VictorJuiz/thesis huggingface dataset:
Identification and characterisation of epigenetic mechanisms in osteoblast differentiation of human mesenchymal stem cells

A major therapeutic challenge in musculoskeletal regenerative medicine is how to effectively replenish bone tissue lost due to pathological conditions such as fracture, osteoporosis, or rheumatoid arthritis. Mesenchymal stem cells are currently investigated for applications in bone-tissue engineering and human bone marrow-derived mesenchymal stem cells (hMSCs) could be a promising source for generation of tissue-engineered bone. However, the therapeutic potential of MSCs has not been fully exploited due to a lack of knowledge regarding the identity, nature, and differentiation of hMSCs. Epigenetic mechanisms regulating the chromatin structure as well as specific gene transcription are crucial in determination of stem cell differentiation. With the aim to systematically identify epigenetic factors that modulate MSC differentiation, the work in this thesis encompasses an approach to identify epigenetic mechanisms underlying, initiating, and promoting osteoblast differentiation, and the investigation of individual epigenetic modulators. Various osteogenic inducers were validated for differentiation of MSCs and an assay allowing assessment of differentiation outcome was developed. This assay was subsequently employed in knockdown experiments with lentiviral short hairpin RNAs and inhibitor screens with small molecules targeting putative druggable epigenetic modulator classes. This approach identified around 100 epigenetic modulator candidates involved in osteoblast differentiation, of these candidates approximately 2/3 downregulated and 1/3 upregulated alkaline phosphatase (ALP) activity. Serving as a proof-of-concept, orthogonal validation experiments employing locked nucleic acid (LNA) knockdown were performed to validate a subset of candidates. Two identified target genes were selected for further investigation. Bromodomain-containing protein 4 (BRD4) was identified as one component of epigenetic regulation; its inhibition led to a decrease in ALP expression, downregulation of key osteoblast transcription factors Runx2 and Osterix, as well as impaired bone matrix formation. Knockdown of lysine (K)-specific demethylase 1A (KDM1A/LSD1) upregulated ALP activity and treatment with a small molecule inhibitor targeting KDM1A led to an increase in ALP, RUNX2, and bone sialoprotein expression. Intriguingly, in a transgenic mouse model overexpressing Kdm1a a decrease in bone volume and bone mineral density was observed, thus supporting the hypothesis that KDM1A is a central regulator of osteoblast differentiation.

Keywords: Stem cells
Demethylase
Osteoblast differentiation
Epigenetics
Mesenchymal stem cells
Tissue engineering
Bromodomain
Regenerative Medicine
Advisor: Oppermann, U
Dunford, J
A history of the Central Council for Health Education, 1927-1968

This dissertation examines the organisational background to the modern British health education movement, largely by reference to the origins and forty years' history of the Central Council for Health Education (1927-1968), the first body attempting to impart leadership and national coherence to a diffuse and eclectic field of educational practice and health promotion which has found secure administrative foundations difficult to establish.
The study begins with a review of nineteenth and early twentieth century influences contributing to the character and status of the movement in its pioneering years. The predominantly propagandist roots and voluntary sector affinities with which it emerged from half and century's precursory endeavours profoundly affected health education's opportunities to advance with other aspects of health care and education in the inter-war years. By then, health education had become a diffuse and unco-ordinated field of minor, local authority initiatives and separatist campaigning by specialist, national health charities, remaining largely outside the remit of health and education professions and neglected officially. How the challenge of countering developmental difficulties fell to a minor professional body rather than an officially promoted one, is a question critical to any interpretation of later developments, and the subject of further enquiry.
Subsequent investigation focuses on the evolution of the central agency which resulted, the Central Council for Health Education, particularly its thirty years' quest for official recognition and stature, and the strategies and services devised in this cause. It is a story of persistent and widespread enterprise, significant in many of its ideas but constrained in their effective development by enduring failure to attract Government support and to progress beyond the limited subscription income and essentially propagandist aspirations of local public health services. Adjudged ineffective by the 'Cohen Enquiry' of 1960-64, Government intervation proved forty years late in seeking to redress the problems of inadequate central provision, when in 1968 an officially funded Health Education Council replaced its neglected predecessor.
The investigation reveals the classical dilemma of a multi-disciplinary field failing to transcend the divisive character of its own interests, in search for developmental coherence, and failing, consequently, to command effective professional and political support.

Keywords: UK
health education
health promotion
health education movement
Central Council for Health Education (1927-1968)
Whose peace? Local ownership and UN peacebuilding

Recent years have seen an increasing emphasis on local ownership in UN peacebuilding. Advocates of local ownership assert that it boosts the legitimacy and sustainability of UN peacebuilding by helping to preserve the principles of self- determination and non-imposition of externally-conceived solutions onto post-conflict countries in an activity that can contravene them. However, while the UN perceives local ownership as enabling it to act in accordance with these principles, it also perceives local ownership to imperil the achievement of its operational goals, thus bringing its normative and operational objectives into conflict. This thesis evaluates the UN’s discourse, understandings, and operationalizations of local ownership in peacebuilding. Drawing on examples from the UN peace operation in DR Congo, it shows that despite the UN’s regular invocation of local ownership discourse, it operationalizes ownership in restrictive and selective ways that are intended to protect the achievement of operational goals but that consequently limit self-determination and increase external imposition on the host country. This gap between the rhetoric and reality of ownership suggests that the UN uses local ownership primarily as a discursive tool for legitimation, one intended to reconcile the organization’s normative and operational imperatives. However, because its actions do not match its rhetoric, the UN’s attempts to generate legitimacy through discourse appear to fall flat, particularly in the eyes of local actors. Moreover, because of contradictions in the ways that the UN operationalizes local ownership, it not only deepens the curtailment of self-determination and the degree of external imposition, it also undercuts its ability to realize the very operational goals it is trying to protect. Ultimately, because it is a contradictory and contested concept, local ownership fails to eliminate or ‘fix’ the trade-offs the UN faces in peacebuilding, suggesting that the UN must instead accept them and incorporate them into its goals and expectations.

Keywords: United Nations
post-conflict reconstruction
peacekeeping
peacebuilding
conflict
local ownership
Democratic Republic of the Congo
intervention
Advisor: Caplan, R
Visuomotor mechanisms in reaching in adults, infants, and children

This thesis investigates how adults, infants, and children use visual information to control reaching movements. To do this, the kinematics of a reaching movement were recorded using a 6 camera motion tracking system.
Adult reaching movements were investigated in three different experiments. The first experiment looked at the effect of visual information about the reach space and the target on reaching movements. Adult reaches are significantly affected by removal of visual information about the reach space and the target, e.g. peak speed decreases as distance information is occluded. Adult reaching movements are also affected by the length of the delay between viewing an object and then reaching for it in complete darkness. Experiment 2 reveals that there is a linear increase in movement duration, decrease in peak speed, and increase in maximum grip aperture with increasing temporal delay. This is due to the decay of dorsal visual information. Experiment 3 found that a cautious reaching movement can be defined as a reach where duration increases, average speed decreases, and peak timing is proportionally earlier in the reach.
The three developmental experiments investigated the changes in reaching in infancy, in typically developing 5-year-old children, and in children with Williams syndrome (WS). Between 9 and 16 months of age, infants develop better coordination of reaching movements. Improved dark reaching behaviour in 16-month-olds may be associated with more mature processing in the dorsal visual stream. Reaching movements in 5-year-old children are straighter and faster than infant reaches but behaviour is not yet stereotyped like adults. WS children generate reaches that are slower and incorporate more movement units than 5-year-old children, and WS behaviour may reflect poor processing of dorsal visual information rather than poor control of arm movement.

Keywords: reaching movements
perception
visual motor control
Developmental psychology
Advisor: Braddick, O
Quantum phase of Bose-Einstein condensates

The quantum phase of a Bose-Einstein condensate has long been a subject fraught with misunderstanding and confusion. In this thesis we provide a consis- tent description of this phenomenon and, in particular, discuss how phase may be defined, created, manipulated, and controlled.
We begin by describing how it is possible to set up a reference condensate against which the phase of other condensates can be compared. This allows us to think of relative phases as if they were absolute and gives a clear and precise definition to 'the phase of a condensate'. A relative phase may also be established by coupling condensates and we show how this can be controlled. We then extend this model to explain how the phase along a chain of coupled condensates can lock naturally without the need for any measurements.
The second part of the thesis deals primarily with the link between entangle- ment and phase. We show that, in general, the more entangled a state is, the better its phase resolution. This leads us to consider schemes by which maximally entangled states may be able to be created since these should give the best prac- tical advantages over their classical counterparts. We consider two such states: a number correlated pair of condensates and a Schrodinger cat state. Both schemes are shown to be remarkably robust to loss.
A comparison of the merits of these two states, as the inputs to an interferom- eter, reveals very different behaviours. In particular, the number correlated state performs significantly better than the cat state in the presence of loss, which means that it might be useful in interferometry and frequency standard schemes where phase resolution is of the utmost importance.
Finally, we propose a scheme for concentrating the entanglement between con- densates, which is an important step in quantum communication protocols. This, along with the ability to manipulate phase and entanglement, suggests that the future for condensates holds not only academic interest but great potential for practical applications.

Advisor: Burnett, K
The tumour suppressor ASPP2 plays a novel role in the maintenance of epithelial cell polarity

ASPP2 has been identified as a haploinsufficient tumour suppressor in mice, and an activator of the apoptotic function of the p53 family. Yeast two-hybrid experiments have also shown that ASPP2 interacts with a large number of proteins involved in other major signalling pathways. The mechanism(s) of action of ASPP2 are therefore complex, and likely to involve more than just the stimulation of the apoptotic programme.
Since a study previously conducted in our laboratory revealed that the deletion of ASPP2 in vivo leads to severe hydrocephalus in the J129/C57BL6 background (Vives et al., 2006), it can be hypothesised that ASPP2 safeguards the normal development of the mammalian central nervous system (CNS), in addition to its role as a tumour suppressor. Deletion of ASPP2 leads to the development of hydrocephalus, most probably by affecting tight junctions (TJs) in the choroid plexus, thereby impairing its bloodcerebrospinal fluid (CSF) barrier function. TJ defects are likely to be the underlying cause of the loss of cell polarity observed in the neuroepithelium of several areas of the CNS. As cell polarity plays a key role in multiple aspects of CNS development, ASPP2 appears to be required for the proper lamination of the cerebral cortex and retina.
In addition to a loss of polarity, ASPP2 mutant neural stem cells (NSCs) exhibit increased proliferation accompanied by a shortening of the cell cycle, and form neuroblastic rosettes which resemble primitive neuroectodermal tumours. Lack of differentiation in the neo and postnatal cerebral cortex is also a feature of ASPP2 mutant mice. The ability of ASPP2 to inhibit the transcription of Notch target genes provides a novel mechanism by which ASPP2 may inhibit cell growth and promote differentiation. Since several tumour suppressors have been identified to be major players in cell polarity, and a loss of polarisation is a hallmark of cancer, the ability of ASPP2 to maintain cell polarity may further contribute towards its tumour suppressive function.

Keywords: CNS development
epithelial polarity
tumour suppressor
Advisor: Lu, X
The paradox of the American state: public-private partnerships in American state-building

From its formation, the American federal government partnered with private organizations to accomplish state goals. With little formal organizational capacity, the American state relied on the resources and credibility of private organizations. This thesis investigates the success of public-private partnerships in American state-building. By looking at alternative enforcement mechanisms, this thesis adds to theories of state-building and private power. The American experience helps us conceive a more nuanced perspective on state formation that recognizes the state’s varying tools rather than focusing solely on the development of formal organizational capacity.
The questions driving this thesis are: How can public-private partnerships expand state capacity? Are there systematic differences in the outcomes and purposes of partnerships based on the branch of government – whether legislative, presidential, bureaucratic, or judicial – that mediates the partnership? My case studies examine the use of partnerships in the early state’s interactions with American Indian tribes. The cases put these general questions into more focus by examining if these partnerships expanded state capacity to dictate the terms of engagement and the content of racial orders. When these partnerships expand capacity, I explore the ways in which this state goal is accomplished. However, I remain acutely aware of the potential for partnerships to both fail to build capacity or become merely means to service a private interest.

Keywords: public-private partnerships
American political development
Office of Indian Affairs
Bureau of Indian Affairs
Advisor: King, D
Elucidating the input of notch ligand  delta-like 4 (dll4) in zebrafish blood stem cell ontogeny

Multipotent haematopoietic stem cells (HSCs) supply the organism with mature blood cells of all lineages throughout adult life. These cells first originate in the dorsal aorta (DA) of the vertebrate embryo, and a multitude of signalling pathways regulate their specification in the embryo. The emergence of HSCs is dependent on appropriate arterial specification and vessel maturation, processes which are heavily dependent on Notch signalling. This arterial involvement of Notch obscures its later roles in HSC specification. The Notch ligand dll4 is crucially involved in arterial development in the mammalian embryo, while zebrafish embryos deficient for dll4 activity only exhibit minor arterial defects at the time of HSC emergence. Here, the zebrafish model has been exploited to reveal the first specific evidence for a role of dll4 in HSC specification.
Dll4 is required for the expression of runx1, a transcription factor (TF) required for HSC specification, prior to any observed effects on vascular development. HSCs and all their derivatives are depleted in dll4 morphants. To disentangle the genetic requlatory cascade downstream of dll4 and upstream of runx1, RNA-seq was employed to discover downstream effectors of this signalling. Expression and functional screening of best candidate genes revealed seven genes with novel roles in HSC development. Foxc1b is a dll4 target predominantly mirroring the dll4 phenotype, and is thus likely to be the downstream effector of dll4, upstream of runx1. Interestingly, foxc1b also has a later dll4-independent role in HSC development, remarkably similar to that of cmyb.
Taken together I show here for the first time a requirement of dll4 upstream of runx1 in HSC specification, mediated by foxc1b, followed by a later dll4-independent phase in HSC development.

Keywords: zebrafish
foxc1
blood
HSC
artery
dll4
notch
haemogenic endothelium
Advisor: Patient, R
Non-algebraic Zariski geometries

The thesis deals with definability of certain Zariski geometries, introduced by Zilber, in the theory of algebraically closed fields. I axiomatise a class of structures, called abstract linear spaces'', which are a common reduct of these Zariski geometries. I then describe what an interpretation of an abstract linear space in an algebraically closed field looks like. I give a new proof that the structure "quantum harmonic oscillator", introduced by Zilber and Solanki, is not interpretable in an algebraically closed field. I prove that a similar structure from an unpublished note of Solanki is not definable in an algebraically closed field and explain the non-definability of both structures in terms of geometric interpretation of the group law on a Galois cohomology group H1(k(x), μn). I further consider quantum Zariski geometries introduced by Zilber and give necessary and sufficient conditions that a quantum Zariski geometry be definable in an algebraically closed field. Finally, I take an attempt at extending the results described above to complex-analytic setting. I define what it means for quantum Zariski geometry to have a complex analytic model, an give a necessary and sufficient conditions for a smooth quantum Zariski geometry to have one. I then prove a theorem giving a partial description of an interpretation of an abstract linear space in the structure of compact complex spaces and discuss the difficulties that present themselves when one tries to understand interpretations of abstract linear spaces and quantum Zariski geometries in the compact complex spaces structure.

Keywords: algebraic geometry
interpretability
model theory
Zariski geometries
Advisor: Zilber, B
Molecular characterisation of bacterial proteins that interact with sulfur or nitrogen compounds

Many bacteria use inorganic nitrogen and sulfur compounds for energy metabolism. These compounds are often toxic and so bacteria must adapt to survive their deleterious effects. Bacteria use specific proteins in order to metabolise, sense and detoxify these compounds. In this thesis protein interactions with inorganic nitrogen and sulfur compounds are examined at the mechanistic level.
Intermediates in the Sox sulfur oxidation pathway are covalently attached to a cysteine on the swinging arm of the substrate carrier protein SoxYZ. An interaction between the Sox pathway enzyme SoxB and the carrier protein SoxYZ is demonstrated. A crystal structure of a trapped SoxB-SoxYZ complex at 3.3 Å resolution identifies two sites of interaction, one between the SoxYZ carrier arm and the SoxB active site channel and the other at a patch distal to the active site. The presence of a distal interaction site suggests a mechanism for promiscuous specificity in the protein-protein interactions of the Sox pathway. Using biophysical methods it is shown that SoxB distinguishes between the substrate and product forms of the carrier protein through differences in interaction kinetics and that the carrier arm-bound substrate group is able to out-compete the adjacent C-terminal carboxylate for binding to the SoxB active site.
The thiosulfate dehydrogenase TsdA has an unusual His/Cys coordinated heme. TsdA catalyses oxidative conjugation of two thiosulfate molecules to form tetrathionate. Mass spectrometry and UV/visible spectroscopy are used to identify an S-thiosulfonate reaction intermediate which is covalently attached to the cysteine heme ligand. A catalytic mechanism for TsdA is proposed using a crystal structure of TsdA at 1.3 Å resolution alongside site-directed mutagenesis of active site residues.
Nitric oxide is produced by the mammalian immune response to kill bacterial pathogens. Part of the killing mechanism occurs through the reaction of nitric oxide with protein-bound iron-sulfur clusters. However, the same type of reaction is also exploited by nitric oxide-sensing bacterial proteins. An infrared spectroscopy approach is developed to detect the products of iron-sulfur protein nitrosylation. Using this methodology it is shown that the presence of trace O2 strongly impacts which products are formed in these nitrosylation reactions. These observations are of physiological relevance because bacteria are often exposed to NO under aerobic conditions during an immune response.

Keywords: carrier protein
Sox
iron-sulfur cluster
cytochrome c
sulfur oxidation
dinitrosyl iron complex
Advisor: Berks, B
Vincent, K
Determination of chargino and neutralino masses at the International Linear Collider

A feasibility study is presented which measures the masses of the chargino X̃₁± and neutralinos X̃₁⁰ and X̃₂⁰ using the processes of e⁺e⁻→ X̃₁+X̃₁- → X̃₁⁰X̃₁⁰W⁺W⁻ and e⁺e⁻→ X̃₂⁰X̃₂⁰ → X̃₁⁰X₁⁰ZZ at the International Linear Collider. The detector simulation is based on the Silicon Detector (SiD) concept and an integrated luminosity of 500 fb⁻¹ is considered at the centre-of-mass energy of 500 GeV. A template-fitting method is employed to measure the chargino and neutralino masses, which results in uncertainties of 0.16 GeV, 0.5 GeV and 1.0 GeV for the mass of X̃₁⁰, X̃₁± and X̃₂⁰ respectively.
A study on the ISIS2 sensor, a technology for the ILC vertex detector, is also presented. The characteristic of the sensors are studied for both its test structure and main array pixels. The operation conditions are optimized and the sensor successfully demonstrated its capabilities of in-situ charge storage and charge transfer. The charge transfer efficiency is measured to be better than 98%.

Keywords: SiD
chargino
supersymmetry
ILC
neutralino
vertex detector
Advisor: Nomerotski, A