VictorJuiz/thesis huggingface dataset:
The Lachish letters: a reappraisal of the Ostraca discovered in 1935 and 1938 at Tell ed-Duweir

The 21 inscribed ceramic sherds (or ostraca) known as the "Lachish Letters", which were discovered during the British Mandate Period excavations of Tell ed-Duweir (Lachish), underwent eighty years of scholarship that improved our understanding of at least some of these inscriptions. The archive is terse and fragmentary, and the least well-preserved and faded ostraca from this collection have been seriously overlooked, ironically when the "Lachish Letters" have more or less been regarded as a homogenous group of documents written during the final decades of the Judahite kingdom. Some of the ostraca were discovered in different stratigraphic contexts and pertaining to different settings, if not timeframes.
The principal aim of this study is to produce an updated edition of these ostraca by objectively and systematically reassessing and understanding these artefacts, the inscriptions they bear, and their respective stratigraphic layers and archaeological contexts. This is carried out by integrating past studies and modern-day developments on the ostraca (and the site itself) from different perspectives: archaeology, palaeography, philology, the Hebrew Bible, and Classical Hebrew studies. This interdisciplinary approach enables a revision of outstanding controversial issues and a dismissal of outdated proposals on the readings, interpretation, and import of these ostraca in their contemporary world. Despite the illegibility of some inscriptions, this study pays attention to all 21 ostraca via physical examination under the lens, to confirm or deny any dubious readings as far as the naked eye can tell us. A crucial criterion is the integration of photographic data and written documentation gathered from unpublished and archived material of the Mandate Period that were accessible to the author at the time of writing.
The study concludes that this surviving group of ostraca is far from homogeneous, and there still exist lacunae in their historico-archaeological contexts and interpretations. Our understanding of the source and function of the ostraca (especially the few legible messages and lists of names) remains riddled with controversies, which derive from the fragmentary nature of the corpus and the limitations in the documentation and preservation of these artefacts.

Keywords: Archaeology of Ancient Israel
British Mandate of Palestine
Book of Jeremiah
Lachish (Tell ed-Duweir)
Lachish Letters
Ostraca
Classical Hebrew
North-west Semitic Epigraphy
Advisor: Williamson, H
Mobilising stone: investigating relations of materiality, movement and corporality in Holocene Saharan rock-art

This project investigates Saharan pastoralist rock-art (7500–3000BP), with a particular focus on the engravings of the Messak Plateau in southwest Libya. Taking an anthropological approach, the art is examined within the context of the lives of its creators – transhumant cattle-herders who occupied the plateau seasonally. Drawing from fieldwork in Libya together with data from multiple expeditions in the Sahara, the study addresses a major lacuna in Saharan research by focusing on materially constituted, as-lived dimensions at the micro scale. A fundamental but archaeologically elusive aspect of lived experience is a consideration of ‘movement’, both physical and esoteric. Its incorporation is central to this project, forming a multi-aspected theoretical framework and a methodological tool. Augmented by input from specialists in geomorphology, pastoralism, stone sculpting and animal behaviour, this movement-driven focus has produced a more developed picture of the Messak herder lives, advancing our understanding of these particular non-text, somatic societies.
A singular contribution is the creation of a hypothetical model for small-scale, quotidian pastoralist practices, which expands upon the archaeological evidence, fleshing out details of a well-systematised form of dairy pastoralism involving controlled breeding and the processing of milk products. At the same time it is proposed that the herders’ relationship with their cattle was one of partnership rather than ownership, involving trans-species empathy and a valuation of animal personhood. This viewpoint is part of a broader set of animal-human relations reflecting a cosmological order that diverges from modern, Western ontological constructs.
Other significant findings include detailed information on the role and identity of the image-maker, revisionist data on the amount of effort and skill expended in carving processes, and an examination of the ways in which rock-art was used to manifest social emotional concerns. These were expressed via animal emotions portrayed in the rock-art, and also through performative, gestural markings associated with the imagery. Such expressions include apotropaic, supplicatory or other interactions involving communication with unseen powers.

Keywords: African Rock Art
Rock Art
Sahara
Relational Ontologies
Ethnoarchaeology
Saharan Rock Art
African Pastoralism
Advisor: Gosden, C
Mitchell, P
Host-gut microbiota interaction in health and disease using Drosophila melanogaster as a model organism

The resident gut bacteria of the gastrointestinal tract (gut microbiota) have been known to influence the immune system. Yet the role of the immune system in shaping the gut microbiota composition across an organism’s lifespan remains unclear. Previous work in mice has been conflicting and thus remains inconclusive. Here, Drosophila melanogaster was used as a model organism with a simpler gut commensal community to address this issue. Using four strains of Drosophila reflecting different immune statuses, we found that wild type and immune-compromised strains had the same Acetobacteraceae-dominant pattern across their adult lifespan. However, flies with a constitutively active immune system had a distinctive gut microbiota structure that persisted even when maternally transmitted bacteria were removed and was distinguishable from its genetic background.
Additionally, co-housing experiments showed that the local environment also played an important role in gut microbiota composition. When the physiology of the gut was explored, it showed that the gut internal environment was affected as a consequence of having a de-regulated immune system. Together, our results in Drosophila showed that a constantly active immune system shaped microbiota in the gastrointestinal tract. Given the evolutionary conservation of innate immunity between insects and mammals our data has implications for the shaping of the gut microbiota structure in humans with a chronically inflamed intestine.

Advisor: Ligoxygakis, P
Modulation of ageing characteristics with an anti-ageing compound

Investigating the cellular processes anti-ageing compounds interact with can identify genes and pathways involved in ageing. The macrolide lactone FK506 was identified in a phenotypic screen as extending lifespan in yeast and C. elegans through an unknown mechanism. FK506 also ameliorates neurodegeneration and age-related weight gain in rodents. Here, the mechanism of action of FK506 has been investigated in two experimental systems: C. elegans and 3T3-L1 mouse adipocytes.
As the general mechanisms of ageing are well conserved between C. elegans and mammals, C. elegans has been used to understand how FK506 acts at an organismal level. Firstly, the result of the phenotypic screen was confirmed. FK506 treatment induced lifespan extension in C. elegans in the presence of population crowding stress, but not in the absence of crowding. FK506 treatment inhibited neither E. coli OP50 growth nor C. elegans pharyngeal pumping, demonstrating that FK506 did not induce dietary restriction to extend lifespan. FK506 treatment increased C. elegans thrashing and pharynx pumping rates in early adulthood and delayed accumulation of gut bacteria, showing that FK506 extended healthspan. A transcriptome analysis of FK506-treated C. elegans allowed the identification of transcripts whose levels change and potential pathways by which FK506 manifests its effect. To explore this and to identify potential targets of FK506, the cellular functions required for FK506 to extend C. elegans lifespan and healthspan were investigated using RNA-seq, RNAi, genetic mutation and co-treatment with small molecule inhibitors and inducers. Interestingly, FK506 was found to have different mechanisms of action on lifespan and healthspan. The mechanism of FK506 on C. elegans thrashing rate was DAF-16 dependent, did not require population crowding stress, had a partial interaction with FUdR and autophagy, and may involve Ca2+ flux. The mechanism of FK506-induced C. elegans lifespan extension overlapped with dietary restriction and was dependent on calcineurin, TOR-independent regulation of autophagy and the presence of population crowding stress.
FK506 may modulate body weight by influencing metabolism and/or acting on adipocytes directly. FK506-treated aged 3T3-L1 adipocytes accumulated significantly less lipid, indicating that FK506 acts directly on adipocytes. RNA-seq of FK506-treated adipocytes found that translation-associated RNAs were upregulated whilst RNAs associated with lipid metabolism were downregulated. An ER-localised FK506-binding protein was up regulated in both C. elegans and 3T3-L1 adipocytes, fkb-4 and Fkbp2 respectively.
In conclusion, FK506 has been confirmed as a potential anti-ageing treatment, through its ability to extend lifespan and healthspan in C. C. elegans. In addition, FK506 has also been shown to act directly on mouse adipocytes, resulting in a reduction in lipid accumulation. This action could explain how FK506 caused weight loss in obese aged rats, restoring body mass to a healthy adult weight.

Keywords: C. elegans
Ageing
Adipocytes
Advisor: Mellor, J
Structural insights into human SNF2/SWI2 chromatin remodeler SMARCAD1 and its role in DNA repair

ATP-dependent chromatin remodelers have been proposed to act sequentially, and to a certain extent non-redundantly, in the priming stages of the DNA Damage Response pathways by establishing chromatin in lesion sites ready to act as a scaffold for repair factors or to be displaced in order to allow DNA repair. Among remodeling factors proposed to play a role in DNA repair is SMARCAD1, a poorly characterized, non-canonical member of the SWR1-like family of SNF2/SWI2 superfamily of ATPases, which has recently been identified as a potential target for ATM/ATR phosphorylation at canonical and non-canonical sites upon DNA damage.
The actual mechanism for SMARCAD1 recruitment and involvement in DNA remodeling is still unknown, and unlike most other chromatin remodelers, SMARCAD1 does not contain DNA- or histone-binding domains frequently accompanying such proteins. Instead, in addition to the core ATPase domain, only two CUE domains (a type of helical ubiquitin-binding domain) have been identified.
This thesis presents the findings of an investigation intended to structurally characterize SMARCAD1 by dissecting and identifying its domain architecture, and examining the activity and ligand selectivity of its binding domains in the functional context of DNA damage repair. The solution NMR structure of the CUE1 domain is presented, describing a triple helix bundle consistent with other members of the family. Furthermore, a novel SUMO interacting motif was identified and through a combination of NMR titrations and phospho-proteomics analysis, shown to be constitutively phosphorylated which excludes the possibility of DNA damage dependent ATM targeting as the recruitment mechanism for DNA repair.
Additionally, it is demonstrated that both CUE domains are poor binders of mono-ubiquitin, however CUE1 specifically mediates the high affinity binary interaction with the transcriptionally repressive master regulator KAP1. This interaction was shown to be independent of post-translational ubiquitylation but rather sustained through direct interaction with the dimeric RBCC domain of KAP1. Finally, mass spectrometry profiling of domain-dependent interactions (based on differential abundance relative to changes due to chemically induced DNA damage) suggests SMARCAD1 may be involved in p53 transcriptional regulation through interactions maintained with CUE1 prior to DNA damage, whereas the SIM domain selectively targets protein interactions upon DNA damage that simultaneously activate p53 transcriptional control and recruit SMARCAD1 to DNA damage repair pathways.

Keywords: Protein Structure
Ubiquitin
SMARCAD1
nuclear magnetic resonance
SUMO Interacting Motif
Chromatin Remodelling
SUMO
CUE Domain
Advisor: Redfield, C
Mancini, E
Development of a camera for tera–electronVolt gamma–ray astronomy

In this thesis I describe the development of a compact camera for ground-based multi TeV gamma-ray astronomy, using the Imaging Atmospheric Cherenkov Telescope (IACT) technique.
The camera is based on multi-anode photomultipliers (MAPM) and is designed for use on the Gamma Cherenkov Telescope (GCT), which is proposed to be part of the Small Size Telescope (SST) array of the Cherenkov Telescope Array (CTA). GCT achieves high performance with a compact and cost efficient design via a Schwarzschild-Couder (SC) dual-mirror optical system.
The GCT optical design allows the use of a compact camera of diameter roughly 0.5 m. The curved focal plane is equipped with 32 tiles of 64-pixels MAPM for a total of 2048 pixels of ∼0.2◦ angular size, resulting in a field of view of ∼9◦. The GCT camera is designed to record the flashes of Cherenkov light from electromagnetic cascades, which last only a few tens of nanoseconds. I give a detailed description of the design, the challenges encountered during testing in the lab, and the performance of the most critical components.
I give details on the custom front-end electronics modules that provide the required fast electronics, facilitating sampling and digitization, as well as first level of triggering. The camera-level triggering system is a custom backplane, developed to reject spurious triggers on the night sky background, which typically is of the order of few tens of millions of photons per pixel per second. This is to be compared with the rate of the astrophysical signal, which is of the order of few hundreds of events per second at the relevant energies. Additionally I provide a detailed description of all the software needed for the data acquisition and control of the camera, from the very low level drivers to high level and user friendly processes.
I follow the commissioning of the camera, from the individual core components to the integration of the system. I then describe the integration of the camera on the GCT prototype telescope structure, and the achievement of "first light", validating for the first time the full proof-of-concept of an IACT with SC optics.
I also report a study I performed on expectations for an extragalactic survey for blazars with CTA. The cumulative source count distribution of blazars is presented, including implications from two different phenomena: axion-like particle (ALP) to gamma-ray oscillations in the intergalactic magnetic field, and secondary gamma rays from hadronic origins. I conclude that a shallow and wide survey will provide the best science return for CTA, that the impact of ALP is modest and that the secondary mechanism of gamma-ray production would allow detection of blazars up to redshift of 1 in the multi-TeV energy band.

Keywords: Axion like particle
Cherenkov Telescope Array (CTA)
High energy gamma ray
Active Galactic Nuclei
Gamma ray Cherenkov Telescope (GCT)
Advisor: Cotter, G
Analysing and evaluating political realism

This thesis analyses and evaluates political realism (realism). Realism is an account of how best to do political philosophy and politics that may be characterised in terms of four interrelated theses: the feasibility thesis, the guidance thesis, the political normativity thesis, and the statist thesis. The feasibility thesis says that we must impose certain feasibility restrictions on our aspirations, prescriptions, and standards. I argue that we should only impose realist feasibility restrictions on our limited lower-order prescriptions. The guidance thesis says that our political theories must constrain their idealisations and avoid abstract, general practical principles if they’re to guide agents who must answer the political question. I argue that abstract, general practical principles and unconstrained idealisation are essential to good political guidance. The political normativity thesis says that political philosophy must source its basic substantive considerations for politics from a distinct, autonomous, and authoritative "political" normative domain. I reject it for two reasons. For one thing, the prospects for demarcating a distinct, autonomous, and authoritative political domain and devising adequate procedures for utilising its resources are very bleak. For another thing, realism fails to justify its turn to the political domain. The statist thesis says that whatever our answer to the question of how best to live alongside one another, this answer should include states. I propose that whilst it may be true that we should have states once we take relevant considerations into account, realism fails to provide us with decisive reasons for favouring them. I conclude with some thoughts on revising realism. I argue that realism stands to benefit from assuming sensible feasibility and guidance restrictions, dumping the political domain, and engaging with classical liberalism and political contractarianism.

Advisor: White, S
On portfolio construction through functional generation

One of the main research questions in financial mathematics is that of portfolio construction: how should one systematically invest their wealth in a financial market? This problem has been tackled in numerous ways, typically through the modeling of market prices and the optimization of an investment objective. A recent approach to portfolio construction is that offered by Stochastic Portfolio Theory, in which a relatively general market model is assumed, and the portfolio selection criterion is to outperform a benchmark with probability one. In order to achieve this, Robert Fernholz developed the method of functional generation, which allows one to explicitly construct and study portfolios that depend deterministically on the currently observable prices.
The typical example of such a strategy is the diversity-weighted portfolio, which we extend in the first chapter of this work with a negative-parameter variation. We show that several modifications of this portfolio outperform the market index in theory, under certain assumptions on the market, and we perform an empirical study that confirms this.
In our second chapter, we develop a data-driven portfolio construction method that goes beyond functional generation, allowing for the inclusion of factors other than current prices. We empirically show that this Bayesian nonparametric approach, which utilizes Gaussian processes, leads to drastically improved performance compared to benchmark portfolios.
Next, we establish a formal equivalence between the method of functional generation and the mathematical field of optimal transport. Our results fortify known relations between the two, and extend this connection to additive functional generation, a recent variation of the method.
In Chapter 4, we apply our results to derive new properties and characterizations of functionally-generated wealth processes in very general market models. Finally, we develop methods for incorporating defaults into functional generation, improving its real-world implementability.

Keywords: Gaussian processes
Probability theory
Stochastic portfolio theory
Financial mathematics
Optimal transport
Advisor: Monoyios, M
Small molecule tools for structural and functional studies of 2OG oxygenases

The work described in this thesis focused on members of the Fe(II), 2-oxoglutarate dependent oxygenase family that are involved in the biosynthesis of L-carnitine in mammals and in hypoxia sensing. Work on metallo β-lactamases was also carried out. N&epsiv;-Trimethyllysine hydroxylase (TMLH) and γ-butyrobetaine hydroxylase (BBOX) catalyse the first and final steps in carnitine biosynthesis, respectively. Chapter 1 provides an overview of the current literature regarding the 2OG oxygenases involved in the biosynthesis of L-carnitine from a therapeutic perspective. A discussion concerning the clinically used inhibitor of carnitine biosynthesis, Mildronate (Meldonium, THP, Met-88), is also included.
In Chapter 2 the stereochemical elucidation of the product of TMLH catalysis as (2S,3S)- 3-hydroxy-N&epsiv;-trimethyllysine is described. This was achieved via the successful implementation of a silver(I) catalysed asymmetric aldol reaction to obtain (2S,3R)-3-hydroxy-N&epsiv;-trimethyllysine which enabled elucidation of the TMLH catalysed product using 1D and 2D NMR spectroscopic techniques.
Chapter 3 explores the use of a 19F labelled cysteine mutant of BBOX from Pseudomonas sp. AK1 to monitor conformational changes upon ligand binding using 19F NMR spectroscopy. The results validate the use of 19F chemical labelling to monitor ligand binding to 2OG-dependent oxygenases and identifies a potential new class of small molecule inhibitor of BBOX. Synthetic work towards novel BBOX inhibitors is described in Appendix I.
Chapter 4 describes the design and synthesis of novel, broad-spectrum class B metallo β- lactamase inhibitors. The predicted binding modes of the potent mercaptopropionic acid derivative RL368 and its diastereomer RL369 were validated by X-ray crystallography. RL368, in particular, showed superior inhibition to the known inhibitors L- and D-captopril, and, pleasingly displays cell-based potential as an antibiotic following antimicrobial susceptibility assays against Gram negative pathogens of clinical origin; E. coli, E. aerogenes and K. pneumoniae.
Chapter 5 concerns the design, synthesis and implementation of a multifunctional PHD2- selective covalent probe compound RL409, which is aimed at irreversibly binding PHD2. By functionalising a reversibly binding PHD2 inhibitor with electrophilic and photoreactive moieties, it was possible to attach a biotin tag to PHD2 using a copper-free ‘click’ reaction with the aim to capture PHD2 from cell lysates.
Overall the results provide new insights into metallo-enzyme catalysis and describe new ways to inhibit them.

Advisor: Schofield, C