclusions. The Soviet manned space programme was an extremely limited state undertaking until 1964. Prior to Khrushchev's ouster, the Soviet Union began several manned lunar space programmes designed to upstage the US Apollo moon landing effort. When all of these efforts failed by 1969, Soviet manned space policy was re-directed toward orbital space stations. One Chief Designer, Sergei Pavlovich Korolev, played a central role in establishing the Soviet manned space programme. However, the ability Chief Designers to influence space policy was systematically restricted after 1960. The manned space programme was essentially a political programme. Throughout the 1960s, it was effectively controlled by a handful of top party leaders to achieve their domestic and international political objectives.
On wide dynamic range logarithmic CMOS image sensors

Logarithmic sensors are capable of capturing the wide dynamic range of intensities available in nature with minimum number of bits and post-processing required. A simple circuit able to perform logarithmic capture is one utilising a MOS device in weak inversion. However, the output of this pixel is crippled due to fixed pattern noise. Technique proposed to reduce this noise fail to produce high quality images on account of unaccounted high gain variations in the pixel. An electronic calibration technique is proposed which is capable of reducing both multiplicative as well as additive FPN. Contrast properties matching that of human eye are reported from these sensors.
With reduced FPN, the pixel performance at low intensities becomes concerning. In these regions, the high leakage current of the CMOS process affects the logarithmic pixel. To reduce this current, two different techniques using a modified circuit and another with modified layout are tested. The layout technique is observed to reduce the leakage current. In addition, this layout can be used to linearise the output of logarithmic pixel in low light regions.
The unique linear response at low light and logarithmic pixel at high light is further investigated. A new model based on the device physics is derived to represent this response. The fixed pattern noise profile is also investigated. An intelligent iterative scheme is proposed and verified to extract the photocurrent flowing in the pixel and correct the fixed pattern noise utilising the new model. Future research ideas leading to better designs of logarithmic pixels and post-processing of these signals are proposed at the end of the thesis.

Keywords: logarithmic
calibration
CMOS
fixed pattern noise
analogue
image sensor
contrast threshold
dark current
VLSI
subthreshold
Advisor: Collins, S
Where there is no evidence, and where evidence is not enough: an analysis of policy-making to reduce the prevalence of Australian indigenous smoking

Background: Evidence-based policy making (EBPM) has become an article of faith. While critiques have begun to emerge, they are predominately based on theory or opinion. This thesis uses the 2008 case study of tobacco control policy making for Indigenous Australians to analyse empirically the concept of EBPM.
Research questions: (1) How, if at all, did the Government use evidence in Indigenous tobacco control policy making? (2) What were the facilitators of and barriers to the use of evidence? (3) Does the case study augment or challenge the apparent inviolability of EBPM?
Methods: Data were collected through: (1) a review of primary documents largely obtained under the Freedom of Information Act 1982; and (2) interviews with senior politicians, senior bureaucrats, government advisors, Indigenous health advocates and academics.
Results: Historically, Indigenous smoking was not problematised because Indigenous people faced other urgent health/social problems and smoking was considered a coping mechanism. High prevalence data acquired salience in 2007/08 in the context of a campaign to reduce disparities between Indigenous and non-Indigenous health outcomes. Ensuing policy proposals were based on recommendations from literature reviews, but evidence contained in those reviews was weak; notwithstanding this, the proposals were adopted. Historical experiences led policy makers to give special weight to proposals supported by Indigenous stakeholders. Moreover, the perceived urgency of the problem was cited to justify a trial-and-evaluate approach.
Conclusion: While the policies were not based on quality evidence, their formulation/adoption was neither irrational nor reckless. Rather, the process was a justifiable response to a pressing problem affecting a population for which barriers existed to data collection, and historical experiences meant that evidence was not the only determinant of policy success. The thesis proposes a more nuanced appraoch to conceptualising EBPM wherein evidence is neither a necessary nor a sufficient condition for policy. The approach recognises that rigorous evidence is always desirable but that, where circumstances affect the ability of such research being conducted, consideration must be given to acting on the basis of other knowledge (e.g. expert opinion, small-scale studies). Such an approach is justifiable where: (1) inaction is likely to lead to new/continued harm; and (2) there is little/no prospect of the intervention causing additional harm. Under this approach, non-evidentiary considerations (e.g. community acceptability) must be taken into account.

Keywords: Aboriginal - Australia - Policy making - Evidence - Evidence-based policy - Smoking cessation
Advisor: Fitzpatrick, R
Rayner, M
Allender, S
Use of genome wide expression profiles in analysis of T cell dysfunction in Hepatitis C virus infection

During the course of infection with chronic pathogens such as Hepatitis C virus (HCV), Hepatitis B virus (HBV) and HIV, virus-specific CD8&plus; T cells differentiate into heterogeneous dysfunctional subpopulations. Advances in multi-parameter flow cytometry have allowed these subpopulations to be further classified into classes of exhausted T cells, primarily by their expression of multiple inhibitory receptors. However, the exact phenotype of CD8&plus; T cells during exhaustion is an area of great interest as many inhibitory receptors are also expressed on functional CD8&plus; T cells. Discovering novel and specific markers of T cell exhaustion is fundamental in developing strategies to restore CD8&plus; T cell function in chronic viral infections. Recently, genome wide expression profiles have identified broad molecular phenotypes in exhausted T cells that could not have been discovered by flow cytometry alone. I show how similar genomic approaches identify and further characterise the ectonucleotidase CD39 as a novel marker of CD8&plus; T cell exhaustion in chronic viral infection. I show that CD39 is highly expressed in HCV and HIV-specific CD8&plus; T cells and that CD39&plus; CD8&plus; T cells are enriched with gene signatures of exhaustion. CD39 is highly co-expressed with multiple inhibitory receptors including PD-1, enzymatically active on CD8&plus; T cells in HCV infection and positively correlated with viral load in both HCV and HIV. I also demonstrate the discovery of a novel CD39High population of cells in the mouse model of chronic Lymphocytic Choriomenigitis Virus (LCMV) infection, which express the highest degrees of PD-1, LAG3 and 2B4 in the CD39&plus; fraction. Thus, CD39 is a novel and specific marker of severe CD8&plus; T cell exhaustion in human and animal models of chronic viral infection.

Keywords: T cell exhaustion
Hepatitis C
Genomics
Advisor: Klenerman, P
Haining, W
Topics in BSM physics: supersymmetry, dark matter and baryogenesis

Under the umbrella of Theoretical Physics, progress in ‘Beyond the Standard Model’ (BSM) physics proceeds broadly along two main avenues of investigation. The first is concerned with constructing theories that attempt to explain observations, or address theoretical problems, which cannot be explained within the tremendously successful Standard Model (SM) of particle physics. The second involves looking for new ways to observe or test BSM physics, and such tests are usually developed with current experimental hints, or attractive theoretical models, in mind. This thesis contains material which falls under both approaches.
Part I is concerned with Supersymmetry (SUSY). We review the basics of SUSY, and the current state of this field, and then present a novel model for SUSY at the TeV scale. This model has a Higgs sector similar to the SM and possesses a continuous U(1)R symmetry, dramatically suppressing contributions to flavour-changing neutral currents, which can be problematic in SUSY models. After this we demonstrate that if more than one SUSY-breaking sector is present then this could lead to a rich spectrum of states with mass roughly twice the gravitino mass. In particular, if SUSY-breaking in a hidden sector arises dynamically then multiple ‘Goldstini’ and ‘Modulini’ states can arise, which couple to visible sector fields via the ‘Goldstino Portal’. We also demonstrate a new phenomenon which can occur in the context of multiple hidden sectors. If one sector breaks SUSY then this can ‘stimulate’ other sectors into also breaking SUSY, even if they are incapable of doing so on their own.
Part II focusses on the matter in our Universe. We review our current understand- ing of how the visible matter in our Universe came into existence, and our current understanding of the nature of dark matter (DM). Following this we describe how DM could potentially be indirectly observed through its effects on cold white dwarf stars. Alternatively, if DM were detected by independent means, then observed cold white dwarfs could be used to place limits on the DM density in globular clusters, giving clues as to how these clusters of stars formed. We then present a new model for the co-generation of both the visible and dark matter in our Universe. This proceeds by generating a particle anti-particle asymmetry in the dark sector, which is then shared with the visible sector. This model predicts the existence of a light, m ≲ 5 eV, scalar particle which derivatively couples to DM, and provides a final state for the symmetric DM component to annihilate away into.
Work completed during the period of this D.Phil is contained in [1–8], however only material in [3–6, 8] is presented in this thesis.

Keywords: supersymmetry
dark matter
Advisor: March-Russell, J
Competition and cooperation in host-associated microbial communities: insights from computational and mathematical models

Our bodies contain a vast number and diversity of microbes. These microbes interact, and these interactions can define how microbes affect us. Microbial ecology and evolution, therefore, are important for both microbiology and human health. However, our understanding of microbial communities remains limited. There is a need for theory that dissects the complexity and identifies the key factors and processes affecting microbial groups. Here I develop realistic computer simulations and population models of microbial communities. My first project seeks to explain microbial communication (quorum sensing) and argues that quorum sensing is a way to infer when competing genotypes are no longer a threat. The second project proposes an evolutionary explanation for another major microbial trait: adhesion. I argue that adhesion is a weapon allowing cells to compete within microbial groups and push competitors out, particularly when growing on a host epithelium. The third project moves from microbes to the host and asks whether a host can control which microbes grow and persist inside it. I develop a model of the human gut epithelium and show that the gut architecture amplifies the ability of hosts to select helpful microbes over harmful ones using nutrient secretion. In addition to selecting particular microbial strains, a host will also benefit from stable symbiotic communities that behave in a predictable manner. But what determines whether host-associated communities are ecologically stable? My final project uses ecological network theory to show that ecological stability is likely to be a problem for gut communities that are diverse and contain species that cooperate with each other. However, I argue that the host should function as an ecosystem engineer that increases ecological stability by weakening the strong dependence of cooperating species upon one another. While host-associated communities are complex ecological systems, my thesis identifies key factors that affect their form and function.

Keywords: systems biology
mathematical biology
evolution
computational biology
ecology
Advisor: Foster, K
The morality of common sense: problems from Sidgwick

Much modern moral philosophy has conceived of its interpretative and critical aims in relation to an entity it sometimes terms 'common-sense morality'. The term was influentially used in something like its canonical sense by Henry Sidgwick in his classic work The Methods of Ethics (1874). Sidgwick conceived of common-sense morality as a more-or-less determinate body of current moral opinion, and traced his ('doxastic') conception through Kant back to Aristotle's Nicomachean Ethics and the practice of Plato's Socrates before him. The Introduction to this thesis traces the influence of Sidgwick's conception both on subsequent (mis)understandings of Socratic practice as well as on the practice of moral philosophy in the twentieth century.
The first essay offers a challenge to Sidgwick's understanding of Socratic practice. I argue that Socrates' questioning of his interlocutors, far from revealing some determinate body of pre-existing beliefs, is in fact a demonstration of the dynamic and partially indeterminate quality of common-sense morality. The value for the interlocutor of engaging in such conversation with Socrates consisted primarily in its forcing him to adopt what I term a deliberative stance with respect to his own practice and dispositions, asking himself not 'what is it that I believe?' but rather, 'what am I to believe?' This understanding of Socratic practice gives us a way of reconciling the often puzzling combination of conservative and radical elements in Plato's dialogues.
The second essay is a discussion of the reception of Sidgwick's conception of ethics in twentieth-century Oxford, a hegemonic centre of Anglophone philosophy. This recent tradition consists both of figures who accepted Sidgwick's picture of moral philosophy's aims and those who rejected it. Of the critics, I am centrally concerned with Bernard Williams, whose life's work, I argue, can be fruitfully understood as the elaboration of a heterodox understanding of Socratic practice, opposed to Sidgwick's. Ethics, on this conception, is a project directed at the emancipation of our moral experience from the many distortions to which it is vulnerable. Williams's writings in moral philosophy, disparate and not entirely systematic, are unified by these emancipatory aims, aims they share with strains of psychoanalysis except in that they do not scorn philosophical argument as a tool of emancipation: in this respect among others, I claim, they are fundamentally Socratic.

Keywords: morality
common sense
plato
bernard williams
socrates
henry sidgwick
Advisor: Crisp, R
Irwin, T