VictorJuiz/thesis huggingface dataset:
On the edges of Borneo: the port towns of Sandakan and Jesselton, 1879–1942

This thesis studies the emergence of Sandakan and Jesselton as the principal urban centres in the State of North Borneo from the late nineteenth to the mid-twentieth century. Despite their small population and physical size relative to the major cities of Southeast Asia, these port towns were gateways to the interior and nodes in regional systems of exchange. This thesis compares the birth, expansion, and maturation of the two towns to examine the nature of urbanization in what was then considered a remote and unexplored land. It contends that geography and colonial capitalism were the primary factors that shaped the economic and social development of the towns. Their different spatial settings created two distinct and discrete hinterland systems within the territory, which were each centred on Sandakan and Jesselton. At the same time, the government built a territorial economy that was geared towards external markets and based on an ethnic stratification of labour, resulting in striking demographic and sociological similarities across the two towns. As a whole, this thesis contributes to the urban history of maritime Asia by stressing the significance of small ports both in connecting the region and in providing counterpoints to studies of major ports.

Keywords: colonial capitalism
port cities
globalization
East Malaysia
urbanization
Southeast Asia
socio-spatial segregation
port towns
Borneo
town-hinterland systems
Sabah
mobility
colonial economy and society
imperialism
trade and development
Advisor: Darwin, JG
Investigating the role of apoptosis-stimulating of p53 protein 2 (ASPP2) in development of the central nervous system

Development of the structurally complicated central nervous system (CNS) involves a set of highly organized events including neurogenesis and neuronal migration. ASPP2 has been reported to be important for CNS development in both humans and mice. ASPP2 plays an important role in inhibiting excessive proliferation of neural stem cells (NSCs) and maintaining the polarity of the neuroepithelium in the developing mouse brain. However, the function of ASPP2 in neuronal migration and potential brain malformations caused by ASPP2 deficiency at postnatal stages remain uncharacterized.
This study found that Aspp2-KO mice show diminished olfactory bulbs, whose development relies on chain migration of neuroblasts in the rostral migratory stream (RMS). Subsequent in vivo and in vitro migration assays demonstrated that ASPP2 deficiency resulted in the impaired formation of the chain-like structure and neuroblasts migrating in the RMS. ASPP2 deficiency also impaired radial neuronal migration in the neocortex leading to periventricular nodular heterotopia (PNH), which was characterized by periventricular clusters of neurons that failed to migrate into the neocortex.
Dynamic regulation of the actin cytoskeleton, mediated by Rho GTPases and their downstream kinases, plays an essential role in developmental neuron migration disorders. A phosphoproteomic analysis using wild-type and ASPP2-KO U2OS cells indicates that ASPP2 may regulate the cytoskeleton through Rho-ROCK signalling. Indeed, my study demonstrated that ASPP2 physically interacted with ROCK2 and potentiated its phosphokinase activity towards MYPT1 and MLC2, thus positively regulating RhoA-mediated actomyosin stress fibre formation and cell migration. This work revealed novel functions of ASPP2 in regulating Rho-ROCK signalling, actin cytoskeleton, and neuronal migration.

Advisor: Lu, X
Szele, F
The dynamics of centrosome assembly in the early Drosophila embryo

Centrosomes are important for many cellular processes. They comprise of a pair of centrioles surrounded by an amorphous pericentriolar material (PCM). In Drosophila, although more than hundreds of proteins localise to PCM, it is believed that the PCM assembly is governed by a small subset of proteins—Polo, Spd-2 and Cnn forming a network-like underlying scaffold. This scaffold appears to be plastic and adopts different behaviours in many cell types. Therefore, Drosophila centrosomes allow us to understand how a simple set of proteins are wired to satisfy biochemical and biophysical needs. In this thesis, I describe my discovery that Cnn scaffold assembly is initiated and timed by a Polo oscillation. Centriolar Ana1 helps recruit Polo, which inhibits Ana1 activity, resulting in a time-delayed negative feedback oscillation. Polo then triggers a Spd-2 oscillation which together build the Cnn scaffold. In the process, I created an automated analysis pipeline to look into the scaffold assembly in different systems efficiently. Moreover, I discovered that in addition to a Cnn solid scaffold centrosomes also possess a liquid TACC scaffold that is organised by Spd-2 and Aurora A. The liquid TACC scaffold can enrich many centrosomal proteins.

Keywords: Organelle biogenesis
Dynamics
Systems biology
Centrosome
Phase separation
Advisor: Raff, J
Body size in early life and risk of diabetes in adulthood

Larger body size in adulthood increases the risk of diabetes in adulthood, whereas, paradoxically, being small at birth is associated with an increased risk of adult-onset diabetes. Direct comparisons of diabetes risks for different trajectories or combinations of body size at birth, childhood, early adulthood and late adulthood will help to better understand the complex relationships between body size throughout life and risk of adult-onset diabetes.
This thesis investigates the effects of early- versus late-life body size on risks of developing diabetes in adulthood among 413,516 women from the Million Women Study, with more than 24,000 diabetes cases identified through electronic linkage to routinely-collected national hospital admissions records. At the beginning of follow-up (mean age 60 [SD 5] years), women reported their birthweight, body size at ages 10 and 20 and current body mass index (BMI), which were validated against values recorded around respective ages. Cox proportional hazards regressions yielded multivariable-adjusted relative risks for adult-onset diabetes by different combinations of these four body size indices.
Within every body size category at younger ages, higher adult BMI sharply increased risks of adult-onset diabetes. The association between low birthweight and higher risks of diabetes was clear, independent and persistent among women with different combinations of body sizes at age 10, 20, and 60 years. Larger body size at ages 10 and 20 years was largely relevant to adult-onset diabetes risk as a predictor of adult adiposity. At every level of birthweight and adult BMI, there were additional risks of diabetes associated with being comparatively thin at age 10 years. However, after allowing for birthweight, size at age 10, and adult BMI, being small at age 20 years had a little additional effect on adult-onset diabetes risk.
In conclusion, as well as the known increased risk with adult adiposity, being small at birth and thin in childhood independently and persistently increase diabetes risk in adulthood.

Keywords: adult diabetes
Advisor: Beral, V
Yang, O
Studying the function and regulation of non-coding transcription in fission yeast by the exosome complex

Recent studies have revealed multiple functions of non-coding (nc) transcripts, challenging our current understanding of RNA biology. In this study, I uncover the molecular mechanism involved in repression of the pho1 gene by the overlapping transcription of prt ncRNA, in the presence of inorganic phosphate (Pi). Upon Pi starvation, nc transcription is abolished and full induction of gene expression takes place. prt transcription results in formation of a transient heterochromatin at this locus. The heterochromatin may play a role in ensuring slow induction of the mRNA upon Pi starvation. The heterochromatin machinery is recruited via the binding of Red1 and Mmi1, RNA binding proteins, suggesting that these proteins are not exclusively restricted to meiotic RNAs. Interestingly, nuclear exosome is also recruited via Mmi1 to the nc transcript. It is required for transcription termination and degradation of prt. These data imply that coupling between 3’ end formation and degradation of unstable nc RNAs is similar to that in S. cerevisiae.
I conclude that nc transcription in response to presence of nutrients can fine-tune gene expression and might also regulate activation kinetics of the inducible gene, pho1. Furthermore, I demonstrate the presence of a transcription termination coupled decay mechanisms relying on the nuclear exosome.

Keywords: Exosome
non-coding RNA
epigenetics
RNA
Advisor: Vasilieva, L
Expression and function of human macrophage heparan sulfate proteoglycans

Among the hundreds of ligands for heparan sulfate (HS) are chemokines, cytokines, and growth factors, giving this proteoglycan a potentially central role in the regulation of immune responses. The biosynthesis of HS is regulated during inflammation with consequent changes to ligand binding and activity in multiple cell types including myeloid cells. In this thesis, I aimed to comprehensively describe the changes in expression of HS core proteins and biosynthetic enzymes in human primary monocytes and polarised monocyte-derived macrophages, and to investigate the contribution of HS proteoglycans to macrophage functions. Using a custom-designed microfluidic array card, I performed transcriptome analysis of HS-associated gene expression and discovered significant changes at all stages of macrophage maturation and polarisation, revealing that maturation is associated with increased capacity for HS biosynthesis and that pro- and anti-inflammatory macrophages have substantially different HS composition. Of particular interest was the reciprocal regulation observed between the 6-O-sulfotransferase (HS6ST1) and its functional partner the sulfatase (SULF2), which add and remove the 6-O-sulfate group to HS chains, respectively. Using siRNA knockdown of HS6ST1 in monocyte-derived macrophages to ablate 6-O-sulfation of HS, I determined that this modification does not contribute to phagocytosis or migration. Moreover, its absence did not affect macrophage polarisation, whereas total sulfate ablation using sodium chlorate did, suggesting that sulfate modifications at other positions are more important. HS6ST1 knockdown altered post-translational regulation of monocyte chemoattractant protein 1 (MCP-1), indicating the 6-O-sulfate group of HS modulates retention of this and potentially other mediators on the cell surface.

Keywords: inflammation
heparan sulfate proteoglycan
matrix biology
macrophage
Advisor: Troeberg, L
Robust and stochastic receding horizon control

Chance constraints, unlike robust constraints, allow constraint violation up to some predefined level and arise in numerous applications. They are often imposed in a pointwise-in-time fashion in control problems. This thesis considers a class of chance constraints imposed in an average-in-time fashion to focus more on aggregate behaviours and discounted to achieve trade-offs between short-term and long-term performance in the model predictive control (MPC) framework.
This thesis designs an MPC law for chance constrained stochastic systems with discrete-time linear dynamics and possibly unbounded additive disturbances. The chance constraint is defined as a discounted sum of violation probabilities over an infinite horizon. By penalising violation probabilities close to the initial time and assigning violation probabilities in the far future with vanishingly small weights, this form of constraints allows for an MPC law with guarantees of recursive feasibility by introducing an online constraint-tightening technique without an assumption of boundedness of the disturbance. We employ Chebyshev's inequality for constraint handling and formulate a computationally simple MPC optimisation problem. To mitigate the conservativeness of Chebyshev's inequality, a dynamic feedback gain is incorporated into the MPC law. This gain is selected online from a set of candidates generated by Pareto optimal solutions of a multiobjective optimisation problem. The closed loop system is guaranteed to satisfy the chance constraint and a quadratic stability condition. With dynamic feedback gain selection, the closed loop cost is reduced and a larger set of feasible initial conditions is obtained.
This thesis also considers an application of stochastic MPC in networked control systems, where constrained linear systems are subject to stochastic additive disturbances and noisy measurements transmitted over a lossy communication channel. An MPC controller is designed to minimise a discounted cost subject to a discounted expectation constraint. Sensor data is assumed to be lost with a known probability. Data losses are accounted for by expressing the predicted control policy as an affine function of future observations, resulting in a convex optimal control problem. Recursive feasibility of online optimisation problems and constraint satisfaction are ensured similarly via the constraint-tightening technique. We show that the discounted cost evaluated along trajectories of the closed loop system is bounded. Under certain conditions, the averaged undiscounted closed loop cost accumulated over an infinite horizon also remains bounded.

Keywords: Packet loss
Model predictive control
Dynamic programming
Chance constraints
Stochastic convergence
Multiobjective optimisation
Advisor: Cannon, M
Goulart, P
A bioarchaeological study of intensification of pig husbandry during the Yangshao Period (7000–5000 cal BP)

China is known as one of the early centres of pig (Sus scrofa) domestication, dating from c. 8500 years BP. Domestication is however a long-term process and less is known about how domestic pigs became central, in a process of intensification, to Neolithic lifeways in China. This thesis explores the nature of pig management practices to better understand how pig husbandry developed in the middle Yellow River region of China from the Yangshao Cultural Period (7000 to 5000 years BP). This region seems to have been particularly successful in integrating pig husbandry with an increasing concentration on millet agriculture. A combination of multi-isotope and geometric morphometric approaches is used to address questions about the pattern of pig husbandry practices, focused on the archaeological sites of Xipo, Yuhuazhai and Yangguanzhai. Stable carbon and nitrogen isotopes in bone collagen are used to explore patterns of pig diets and confinement, oxygen and carbon isotopes in tooth enamel to refine the isotopic records of these practices on seasonal scales and to infer birth seasonality. A geometric morphometrics approach is taken to detect the differences and similarities in shape and size of Sus molars in distinct sub-regions and phases. All of these approaches are compared, where appropriate, with similar analyses of wild boar. The results show that the sites’ inhabitants had developed an intensive strategy of pig management with strong human control over diet, movement, birthing and breeding from c. 6000 years BP, along with little entanglement with indigenous wild boar. Humans had established a close relationship with domestic pigs through provision of millet fodder and household waste and tight confinement of pigs within or around settlements all year round, thereby integrating pigs into the local agricultural cycle. Based on a literature comparison, incorporation of millets in pig and human diets followed very similar increasing trajectories throughout the Neolithic, but this particular agricultural system showed inter-regional distinctions that are visible in pig diets and morphologies. As a result of locally isolated breeding and diverse selective pressures, different ‘landraces’ of domestic pigs had already appeared at these three sites across the middle Yellow River region by at least c. 5500 years BP.

Keywords: millet fodder
Neolithic China
geometric morphometrics
light stable isotopes
birth seasonality
Sus scrofa
diets
Advisor: Lee-Thorp, J
Styring, A
Developing single molecule methods to study DNA replication dynamics in yeasts

To ensure the faithful transmission of genetic information during the cell division cycle, the entire genome must be accurately and completely duplicated prior to segregation of the identical sister chromatids. Perturbation of this process can have severe consequences for a cell, potentially resulting in cell death or genomic instability defects that can contribute to the development of disease. Therefore, it is important to understand how such events are avoided during normal genome replication and the impact of both endogenous and exogenous stresses on the process. For decades, various experimental techniques have been developed and applied to gain insight into the dynamics of genome replication, each contributing to an ever- growing knowledge base on the subject. More recent advances have included the increasing progression towards single cell and single molecule approaches to expand the understanding of cell-to-cell heterogeneity in how replication proceeds.
The current work aimed to contribute to these efforts by developing a novel approach for the analysis of single molecule replication dynamics. It was postulated that detecting DNA polymerase usage or lagging strand synthesis by optical mapping in ultra-long single molecules would enable the evaluation of each molecule’s pattern of replication. A protocol for mapping Okazaki fragments was established and tested by Bionano Genomics Saphyr analysis. Preliminary results supported the detection of labelled Okazaki fragments, showing potential for further protocol and analytical optimisation to validate this new method.
Furthermore, the experimental procedure for the application of an existing single molecule technique in a different model organism was explored. Nanopore sequencing-based detection of nucleotide analogue incorporation during replication was tested in Schizosaccharomyces pombe. Initial analyses indicated that the experimental system was not fully optimised for the approach and required alterations to enable the inference of replication dynamics information from long sequencing reads.

Advisor: Müller, C
Structural and functional characterisation of the group II chaperonin CCT/TRiC

Cellular health is dependent on the proper folding of proteins and dysregulation of this pathway can lead to many diseases including neurodegeneration and cancer. This thesis describes efforts undertaken to characterise the mechanism by which one eukaryotic protein chaperonin, CCT/TRiC (TRiC), assists the folding of client substrates. TRiC folds nascent polypeptides using a built-in lid mechanism that can open and close to allow substrate access/restriction in an ATP-dependent manner. TRiC is composed of eight individual subunits, some of which can form synthetic homo-oligomers that retain biological function to a varying degree. The native TRiC complex has proven difficult to isolate recombinantly due to the presence of eight subunits in the complex. Strategies to overcome this difficulty include isolation via nanobody (Nb)-mediated affinity pull-down and by using CRISPR/Cas9 genome editing to insert an affinity tag in the genomic locus of a single TRiC subunit, CCT5, the latter of which can produce large quantities of pure endogenous TRiC from human cells. Structural investigations of native TRiC reveal new details into its substrate-folding mechanism by observing several intermediate states including TRiC-tubulin bound and TRiC-Actin/PhLP2A bound structures. These results suggest a mechanism whereby substrates bind TRiC in an unfolded state and achieve their near-native fold while bound in the closed state. Additionally, the interaction between the co-chaperone PhLP2A and actin shows a novel binding mechanism whereby each TRiC cavity is occupied. These results provide new insights into the TRiC-mediated substrate folding cycle and provide further therapeutic potential for human diseases caused by disruption of proteostasis.

Keywords: chaperone
proteostasis
CCT
chaperonin
TRiC
cryo-EM
Advisor: Yue, W
Huiskonen, J
Modelling the spatial and temporal epidemiology of antimicrobial resistant Salmonella Typhi and Paratyphi A infections

Enteric fever caused by Salmonella enterica Typhi and Paratyphi A infers a large burden of disease in low- and middle-income countries (LMICs). Antimicrobial resistance (AMR) reduces our ability to treat these infections, increasing morbidity and mortality.
The aim of this thesis was to improve our understanding of the spatial and temporal trends in the prevalence of AMR in enteric fever and its drivers, such as antibiotic consumption, in order to guide policy and combat the growing threat of AMR.
A systematic review was performed to collate a contemporary dataset of multidrug resistance (MDR) and fluoroquinolone non-susceptibility (FQNS) in S. Typhi and S. Paratyphi A. A meta-analysis was used to assess broad scale trends in resistance.
Estimates of antibiotic usage in LMICs, and estimates of antibiotic consumption for 204 countries were produced for the years 2000 to 2018 using statistical models. These estimates were then combined with the systematic review data and additional covariates to model the prevalence of MDR and FQNS in S. Typhi and S. Paratyphi A for each endemic country and year from 1990 to 2018.
Large national and subnational variations in antibiotic usage are identified. Antibiotic consumption was estimated to vary almost 10 fold, from 5·0 [4·8-5·3] defined daily doses (DDD) per 1,000 population per day in Philippines to 45·9 DDD/1,000/day in Greece.
The prevalence of MDR S. Typhi decreased between 1990 and 2018 in South and Southeast Asia, but increased greatly in sub-Saharan Africa. FQNS S. Typhi increased considerably in South and Southeast Asia over the study period and increased, albeit to a lesser extent, in sub-Saharan Africa. MDR S. Paratyphi A remained low throughout, but the prevalence of FQNS S. Paratyphi A increased.
This thesis identifies both high rates of antibiotic consumption and a lack of access to antibiotics in various locations. It provides detailed estimates of the prevalence of AMR in enteric fever and analyses the trends over space and time. These estimates can be used as a benchmark from which to measure future interventions and to guide policy implementation to tackle AMR.

Keywords: Spatial modelling
Antibiotic consumption
Antimicrobial resistance
Salmonella Typhi
Machine learning
Advisor: Dolecek, C
Chipeta, M
Hay, S