VictorJuiz/thesis huggingface dataset:
The dynamics of centrosome assembly in the early Drosophila embryo
Keywords: Organelle biogenesis
Dynamics
Systems biology
Centrosome
Phase separation

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.
Body size in early life and risk of diabetes in adulthood
Keywords: adult diabetes

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.
Studying the function and regulation of non-coding transcription in fission yeast by the exosome complex
Keywords: Exosome
non-coding RNA
epigenetics
RNA

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.
Expression and function of human macrophage heparan sulfate proteoglycans
Keywords: inflammation
heparan sulfate proteoglycan
matrix biology
macrophage

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.
Robust and stochastic receding horizon control
Keywords: Packet loss
Model predictive control
Dynamic programming
Chance constraints
Stochastic convergence
Multiobjective optimisation

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.
A bioarchaeological study of intensification of pig husbandry during the Yangshao Period (7000–5000 cal BP)
Keywords: millet fodder
Neolithic China
geometric morphometrics
light stable isotopes
birth seasonality
Sus scrofa
diets

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.
Structural and functional characterisation of the group II chaperonin CCT/TRiC
Keywords: chaperone
proteostasis
CCT
chaperonin
TRiC
cryo-EM

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.
Modelling the spatial and temporal epidemiology of antimicrobial resistant Salmonella Typhi and Paratyphi A infections
Keywords: Spatial modelling
Antibiotic consumption
Antimicrobial resistance
Salmonella Typhi
Machine learning

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.
The text and transmission of Cicero's Brutus
Keywords: Textual Criticism
Textual Transmission
Brutus
Cicero

This thesis is composed of three parts: a study of the transmission of Cicero’s rhetorical work Brutus, a critical edition, and a textual commentary. I begin Part One with a catalogue of the c.109 extant manuscripts of Brut. The second chapter of this part is devoted to the oldest surviving manuscript, the Cremona fragment. I demonstrate, against the view of earlier scholars, that the Cremona fragment is a part of the long-lost Codex Laudensis (L), the archetype of the entire tradition. In the following chapters, I use the stemmatic method to establish the relationships between the fifteenth-century copies of L. In Chapter 3, I prove that there are three independent lines of descent from L for the first part of the text, and four for the second. In Chapters 4 and 5, I study the manuscripts and printed editions which derive from the independent descendants of L, placing them into families and sub-families. In particular, I show that one manuscript, F, copied by Niccolò Niccoli, is the source of the majority of the tradition. The final chapter of this part, Chapter 6, is a textual history of Brut.: I connect my conclusions from Chapters 3-5 to the historical data, shedding fresh light on the roles played by various humanists of the Italian Renaissance, including Gasparino Barzizza, Flavio Biondo, and Niccolò Niccoli, in the dispersion of the text. No comprehensive study of the transmission of Brut. has been undertaken before, and many of my conclusions are completely new.
In Part Two, I present a new text of Brut., together with an apparatus criticus. I diverge from Malcovati (1970) in c.100 places, sometimes reverting to the paradosis and sometimes printing a conjecture, whether my own or that of another scholar; these differences are listed in an appendix. In Part Three, I discuss all the most significant textual problems and explain many of my editorial decisions in a textual commentary.
Explanations for ontology-mediated query answers
Keywords: existential rules
description logics
computational complexity
ontology-mediated query answering

Ontology-mediated query answering is a paradigm that seeks to exploit the semantic knowledge expressed in terms of ontologies to improve query answers over incomplete data sources. In this thesis, we consider explanations for ontology-mediated query answers under the classical semantics. We provide a comprehensive complexity analysis of a wide range of computational problems, associated with explaining ontology-mediated query answers. We study explanations both for positive and negative ontology-mediated query answers under different minimality criteria, both for existential rules and description logics. This allows us to indicate similarities and point out differences in the complexity of explaining ontology-mediated query answers for these different settings.
Courts and prisons: practices of criminal imprisonment in the London metropolis, 1750-1845
Keywords: Legal history
British history
Prison and Imprisonment
London

This dissertation looks at the development of criminal imprisonment and the evolution of prison systems in the London metropolis between the mid-eighteenth and mid-nineteenth centuries. It combines a study of the processes through which individuals came to be incarcerated with an examination into the regulation and experience of confinement with the aim of explaining the functions that London’s prisons came to serve and the forms that they assumed.
Drawing on court records, prison commitment books, and newspaper accounts of judicial hearings, this dissertation explores how committing bodies in London, from the lowest levels of justice to the highest, used imprisonment to detain and punish criminal offenders. It looks not only at how often imprisonment was used and for what sort of offenders, but also at the particular prisons where the sentences were carried out. It shows how magistrates, both as a bench making policy decisions and as individuals in their commitment practice, used their stock of prisons to target commitments and create distinctive penal regimes.
Though most studies of English imprisonment posit that the main criminal prisons effectively merged in form and function from the late seventeenth or early eighteenth century, this dissertation instead argues that the prisons became increasingly specialised. Specialisation was locally driven, so the particular arrangements adopted differed by jurisdiction, but in all parts of the metropolis, there was a general trend towards treating prisons as either custodial or punitive. As a result, prisoners for punishment increasingly served their sentences in prisons distinct from those where prisoners for detention were held.
These changes in commitment practice provide a crucial, but heretofore neglected, context for understanding changes in the administration and internal operation of London prisons. This dissertation draws on a wide range of surviving evidence relating to the administration of prisons and to the conditions of confinement—including parliamentary reports; quarter sessions’ books and papers; papers, minutes and reports of prison committees; journals of prison officers; prison plans; and codes of regulations—to detail and explain the particular shape that prisons took. It argues that this period saw the crystallisation of two distinct regimes of confinement: punitive imprisonment and custodial incarceration.