VictorJuiz/thesis huggingface dataset:
An investigation into the molecular mechanism of the fibrillin1 - LTBP1 interaction
Keywords: LTBP
TGFbeta
NMR
extracellular matrix
microfibril
surface plasmon resonance
structural biology
TGFb
SPR
marfan syndrome
fibrillin
EGF
Latent TGF beta binding protein
fibrillin 1
nuclear magnetic resonance
LTBP1
transforming growth factor beta

Many studies have demonstrated a connection between the fibrillin matrix and TGFβ signalling, but at present the mechanistic basis for this link is unclear. An interaction between the C-terminus of Latent TGFβ Binding Protein 1 (LTBP1) and the N-terminus of fibrillin1 has previously been identified, and may have the potential to directly link the fibrillin matrix to TGFβ signalling.
To investigate the structural basis for this interaction, several multi-domain fragments of fibrillin1 and LTBP1 were expressed prokaryotically and refolded in vitro. After initial characterisation to confirm folding, the structure, dynamics, and interdomain interactions of these fragments were investigated in more detail using NMR techniques. Domains in both LTBP1 and fibrillin1 appear to demonstrate folds consistent with homologous structures, and while the LTBP1 C-terminal cbEGF14-TB3-EGF3-cbEGF15 region contains many flexible linkers and few interdomain interactions, the fibrillin1 EGF2-EGF3-hyb1-cbEGF1 region appears rigid, with interfaces forming between all domains present.
SPR studies were used to demonstrate binding between distinct LTBP1 and fibrillin fragments, suggesting interactions between multiple domains are involved in the LTBP1-fibrillin1 interaction. The binding sites involved were then mapped to specific residues using HSQC titration studies, and structural models for the LTBP1-fibrillin1 interaction were generated based on these data. Predictions from these models were used to target residues for site-directed mutagenesis, based on their potential involvement in salt bridges, and when certain residues were replaced with those of opposite charge, reductions in binding could be seen in the SPR assay. These key residues were consistent with a particular model of the LTBP1-fibrillin1 interaction, as derived from the HSQC titration data. The conservation of potential binding site residues through deuterostome evolution also supports an important biological role for the LTBP-fibrillin interaction.
The expected signature of a stochastic process
Keywords: diffusion process
Rough Path Theory
expected signature

The signature of the path provides a top down description of a path in terms of its eects as a control. It is a group-like element in the tensor algebra and is an essential object in rough path theory. When the path is random, the linear independence of the signatures of different paths leads one to expect, and it has been proved in simple cases, that the expected signature would capture the complete law of this random variable. It becomes of great interest to be able to compute examples of expected signatures. In this thesis, we aim to compute the expected signature of various stochastic process solved by a PDE approach. We consider the case for an Ito diffusion process up to a fixed time, and the case for the Brownian motion up to the first exit time from a domain. We manage to derive the PDE of the expected signature for both cases, and find that this PDE system could be solved recursively. Some specific examples are included herein as well, e.g. Ornstein-Uhlenbeck (OU) processes, Brownian motion and Levy area coupled with Brownian motion.
Cascade approaches to decahydroquinoline ring systems
Keywords: complex synthesis
decahydroquinolines
cascades

The aims of this project were to develop a cascade approach towards decahydroquinoline frameworks (Scheme I) and apply this to the synthesis of decahydroquinoline-containing natural products such as lycopodine, cermizine B and lepadin D (Scheme I).
Scheme I.
Several linear precursors were synthesized via a modular strategy. For example, lycopodine linear precursor i was synthesized in a total of 12 steps (Scheme II).
Scheme II.
Conditions for cyclization and hydrogenation were tested, with the diastereoselectivity examined in each system. For example, the lepadin linear precursor ii produced two decahydroquinolines iii and iv upon cyclization (Scheme III).
Scheme III.
It was found that the diastereoselectivity was dependent on the ring substituents and variation of the hydrogenation conditions could change the facial selectivity of enamine reduction.
Regulation of E2F-1 by methylation and NEDDylation
Keywords: post translational modification
E2F-1
methylation
NEDDylation
UHRF1
Set7/9

E2F-1 has a central role in cell cycle orchestration, and its activity is tightly regulated. One of the ways E2F-1 activity is controlled is by direct modification by post translational modifications such as acetylation, ubiquitination and phosphorylation. Here it was demonstrated that E2F-1 is targeted by two novel modifications, namely methylation by Set7/9 and NEDDylation, both within the DNA binding and heterodimerisation domain of the protein. NEDDylation and methylation of E2F-1 both decrease the stability and diminish the transcriptional activity of E2F-1. Lysine residues in E2F-1 involved in NEDDylation are also targeted by methylation, allowing the potential for interplay between these modifications. Methylation of E2F-1 was demonstrated to be a prerequisite for its NEDDylation and the multi-domain protein UHRF1 implicated in mediating this effect. The results define a new level of control on E2F-1 and suggest a protein code with pleiotropic effects involved in E2F-1 regulation.
Synthesis and conformational analysis of fluorinated pyrrolidines
Keywords: NMR
Fluorine chemistry

The aim of this thesis was to investigate the synthesis and the conformational analysis of fluorinated pyrrolidines. We focused on two strategies namely, the iodoamination and fluoroamination of fluorinated precursors.
Iodoamination
Our first approach for the synthesis of fluorinated pyrrolidines relied on the iodocyclisation of allylic fluorides bearing pendant nitrogen nucleophiles. These allylic fluorides were obtained by fluorodesilylation of suitably functionalised allylsilanes. After validation of this methodology, the scope and limitations of the iodoamination were investigated. Furthermore, we were able to probe the influence of the fluorine moiety on the level of diastereocontrol of the cyclisation.
Fluoroamination
The second route focused on a key reaction: an unprecedented electrophilic fluoroamination of an aminated allylsilane. From a mechanistic point of view, the presence of the silyl group act as a 1,2-dipole and activate the double bond towards electrophilic fluorination. This methodology required the initial screening of a silyl directing group that would promote electrophilic addition, without subsequent desilylation. Finally, we investigated the level of diastereocontrol displayed by these cyclisations as a function of the E/Z geometry of the starting aminated allylsilane.
Conformational analysis
Moreover the 3-fluoropyrrolidines obtained via iodoamination served to investigate the stereoelectronic influence of the fluorine gauche effect on ring conformations. Solid state single crystal X-ray analysis and solution phase NMR spectroscopy were used for this purpose. Due to complicated conformational analysis of saturated five-membered rings in solution, 1D 19F-1H heteronuclear nOe (HOESY) experiments have been optimised for applications to this type of small molecules. These have been employed to estimate 19F-1H internuclear distances and were combined with vicinal 3JFH and 3JHH scalar coupling constants in order to analyse the ring conformations.
Fast growing and interpretable oblique trees via logistic regression models
Keywords: pattern recognition
oblique
trees
machine learning
R
classification

The classification tree is an attractive method for classification as the predictions it makes are more transparent than most other classifiers. The most widely accepted approaches to tree-growth use axis-parallel splits to partition continuous attributes. Since the interpretability of a tree diminishes as it grows larger, researchers have sought ways of growing trees with oblique splits as they are better able to partition observations. The focus of this thesis is to grow oblique trees in a fast and deterministic manner and to propose ways of making them more interpretable. Finding good oblique splits is a computationally difficult task. Various authors have proposed ways of doing this by either performing stochastic searches or by solving problems that effectively produce oblique splits at each stage of tree-growth. A new approach to finding such splits is proposed that restricts attention to a small but comprehensive set of splits. Empirical evidence shows that good oblique splits are found in most cases. When observations come from a small number of classes, empirical evidence shows that oblique trees can be grown in a matter of seconds. As interpretability is the main strength of classification trees, it is important for oblique trees that are grown to be interpretable. As the proposed approach to finding oblique splits makes use of logistic regression, well-founded variable selection techniques are introduced to classification trees. This allows concise oblique splits to be found at each stage of tree-growth so that oblique trees that are more interpretable can be directly grown. In addition to this, cost-complexity pruning ideas which were developed for axis-parallel trees have been adapted to make oblique trees more interpretable. A major and practical component of this thesis is in providing the oblique.tree package in R that allows casual users to experiment with oblique trees in a way that was not possible before.
Reassessing relocation: a comparative analysis of legal approaches to disputes over family migration after parental separation in England and New Zealand
Keywords: Practitioners' Experiences
Comparison Between England and New Zealand
Welfare Principle
Law
Family Law
Relocation

Relocation cases are disputes between separated parents which arise when one proposes to move to a new locality with their child and the other objects. Relocation disputes are increasingly common and are becoming a topic of international concern. This thesis takes a comparative socio-legal approach to examining the legal responses to relocation cases in England and New Zealand.
In England, Payne v Payne [2001] 1 FLR 1052 continues to apply principles first enunciated in Poel v Poel [1970] 1 WLR 1469, and generally sees children’s welfare as being promoted by allowing primary carers to relocate, so long as such moves are bona fide and well-considered. New Zealand rejected this approach in the mid-1990s, and now places more emphasis on children having strong relationships with both parents. Consequently, where England is characterised as ‘pro-relocation’, New Zealand is ‘anti-relocation’.
Qualitative interviews with legal practitioners in both countries suggest that these characterisations are reflective of the law in practice. Looking at hypothetical case-studies, English practitioners are more likely to support proposed relocations than New Zealanders. Many English practitioners think their law to be outdated, and in particular that it gives too much weight to applicants well-being and too little to the value of children having strong relationships with both parents. However, in New Zealand, where an approach similar to that favoured by many English participants is applied, practitioners have the opposite concern, that applicants’ well-being is given insufficient weight, and promoting strong relationships with both parents has become overly dominant when assessing children’s welfare.
It is suggested that the current variation in approaches to relocation may fit broader trends in post-separation parenting in different countries. However, given the current ‘search for common principles’ which can be applied to relocation cases internationally, this thesis raises questions about the likelihood of international agreement being reached.
The Hungarian Air Service, 1918-45
Keywords: military history
airpower theory
Second World War
aviation history
inter-war innovation
Hungary

This thesis is a narrative and analytical history of the Hungarian air service. It follows its development from the Allied intervention of 1919 through the end of the Second World War. Denied an air force by the Treaty of Trianon, Hungarian airmen determined to thwart the inspection system and preserve national air power. The prohibition against military aviation persisted after the Commission was withdrawn, and through Hungarian diplomatic efforts, a relationship was established with Italy that included substantial assistance to the clandestine Hungarian air service.
This low-grade arms build-up continued through the 1930s, during which there was a robust discussion about air power theory and the nature of future aerial warfare in Magyar Katonai Szemle [Hungarian Military Review]. After the rise of Hitler, Germany offered arms credits and support for Hungary’s obsession with regaining the territory lost in the post-war settlement. The air service grew mainly through imported aeroplanes, the purchase of which ceased to be secret after the Little Entente recognised Hungary’s equality of arms.
The Hungarian air force became independent in 1939, and enjoyed public acclaim after decisive air-to-air victories over Slovak pilots during the occupation of Upper Hungary. The General Staff never accepted its autonomy, however, and succeeded in reclaiming control of the air force in 1941. After Hungary joined the Axis invasion of the Soviet Union, the air force provided air defence and interdiction in support of the Rapid Corps. Its mounting losses were made good by German aeroplanes, some of which were produced in Hungarian factories. As the Allied bombing campaign against Hungary intensified in 1944, most of its aircraft were devoted to homeland defence. The force ceased to exist as a true national service after the German-led coup in October 1944, but continued a fighting withdrawal to the west until captured by American forces.
Natural and therapy-induced immune control of HIV-1
Keywords: cytotoxic T-lymphocytes

The human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) response is important in the control of HIV-1 infection. Due to the virus having a high rate of mutation, immune pressure can select for variants that are no longer recognised by CTLs to dominate the viral quasispecies. This is similar to how antiretroviral resistance emerges. HIV-1 is therefore adapting to both human leukocyte antigen (HLA)-restricted immune responses and antiretroviral therapy. This thesis initially focused on the natural CTL response to an HLA-B*51-restricted epitope in integrase. This HLA class I allele is associated with slow progression to AIDS; however, as no CTL-driven escape mutation has been fully defined within this integrase epitope, we cannot determine what contributes to the association of HLA-B*51 and natural control of infection. By longitudinally studying a cohort of early HIV-infected individuals, we observed the emergence of polymorphisms that abrogate a CTL response to this epitope. CTL escape may also prove to be the downfall of current immunotherapy strategies attempting to combat HIV infection. T cell receptors (TCRs) have been genetically modified to enhance their binding affinity to an HLA-A*02-peptide complex and transduced into CD8+ cells to create an HIV adoptive therapy. We demonstrate through in vitro selection pressure assays that escape from these cells may be a difficult task for the virus given that the TCR is able to recognise the majority of variants of this epitope. Antigen processing mutations may represent the only option for escape. How this may translate clinically will only be determined through in vivo studies, which must be meticulously monitored. Finally, when this high affinity TCR was fused to an anti-CD3 single chain variable fragment to create proteins capable of redirecting non-HIV-specific CTLs to HIV-infected cells, we found that the result was specific lysis. These proteins may supersede the use of TCR-transduced cells when used in synergy with antiretroviral therapy.
Intergroup contact and collective action: an integrative approach
Keywords: collective action
intergroup contact

This thesis investigated the effects of intergroup contact on different types of collective action tendencies among advantaged and disadvantaged groups. Studies 1 and 2 tested the simultaneous effects of intergroup contact and established predictors of collective action on collective action tendencies and ingroup and outgroup oriented policies among Blacks and Whites in South Africa, and compared the effects of intergroup contact and social identity on collective action tendencies via relative deprivation and group efficacy. The findings revealed that while social identity was positively associated with collective action tendencies, both directly and indirectly, effects of contact were negative and indirect via relative deprivation and group efficacy. Studies 3 and 4 investigated the effects of contact and social identity on collective action tendencies via perceived threats. Using data from Turkish and Kurdish groups in Turkey, I found that social identity predicted collective action tendencies positively, both directly and indirectly, while it predicted outgroup attitudes negatively and indirectly via perceived threats. Intergroup contact, on the other hand, predicted outgroup attitudes positively, both directly and indirectly, and collective action tendencies negatively via perceived threats. In Study 5, intergroup contact was positively associated, both directly and indirectly, via perspective taking and collective guilt, associated with outgroup oriented collective action tendencies. In Study 6, the effect of social identity on ingroup oriented collective action was positive and direct. Intergroup contact with the weaker minority group, on the other hand, was positively associated with outgroup oriented collective action tendencies via perspective taking. Additionally, intergroup contact with the majority outgroup moderated this relationship. When participants reported more contact with the majority group, intergroup contact with the weaker minority was not associated with outgroup oriented collective action tendencies. However, when the participants reported less contact with the majority group, intergroup contact positively predicted outgroup oriented collective action tendencies. Finally, Study 7 investigated the effects of two different dimensions of contact, contact with the majority and minority on collective action, via outgroup attitudes, dual-identification, and common ingroup identity in a three wave longitudinal design (N=610) among Turkish Cypriots in northern Cyprus. While the results did not support findings from the previous studies on the so-called paradoxical effects of contact on collective action tendencies, they revealed a robust negative reciprocal relationship between outgroup attitudes toward Greek Cypriots and collective action tendencies.
The role(s) of hypoxia-inducible factors (HIFs) in the development of renal cysts in mice deficient in fumarate hydratase (Fh1)
Keywords: hypoxia inducable factors
renal tumours
fumarate hydratase
renal cysts

Fumarate hydratase (FH) encodes a Krebs cycle (also called TCA cycle) enzyme which converts fumarate to malate and also functions as a tumour suppressor gene. Germline mutations in FH predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC). Affected individuals develop benign smooth muscle tumours (leiomyomas) of the skin and uterus and renal cysts and cancers; specifically type II papillary and collecting duct carcinomas. Kidney-specific deletion of Fh1 (the murine orthologue of FH) recapitulates HLRCC in part and mice develop renal cysts that are proliferative and express constitutively hypoxia inducible factors -1α and -2α (Hif-1α and Hif-2α). This phenomenon of pseudo-hypoxia (HIF expression in normal oxygen tension) is also evident in cultured cells deficient in FH and is proposed as a possible mechanism for initiation and/or progression of carcinogenesis. We have utilised our mouse model to investigate the role of Hif-1α and Hif-2α and Fh1 in renal cyst development and show remarkably that combined genetic inactivation of Hif-1α and Fh1 increased both cyst size and frequency. However, kidneys deficient for both Fh1 and Hif-2α were comparable to those deficient for Fh1. Immunohistochemical analyses show that Fh1 inactivation leads to increased proliferation, DNA damage and affects the cell cycle in the renal cysts. Hif-1α and Hif-2α inactivation is not shown to contribute to these. Through genome-wide mRNA expression analysis we have identified that Ccnd1 is significantly upregulated (or the most significantly upregulated gene) in Fh1/Hif-1α knockout kidneys compared to wild type and Fh1 knockout kidneys. Other upregulated genes in the double knockout kidneys include genes involved in cell cycle, proliferation and structural organization of the cell.
Multi-channel security protocols in personal networks
Keywords: network
mobile computing
security
sensor network
body area network

Personal computing devices are becoming more and more popular. These devices are able to collaborate with each other using wireless communication technologies, and then support many applications. Some interesting examples of these are healthcare, context-aware computing, and sports training.
In any such applications, security is of vital importance. Firstly, sensitive personal data is always collected in these applications, thus confidentiality is usually required. Secondly, authenticity and integrity of data or instructions are always critical; incorrect data or instructions are not only useless, but also harmful in some cases.
This thesis analyses the security requirements of personal networks, and develops a number of multi-channel security protocols. With the help of out-of-band channels, especially no-spoofing and no-blocking out-of-band channels, these protocols can bootstrap security in personal networks. In particular, three kinds of security protocols have been studied: protocols that use human-controlled channels, protocols that use visible light communications, and protocols that use intra-body communications. Interesting trade-offs have been discovered among communication, computation and security, resulting from different channel implementations and protocols.