VictorJuiz/thesis huggingface dataset:
Ancient DNA perspectives on pathogen evolution in domestic animals
Keywords: zoonotic pathogens
pathogen evolution
metagenomics
ancient DNA

Pathogens, animals (domesticated or not) and humans have intertwined evolutionary trajectories for millennia now, with this relationship intensifying after the Neolithic Demographic Transition and its subsequent epidemiological transition that increased the exposure of animal populations to pathogenic reservoirs. Incorporating the temporal dimension in the study of disease evolution requires the incorporation of ancient pathogen DNA data in phylogenetic and population genetic analyses, which is not a simple task. Limited DNA survival and DNA damage, however, have hindered the search for ancient pathogens. For these reasons the accurate identification of microbial species from archaeological samples is integral and has the potential to provide an unprecedented perspective on the evolutionary history of major diseases that have affected humans and domestic animals. In the first chapter of this thesis I propose a novel analytical method for metagenomic identifications, HAYSTAC, which can also be applied for direct hypothesis testing regarding the presence of pathogens in metagenomic samples. By employing a clear probabilistic model for species identification from shotgun sequencing DNA data, along with incorporating additional algorithmic steps for taxonomic result validation, robust metagenomic identifications from sequencing data generated from archaeological samples become possible, with a significantly lower false positive rate when compared to pre-existing and established methods. In the second chapter of this thesis I used HAYSTAC to screen more than one thousand archaeological and modern chicken samples for Marek’s Disease Virus (MDV), a devastatingly virulent virus threatening the modern poultry industry. Following the DNA sequencing of archaeological chicken samples positive for MDV, I reconstructed the genomes of these ancient strains and compared them to modern ones. Through a time dependent phylogenetic reconstruction approach, I identified the possibility that modern MDV strains are evolving at an accelerated rate compared to ancient ones, with modern highly virulent strains possibly evolving from a potentially non-virulent (ancient) form (prior to 1907) of MDV, a finding that can have a significant impact on improving the health status of domestic chicken population globally. In the third chapter of this thesis, I examine if the process of domestication has had an impact on the disease burden of domestic pigs and dogs, by applying HAYSTAC. By applying hypothesis-driven species identification methods, I focused on screening animal derived metagenomes for zoonotic bacterial pathogens. Since many of the causative agents of these zoonotic diseases became prevalent in a post-industrial context, the results of this approach will be able to offer insights into how human activity has reshaped the landscapes of both the natural environment and animal diseases.
Microstructure imaging with diffusion MRI and microscopy
Keywords: diffusion modelling
polarised light imaging
microstructure Imaging
brain imaging
microscopy
diffusion MRI
white matter
data fusion
histology

Diffusion MRI is a powerful, non-invasive tool for microstructure imaging because of its sensitivity to structures on the microscopic scale. By analysing the diffusion signal we can infer the structural connectivity of the human brain or changes in the myelo- and cyto-architecture. This inference requires biophysical signal modelling, where we aim to map macroscopic diffusion signals onto biologically-meaningful tissue parameters. However, this mapping is often ill-posed, with multiple parameter sets fitting the signal equally well, and our parameters are said to be degenerate. Because degenerate parameters lack tissue specificity and are thus difficult to interpret, they present a serious challenge to diffusion modelling and limit the widespread application of diffusion MRI in both neuroscience research and clinical medicine.
This thesis explores various ways in which we can overcome parameter degeneracies to enable more specific microstructural interpretation of the diffusion signal. Consequently, this work spans species (human and macaque), tissue states (in vivo and postmortem), modalities (MRI and microscopy) and signals over four orders of magnitude, from sub-micron microscopy images to MRI at the millimetre scale. In particular, we develop two biophysical models of the white matter that aim to separate the diffusion characteristics from the tissue architecture (i.e. the fibre orientation, dispersion and density) and present a truly unique, multimodal dataset: the BigMac dataset. This dataset combines extensive MRI data with multi-contrast microscopy to characterise a single macaque brain in exquisite detail and will establish an innovative data platform from which we can interconnect microstructural features with MRI signals throughout the brain.
Overall, the models and data presented in this thesis aim to further our understanding of how microscopic tissue features influence the observed diffusion signal. We hope that this work will enhance the biophysical interpretation of diffusion MRI and ultimately advance in vivo quantification of the brain tissue microstructure.
The literary form of the Middle English pastoral manual with particular reference to the Speculum Christiani and some related texts
Keywords: literary form
Middle English
doctrines
pastoral theology
pastoral manual
clergy
Christian literature
Speculum Christiani

Pastoral manuals are designed as practical aids to the proper execution of the cura animarum and address themselves to the most immediate problems of parish life: basic catechesis of the laity and the administration of the Sacraments. By looking at the provision made in such works for teaching the rudiments of the Christian faith, it is possible to see how such books developed and evolved to meet the changing needs of the parish clergy (and ultimately of the literate layman), and to see the place of one of the most popular of such works, the Speculum Christiani, in this tradition of pastoral aid.
The first section, â€˜Contextâ€™, opens with an analysis of the legislation issued by the bishops in the thirteenth and fourteenth centuries, and shows how it influenced and encouraged the emergence of manuals of pastoral care which were distinct from the larger penitential reference books. It examines the developing concern with ignorantia sacerdotum and discusses the ways in which the syllabus of instruction included in many sets of constitutions became a structural norm for the contents of the pastoral manual. Chapter two examines the elementary and grammar schools and their books to show the ways in which pastoral handbooks were perhaps influenced by and overlapped with the 'set-texts' in the medieval English schools. Chapter three is a study of some of the Latin and vernacular pastoral manuals found in clerical miscellanies from early in the thirteenth century to early in the sixteenth. It examines the form of these manuals, how their contents changes and how their authors developed techniques for presenting and enlivening basic teachings. The influence of the pastoral tradition on works such as Piers Plowman is also considered.
Section two, â€˜The Evolution of the Speculum Christianiâ€™, is in the nature of a case history. In chapter four 1 discuss the Latin summa called Cibus Anime which seems to have provided most of the Latin quotations which make up the Speculum. An account of the versions of the text is given and the character of the text is discussed. An attempt is made to suggest the provenance and date of the work, which is anonymous. Chapter five provides a detailed analysis of the Speculum Christiani showing how its compiler exploited the resources of the Cibus Anime, reorganising the material into a working handbook of the pastoral care. A series of analytical tables chart the dependence of the Speculum upon the Cibus Anime and analyse the contents of some anomalous copies. The circulation of additional Latin texts (not included in the EETS edition of the Speculum but often found in the manuscripts) is charted and transcriptions of the texts provided. Some other works which also appear to draw on the Cibus Anime to support vernacular and Latin texts are discussed.
Social evolution in viruses
Keywords: Virology
Conflict
Cooperation
Altruism
Social evolution
Adaptation
Viruses
Evolutionary Biology
Sociovirology

Viruses are the most diverse and abundant lifeforms on Earth. In this thesis, I argue that they are also social organisms, and that it can be useful to study viruses within the framework of social evolution theory. Specifically, I: (i) define how cooperating and cheating can occur in viruses, review the diversity of viral cheats, and suggest why studying them can be useful for both virology and evolutionary biology; (ii) model how beneficial interactions between different viral variants can increase the genetic diversity of viral infections; (iii) model how beneficial interactions between viruses can promote the evolution of group dispersal in viruses; (iv) model distinct reasons for why vertically transmitted symbionts, viral or otherwise, are more cooperative than horizontally transmitted ones; (v) investigate the abundance of defective interfering ‘cheat’ genomes in natural infections of Influenza and SARS- CoV-2. Overall, I suggest that the nascent field of sociovirology has much to offer virologists and evolutionary biologists alike.
Selection among replicators and protocell chemotaxis
Keywords: nonlinear effects
Origins of life
lipid world
nonlinear kinetics
asymmetric autocatalysis
protocells
organocatalysis
oscillating reactions
lipid replicators
small molecule replicators
synthetic chemotaxis

This thesis describes a series of projects which have autocatalysis as the overarching theme.
Chapter 1 is a general introduction to the construction of chemical models of biological systems. There is a discussion of what mechanisms are used to achieve autocatalysis. The biomimetic work of chapters 3 and 4 use lipid replicators, so there is particular focus on the physical autocatalysis of lipid aggregates and their use in prebiotic models. The roles that lipids play in life are used as an illustration of the promise they offer to systems chemists. A brief history of biological homochirality is given.
Two designs for novel asymmetric autocatalytic reactions are described in chapter 2, both based on hydrogen bonding catalysis. Though neither system showed the desired amplification of chirality, this work led to the study of positive nonlinear effects within thiourea catalysis.
Projects which attempt to couple lipid replication with protocell behaviour are presented in chapter 3. In this chapter oil droplets are used as simple model protocells. Interestingly, feedback between the motion of droplets and a lipid forming reaction are observed, with the system showing striking chemotaxis. In the second part of this chapter other systems are used to explore the relationship between lipid formation and compartment division.
Chapter 4 describes observations relating to transient lipid replicators which can be fuelled to be maintained out of equilibrium. An initial finding shows that fuelling can result in dramatic oscillations, as well as stable concentrations. When lipids compete for resources, they typically show a succession through time, an interesting protocell model. Which replicating species dominates results from a multitude of combined effects which cannot be predicted simply using rates of formation of each lipid in isolation.
Finally, chapter 5 outlines the conclusions that can be drawn from these results and what future work remains.
Illegal jaguar trade in Latin America: an evidence-based approach to support conservation actions
Keywords: Jaguar
Decision-making
Illegal Wildlife Trade
Panthera onca
Big cats
Human-Wildlife Conflict
Carnivore conservation

The Illegal Trade in Wildlife (IWT) is one of the most cumbersome threats currently facing biodiversity, with broad implications for the health and wellbeing of humans and nature. Over the past decade, reports of international illegal trade in jaguars (Panthera onca), with links to demand from Asian wildlife markets, have emerged throughout Latin America, raising the profile of jaguars as the emblem of Latin America’s fight against IWT. This DPhil is among the first to explore the characteristics, prevalence, and drivers of this threat to jaguars, with the goal of providing scientific evidence in support of ongoing and future projects and policies aimed at addressing it. Data collection efforts centred in Mesoamerica and Bolivia, two areas with varying degrees of evidence of international trade, and were based on interviews with enforcement agents and conservation practitioners, and questionnaire surveys with rural communities coexisting with jaguars. In both study areas, the illegal jaguar trade was found to be a prevalent, domestically-focused, and opportunistic activity, driven largely by the confluence of cultural traditions surrounding wildlife uses, forest-dependent livelihoods, and negative perceptions and interactions with jaguars, manifested through human-jaguar conflict. To a lesser degree, the trade was also influenced by a more diverse set of external actors and drivers than originally expected, including tourists of diverse backgrounds, regional immigrants, and traders of Asian-decent. Enabling factors ranged from critical limitations in the enforcement capacity of wildlife authorities, to a high social acceptability of jaguar killing in rural communities. Additionally, the DPhil highlighted biases in how those in charge of addressing the illegal trade in jaguars perceive and use evidence on the trade, with a tendency to disregard its reliability and conservation relevance. To address this issue, the DPhil provides guidelines towards a more objective decision-making on the illegal wildlife trade, and reinforces the need for evidence-based, multifaceted, counter-trafficking approaches that consider the complex interacting domestic and international, cultural and commercial drivers behind the illegal trade in jaguars.
Structural studies of the Type IX secretion system inner membrane complex
Keywords: bacterial secretion
type IX secretion system
cryoEM
gliding motility

The Type IX Secretion System (T9SS) is a protein transport system found exclusively in the Bacteroidetes phylum of Gram-negative bacteria. The T9SS transports folded substrates across the outer membrane, including virulence factors of human pathogens, polysaccharide utilisation enzymes of environmental bacteria, and cell-surface adhesin molecules involved in Bacteroidetes gliding motility
The inner membrane proteins GldL and GldM use the proton-motive force to energise both the T9SS and the gliding motility apparatus. I present structures from five different species of the transmembrane core of the GldLM complex, solved using electron cryo-microscopy. The GldLM complex has two copies of GldM with one transmembrane helix each, surrounded by five copies of GldL with two transmembrane helices each. Most of the cytoplasmic domain of GldL was unresolved. I also present a low-resolution structure of the full length orthologous PorLM complex from Porphyromonas gingivalis.
Several polar residues are present in the transmembrane helices of GldL and GldM, suggesting that they may have a role in conducting protons across the inner membrane. I generated mutant strains where these polar residues were substituted with non-polar alternatives and found that some of these strains were deficient in T9SS and gliding motility. A universally conserved glutamate residue in GldL was essential to T9SS and gliding motility activity. In the structures of GldLM, one copy of this glutamate residue appears to form a salt bridge with a conserved arginine residue in one copy of GldM. I propose that a proton flow-dependent alternation of which copy of GldM is involved in salt bridge formation drives rotation of the GldM dimer, which spans the periplasm to connect the inner membrane and outer membrane components of the T9SS.
These results reveal the GldLM complex to be a third class of ion-driven rotary motor after the ATP synthase and the MotAB flagellar stator family.
Anti-microbial activity and inflammation in Hermansky-Pudlak Syndrome type 1
Keywords: Inflammation
Hermansky-Pudlak Syndrome
Anti-microbial activity
Monogenic disease
Inflammatory bowel disease

Inflammatory bowel disease (IBD) is caused by a breakdown in tolerance of the immune system to the gut microbiota in genetically predisposed individuals. The mechanisms underlying IBD are complex and multifactorial. Monogenic diseases with intestinal inflammation provide important puzzle pieces in identifying key mechanisms of barrier function. Hermansky-Pudlak Syndrome type 1 (HPS-1) features defective vesicle trafficking and can include complications such as Crohn’s-like intestinal inflammation and pulmonary fibrosis. In this thesis, I pinpoint aberrant immunometabolism in HPS-1 patient macrophages using transcriptomics and functional assays. Following bacterial infection, HPS-1 macrophages feature an augmented TNF/OSM signature, which underlies polygenic IBD. I validate the deregulated immunometabolism in HPS1 knockout HAP1 cells, which have defective cholesterol metabolism and enhanced low density lipoprotein uptake. Using lysosomal immunoprecipitation and proteomics, I identify increased mTOR levels on HPS1 knockout lysosomes, which translates into enhanced mTORC1 signaling. The amplified mTORC1 signaling in HPS1 deficiency is mediated by Rab32. The alterations in metabolism and mTORC1 activation cause impaired anti-bacterial immunity in HPS1 knockout cells and HPS-1 patient macrophages. Mass cytometry of HPS-1 peripheral blood reveals an expansion of inflammatory monocytes, while serum proteomics uncovers a TNF/IL-1α signature in HPS- 1. Suppression of mTORC1 signaling through rapamycin treatment rescues the bacterial clearance defect in HPS-1 patient macrophages, providing a novel therapeutic target for HPS- IBD. These findings have implications beyond HPS, since augmented mTOR signaling and derailed metabolism can trigger inflammation in several diseases, such as lysosomal storage disorders.
Combining digital histology with magnetic resonance imaging in amyotrophic lateral sclerosis
Keywords: biomedical imaging
multimodal
histology
MRI
software
tensor image registration library
amyotrophic lateral sclerosis
post-mortem
neuroscience
image registration
magnetic resonance imaging
TIRL

There is an increasing demand for non-invasive biomarkers that can reliably indicate the presence and extent of neurodegeneration in its early stages. Various magnetic resonance imaging (MRI) methods have shown great potential to indicate the event of upper motor neuron involvement in the progression of amyotrophic lateral sclerosis (ALS) at the population level, but almost none of these have been systematically validated against traditional histological markers at the individual level. Validation relies on a precise and preferably automatic method to align a large number of MRI and histology images of the same tissue, which poses unique challenges compared to more conventional MRI-to-MRI registration.
The thesis summarises the development and evaluation of a novel image registration framework (Tensor Image Registration Library) that is designed to achieve automated registration between sparsely sampled histology sections and whole-brain post-mortem MR volumes derived from an ALS study cohort. A multistage automated pipeline is developed, in which two types of histology sections are registered to an MRI volume via one or two photographic intermediates. The research chapters explain the rationale behind each stage, describe the algorithm, and report the experiments that were carried out to verify the accuracy and robustness of the implementation.
The proposed method uniquely integrates part-to-whole matching and 2D-to-3D registration, allowing conventional small histology samples to be registered without serial sectioning. Furthermore, the orthogonal deformations of a slice are estimated to account for the imperfections of a free-hand cut, which are shown to be as large as several millimetres. The pipeline achieves sub-millimetre accuracy in each stage and equally accurate alignment between histology and MRI when the stages are combined. This registration approach alleviates the need for specialist cutting or stain automation hardware, and is therefore suitable for integration into a wide range of studies that utilise routine neuropathology practices.
Foreign influence operations in the cyber age
Keywords: influence operations
public opinion
social media
disinformation

After Russia’s interference in the 2016 U.S. election, influence operations gained great prominence in the public consciousness. Yet, International Security Studies lags behind. Our theories of public opinion formation are primarily from a pre-cyber age, and we lack answers to fundamental questions about influence operations as a tool of statecraft. How can we conceptualize influence operations? Is pretending to be a member of another state to influence foreign citizens a viable strategy? Does plausible deniability afford states the benefits theorized by existing covert action literature? I interrogate these questions to provide a better understanding of the psychological mechanisms and potential effects of foreign influence operations, contributing to the academic study of secrecy and to illuminating the threat democratic societies now face.
I begin with a concept-building paper, which proposes and defends a definition of influence operations and explains their prevalence today. This prepares the ground for an emerging research field and motivates the investigation of the benefits of secrecy. In the second paper, leveraging cross-national experiments, I challenge the conventional top-down model of cue-taking in International Relations. I show that elite cues do not have a significantly stronger impact than public cues on citizens’ attitudes towards a cyber-attack. This suggests that influence operations that attempt to influence mass attitudes by falsifying peer cues may allow foreign actors to benefit from secrecy for operational success. The third paper builds from the observation that politicians increasingly outsource disinformation work to private firms, but the assumption that they benefit from plausible deniability is untested. Results from an original experiment show that when governments are not implicated in an operation that originates in their country, they can avoid blowback and yet are no less effective at stirring paranoia or appearing omnipotent. I add the novel insight that the country of origin matters much more to Americans than the specifics of attribution.