VictorJuiz/thesis huggingface dataset:
The role of subchondral circulation in the physiology of load transmission

Although the blood supply of bone at rest is well defined, the way in which skeletal activity might affect perfusion under active joints has received little attention. Intraosseous pressure (IOP) has been studied for several decades and was thought to be raised in osteonecrosis, arthritis and bone pain but there has been difficulty in defining IOP and using it for clinical purposes. This work aims to explore subchondral physiology during loading and to seek supporting evidence for a specialised subchondral circulation adapted to load transmission.
Originally in 1985 IOP was studied in an animal model. IOP at rest was found to be variable and sensitive to measurement technique. It had underlying cardiac, respiratory and circulation waves. It was correlated with blood pressure and had a proportionate pulse pressure (PP). Subchondral IOP was raised by proximal venous occlusion and loading. Steroid treatment increased IOP, probably by reducing intraosseous fat volume.
For this thesis in 2014 an in vitro calf foot model was developed and used to further investigate IOP at rest and with combinations of perfusion. The model was then used to study different patterns of loading. Load was found to be transferred partly by hydraulic forces from subchondral to cortical bone through high pressure tolerant tissues. There appeared to be a one way valve within the bone.
Previously undescribed upper tibial vascular marks were found on MRI scans. 60 pairs of scans were scored against osteoarthritis (OA) by Kellgren-Lawrence grade on plain x-rays. Vessels were reduced or lost in early OA. A second study of 200 paired X-ray and MRI scans confirmed the initial results and examined the femoral subchondral vascular marks.
Axial subchondral histology in animal and human tissue showed the presence of subchondral vessels. The subchondral vascular network was found to be present in healthy bone but absent in osteoarthritis. A subcortical valve like structure appears to exist that might allow high pressure hydraulic force transmission without vascular damage. Finally, other evidence in support of the thesis is advanced.
IOP measurement is only a reflection of perfusion conditions in the blood pool at the needle tip. A new understanding of IOP and its use in exploring bone perfusion by a subtraction technique is offered. Load is transferred partly by hydraulic force from the subchondral bone to the cortical shaft. Histologically there are subchondral vessels with possible valves in the subcortical region. A fine subchondral capillary plexus exists under healthy cartilage. Subchondral tissues support hydraulic pressure transmission during weight bearing. Vessels are lost in early OA. Osteoarthritis may be due to failure of vasculo-mechanical circulation in the subchondral region.

Keywords: Intraosseous pressure
Microangiogram
Subchondral anatomy
Vascular oclusion
Subchondral vessels
Osteoarthritis
Osteonecrosis
Steroids
Kellgren-Lawrence
MRI
Bone flexibility
Choke valve
Loading
Subtraction
Hydraulic
Bone pain
Advisor: Urban, J
Murray, D
Mechanisms underlying the efficacy of normothermic machine perfusion in human liver transplantation

Introduction:
By perfusing a liver with oxygenated blood, medications and nutrients at 37C, normothermic machine perfusion (NMP) may improve outcomes after liver transplantation when compared with conventional static cold storage (SCS). Herein is reported the first randomised controlled trial (RCT) comparing continuous NMP with SCS in human liver transplantation. Additional work exploring the mechanisms behind the effects of NMP is also described.
Methods:
This multinational RCT was initiated by the Consortium for Organ Preservation in Europe (COPE) and involved seven European transplant centres. Adult DBD and type III DCD livers were randomly assigned (1:1) to continuous NMP or SCS. The primary end point was the difference in peak-AST, requiring 220 transplants (90% power). Secondary endpoints included: organ utilisation, preservation time, early allograft dysfunction (EAD), six month graft and patient survival and ischaemic cholangiopathy on MRCP. During NMP, perfusate and bile samples were collected and subsequently analysed to provide information regarding bile salt utilisation and identify markers that may indicate organ quality.
Results:
272 livers (135 SCS, 137 NMP) were enrolled, consisting of 194 DBD and 78 DCD organs. 48 livers were discarded (32 SCS [15 DBD, 17 DCD] vs 16 NMP [10 DBD, 6 DCD]; p=0.01). NMP livers experienced significantly longer preservation times than SCS (7hr 21min vs 11hr 39min; p&LT; 0.01). Despite this, better early graft function was observed in the NMP group with regards to peak AST (974 IU/L SCS vs 485IU/L NMP; p&LT; 0.001) and EAD (29.9% SCS vs 12.6% NMP; p=0.002) with the magnitude of these effects being greater for DCD organs (p=0.02). No measurable difference was found in radiological rates of ischaemic cholangiopathy with no demonstrable correlation between MRCP findings and clinically relevant strictures. NMP livers were found to utilise bovine bile salts effectively with bile production and several other biochemical parameters found to correlate with graft quality.
Discussion:
NMP livers show better early graft function than SCS in terms of peak-AST and EAD, both of which are surrogates for long-term graft outcomes. This is despite better organ utilisation and longer preservation times in the NMP group. NMP can be used to predict organ quality although it is not possible to draw conclusions about markers that may predict viability. If translated to clinical practice, these results would have a major impact on liver transplant outcomes and waiting list mortality. The fact that the study has definitively met its primary endpoint should now enable the exploration of the technology’s wider potential.

Keywords: Organ preservation
Normothermic machine perfusion
Liver transplantation
Advisor: Friend, P
The politics of the English royal court, 1247-65, with special reference to the role of aliens

This thesis is not a straightforward account of the aliens under Henry III 1247-65 but rather an attempt to use the aliens as a pathway into the inner political life of Henry III's court. Previous generations of political historians have concentrated on the growth of the 'baronial opposition' to Henry while paying little attention to the point that the focus of political opposition for much of the reign came from the 'court', and especially members of the royal family: Richard of Cornwall, the lord Edward and Simon de Montfort. Similarly, while historians have assumed, perhaps with the exception of F.M. Powicke, that the baronage moved in 1258 against a united royal government and, foremost against the aliens in it, they have failed to observe that King Henry III's favourites took different sides over the Provisions of Oxford: the Savoyards supported it but the Poitevins were exiled from the realm. Contrary to what has become the standard interpretation, there was no united alien force at court before or after 1258 - until 1264 at the very least. The Savoyards and Poitevins at court and in the provinces had always played a distinct role in royal government and in politics; they were men of very different character, outlook and connexions. It is the purpose of this thesis to describe and explain these divergent political paths and to draw conclusions from them about the nature of government and politics in the reign of Henry III.
Continued in thesis …

Keywords: English
households
court
royal
king
courtiers
aliens
politics
England
Genetic susceptibility and severity factors in rheumatoid arthritis

The aim of this D.Phil. thesis was to enrich current knowledge of genetic susceptibility and severity factors in rheumatoid arthritis (RA), a common complex disease with an estimated heritability of approximately 60% in the Northern European population. A DNA resource from 760 clinically well-characterised British Caucasian RA patients was established for use in association studies to investigate candidate genes.
The previously reported association of PTPN22 (1858C/T rs2476601) and rheumatoid factor positive disease was observed (p=0.004). Examination of PTPN22 gene for differential allelic expression (DAE) in different peripheral blood mononuclear cell populations from RA patients was undertaken. A DAE of 20% or more in 8 RA patients (p< 10-5) was observed, indicating possible existence of cis-acting genetic variation. PTPN22 DAE in a number of cell types was demonstrated in 4 RA patients and there were also different allelic ratios between these cell populations (pc < 0.05).
MHC class II expression is controlled at the transcription level by MHC class II transactivator (CIITA) and is mainly dependent on the transcription of its gene MHC2TA. The frequency of MHC2TA (-168A/G, rs3087456) polymorphism in RA cases did not differ from those in controls. Minor allele frequencies were higher in HLA-DRB1 shared epitope negative and DRB1*04 negative patients (p=0.01 and p=0.03 respectively). Further direct sequencing followed by single nucleotide polymorphism genotyping and haplotype analysis did not reveal significant skewing in the haplotype distribution.
Polymorphisms in the IL-1A and IL-1B promoter can influence gene expression and these were investigated for association. The IL-1B (-1464 C/G, rs1143623) G allele was found to be less common in the RA group (p=0.01). Meta-analysis revealed statistically significant association between IL-1B (-511 A/G, rs16944) and RA (p=0.02).
Although the importance of studied markers in predicting disease susceptibility is modest, together with future findings these results may help to provide better insight concerning the RA disease process.

Keywords: susceptibility
rheumatoid
severity
factors
genetic
arthritis
Advisor: Wordsworth, B
Pointon, J
Insect-mediated indirect interactions in tropical forest plant communities

A key aim in ecology is to understand the mechanisms that contribute to structuring diverse communities such as tropical forest plant communities. Much focus has been on the role of highly host-specific natural enemies. With data on the diet breadths of plant enemies accumulating, it is becoming increasingly clear that enemies are rarely strict specialists. It is therefore necessary to broaden investigations to non-specialist enemies contributing to structuring plant communities.
In this thesis, I investigated the role of non-specialist insect enemies of seeds and seedlings in structuring plant communities in a forest in Panama, using a series of field investigations. Firstly, I used a quantitative food web approach to investigate the potential for indirect interactions between plant species in the Lauraceae family via their internally-feeding seed predators. I found high potential for enemy-mediated indirect interactions between species in this study system. These interactions are likely asymmetric and driven by the volume of fruit produced by each species. Secondly, using the same study system, I investigated patterns of seed predator attack across space and in response to the presence of conspecifics and alternative host species in the neighbourhood. I found that local and neighbourhood resource densities affected rates of insect attack and premature fruit abscission. Finally, using seedlings of Cordia trees and their associated insect herbivore I investigated the role of shared enemies at a later life stage. I detected negative conspecific density dependence as well as the potential for indirect interactions between plant species mediated by the shared herbivore.
Overall, I show that insects caused significant amounts of damage to early life stages of plants, and that they have the potential to link the regeneration dynamics of their host species via enemy-mediated indirect interactions. This work contributes to a better understanding of the factors influencing the reproduction and recruitment of plant species in tropical forests.

Advisor: Gripenberg, S
Lewis, O
From Arabidopsis model to green revolution cereal crop varieties: studies of the co-regulation of plant growth and nitrogen metabolism

Modern semi-dwarf “Green Revolution” varieties (GRVs) of wheat and rice dramatically increased global grain yields during the mid to late 20th Century. GRVs are dwarf because they accumulate growth-repressing DELLA proteins. GRVs are thus high yielding because they apportion more resource to grain filling than to stem elongation, and are less susceptible to the yield-reducing effect of “lodging”. However, recent evidence suggests that GRVs have a low nitrogen-use efficiency (NUE) as a result of the negative pleiotropic effect of stabilised DELLAs. Therefore, the cultivation of GRVs requires environmentally unsustainable levels of inorganic fertiliser application.
The aim of this study is to uncover the underlying mechanism of DELLA-mediated inhibition of the metabolism of nitrate (the major form of nitrogen in most agricultural soils), using the Arabidopsis semi-dwarf GRV model mutant ga insensitive (gai). It was first established that gai is more resistant to chlorate, the toxic chemical analogue of nitrate, suggesting that like GRVs, Arabidopsis gai also exhibits compromised nitrate metabolism. Chimeric analyses and enzymatic assays discovered an inhibitory effect of DELLA proteins on shoot nitrate reductase activity. A similar effect of DELLAs was found to be conserved in rice, providing a potential explanation for the low NUE observed in GRV crop plants. Moreover, as DELLA-interacting proteins (DIPs), PHYTOCHROME-INTERACTING FACTOR3 (PIF3) was identified as a positive regulator of nitrate assimilation, potentially acting downstream of DELLAs.
Simultaneous forward screens for mutagenized gai isolated multiple mutants which genetically uncoupled gai-mediated inhibition of stem elongation and nitrate metabolism, with usually multiple acids move in and out transporter32 (umamit32) identified as a potential novel mutation conferring enhanced chlorate resistance. Meanwhile, several tall gai mutants were selected and initially characterised, which provided new insights into the GA-DELLA signalling pathway and how it relates to the regulation of plant growth. The ultimate goal of this research is to apply the knowledge obtained from Arabidopsis to modern crops, in the hope of improving their NUE and thereby contributing to the development of the next generation of GRVs of crops.

Keywords: Genetics
Mutant screen
Plant nutrition
Advisor: Harberd, N
Smith, A
A muse of fire: why the U.S. Military forgets what it learns in war

Wars are expensive and relatively rare, and so states have strong incentives to learn from war and improve their military performance over time. And yet, even in highly capable great power militaries, the lessons of previous wars are routinely lost. Why do militaries forget what they learn in war? Examining evidence from two cases across the American experiences in Vietnam and Iraq, I find that the strongest causal evidence for why the US military forgets what it learns in war is in organizational selection. The demobilization and post-war retooling process destroys the specific sub-organizations which learn in war, namely joint task forces and ad hoc task-built organizations. This research has the potential to make a significant and novel contribution both to our understanding of repeated American foreign policy mistakes and to the broader literature on military adaptation and effectiveness.

Keywords: Vietnam War
Organizational Learning
Iraq War
Assessments
Intelligence
Foreign Policy
Military
Military Adaptation
U.S. Military
Advisor: MacFarlane, N
The Bronze-Iron Age transition in Achaea, western Greece: continuity and change from the 12th to the 8th century BC

Achaea in the Northwest Peloponnese presents unique opportunities for the study of the Late Bronze-Iron Age transition in Western Greece. During the 12th century BC, its archaeological record suggests the existence of a thriving network of sites, with a high concentration in Western Achaea, whose elites propagated their warlike ethos in the funerary record and were able to nurture and sustain interregional and overseas contacts long after the demise of the palatial economies.
The beginning of the Iron Age saw the disappearance of the conditions that prompted these developments, and brought drastic changes to burial customs and settlement patterns, with the shift of the regional centre of gravity towards Northeast Achaea. By the 8th century new political economies and social dynamics are manifested in the growth of local cult-sites.
The present study explores these issues through the examination of the published settlement, funerary, and ceramic evidence. It also considers Achaea’s position in the wider context of Western Greece, through the lasting interactions visible in the ceramic production. Moreover, it addresses the character of the Achaean engagement in the communication networks towards the West, and peninsular Italy in particular, as these contacts were manipulated by the post-palatial elites and re-surfaced in a completely different framework in the late 8th century, with the Achaean involvement in the colonisation movement.
The study of Achaea thus offers a regional perspective into the diverse socio-political and cultural transformations that occurred in the Aegean between the 12th and the 8th centuries BC. By elucidating aspects of continuity and change across this crucial transitional period it is possible to observe a regional shift from local chiefdoms with warlike ruling ideology communicated in the mortuary record, to communities structuring their identities in the sphere of communal cults.

Keywords: Western Greece
Late Bronze Age
Early Iron Age
Advisor: Lemos, I
Modulation of oscillatory activity in the cortico-subthalamic pathway by electrical stimulation in rodents and humans

Parkinson’s disease (PD) is a debilitating motor disorder characterized by degeneration of dopaminergic cells in the Basal Ganglia (BG). This loss of dopaminergic neurons gives rise to abnormal synchronization of neuronal activity in the beta frequency range (around 20 Hz) across the cortico-basal ganglia network in parkinsonian humans and animals. Interestingly, in tremor patients the phase of ongoing peripheral oscillation can be exploited with electrical ‘phase interference’, whereby cortical stimulation on specific phases of the tremor dampens both the pathological neuronal activity and resulting symptoms. Computational modelling suggests that the amplitude of beta oscillations could be modulated by applying stimulation at a specific phase. Such a strategy would allow selective targeting of the oscillation, with relatively little effect on other activity parameters. Harnessing the phase of a pathological neural activity, therefore, may be a promising way to increase the specificity and efficacy of stimulation protocols for deep brain stimulation (DBS) treatment of motor disorders. The principal aim of this study was to examine the 1) effect of stimulation phase-in supressing and amplifying the amplitude of the ongoing pathological beta oscillations of the motor cortex and subthalamic nucleus (STN); and 2) investigate the phase relationship between and the power of ongoing beta oscillations in these brain areas. Complimentary experiments were carried out in PD patients undergoing microelectrode mapping for the implantation of DBS electrodes as well as in the 6-OHDA hemi-lesioned rat model of PD. In awake PD patients displaying beta oscillations we recorded cortical EEG, STN LFP as well as multiunit activity from the STN. The data obtained from these human intraoperative recordings revealed that electrical stimulation arriving on consecutive cycles of a specific phase of the subthalamic oscillation can suppress its amplitude and coupling to cortex. Additionally, combining data recorded from Parkinsonian rats and awake PD patients we demonstrate that the amplitude of beta oscillations in the cortex and the STN ramp up when these assemblies were at their most common phase alignment (“preferred phase”). Our data suggests that phase-dependent stimulation could thus be a valuable strategy for treating brain diseases and probing the function of oscillations in the healthy brain. These results provide further evidence that periods of particular phase alignments between nodes of the cortical-basal ganglia circuit can lead to amplification of oscillations at the same frequency.

Advisor: Sharott, A
Brown, P
How did mammals evolve into their ecological niches through time? Quantitative tests for classic macroevolutionary questions

Observations that the taxonomic and ecomorphological diversity of mammals increased across the Cretaceous/Paleocene (K/Pg) boundary led to the model of adaptive radiation. These rapid and large-scale increases in diversity and disparity are thought to have resulted from unprecedented ecological opportunity for mammals in the wake of the K/Pg event, during which numerous niches previously occupied by the non-avian dinosaurs and other components of the Mesozoic fauna were cleared. Although patterns of increased body size and body size disparity have been thoroughly explored, fundamental questions remain regarding both the magnitude and exact nature of mammalian ecomorphological change across the K/Pg boundary. It has long been established that Cenozoic mammals appear to exhibit a wider range of ecomorphotypes associated with feeding ecology in comparison to the Mesozoic. Here I use a dataset of six functionally-relevant traits made up of ten continuous character measurements across 276 fossil and 730 modern (including 23 recently extinct Pleistocene megafauna) mammal jaws to quantify and explore patterns of jaw ecomorphological disparity from the Late Triassic– end-Eocene and Pleistocene–Recent. I further explore the evolutionary rate across the K/Pg boundary by analysing six functional jaw traits for 69 Jurassic- Eocene mammals in a phylogenetic framework. The results presented herein demonstrate that, despite an immediate increase in therian mammal jaw ecomorphological disparity across the K/Pg boundary, mammals as a whole did not show an increase until the Paleocene/Eocene boundary. This lag of ~10 My is interpreted as an interval of ecological recovery, during which high rates of mandibular ecomorphological trait evolution are detected. Much of the Paleocene/Eocene increase in disparity can be attributed to mammals with larger body sizes. My results are indicative of an adaptive radiation of placental mammals in the early Paleogene, in response to large-scale niche clearing.

Keywords: Mammalogy
Palaeontology
Evolution
Palaeobiology
Macroevolution
Advisor: Friedman, M
Benson, R