VictorJuiz/thesis huggingface dataset:
Proteomics in viral disease

The separation, identification, and characterisation of the proteins present in a tissue or biological sample is called ‘proteomics’. This technique can be used for example to identify biomarkers and investigate signalling pathways. Increasingly, proteomics is being applied to the analysis of virus related samples; here two such examples are described. Presently there is no reliable non-invasive way of assessing liver fibrosis. Here a novel 2D-PAGE based proteomics study was used to identify potential fibrosis biomarkers. Serum from patients with varying degrees of hepatic scarring induced by infection with the hepatitis C virus (HCV) was analysed. Several proteins associated with liver scarring and/or viral infection were identified. The most prominent changes were observed when comparing serum samples from cirrhotic patients with healthy controls: Expression of inter-α-trypsin inhibitor heavy chain H4 fragments, α1 antichymotrypsin, apolipoprotein L1 (Apo L1), prealbumin and albumin was decreased in cirrhotic serum, whereas CD5 antigen like protein (CD5L) and β2 glycoprotein I (β2GPI) increased. In general, α2 macroglobulin (a2M) and immunoglobulin components increased with hepatic fibrosis whereas haptoglobin and complement components (C3, C4 and factor H-related protein 1) decreased. Novel proteins associated with HCV-induced fibrosis include the inter-alpha-trypsin inhibitor heavy chain H4 fragments, complement factor H-related protein 1, CD5L, Apo L1, β2GPI and the increase in thiolester cleaved products of a2M. The relationship between these changes is discussed. One of the accessory genes of the HIV viral genome encodes for the Nef protein. Nef is present in lipid rafts and increases viral replication within infected host cells by binding to a guanine nucleotide exchange factor, Vav. This leads to activation of a GTPase, Cdc42, however, the signalling pathway is poorly understood. 2D-PAGE based proteomics was used to identify differentially expressed raft-associated proteins by comparing T cells in the presence and absence of Nef. A ubiquitin conjugating enzyme UbcH7, which acts in conjugation with c-Cbl, was absent from the rafts of Nef-transfected cells. Vav ubiquitination was also absent from these rafts. In collaboration with Dr. Alison Simmons and Prof. Andrew McMichael the absence of UbcH7 in rafts was found to be caused by β-Pix forming a ternary complex with c-Cbl and activated Cdc42. Vav ubiquitination was restored and viral replication was diminished when β-Pix was knocked down providing a new candidate target for inhibiting HIV replication. This thesis demonstrates the use of proteomics in providing novel information for virus related samples. This influential technology benefits in both biomarker discovery to aid clinicians with early diagnosis of diseased individuals and in the elucidation of novel signalling pathways in infected cells to provide new candidate targets.

Keywords: cirrhosis
biomarkers
hepatitis C
fibrosis
HIV-Nef
proteomics
Advisor: Zitzmann, N
Dwek, R
X-ray and neutron diffraction analysis and fem modelling of stress and texture evolution in cubic polycrystals

The thesis reports improvements in the characterization techniques for stress and texture in crystalline materials by x-ray and neutron powder diffraction. Furthermore, advances are made in texture evolution modelling and validation against experimental observations.
In the beginning, the fundamental assumption of diffraction strain analysis is numerically examined and verified, namely, that the lattice parameter value determined from fitting the diffraction pattern is equal to the average lattice parameter within the gauge volume.
Next, the task of shear strain determination from powder diffraction measurements is addressed. A method is developed and implemented for the complete 2D strain tensor determination from the multi-directional energy-dispersive x-ray diffraction patterns. The method not only offers a way to evaluate the shear strain, but also provides a better overall strain averaging approach.
Rotation and translation of sample and/or detectors in powder diffraction mode can effectively increase the pole figure coverage and thus the accuracy of texture determination. However, the movements also introduce uncertainties and aberrations into data analysis due to the changes in the diffraction volume and transmitted intensity. In order to overcome these problems, accurate single exposure texture characterization techniques are proposed based on several different powder diffraction setups. Numerical analyses are carried out to prove that any simple texture in cubic polycrystals can be effectively determined using single exposure Debye-Scherrer diffraction pattern analysis. Several experiments are reported on collecting Debye-Scherrer diffraction patterns, multi-directional energy-dispersive x-ray diffraction patterns and multi-directional TOF neutron setup. Efficient data processing procedures of the diffraction patterns for ODF determination are presented.
Crystal plasticity finite element models are developed to model the texture evolution in polycrystalline engineering samples during manufacturing. In the present thesis, quantitative measures extracted from orientation distribution function are employed to make precise comparison between the model and experiment. Unlike the simple uni-axial compression and tension considered in the literature, in the present thesis the complex texture evolution during linear friction welding is modelled as a sequence of different shear deformations.

Keywords: neutron diffraction
synchrontron x-ray diffraction
crystal plasticity
residual stress
texture
finite element methods
Advisor: Korsunsky, A
Molecular and biological analysis of the putative golgi mannosidase II and other enzymes involved in N-linked glycosation in drosophila melanogaster

Glycosylation is a fundamental post-translational modification of proteins that occurs in all eukaryotes, but the biological significance of specific glycosylation structures is still largely unknown. We have chosen to study this process by cloning and characterizing the genes involved in the N-linked glycosylation pathway in Drosophila melanogaster and analysing mutants of these genes. Since this biochemical pathway for the production of N-linked glycans is considerably conserved, studying it in Drosophila, a useful organism for genetic research, should yield results applicable to other eukaryotes.
This thesis describes the attempt to identify a Drosophila homologue of rat ER mannosidase and how this investigation resulted in the identification of a Drosophila cDNA with considerable homology to calnexin, an enzyme involved in the folding of N-glycosylated proteins. It also describes the cloning and characterization of the genomic sequence for the putative Golgi mannosidase II (GmII)* in Drosophila. The expression and control of expression of GmII have been investigated further, and have suggested expression of this gene throughout Drosophila development. Analysis of the GmII promoter region has shown expression from a TATA-less promoter contained within 288bp of sequence 5' to the start of transcription.
Forensic risk assessment: a metareview, novel meta-analysis, and empirical study developing a violence screening tool for schizophrenia

Mental health professionals are routinely called upon to assess the violence risk of their patients. An increasingly common method for conducting such assessments is the use of structured risk assessment tools. The aim of this thesis was to investigate the utility of such instruments: to identify and explore current uncertainties concerning their applicability and to design a novel measure that could be used as part of a stepped strategy to risk assessment. Though a number of risk assessment tools have been developed and there is a considerable literature concerning their psychometric properties, uncertainty remains regarding their effective use. In order to identify key contemporary uncertainties, a metareview of the forensic assessment literature was conducted. The metareview found that previous systematic reviews and meta-analyses of the risk assessment literature have come to conflicting conclusions on a number of issues, including the comparative predictive validity of risk assessment tools, the efficacy of actuarial tools versus clinical judgement, and the influence of demographic factors and study design characteristics on predictive accuracy. These uncertainties were then investigated in a comprehensive meta-analysis of nine commonly used risk measures. The meta-analysis concluded that there were significant differences between the predictive validity of the risk assessment tools, with instruments designed for more specific purposes performing better than those designed for more general use. Tools performed best when administered to samples demographically similar to their calibration sample. Actuarial instruments and structured clinical judgement were found to perform comparably. The final study presented in this thesis explored the feasibility of a stepped approach to risk assessment in which individuals at very low risk of future violence are screened out prior to resource-intensive clinically based assessment. High-quality national registers were used to construct a simple tool to identify patients with schizophrenia at very low risk of violent conviction after being discharged from hospital. The tool was found to produce high rates of sensitivity as well as high negative predictive values at 1, 2, and 5 years follow.up. In light of the findings of these three studies, risk assessment procedures and guidelines by mental health services and criminal justice systems may need review.

Keywords: risk assessment
meta-analysis
violence
forensic
Advisor: Fazel, S
Chemical reactivity of group 14 [E9]4– and 15 [E'7]3– Zintl ions

This thesis describes the reactivity of Zintl ions of groups 14 [E9]4– (E = Ge and Sn)and 15 [E'7]3– (E' = P and As) towards a number or transition, post-transition and main group reagents. The synthesis and characterisation of the resulting novel cluster anions is described herein.
Coordination compounds of group 14 Zintl ions were synthesised when K4Ge9 was reacted with Zn[N(SiMe3)2]2 to give the simple coordination compound [Ge9ZnN(SiMe3)2]3–. The heavier analogue K4Sn9 reacts with the same metal precursor to give the paramagnetic species [Sn9ZnNSiMe3]3– where a trimethylsilyl group has been lost.
K4Ge9 reacts with [Ru(COD)(η3-CH2C(CH3)CH2)2] to form the paramagnetic endohedral compound [Ru@Ge12]3– and with [Co(PEt2Ph)2(mes)2] to form the prolate endohedral compound [Co2@Ge16]4–, which has two metal centres encapsulated inside the sixteen atom germanium cage.
Regarding group 15 Zintl ion reactivity, the reactions between pyridine solutions of [HP7]2– and E[N(SiMe3)2]2 (E = Ge, Sn and Pb) have been found to yield coordination compounds of the type [P7E(N(SiMe3)2]2–. The germanium containing species [P7GeN(SiMe3)2]2– quickly decomposes at room temperature to give rise to the thermodynamic product [(P7)2Ge2N(SiMe3)2]3–, a process that involves the loss of an amide moiety.
Activation products were also synthesised from the reaction of [E'7]3– with varying stoichiometries of VCp2. The reaction with 0.7 equivalents of VCp2 yields the sandwich complexes [CpV(η5-E'5)]n– (E' = P: n = 1; E' = As, n = 1 and 2) whereas with 2.5 equivalents the products are the triple-decker sandwich complexes [(CpV)2(ηx-E'x)]– (E' = P: x = 6; E' = As: x = 5).

Keywords: coordination chemistry
Zintl ions
anionic main group clusters
Advisor: Goicoechea, J
Organometallic reagents for catalytic cross-coupling

Phosphine complexes of nickel and palladium provide the best catalysts for the homogeneous catalysed carbon-carbon bond forming reaction between an organometallic nucleophile and an organic electrophile. Use of a homochiral ligand on the catalyst can lead to stereoselectivity in the cross-coupling reaction, with high ee's of coupled product being obtained. The processes of selectivity in the transmetalation step of the catalytic cycle have not been elucidated and the initial aim of the project was to study these processes.
Initial experiments using organotin derivatives as the organometallic nucleophile highlighted the problems of selectivity and the forcing conditions needed in the attempted transfer of a benzyl group from the tin to the palladium catalyst. The compounds [8- (dimethylamino)-1-naphthyl]methyldiphenyltin (60) and [2-((dimethylamino)methyl) phenyl]methyldiphenyltin (70) were prepared and their reactivity in the palladium catalysed cross-coupling with 2-furoyl chloride, to give 2-benzoylfuran, was investigated. These molecules were found to undergo facilitated transfer of a phenyl group compared to transfer from control molecules. The effect was tested and attributed to the internal nucleophilic attack at the tin atom by the lone pair on the nitrogen atom. The compound [2- ((dimethylamino)methyl)-3-trimethylsilylphenyl]methyldiphenyltin (79) was prepared to test the effects of steric buttressing within the molecule, but was found to be of the same order of magnitude of reactivity as (60) and (70). All three molecules showed a reactivity of at least an order of magnitude greater than control compounds. The effect did not prove applicable to the transfer of a benzyl group or in other coupling reactions. The effect of palladium ligation was tested and the ligand triphenyl arsine found to increase the rate of the coupling reaction. The two facilitating processes were found to work in a co-operative fashion, giving a rate enhancement of ca. one hundredfold over control reactions.
The nickel catalysed cross-coupling of α-substituted sp3 hybridised Grignard reagents with allylic esters was attempted, but proved unsuccessful. Stoichiometric reactions with nickel complexes were also found to be unsatisfactory in yielding coupled products.
The synthesis of α-substituted diorganozinc reagents was attempted, but furnished only homocoupled products. The reaction of dibenzylzinc with aldehydes was found to proceed in the absence of catalyst, highlighting the reactivity of a benzylzinc moiety.

Advisor: Brown, J
Subjectivity and temporariness

Non-reductivists about phenomenal consciousness believe that physical facts are insufficient to ground the existence of phenomenal consciousness. It will be argued that if one is going to be a non-reductivist, then one should not limit oneself to expanding one’s catalogue of the world’s basic features, as recommended in the paradigmatic non-reductivist approach developed by David Chalmers. One should rather take a realist stance towards subjectivity. A realist about subjectivity thinks that at least some of the propositions needed to state how things are in reality are such that their truth-value is capable of changing ‘from one subject to another’. Realism about subjectivity will be introduced by means of an analogy with the so called ‘A-theory’ of time. An A-theorist claims that at least some of the propositions needed to state how things are in reality are such that their truth-value is capable of changing ‘from one time to another’. It turns out that a robust notion of metaphysical reality is necessary to make sense of both realism about subjectivity and the A-theories of time.

Keywords: perspectival facts
A-theory
subjectivity
consciousness
Advisor: Hawthorne, J
Korngold's merry men

This study examines the critical issue of artistic 'collaboration' in the Hollywood studio system as it relates to the composition of a film score. It suggests what a postmodern critical edition of the score to The Adventures of Robin Hood (Warner Bros., 1938) might look like and, through an engagement with poststructuralist thought, exposes the collaborative reality of its authorship, both in production and reception. The epilogue places the study in a wider scholarly context, assessing its possible impact on the emerging discipline of film musicology and upon current debates within musicology.
Chapter 1 discusses theoretical approaches to authorship and their application both to Hollywood studio era cinema and film music of the same period. It proposes an alternative conceptual framework to the work-concept when thinking about the film score, bringing film musicology more in line with trends in film studies. Chapter 2 is a theoretical discussion of the problems inherent in producing a postmodern critical edition of a film score, suggesting some possible solutions. Chapter 3 takes an indepth look at the circumstances surrounding the production of the score for The Adventures of Robin Hood, beginning with a detailed description of the sources (both manuscript and audio-visual), followed by a discussion of the 'origin' of some of the music contained within, and concluding with a 'reconstruction' of the score's production process. Chapter 4 comprises a discussion of musical meaning in the cinema and a 'reading' of a cue from the film that is dependent on the existence of the critical edition found in the appendices; the reading uses a methodology adapted from Roland Barthes's work of literary criticism, S/Z. The appendices include four edited cues from The Adventures of Robin Hood, complete with accompanying editorial apparatus.

Advisor: Franklin, P
Connectivity, flow and transport in network models of fractured media

In order to evaluate the safety of radioactive waste disposal underground it is important to understand the way in which radioactive material is transported through the rock to the surface. If the rock is fractured the usual models may not be applicable.
In this work we look at three aspects of fracture networks: connectivity, flow and transport. These are studied numerically by generating fracture networks in a computer and modelling the processes which occur.
Connectivity relates to percolation theory, and critical densities for fracture systems are found in two and three dimensions.
The permeability of two-dimensional networks is studied. The way that permeability depends on fracture density, network size and spread of fracture length can be predicted using a cut lattice model.
Transport through the fracture network by convection through the fractures and mixing at the intersections is studied. The Fickian dispersion equation does not describe the resulting hydrodynamic dispersion.
Extensions to the techniques to three dimensions and to include other processes are discussed.

Advisor: Rae, J
Internet non-­use: a comparative study of Great Britain and Sweden

Digital inequalities continue to concern researchers across highly technologised countries. In recent years, however, most research on digital inequalities has focused on distinguishing different patterns of Internet use rather than examining Internet non-users. The few quantitative studies of non-use and reasons for non-use often stay on a descriptive level, while qualitative studies mostly investigate subpopulations, such as those living in specific neighbourhoods. Although there are a number of studies of digital inequalities among young people and the elderly, a systematic literature search finds no research focusing on middle-aged individuals, who might face specific problems with being offline, as they are of working age and more likely than other age groups to have children living in the household.
On the basis of a mixed-methods research design that compares non-users in Great Britain and Sweden, the overarching research question for this study sheds light on the mechanisms contributing to Internet non-use, as it examines the socio-economic backgrounds, attitudes, perceptions, and everyday life experiences of non-users with a focus on 25 to 55 year-olds. It applies advanced statistical analyses of secondary nationally representative survey data as well as in-depth analysis of qualitative interviews with 10 middle-aged non-users from each country.
The analysis of these combined data shows that while socio-economic variables still play an important role in influencing who is on- and offline, general attitudes towards technologies are even more influential. The study finds that there is a lack of life-fit (Selwyn 2006) of ICTs for a number of non-users and a potentially negative impact of warm experts (Bakardjeva 2005) who have previously been regarded as a positive influence. Moreover, vulnerable groups (e.g. immigrants) are facing more substantial problems, such as issues with literacy and language, which need to be tackled first.
The deliberation of similarities and differences between Britain and Sweden against the backdrop of policy interventions and cultural values shows that being offline is not problematic for all Internet non-users; some of them thrive in highly technologised societies. The conclusion offers proposals for both future research and policy interventions for those, currently offline mainly due to socio-economic reasons, who would like to go online in the future.

Keywords: Digital inequalities
quantitative
Sweden
qualitative
mixed-methods
policy
Great Britain
Advisor: Eynon, R
Blank, G
Failure of unicompartmental knee replacement

Unicompartmental knee replacement (UKR) is the principal alternative to total knee replacement (TKR) in the treatment of end-stage knee osteoarthritis. It involves less tissue resection, resulting in lower rates of morbidity and faster recoveries compared to TKR. However, UKR has a significantly higher revision rate compared to TKR. As a result, whilst over a third of patients are eligible for UKR, only around 8% receive it.
A comprehensive comparison of matched patients undergoing TKR and UKR was undertaken using a large dataset from the National Joint Registry for England and Wales (NJR). Failure rates (revision, reoperation, complications and mortality), length of stay and patient-reported outcomes (PROMs) were studied. Whilst patients undergoing TKR had lower reoperation and revision rates, they had higher rates of morbidity and mortality, longer hospital stays, and inferior PROMs compared to UKR. The main reason for revision in UKR was loosening.
In view of the high revision rate in UKR, NJR data was studied to identify modifiable risk factors for failure in UKR. Important patient factors were identified including age, gender and pre-operative function. Surgeons with a higher UKR caseload had significantly lower revision rates and superior patient-reported outcomes. Increasing usage (offering UKR to a greater proportion of knee replacement patients) appears to be a viable method of increasing caseload and therefore of improving results. Surgeons with optimal usage (around 50% of patients, using appropriate implants) achieved revision/reoperation rates similar to matched patients undergoing TKR.
Two clinical studies were conducted to establish whether the use of cementless fixation would improve fixation and reduce the revision rate of UKR. Cementless UKR was demonstrated to be safe and reliable, with PROMs similar or superior to those demonstrated in cemented UKR. Patients with suboptimal cementless fixation were examined and pre-disposing technical factors were identified. Finally, using NJR data, the effect of the introduction of cementless UKR on overall outcomes was examined. The number of cementless cases was small, and no significant effect on implant survival was demonstrated. However, patients undergoing cementless UKR demonstrated superior PROMs.
These studies demonstrate that UKR has numerous advantages over TKR in terms of morbidity, mortality and PROMs. If surgeons perform high volumes of UKR (achievable by increasing their UKR usage), these advantages can be attained without the large difference in revision rates previously demonstrated. Cementless UKR is safe and provides superior fixation and outcomes in the hands of high-volume surgeons. Further work is needed to quantify the revision rate of cementless UKR, and to assess its results in the hands of less experienced surgeons.

Keywords: national joint registry
patient reported outcome measures
cementless
unicompartmental knee replacement
Total knee replacement
Advisor: Murray, D
Gill, H
Pandit, H
Judge, A