VictorJuiz/thesis huggingface dataset:
Investigating strategies to modify PARP14 function through macrodomain inhibition

Macrodomains are conserved protein interaction modules that are present in all domains of life and mediate recognition of sequence motifs harbouring adenosine diphosphate ribose (ADPR) modifications. In addition, some of them are able to control the turnover of ADPR signalling through their catalytic activity removing these modifications. Macrodomains are hence implicated in a variety of cellular processes as well as in diseases including cancer and viral pathogenesis. The polyadenosine-diphosphate-ribose polymerase (PARP) family member PARP14 is one of twelve human macrodomain-containing proteins; it contains three macrodomains in addition to its catalytic PARP domain. PARP14 was shown to be involved in several cellular processes linked to cancer development in for example B-cell lymphoma and hepatocellular carcinoma. Therefore PARP14 including its macrodomains has emerged as a potential therapeutic target. However, the lack of specific small molecule inhibitors has hampered domain-specific target validation studies so far. Current approaches focus on inhibitor development for its PARP domain, yet attaining selectivity of these inhibitors over other PARP enzymes has been challenging.
The aim of the work described in this thesis was therefore to evaluate the possibility of targeting PARP14 via inhibition of its macrodomains with small molecule inhibitors as an alternative to PARP domain inhibition. These studies revealed that displacing PARP14 from its target sites requires inhibitor development for both its second and third macrodomain. Druggability of both macrodomains has been demonstrated by the highly selective allosteric macrodomain 2 inhibitor GeA-69 and by several fragment hits targeting the ADPR binding site of macrodomain 3. Finally, PARP14 was confirmed to be implicated in DNA repair mechanisms protecting cells against replication stress, suggesting that a dual PARP14 macrodomain inhibitor may provide the possibility to potentiate genotoxic chemotherapy for cancer treatment.

Advisor: Knapp, S
Kessler, B
One startup's dream: an ethnography of a vision

This is the story of how four people invented a whole new world and way of life—and how they attempted to establish it across the globe. Copass, a Parisian startup consisting of four cofounders, aimed to connect hundreds of the world’s shared workspaces under their new global federation. But the main objective of this startup, in contrast to most, was not to build capital. It was to build a universe: a future where white-collar workers would be liberated from the shackles of office life to work anywhere in the world, to meet exciting people and to have amazing experiences. Here, workdays were permanently mixed with holidays. Work was fun, workplaces were play-places and workers were adventurers. The ambition of these four cofounders was to turn the way they wanted things to be for them into the way things ought to be for everyone else. To turn their desired lifestyle into a global social movement that enrolled, as they saw it, hundreds of cities and thousands, tens of thousands, even millions of people. In short, they created a company to fulfil a dream. This is an ethnography of that one startup’s dream, analysed at length to demonstrate innovative ways of worldmaking employed by an ambitious tech company seeking success. A company dissatisfied with the world that, instead of changing it, decided to create a new one.

Keywords: digital nomads
coworking spaces
ethnography
startups
paris
flexible work
coworking
worldmaking
startup
france
ethnomethodology
digital anthropology
marketing
western europe
entrepreneurship
workplace studies
digital nomadism
Advisor: Zeitlyn, D
Essays on labor market dynamics with worker heterogeneity

This thesis is comprised of three chapters which discuss topics related to labor market dynamics from a macroeconomic perspective. Although each chapter is self-standing in terms of research question and methodology, they are united by a common interest for the macroeconomic implications of worker heterogeneity. The chapters vary with respect to the time horizon over which they study aggregate dynamics, covering business cycle frequency, the economy's long run steady state, and households' life cycle. Furthermore, they develop the concept of heterogeneity across different dimensions: stages of the life cycle, households' income and wealth, observed worker characteristics, and worker-firm productivity levels. The overall purpose of this thesis is therefore to contribute to the study of labor markets and labor policies through a multi-faceted approach.

Keywords: Life cycle models
Labor economics
Search and matching models
Advisor: Zanetti, F
Rousakis, M
Judges, social rules and the Constitution: an empirical inquiry into the foundations of South African law

This thesis examines whether HLA Hart’s theory of the nature of law has explanatory power for the South African legal system. The thesis discusses and elaborates on the empirical conditions necessary for the existence of the master rule of recognition that Hart posits as the foundation of every legal system properly so-called, and addresses certain difficulties associated with attempts to apply Hart’s theory to the concrete facts of any particular legal system. Drawing on a series of in-depth interviews with 12 past and present Justices of the Constitutional Court of South Africa, the thesis then explores whether the existence conditions for a Hartian rule of recognition can be observed in the practices and attitudes of the Justices, insofar as these relate to their judicial decision-making processes. The thesis concludes that many such existence conditions are absent from the Justices’ practices and attitudes: (i) the Justices do not appear to converge in their ultimate criteria of legal validity; (ii) the Justices do not perceive a common standard of judicial decision-making amongst their colleagues, but rather see fundamental differences; (iii) at least partly on account of their strong sense of judicial independence, the Justices are unconcerned with the kind of official criticism that is essential to motivate conformity to a Hartian rule of recognition; and (iv) the Justices celebrate, rather than condemn, decision-making processes that depart from their own. The thesis concludes that these findings provide strong prima facie evidence that Hart’s theory lacks explanatory power for the South African legal system. It also reflects on the implications of its findings for Hart’s theory more generally, and for the project of analytic legal philosophy as it is now conceived by its most prominent advocates.

Advisor: Galligan, D
Landscape and connections: petroglyphs of the Altai in the 2nd and 1st Millennium BCE

This thesis presents a holistic study of connections in the Altai Mountains of the eastern Eurasian Steppe, as shown by rock-art. Currently divided by four countries, pecked images (petroglyphs) and painted images from the 2nd–1st millennium BCE have been subjected to very separate research traditions, exacerbated by language barriers. This thesis focusses on the entire Altai Mountain range as a study area, integrating research published in Chinese and Russian, with supplementary literature in Kazakh and Mongolian consulted.
To demonstrate the potential for connectivity and, consequently, movement, a map of accessibility was generated, showing that there are various optimal routes for movement throughout the Altai. The locations of rock-art sites relative to these routes indicate that movement was a key feature contributing to the creation of rock-art. Examining topographic features in the vicinity of rock-art sites of three regions (Mongolia, Russia, PRC) highlighted an association between watercourses and sites, whilst studying the micro-landscape within panels found that the creators of rock-art were not representing the tangible spatial relationship of figures to the landscape. More broadly, similarities between motifs at rock-art sites, as well as on portable art, demonstrate that the people making them, regardless of whether they were aware of it or not, were part of a wider understanding of how to depict subjects. Evidence of this understanding can be found even in regions with very different cultural backgrounds to the Steppe, such as the Chinese Central Plains, demonstrating that groups outside of the Steppe were aware of and using this way of representing. By combining analysis of motifs with that of the landscape, this thesis demonstrates that rock-art as a practice was inherently linked with to the landscape, whereas content and style are more indicative of a wide-ranging belief system amongst Steppe pastoralists, which was expressed aesthetically.

Keywords: 1st millennium BCE
Mongolia
Connections
ArcGIS
Xinjiang
Landscape
Altai Republic
Altai
GIS
2nd millennium BCE
Northern China
Advisor: Rawson, J
Nimura, C
Investigations into the regulation of subventricular zone neuroblast migration by protein kinases

The subventricular zone (SVZ) of the mammalian brain serves as one of only two sources of adult born neurons. Adult born neural progenitors – known as neuroblasts – acquire the ability to migrate and travel large distances to their destination in the olfactory bulb. Disruption of neuroblast migration is associated with learning and memory deficiencies and, following injury, neuroblasts are re-routed to promote neurodegeneration. While a lot of research has attended to augmenting the production and survival of neuroblasts, the body of evidence for pharmacological targets or compounds that promote migration is comparatively sparse.
This thesis set out to identify novel strategies to modulate neuroblast migration for brain repair by studying proteins known to modulate migration and identifying new ones through compound screening.
Firstly, an explant migration assay from the mouse SVZ was used to investigate the potential to use growth factors to stimulate neuroblast migration. This confirmed that that insulin-like growth factor 1 (IGF1) and IGF2 regulate neuroblast migration, as previously reported by other research groups. The role of IGF2 is investigated further using a mouse model in which the binding of IGF2 to IGF2R is disrupted, resulting in increased proliferation in the embryonic cortical SVZ, brain overgrowth and perinatal lethality.
In the second half of this thesis I try to tackle one of the major bottlenecks limiting the search in for pharmaceutical interventions targeting neuroblast recruitment: the lack of high-fidelity in vitro migration assays. Drawing concepts from existing in vitro migration assays and cerebral organoid models, I developed a novel neuroblast spheroid migration assays that permits the investigation of large numbers of interventions, concurrently, in 3 dimensions.
Using the spheroid assay I successfully screened 1012 small molecule kinase inhibitors for their effects on neuroblast migration. Several compounds were identified that significantly increased or decreased neuroblast migration. Two genes: MUSK and PIK3CB were selected from the screen as putative biological targets and genetic knockdown of these genes validated that interruption of their activity increased neuroblast migration. In the future these compounds could be studied further to explore their potential for augmenting the recruitments of new neurons to sites of injury so support neuroregeneration, or for decreasing invasion of brain malignancies.

Keywords: Migration
Kinase
Regeneration
Subventicular Zone
Neurogenesis
Advisor: Szele, F
Waters, S
Macroautophagy, alpha-synuclein and dopamine neurotransmission: implications for Parkinson’s disease

Parkinson’s disease (PD) is an incurable neurological disease characterised by impairment of motor function, death of substantia nigra pars compacta (SNc) dopamine (DA) neurons and accumulation of the protein α-synuclein. Macroautophagy, a major process by which deleterious cellular contents are degraded, is implicated in both sporadic and genetic PD, and macroautophagy inducers are currently in PD clinical trials. However, little is known about the interaction between α-synuclein and macroautophagy in vivo.
In this thesis, the interaction between impaired macroautophagy in DA neurons and α-synuclein was studied by generating novel transgenic mice. Mice were bred featuring conditional knockout of ATG7, a gene essential for macroautophagy, in DA neurons (ATG7cKODAT-IRES-cre), and expressing the full-length human α-synuclein gene (hSNCA). Mice carrying the ATG7cKODAT-IRES-cre genotype developed key features of PD, including loss of SNc DA neurons, reductions in caudate-putamen DA and the development of protein aggregates in DA neurons. Presence of the hSNCA gene had minimal effect on histological phenotypes. Paradoxically, ATG7cKODAT-IRES-cre mice displayed improvements in some elements of motor function, including increased locomotion, increased gait swing speed and improved motor coordination in old age. There was no effect of the hSNCA gene on behavioural phenotypes.
In order to determine a physiological basis for the discrepancy between the neuropathological and motor phenotypes associated with the ATG7cKODAT-IRES-cre genotype, DA neurotransmission was examined using fast-scan cyclic voltammetry (FCV). FCV demonstrated that the ATG7cKODAT-IRES-cre genotype increased evoked DA levels, reduced the rate of DA reuptake, and increased evoked DA in response to repeated stimuli. The finding that impaired macroautophagy in DA neurons enhances DA neurotransmission was confirmed in a second transgenic mouse model. These data demonstrating that impaired macroautophagy enhances dopamine neurotransmission, thus improving behavioural phenotypes while worsening some pathological phenotypes, has direct implications for PD pathogenesis, drug discovery and clinical trials.

Keywords: Parkinson's disease
Autophagy
Neurology
Advisor: Cragg, S
Wade-Martins, R
Zhao Ziyang and the elite politics of the People's Republic of China, 1980–1989

This doctoral dissertation examines the history of the elite politics of the People's Republic of China (PRC) in the crucial period 1980–1989 by centering on Zhao Ziyang (1919–2005), who served as Premier of the State Council (1980–1987) and then as General Secretary of the Chinese Communist Party (1987–1989) before his purge, house arrest, and official erasure. Using newly available, exceptionally rich primary source material, this dissertation analyzes Zhao's roles and the complex dynamics of his time in Beijing and engages in a substantial scholarly reappraisal of the elite politics and economic reform policies of the transformational decade of the 1980s. Drawing on new insights into the political, economic, and ideological debates of the 1980s, this dissertation deepens scholarly assessments of the politics of economic reform by arguing that the specific reform agenda that China pursued and which has been ascribed to Deng Xiaoping was, to a far greater degree than the dominant historical writing has acknowledged, the product of Zhao's vision and policymaking. His erasure has led to a major distortion of both scholarly and popular narratives of China's post-Mao development of “reform and opening” policies. On wide-ranging fronts as diverse as urban and industrial reforms, science and technology policy, and adjustments to China's governing formulations and ideology, Zhao must be restored to the center of the narrative. The dynamics of Zhao's time in power demonstrate that numerous different possibilities for China's development remained open throughout the decade and were contested as the leadership determined China's path through a process of policy development and competition in which ideas and individuals competed for influence. This dissertation concludes that despite Zhao's status as a historical non-person, both his actual historical role and his erasure by the CCP remain at the heart of enduring questions about China's future.

Advisor: Mitter, R
The Characterisation of root exudation and colonisation in the rhizosphere of land plants

The rhizosphere of land plants is a diverse and complex environment that is critical to the life cycles of plants. Plants release photosynthetically fixed carbon into the rhizosphere that can act to solubilise nutrients, detoxify metals, and modify soil microbial communities. Within these soil microbial communities a diverse range of microbes exist, ranging from the beneficial plant growth promoting rhizobacteria to plant pathogens. These microbes must be able to effectively colonise the rhizosphere and plant rooting systems for their survival. To study root exudation and the bacterial colonisation of the roots two separate techniques were used.
To study the spatial and temporal release of exudation in Oryza sativa, Zea mays, Arabidopsis thaliana, and Marchantia polymorpha, luciferase based bioreporters, which respond to plant derived carbon were used. These bioreporters based in Rhizobium leguminosarum allowed for the production of maps showing the spatial nature of exudation from plant roots, alongside changes in exudation temporally. In this work I showed that the release of the C4-Dicarboxylic acids was conserved across all plant species tested. Moreover, the release of these exudates occurred on specific rooting structures, such as lateral roots, and not across the whole rooting system. This work has shown that R. leguminosarum based bioreporters can be flexibly used across a range of different plant species.
For studying the genetic basis of Azorhizobium caulinodans colonisation of the O. sativa rhizosphere, a technique known as insertion sequencing was used. This technique highlighted bacterial genes involved in rhizosphere and root colonising growth. Using these data, several interesting gene operons were identified that played a crucial role in rhizosphere growth. One example was a putative propionate catabolism operon, indicating that A. caulinodans is using plant-derived propionate as a carbon source for growth. Insertion sequencing was also used to probe the genetic basis of nitrogen fixation in A. caulinodans, here I showed that insertion sequencing was applicable to this study and could identify a number of genes involved in low nitrogen growth.

Advisor: Poole, P
Dolan, L
Optimizing the operation of direct-flow hollow fibre filtration

In current water industry, direct-flow hollow fibre filtration is increasingly used as an intermediate or complete water purification technique. Compare to classical crossflow filtration, direct-flow filtration avoids high pressure drop that incurs high energy cost in the feed channel and permits the use of smaller diameter fibres which increases the filtration area per unit volume. Such filtration is achieved by efficiently capping one end of the crossflow device and it is usually operated in dead-end mode with regular intermittent backwash. Direct-flow filtration therefore forms the dominant method for producing potable water from ground or surface water. This thesis focuses on the operational considerations and design aspects of the direct-flow filtration membrane modules, specifically those of the pressure driven inside feed format. From a comprehensive literature survey of direct-flow filtration it was established that there was a general lack of information on direct-flow filtration behaviours. In particular there were no tools to simulate the hydrodynamic efficiencies within these devices. This study therefore set out to develop various direct-flow filtration models which one can also apply in various industrial processes. With a dimensionless mathematical model for the fluid flow in an axisymmetric direct-flow pipe, simple investigations on direct-flow filtration was achieved. Then two realistic hollow fibre models which included finite wall thicknesses and fouling effects were developed. These models were used to investigate various influences upon the axial dependence of the transmembrane pressure and the cumulative filtration volume under non-fouling and fouling conditions. The current fouling model is limited to chemically inert, incompressible, suspended solids. Geometrical parameters including fibre radius, fibre wall thickness, fibre length, module void fraction and imposed average flux were varied over a broad range values encompassing the values applied in today’s water industry. Various scenarios of membrane fouling and cleaning process in which fibres were subject to identical hydrodynamic conditions have been investigated. The study has proposed two important metrics and a strategy for optimizing them to promote the best filtration performance: the module productivity parameter, and the filtration uniformity factor. Overall, optimized design ranges and operating regimes of the direct-flow hollow fibre filtration devices were summarised, and the modelling results accord with commercial products as used in industrial practice that has evolved over the last 20 years and show guidance for future designs.

Advisor: Field, R
Silicon nanowires, cryogenic control and radio-frequency read-out for quantum devices

For the last two decades research on grown nanowires has been motivated by their potential application as efficient transistors, sensors and building blocks of quantum information processing architectures. While these applications can benefit from quantum effects, such as tunneling and quantum interference, the integration of bottom-up grown nanowires into larger circuits is technologically challenging. Top-down fabricated nanowires, that recently became available due to progress in semiconductor fabrication, provide a means of overcoming this barrier. In combination with silicon spin qubits, they could enable a fully integrated quantum processor with silicon nanowire control electronics that comply with the cooling requirements in a cryogenic environment.
I will present silicon nanowire transistors that were fabricated using CMOS-compatible processing and operate at room temperature as well as in the cryogenic regime. With a diameter of only 8 nm, the nanowire devices exhibit excellent electrostatic control of the channel and show evidence for one dimensional transport. Transport in these nanowires is dominated by scattering off dopants and off the nanowire walls rather than off the rough nanowire surface or other surface defects that often dominate in nanowire devices. Optimized nanowires with lower doping and shorter channels could therefore enable ballistic cryogenic CMOS with ultra low heating in a cryogenic quantum processor.
In addition to DC experiments, I will use a measurement technique where the impedance of a quantum device in a resonant circuit can be inferred from the reflection of radio-frequency signals. The sensitivity to a changing device impedance is improved via in-situ impedance matching of the resonant circuit to the measurement electronics. As a result charging events in a silicon nanowire device can be detected with a good charge sensitivity. In case the quantum device requires small input powers, for example if measurement back-action is significant, further improvement is achieved by employing a low noise SQUID amplifier. The measured sensitivity to changes in the quantum capacitance enables the read-out of a singlet-triplet qubit much faster than the typical decay time of the quantum state. Since the technique does not require additional sensing devices and the read-out circuit can be connected directly to a gate electrode of the qubit, this type of read-out is promising for scalable quantum information processing architectures.

Advisor: Mol, J
Laird, E
Briggs, A