VictorJuiz/thesis huggingface dataset:
The decline of the infinitive in Bulgarian

The change from infinitives to clausal constructions is a character- istic of languages of the Balkan area - Greek, Bulgarian and Macedonian, Roumanian and Aroumanian, Albanian - which distinguishes them from their Indo-Europeancognates,andfrommostotherlanguagesoftheworld. It is therefore, interesting both as an unusual linguistic development and as a probable instance of syntactic interaction between geographically con- tiguous languages. The thesis is an attempt to examine, in as much detail as the scanty historical records permit, how this change took place in Bulgarian, and to consider in the light of their evidence the relative merits of the various explanations which have been offered for the change, whether as aBulgariandevelopmentorasaBalkanphenomenon. Thus,althoughatten- tion is given mainly to Bulgarian, it is hoped that the conclusions may beinsomepartacontributiontoBalkanstudies. Itisalsohopedthat the body of factual material presented, which is drawn from published sources either not previously studied from this point of view or not studied so fully, may be of use to other investigations of the history of Bulgarian. Thefindingsareheldtoaddfreshevidencetothoseinthe most detailed work on the subject, Mirchev's monograph of 1937, some of whose conclusions are disputed in the thesis. The object of research is defined as the Bulgarian language from the tenth to the seventeenth centuries, that is, from its first written re- cords to the date when its syntax had developed to approximately its modern state. For practical reasons Bulgarian and Macedonian are not dis- tinguished in the thesis, although their separate status as modern lan- guages is recognized. [Abstract continues in thesis]
Evidence based hypothermic preservation of the kidney and liver for transplantation

Improving the techniques used for the preservation of livers and kidneys for transplantation has the potential to enhance the outcomes of transplant procedures. With an ever increasing demand for suitable organs, we now turn to the use of organs that may once have been considered to have lower success rates. The importance of preventing further damage to these organs during preservation is even greater than for standard organs. National and international guidelines for the use of such techniques in health service provision should be based upon the best level of evidence available; this is a particular challenge in a specialty with relatively few numbers of procedures each year.
This thesis describes a cohesive group of complementary studies which analyse the comparative effectiveness of preservation fluids for the cold storage of kidney and liver allografts from deceased donors. It also describes the comparison of hypothermic machine perfusion with static cold storage of kidneys. The systematic reviews carried out have a wider scope than any previously conducted. A novel approach was also taken towards the analysis of survival outcomes after transplantation as described in multiple studies. This work includes an analysis of national registry data that is the only large-scale comparison between Marshall’s Solution and University of Wisconsin Solution for kidney preservation.
There is limited trial evidence that suggests similarity between the effectiveness of current preservation fluids for kidney preservation, and good evidence that Celsior and University of Wisconsin Solutions are equivalent for liver preservation. Good randomised trial evidence suggests that hypothermic machine perfusion reduces delayed graft function of kidneys. Hypothermic machine perfusion may also result in improved graft survival, but robust evidence is not available for this. The continued use of Marshall’s Solution for kidney preservation in the UK results in equivalent adjusted outcomes compared to University of Wisconsin Solution.

Keywords: systematic review
organ preservation
transplantation
surgery
Advisor: Morris, P
Friend, P
Natural language variables: variable-based semantic theories of pronouns and proper names

Semanticists, philosophers and logicians have standardly analyzed a range of natural language expressions on the model of the variables of formal languages. This dissertation explores variable- based semantic theories of pronounsand proper names.
The first two chapters argue that a variable-based, presuppositional semantics for pronouns proposed by Cooper (1979, 1983) resolves an apparent trilemma arising from the conjunction of three plausible commitments concerning the semantics of pronouns: that some anaphoric pronouns with quantifier antecedents are bound variables, that referential pronouns have context-independent meanings, and that the relation between bound and referential pronouns is not ambiguity or homonymy.
The first chapter argues that Cooper’s semantics is descriptively and empirically superior to alternative theories, including Kaplan’s account, which does not resolve the trilemma. The second addresses an important objection to the view that bound and referential pronouns make the same semantic contribution, involving cases where bound pronouns do not appear to trigger semantic presuppositions. I argue that this appearance is misleading: bound pronouns do trigger semantic presuppositions and have the same (Cooper-style) denotations as referential pronouns.
The third chapter addresses the phenomenon of non c-command or ‘donkey’ anaphora. These anaphors appear to require a departure from Cooper’s semantics and, more generally, from the view that anaphoric pronouns correspond to (classical) bound variables. I consider D-type accounts of donkey anaphora and argue that these accounts must be revised in ways that bring the denotations of donkey anaphors closer to those of ordinary bound and referential pronouns.
The last chapter asks whether proper names require a variable-based semantics. I consider a pair of recent anaphoric theories of proper names, according to which proper names have anaphoric uses and are thus better modeled as variables. I argue that there are important reasons to reject a variable-based model for proper names, in contrast with pronouns.

Keywords: pronouns
variables
anaphora
Advisor: Williamson, T
The evolution of cooperation, especially in humans

I develop social evolution theory to study the evolution of cooperation as follows: (1) Many organisms undergo a dispersal phase prior to breeding; I demonstrate that knowing ones dispersal status aids the evolution of helping (by non-dispersers) and harming (by dispersers). (2) Policing driven by group-benefits may be selected to enforce cooperation in human and animal societies. I extend existing theory to show that policing may be harder to evolve that previously thought, but that it is maintained more readily than it evolves. (3) Archeological and anthropological evidence suggests that warfare was prevalent during our evolution. I show that, contrary to previous suggestions, between-group competition can favour any social behaviour (pro-social or anti-social) so long as it helps the group compete, and that such traits can be altruistic or mutually beneficial. (4) Reproductive leveling is analogous to policing; in the human literature there is doubt as to whether it can evolve. I extend my previous work to consider the coevolution of culturally and genetically inherited traits for reproductive leveling and selfishness. I find that cooperation can evolve between non-kin if they share the same culture. (5) Monogamy is thought to favour the evolution of cooperative breeding. I show that in the simplest case, because of the cost of competition between non-dispersing siblings, the level of promiscuity has little or no effect on the evolution of cooperation. (6) Spatial structure (limited dispersal) is thought to favour the evolution of inter-specific mutualisms as it aligns the partners’ interests. I consider the case of plant-fungi mutualisms and show that spatial structure can disfavour cooperation if it limits the potential fungal partners available to the plant.

Keywords: Evolutionary biology
Human Evolution
Sociobiology
Inclusive Fitness
Cultural Evolution
Kin Selection
Advisor: West, S
Gardner, A
Statistical models for single-cell data

The growing use of single-cell gene expression data (scRNA-seq data) has made it possible to more precisely identify cellular subpopulations with distinct characteristics. This offers insight both into normal cellular function and into diseases such as cancer. However, single-cell data presents new challenges which standard clustering and dimensionality reduction methods are not designed to confront. Rather than being drawn from Gaussians as assumed by most models, single-cell datasets contain an overabundance of zeros. We use several scRNA-seq datasets to investigate how zeros are distributed in real biological data. Based on our findings, we perform a series of simulations to examine how standard clustering and dimensionality reduction methods perform on high-dimensional, zero-inflated data. We show that performance suffers as the fraction of zeros increases and that more complex non-linear models fail to alleviate this problem. Based on this, we then present two new models that account for zeros: one to perform dimensionality reduction, and one to perform clustering. For dimensionality reduction, we present an extension of the factor analysis model which accounts for zero-inflation by adding a single parameter which describes how the probability of technical zeros decreases with the expression level of a gene. We show that our model, ZIFA, outperforms factor analysis and probabilistic principal components analysis on simulated data. For clustering, we present a extension of the Gaussian mixture model which accounts for zero-inflation. We show that our model, ZIMM, outperforms k-means and Gaussian mixture models on simulated data. We also show that both ZIFA and ZIMM better fit real data from several scRNA-seq experiments, and provide fast software implementations of both models. Lastly, we explore applications of our models to several other classes of non-biological datasets.

Keywords: dimensionality reduction
statistics
cancer
single-cell data
Advisor: Yau, C
Investigation of binding preferences and identification of novel binding partners for the SH3 domains of the multifunctional adaptor protein CD2AP

CD2AP is a member of the CD2AP/CIN85 family of adaptors and involved in several cellular processes, such as kidney podocyte development, actin mediated membrane trafficking and T cell activation. It contains three SH3 domains whose binding properties and interaction partners remain largely unexplored.
The CD2AP SH3 interaction with the novel partner Rab5-activating GEF RIN3 was studied extensively by isothermal titration calorimetry (ITC), peptide scanning arrays, mutagenesis and X-ray crystallography. Mapping of the interaction regions showed that human RIN3 contains two binding sites for the CD2AP SH3 domains. From these studies, the CD2AP SH3 recognition motif P-x-P/A-x-x-R emerged. Two crystal structures (1.65 Å and 1.2 Å) of the SH3 1 and SH3-2 domains in complex with RIN3 epitopes 1 and 2 respectively revealed that these residues serve as anchoring points. With the aid of bioinformatics tools, this motif was used to conduct a peptide array-based screen for additional signalling partner candidates. One of the hits was the Arf-GAP ARAP1. ITC data indicate that the three SH3 domains differentially recognise three ARAP1 epitopes, with the first ARAP1 epitope binding to SH3-2 in the nanomolar range. A crystal structure (1.6 Å) of the SH3-2 domain in complex with the first ARAP1 epitope implicates two additional anchoring residues that extend beyond the PPII helical region of the canonical motif. The CD2AP/ARAP1 interaction was confirmed in podocytes and cancer cells at the endogenous protein level. Even though RIN3 and ARAP1 are involved in membrane trafficking, a direct link to CD2AP had not been reported before. Other candidates from the peptide array analyses were also investigated by ITC.
In conclusion, this study led to the elucidation of the CD2AP SH3-1 and SH3-2 domain binding signatures and the identification of putative novel binding partners for all three SH3 domains. Lastly, insight was gained into the binding preferences of CD2AP SH3-3.

Keywords: isothermal titration calorimetry
SH3 domain
cell culture
podocyte
peptide array
protein crystallography
CD2AP
ARAP1
RIN3
Advisor: Feller, S
Numerical modelling of shallow flows with horizontal density variation

A numerical model is presented of vertically homogeneous shallow flows with variable horizontal density. The governing equations represent mass and momentum conservation of a liquid-species mixture, and mass conservation of the species within a control volume. Here, the term species refers to material transported with the liquid flow. For example, when the species is taken to be suspended sediment, the model provides an idealised simulation of hyper-concentrated sediment-laden flows. The volumetric species concentration acts as an active scalar, allowing the species dynamics to influence the flow structure. The model can simulate flows driven by depth and density differences in the horizontal. The governing equations are written in a deviatoric, hyperbolic form to facilitate their solution by means of a Godunov-type finite volume scheme appropriate for flows containing sharp fronts. The deviatoric governing equations ensure that flux gradient and source terms are balanced (and there is no need for further numerical balancing).
The numerical model is first verified for constant density cases, for which the governing equations reduce to the conventional coupled shallow water and species transport equations. Close agreement between numerical predictions and benchmark test solutions illustrate the model's ability to capture rapidly-varying flow features over uniform and non-uniform bathymetries.
For variable-density cases, analytical steady-state solutions are derived for two simple cases, one with uniform bathymetry and the other with sinusoidal bathymetry. Detailed parameter studies are then undertaken to examine the effects of varying the initial density and depth in different regions. The shock-capturing scheme resolves all sharp features in the flow such as bore, shear waves, shock diamond like features, contact discontinuities and locally intense vortices. These interesting and novel nonlinear features are unique to variable density flows.
The validated numerical model is applied to an idealised case of a hyperconcentrated sediment-laden debris-type flow along a tributary entering a river. The predicted evolution of the free surface flow field is qualitatively similar to observations of an actual debris flows into a river connected to the Upper Yangtze.

Advisor: Borthwick, A
Development of clinical biomarkers of DNA double strand breaks for cancer care

Many anticancer therapies, including radiotherapy, act by damaging the deoxyribosenucleic acid (DNA) that is fundamental to cell function and proliferation. H2AX is a histone protein associated with DNA that is phosphorylated to produce γH2AX in response to DNA double strand breaks (DSBs), the most lethal lesions caused in cancer cells. This thesis examines the translation of γH2AX detection assays to clinical situations in order to provide biomarkers of response that might help to guide the treatment of cancer patients.
γH2AX immunohistochemistry was developed in preclinical xenograft models, and validated over a range of radiation doses and over time after irradiation. The method was prepared for translation to archived clinical biopsy and surgical specimens.
The DSB Biomarkers Pilot Study was established in order to develop a method for γH2AX quantification in direct tumour cell specimens obtained using the clinical technique of fine needle aspiration (FNA) cytology. Eleven patients undergoing anticancer therapy were recruited to the study, and the method evaluated. The coefficient of variation of the measure was 49%.
Non-invasive imaging for γH2AX would allow DNA damage to be quantified in all tumour sites, and on multiple occasions. An antibody-based nuclear medicine imaging agent was re-engineered using Fab fragments of the antibody. The novel agent demonstrated improved pharmacokinetics when compared to the whole antibody agent, but reduced target specificity.
The findings further develop the potential to exploit DNA damage biomarker measurements in clinical oncology.

Keywords: functional imaging
DNA damage
biomarker
Advisor: Vallis, K
Autophagy in hematopoiesis and acute myeloid leukemia

Acute myeloid leukemia (AML) develops following oncogenic alterations to hematopoietic stem (HSC) and progenitor cells (HSPCs) in the bone marrow, resulting in dysregulated proliferation of immature myeloid progenitors that interferes with normal hematopoiesis. Understanding the mechanisms of HSPC protection against damage and excessive division, and how these pathways are altered during leukemic progression, is vital for establishing effective therapies. Here, we show that autophagy, a lysosomal degradation pathway, is increased in HSPCs using a novel imaging flow cytometry autophagy assay. Loss of hematopoietic autophagy following deletion of key gene Atg5 resulted in increased HSC proliferation, leading to HSC exhaustion and bone marrow failure. Although erythrocyte and lymphocyte populations were negatively impacted by autophagy loss, myeloid cells showing immature characteristics were expanded. Deletion of Atg5 in an AML model resulted in increased proliferation under metabolic stress, dependent on the glycolytic pathway, and aberrant upstream mTOR signaling. Moreover, modulation of Atg5 altered leukemic response to culture with stromal cells. Finally, primary AML cells displayed multiple markers of decreased autophagy. These data suggest a role for autophagy in preserving HSC function, partially through suppression of HSPC proliferation, and indicate that decreased autophagy may benefit AML cells. We postulate that modulation of autophagy could help maintain stem cell function, for example during transplantation, and aid AML therapy in a setting-specific manner.

Keywords: Metabolism
Autophagy
Acute Myeloid Leukemia (AML)
Hematopoietic Stem Cell
Glycolysis
Cancer
Hematopoiesis
Myeloid cells
Advisor: Simon, A
Selective routes to substituted dihydropyridones

Introduction: The introduction provides a survey of the natural product and pharmaceutical targets accessible from dihydropyridines and dihydropyridones as well as an overview of previous work carried out towards the synthesis of these valuable intermediates. The mechanism, scope and limitations of the various approaches are covered, along with the goals of this project.
Results and Discussion: A Regioselective Route to Dihydropyridones. The regioselective addition of nucleophiles to a range of disubstituted pyridinium salts has been achieved, with selectivity determined by hard/soft factors. Certain nucleophiles can be added with complete regioselectivity to either C-2 or C-6 of these salts, depending on the conditions employed. Addition at C-2 allows the generation of a quaternary centre in high yield. The conditions discovered can be applied to pyridinium salts with different substitution patterns and an effective procedure has been developed for the removal of the nitrogen protecting group post reduction.
The Preparation of Enantiopure Dihydropyridones.After unsuccessful attempts to find a reagent-controlled asymmetric synthesis of dihydropyridones, a highly diastereoselective and non-chiral auxiliary based substrate-controlled procedure has been developed. By prompting an intramolecular hydride migration from a secondary silyl ether onto the pyridinium core, the corresponding dihydropyridones are available in high yield, with the diastereoselectivity being controlled by the minimization of 1,3-allylic strain between the N-allyl group and the hydride-bearing side chain. Thus, an enantiopure pyridyl alcohol may be converted to the corresponding dihydropyridone without loss of enantiomeric purity. Furthermore, the dihydropyridones can be easily converted to complex bicyclic systems via a ring closing metathesis reaction.
Experimental: Full experimental procedures and spectroscopic characterization of compounds are provided.

Keywords: dihydropyridones
reduction
asymmetric synthesis
pyridines
Advisor: Donohoe, T
Mathematical model of plant nutrient uptake

This thesis deals with the mathematical modelling of nutrient uptake by plant roots. It starts with the Nye-Tinker-Barber model for nutrient uptake by a single bare cylindrical root. The model is treated using matched asymptotic expansion and an analytic formula for the rate of nutrient uptake is derived for the first time. The basic model is then extended to include root hairs and mycorrhizae, which have been found experimentally to be very important for the uptake of immobile nutrients. Again, analytic expressions for nutrient uptake are derived. The simplicity and clarity of the analytical formulae for the solution of the single root models allows the extension of these models to more realistic branched roots. These models clearly show that the `volume averaging of branching structure' technique commonly used to extend the Nye-Tinker-Barber with experiments can lead to large errors. The same models also indicate that in the absence of large-scale water movement, due to rainfall, fertiliser fails to penetrate into the soil. This motivates us to build a model for water movement and uptake by branched root structures. This model considers the simultaneous flow of water in the soil, uptake by the roots, and flow within the root branching network to the stems of the plant. The water uptake model shows that the water saturation can develop pseudo-steady-state wet and dry zones in the rooting region of the soil. The dry zone is shown to stop the movement of nutrient from the top of the soil to the groundwater. Finally we present a model for the simultaneous movement and uptake of both nutrients and water. This is discussed as a new tool for interpreting available experimental results and designing future experiments. The parallels between evolution and mathematical optimisation are also discussed.