VictorJuiz/thesis huggingface dataset:
Inscribing manumission in the Hellenistic world
Keywords: epigraphy
Manumission
Ancient Greece
Hellenistic period

This thesis is a study of Greek manumission inscriptions, their contexts and their functions. In total, more than 2,000 documents on stone recording the release of enslaved persons have been identified at dozens of sites across the Greek world. The majority of these cluster around the central and northern Greek mainland, and belong to the second and first centuries BCE. The procedures recorded are often cloaked in religious forms, and attest to the involvement of civic institutions. The primary aim of this study is to come to a better understanding of the motivations behind this peculiar epigraphic phenomenon.
The Introduction outlines some of the key conceptual and legal problems involved in the freeing of slaves, and provides an overview of the scholarship on manumission in ancient Greece. Chapter 1 sets some parameters for defining a manumission inscription, and for identifying shared cultural features in the practice and recording of manumission across the sites which produced these inscriptions. Chapter 2 explores the performances of the act of manumission which lie beneath our epigraphic texts, revealing the ceremonies and procedures, as well as the locations and the occasions at which Greek slaveowners effected the release of their slaves. Chapter 3 provides an overview of the documentary habits which accompanied the epigraphic evidence, and probes the extent to which the inscriptions themselves were considered valid and consultable documents. It concludes with a summary of the physical aspects of these inscriptions: the material upon which they were inscribed, their appearance and legibility, and their relationship with other epigraphic genres, are crucial factors to understanding the purpose of these objects. Chapter 4 details the multifunctionality of manumission inscriptions: in line with recent approaches to a variety of epigraphic documents, which have stressed both the practical and symbolic elements of Greek inscriptions, I argue that documents of manumission also served a number of overlapping purposes. Alongside the traditional explanations of their functions as being those of proof and publicity, they can be interpreted as reflecting certain values and ideals belonging to the individuals and communities which produced them. Chapter 5 is a case study of the manumission inscriptions from Seleukid Iran, which are broadly contemporary with our evidence from the Greek mainland, but present some interesting particularities.
A sociodemographic study of only-children and only-child fertility
Keywords: demographic transition
cross-country
only-children

This thesis explores only-child fertility from a sociodemographic perspective across three main chapters. The first substantive chapter examines trends in the proportion of women with an only-child across 125 countries, from 1920-79 birth cohorts, with combined data from different sources. The results show that the prevalence of only-child fertility has increased across the globe. However, as overall fertility reaches below-replacement, trends become more heterogeneous, and factors beyond a country’s cohort fertility rates and mean ages at childbearing become more important in dictating these prevalences. The second substantive chapter, with data from four countries in the first two waves of the Generations and Gender Surveys, explores fertility intentions and the realisation of those intentions in Eastern and Western Europe for a first and second child with the use of probit models with sample selection. The results show that while people seem to consider families and friends’ opinions, as well as what they believe to be the pros and cons of having a child when forming their fertility intentions, the actual realisation of intentions is more strongly guided by their perceived financial and physiological conditions for having and raising a child. The chapter further discusses differences between Eastern and Western Europe, and between those having a first and second child. The final substantive chapter explores behaviour differences between only-children and children with siblings in the British context with data from the Millennium Cohort Study. Results of a series of logistic models for children aged 3-14, show that only-children have higher odds of presenting abnormal peer behaviours, but fared better than children with siblings in conduct scores. However, the conduct score advantage for only-children disappears when only firstborns or only children with a resident father are considered.
Unravelling the genetic and molecular mechanisms of the left-right patterning genes Pkd1l1 and Pkd2
Keywords: Pkd1l1
left-right patterning
nodal cilia
development
polycystins
Pkd2

Pkd1 and Pkd2 encode the polycystin proteins which underlie human ADPKD, a major cause of end stage renal failure. Recently, by analysing the Pkd2lrm4 mouse, a previous member of the lab provided evidence that loss of ciliary PKD2 underlies kidney cyst formation. Furthermore, the Pkd2lrm4 mouse highlights a requirement for PKD2 in nodal cilia for correct L-R patterning. However, we are yet to fully understand its cilia-specific role and the mechanisms controlling its ciliary trafficking and entry. PKD1L1 (a PKD1 Paralog) functions with PKD2 in the embryonic node to allow correct L-R patterning and its expression and localisation during this process remain to be fully characterized.
By generating endogenously tagged alleles of PKD1L1 and PKD2, I have investigated their localisation and co-localisation, in the embryonic node during L-R determination. Using these tagged alleles, Pkd1l1mTFP1 and Pkd2mNG, I have been able to evaluate their localisation in Pkd2-/- and Pkd1l1-/- embryos respectively. Enabling us to further understand the role of their co-localisation, and assess the co-dependent relationship between PKD2 and PKD1L1 for ciliary localisation. Using Pkd2lrm4/lrm4 samples, I have been able to identify a selection of candidate interacting proteins that may be involved in trafficking to cilia and ciliary entry of PKD2.
The work in this thesis provides a new insight into the genetic and molecular mechanisms involved with the polycystins, and their roles in left-right pattern determination.
Transcriptional changes and regulation of voltage gated calcium channels across human stem cell differentiation
Keywords: transcription factors
voltage gated calcium channels
differentiation
alternative splicing
human induced pluripotent stem cells

Human neural development comprises a phase during which a risk for psychiatric conditions such as schizophrenia is established. Robust evidence has linked voltage-gated calcium channels (VGCCs) to psychiatric illness. However, the biology of VGCCs in the context of human neural development, and particularly the prenatal stages, has not been sufficiently studied. This thesis examines the transcriptional regulation of VGCCs in a model system of neural development, the differentiation of human induced pluripotent stem cells (hiPSCs) into neurons. By applying bioinformatics tools to hiPSC and hiPSC-derived neuron data from dozens of donors, I characterized changes in the abundance and splicing of VGCCs across hiPSC differentiation into neurons. Additionally, motif-based bioinformatics tools were applied to identify candidate regulators of VGCC splicing and abundance. The analyses revealed that as hiPSCs differentiate into neurons, VGCC transcript levels robustly increase. The alternative splicing of CACNA1C, CACNA2D1, and CACNA2D2, including a cell state-specific switch in the utilization of Exons 21 and 22 in CACNA1C, were identified. Analyzing the regions of interest using two different bioinformatics tools identified a binding site for BRUNOL4 and BRUNOL5 upstream of CACNA1C Exon 21, which showed neither evolutionary conservation nor acceleration; and a binding site for HNRNPL near CACNA2D2 Exon 26 showing evolutionary acceleration in primates. Finally, transcription factor (TF) footprinting analyses of ATAC-seq data identified candidate TFs that might regulate multiple VGCC loci, several of which are expressed more highly in human fetal compared with postnatal brain development, including KLF7 and TCF4. Altogether, the results provide a foundation for future research investigating the functions of the identified RBPs and TFs in VGCC transcriptional regulation. The findings also indicate that hiPSCs possess the potential for providing insights into the changes that occur in VGCC transcription and putative mechanisms of VGCC regulation in human neural development and different cell states.
Motives beyond markets: state ownership, stranded assets, and decarbonisation in the power sector
Keywords: just transition
state-owned enteprise
carbon neutrality
climate policy
decarbonization
stranded assets
coal power
China
coal phase-out

State-owned enterprises (SOEs) will play a central role in the decarbonisation of the global economy. They are also the dominant type of actor in the power sector by both installed power generation capacity and investment, with China accounting for the largest share. Despite their obvious prominence, SOEs remain an understudied element in climate policy analysis, design and implementation. The papers in this thesis begin to address this research gap, focusing on state- owned power companies (SPCs). The three papers employ, respectively, comparative case study analysis, a modified version of discounted cash flow analysis, and microsimulation techniques. Together, they make some initial progress towards more explicit integration of SOEs and government shareholders into climate policy research. Paper 1 develops a framework for analysing how SPCs’ characteristics and the context in which they operate affects their response to government interventions. It finds that SPCs can, under certain circumstances, be more effective conduits for climate policy than private companies, and that market-wide policies may have less effect on SPCs than on their privately-owned counterparts. Paper 2 adapts and extends traditional stranded asset analysis to consider cases in which the asset owners are SOEs, focusing on coal power in China. It concludes that new coal power investments by Chinese SOEs are unlikely to deliver positive economic returns, and that dispatchable renewable power will soon be economically competitive as an alternative even without accounting for the social cost of carbon. Paper 3 simulates the effect of thermal coal phase-out in China on employment and tax revenue in the thermal coal value chain. The results show that delaying coal phase-out cannot prevent losses in employment and tax revenue in China’s coal sector from being realised, and that these losses are both geographically concentrated and associated with a small number of large SPCs. Overall, this thesis demonstrates the importance of explicitly accounting for SOEs both in formulating climate policies and analysing their effects.
What actually happened? Novel econometric methods to improve estimates of climate impacts and policies
Keywords: climate change
climate impacts
econometrics
economics

Climate change is one of the most crucial societal challenges of the 21st century, affecting a wide range of social, economic, and environmental aspects of modern society. To design and implement policies that can deal with the climate challenge requires an accurate and robust understanding of the physical impacts of climate change as well as understanding the potential impacts of different policy instruments, their limitations, as well as their successes and failures in the past. Despite this necessity, there remains substantial empirical uncertainty around the effectiveness of policy approaches both in the context of mitigation and adaptation. In this doctoral thesis, I present a total of five papers that advance the field of impact estimation in the context of climate change. By using and developing novel econometric methods, I show how existing gaps in this literature can be addressed. In Paper 1, I develop a novel statistical test to illustrate the impact that outlying observations have on regression coefficients of econometric climate impact estimates. In Paper 2, I use these methods and advance climate impact estimates further by presenting a first set of economic climate damage projections that incorporate the effects of extreme weather events and adaptation. While current climate and weather impact data collection approaches focus on manual bottom-up database records, Paper 3 uses machine learning algorithms to predict the occurrence of weather impact events reliably without manual input or on-the-ground knowledge. In Paper 4, I operationalise an alternative way to empirically evaluate policy, which is used in Paper 5 to identify the effects of 10 distinct road transport mitigation policies in the EU15. Overall, I argue that when econometric methods are specified correctly, are applied to the most pressing research questions, and make use of appropriate data then using these methods can allows us to direct adaptation funding more efficiently, track Loss and Damage events around the world, and allow policy-makers to focus on those policy packages that have the largest chance of making a difference.
Multiparametric characterisation of peripheral immunity in recipients of checkpoint immunotherapy across a large patient cohort
Keywords: T-cells
CMV
melanoma
B-cells
MAIT cells
immune checkpoint blockade

Immune checkpoint blockade (ICB) has revolutionised the treatment of metastatic melanoma (MM) which was historically resistant to conventional therapies, yet only a minority of patients experience durable clinical benefit. Dissecting peripheral immune responses to ICB may discern predictive markers of clinical outcome. However, infection with human cytomegalovirus (CMV) can have profound effects on immunity and the extent to which this affects the peripheral immune response to ICB is unclear. Using an agnostic transcriptomic and cytometric assessment of peripheral immune ICB responses across a large cohort of MM patients, I identify dynamic changes in immune composition, activation and adaptive immune cell repertoires. I also determine the contribution of CMV to these changes and describe predictors of clinical outcome.
Firstly, I identify CD8+ T-cells as being the most responsive cell type to ICB treatment and that responses in other peripheral blood mononuclear cell subsets are secondary to CD8+ T-cell ICB response. Next, I find that only B-cell proportion and subset composition are sensitive to ICB treatment. This includes a transient depletion of B-cells and an induction of antibody-secreting cells which associate with clinical outcome. I then characterise these changes and determine that these ICB-mediated effects are largely dependent on CD8+ T-cell activation and production of B-cell chemoattractant CXCL13. Finally, I describe the effects of ICB and CMV on corresponding B-cell receptor and T-cell receptor repertoires. Significantly, I find that B-cells undergo accelerated class switch recombination and somatic hypermutation following ICB, whilst MAIT cells are depleted and associate with clinical outcome. Although CMV infection is a major determinant of MAIT cell changes following ICB, all other identified ICB-mediated effects are independent of CMV serostatus.
In this thesis I present novel findings surrounding B-cell and T-cell responses to ICB treatment and identify predictive markers which may have clinical utility in monitoring patient treatment responses as well as guiding treatment stratification. My observations demonstrate that the response to ICB is multifaceted, involving a coordinated interaction between different cell subsets, driven by CD8+ T-cells. Notably, B-cells cannot be assumed to play a bystander role and my work highlights the importance of B-cell:CD8+ T-cell interactions in the response to ICB and long-term clinical benefit.
Structural, functional and computational studies on the SLC7 family of amino acid transporters
Keywords: protein-lipid interactions
SLC7 transporters
structural biology
membrane proteins
electron cryomicroscopy
CAT4
SLC7A4
amino acid transporters
synthetic nanobodies
cholesterol interactions

Amino acids are central components of the cell as protein building blocks, nitrogen sources and metabolic and cell signalling regulators. As such amino acid concentration in the cytosol and cellular compartments must be regulated. The SLC7 family of amino acid transporters provides a central gateway of amino acids to the cell. There is increasing understanding of mammalian SLC7 members, primarily, through structural and functional studies on prokaryotic and, recently, some human homologues. However, a member of the cationic amino acid transporter (CAT) subfamily remains of unknown function, prompting us to uncover its structure-function relationship. This thesis reports the first cryoEM structure of a eukaryotic SLC7A4 homologue, from Arabidopsis thaliana (AtCAT4), closely related to the mammalian SLC7A4 by conserving a key acidic residue, and other CATs responsible for the transport of L-arginine, L-lysine, and L-ornithine into the cell. AtCAT4 structural elucidation required the selection and generation of a nanomolar affinity sybody binder. The structure was solved in the apo outward-open state and showed AtCAT4 has an APC fold with two additional TM helices previously unobserved, likely involved in homodimerisation. Structural comparisons revealed an intricate electrostatic gating mechanism, which rearranges upon substrate binding, uncovering early steps of the transport cycle. AtCAT4 binding assays and MD simulation showed recognition of L-arginine, L-lysine, and L-ornithine with differential preferences for each. Human SLC7A4 however did not transport cationic amino acids, but preliminary data support a role for L-leucine transport. Structural analyses and mutagenesis suggested the root of the homologue discrepancy to be two bulky, hydrophobic residues absent from AtCAT4 and other CATs. The current structure serves as a template to further understand mammalian cationic amino acid transport via the SLC7 family. AtCAT4 was solved with a steroid lipid bound, similar to other SLC7s. With multiscale-MD and in vitro transport assays we suggest two cholesterol binding sites for HATs which stabilise transporter SLC7-SLC3 heterodimerisation and conformational state.
The maintenance and spread of cooperation in social networks in natural populations
Keywords: social network
cooperation
individual recognition
fitness
sociality

Social interaction is crucial for social animals to thrive, but it comes with both benefits and costs. The social network approach helps to identify how social processes like cooperation are influenced by individual and population-level characteristics. Factors like individual recognition, familiarity, and social stability play a role in promoting tolerance and cooperation; and understanding these factors can provide insights into how social networks, cooperation, and other social behaviors evolve in different species. In this thesis, I examine how social processes interact with spatial and temporal factors to influence fitness and other outcomes in wild birds (Paridae).
I begin by establishing a theoretical foundation for my work by reviewing the concepts of cooperation and individual recognition and how they can be better understood through a social network approach (Chapters 2 & 3). Using experimental data, I explore the processes that may impact cooperative behavior by examining leading behavior during mixed-species foraging (Chapter 4) and demonstrate that motivation and dominance, as well as spatio- temporal effects, are determinants of this behavior. Drawing on these insights, I then use long-term breeding data to show that familiarity among neighbors as well as familiarity within breeding pairs influences fitness (Chapter 5). I also demonstrate that different kinds of social relationships have different effects on reproductive outcomes (Chapter 6).
All in all, I demonstrate that social connections have implications for fitness, and highlight the importance of accounting for spatial, temporal, and cognitive components when studying the ecology and evolution of sociality.
Development of a microfluidic-based platform for delayed vaccine delivery
Keywords: Microparticles
Microfluidics
Vaccine
Microcapsules
Delayed Drug Delivery
Single-Shot Vaccine
Vaccine Delivery

Incomplete vaccination poses a significant challenge to disease eradication efforts, resulting in approximately 1.5 million preventable deaths each year. A single-injection method for administering a full course of immunisation would help to improve global coverage, reduce preventable deaths, and alleviate logistical and cost burdens during outbreaks. Biodegradable polymer microparticles have been studied previously for controlled vaccine release, but traditional manufacturing methods lead to particles with inconsistent size, vaccine loading, and release rates, preventing the development of encapsulated delayed release or single-dose vaccines.
The goal of this thesis was to develop and assess a delayed vaccine delivery system using microfluidics. Firstly, a microfluidic emulsification system within a chip was designed for the production of double emulsion formulations by introducing a step in the height in the microfluidic channel. This enabled reliable production of double emulsions required for creating uniform liquid core – solid shell particles (LCSS particles). The system produced fully loaded particles of varying size and thickness, suitable for the application by injection delivery, with throughput rates of 300Hz and higher. Compared to previously reported systems, this microfluidic system offers significant advantages, including better emulsification reliability and uniformity, postproduction quality control of particles, and scale-up potential.
The ability of particles to achieve delayed release was studied in vitro demonstrating pulsatile release after a lag phase. Duration of the lag phase was determined by the molecular weight and L:G ratio of the PLGA polymer used as the shell and could be extended from a couple of weeks to months. Finally, in vivo proof-of-concept of the utility of the particles was demonstrated in the context of a leading malaria candidate vaccine R21 in a mouse challenge model. Changing the particle formulation enabled to achieve different immune response delays. Moreover, a single injection of a priming vaccine with the booster dose encapsulated within particles resulted in higher immunogenicity and efficacy than a dose-matched priming vaccine alone. These findings provide key evidence for the potential of this system to achieve high vaccine efficacy with a single injection.