VictorJuiz/thesis huggingface dataset:
How fast can we see? The latency development in human infants to pattern, orientation, and direction-reversal visual evoked potentials
Keywords: visual evoked potentials
motion
direction
pattern reversal
ERP
orientation
VEP

The goal of this thesis is to track latency changes in three visual evoked potentials (VEP) stimuli as an indication of overall brain development, in order to provide a normative baseline to differentiate visual and neurological development from pathological processes.
VEP- neural electrical activity recorded from the scalp surface and synchronized with visual stimulus transitions- is one of the common techniques in understanding infant vision development. Past work has concentrated on responses to pattern reversal and to the latency of the initial positive peak. Here we compare the timing of responses to pattern, orientation, and direction-reversal VEPs, and transient peak latencies to those calculated from the gradient of steady-state phase against reversal rate. The three stimuli were tested in 81 adults at 1- 16 r/s and 137 infants (3.6- 79.0 weeks) at 2- 8 r/s. Initial responses to orientation and direction were as fast as for contrast- around 100 ms, consistent with other findings that V1 is orientation selective. Cortical processing for both OR and DR yielded longer latencies (200 ms) by the calculated method, perhaps reflecting more involvement of higher visual processing in comparison to PR. Orientation and direction latencies also had a delayed onset and longer developmental period to reach maturity. Infants reached adult transient PR latency values by 15 weeks, for OR by 50 weeks, and for DR by 10 weeks. For the calculated latency, infants reached both adult PR and DR latencies by 30 weeks while OR showed little change across age.
We successfully confirmed that (1) phase-based calculation of latency is effective, easy to use, and taps into a different cortical pathway; (2) motion processing has an additional, faster, subcortical pathway; (3) a parallel processing of initial contrast and orientation; and (4) later visual processing is not only developmentally delayed for all three stimuli but also more vulnerable to perinatal brain damage. These latency differences provided a baseline for clinical evaluations where identification of delayed latencies should aid early diagnosis and guide therapies for adults and infants.
A dynamic logistic model for combining classifier outputs
Keywords: dynamic classification
online learning
multiple classifier systems

Many classification algorithms are designed on the assumption that the population of interest is stationary, i.e. it does not change over time. However, there are many real-world problems where this assumption is not appropriate. In this thesis, we develop a classifier for non-stationary populations which is based on a multiple logistic model for the conditional class probabilities and incorporates a linear combination of the outputs of a number of pre-determined component classifiers. The final classifier is able to adjust to changes in the population by sequential updating of the coefficients of the linear combination, which are the parameters of the model. The model we use is motivated by the relatively good classification performance which has been achieved by classification rules based on combining classifier outputs. However, in some cases such classifiers can also perform relatively poorly, and in general the mechanisms behind such results are little understood. For the model we propose, which is a generalisation of several existing models for stationary classification problems, we show there exists a simple relationship between the component classifiers which are used, the sign of the parameters and the decision boundaries of the final classifier. This relationship can be used to guide the choice of component classifiers, and helps with understanding the conditions necessary for the classifier to perform well. We compare several "on-line" algorithms for implementing the classification model, where the classifier is updated as new labelled observations become available. The predictive approach to classification is adopted, so each algorithm is based on updating the posterior distribution of the parameters as new information is received. Specifically, we compare a method which assumes the posterior distribution is Gaussian, a more general method developed for the class of Dynamic Generalised Linear Models, and a method based on a sequential Monte Carlo approximation of the posterior. The relationship between the model used for parameter evolution, the bias of the parameter estimates and the error of the classifier is explored.
Optimising mobility outcomes after severe ankle injury in adults
Keywords: ankle
orthopedic apparatus
sprains
gait disorders
fractures

Severe ankle injuries can result in ligament rupture or a fracture. A major problem after such injuries is limitation in mobility. Weight bearing tasks, such as walking, become a problem because of pain, deficits in joint range of motion and muscle strength. This thesis studies a key dilemma in early rehabilitation, whether to immobilise the ankle or allow joint motion to improve mobility outcomes. Studies have focused on two scenarios, severe ligament rupture, and unstable fractures managed through open reduction and internal fixation (ORIF). The analysis of gait outcomes was an important component of this thesis and a novel analytical method was developed to normalise gait velocity in the estimation of speed-dependent gait outcomes.
A systematic review and meta-analysis was conducted including evidence to July 2014. The reporting and design of trials was universally poor. In the 6 weeks of recovery following ankle ORIF surgery, there was insufficient evidence that early ankle movements offered a benefit to mobility recovery compared with immobilisation in a cast. Ankle movements compared with immobilisation reduced the risk of venous thrombosis/thromboembolism. However, compared with cast immobilisation, the risk of deep and superficial surgical site infection and fixation-related complications were higher when ankle movements were permitted.
To investigate the role of ankle supports in rehabilitation of walking after ORIF, two randomised cross-over studies were completed. In healthy participants with non-pathological gait, a walker boot induced gait abnormalities when compared with Tubigrip (elasticated bandage). There were no important differences in gait between a stirrup brace and Tubigrip. In people who had undergone ankle ORIF 6 weeks previously, a walker boot and to a lesser extent a stirrup brace offered improvements in gait symmetry and lower pain scores when compared with Tubigrip. Finally, a secondary analysis of the Collaborative Ankle Support Trial cohort (n=584) was conducted, which concluded that, in comparison to Tubigrip, 10 days of cast immobilisation provided greater probability of recovery of a range of mobility outcomes 4 weeks following injury.
This thesis contributes evidence favouring a role for ankle immobilisation in improving mobility following severe ankle injury in adults. Clinicians should be aware of the benefits and risk of harms outlined, as well as the limitations in the current evidence base.
Structural studies of integral membrane GPCR accessory proteins
Keywords: NMR
RAMP
MRAP
structural biology
GPCR accessory proteins
membrane proteins

GPCR accessory proteins regulate the strength, efficiency and specificity of signal transfer upon receptor activation. Due to the inherent difficulties of studying membrane proteins in vitro and in vivo, little is known about the structure and topology of these small accessory proteins. Two examples of GPCR accessory proteins are the Melanocortin-2 receptor accessory protein (MRAP) and the Receptor-activity-modifying protein (RAMP) family. MRAP and RAMP1 are the main focus of this thesis in which they are thoroughly characterised by solution-state NMR and further biophysical techniques.
The single-pass transmembrane domain protein MRAP regulates the class A GPCR melanocortin receptors. It is specifically required for trafficking the melanocortin-2-receptor from the endoplasmic reticulum to the cell surface and subsequent receptor activation. A remarkable characteristic of MRAP is its proposed native dual-topology, which leads to an antiparallel homodimeric conformation. Investigation of the biochemical and biophysical properties of MRAP revealed an α-helical transmembrane domain, and an α-helical N-terminal LD(Y/I)L-motif. Further efforts concentrated on establishing the homodimeric conformation of MRAP in vitro.
RAMP1 facilitates receptor trafficking and alters the ligand specificity of the GPCR Class B receptors calcitonin receptors and calcitonin receptor-like receptors. Moreover, RAMP1 is required to act as a Calcitonin-gene-related peptide (CGRP) receptor (RAMP1). RAMP1 has been shown to form stable parallel homodimers in the absence of its cognate receptor. Its dimerisation and the possible dimerisation motif PxxxxP-motif were studied extensively.
With the goal of understanding the mechanism of dimerisation and the role of GPCR accessory proteins I have used solution-state NMR in detergent micelles as my main technique. NMR provides unique possibilities for understanding the structure and dynamics of such small membrane proteins.
Arginine methylation in the E2F1 pathway
Keywords: PRMT1
PRMT5
E2F1
Cancer
Methylation

The E2F1 pathway plays an important role in coordinating early cell cycle progression. Deregulation of the E2F1 pathway, which may be brought about by somatic mutations in genes such as INK4A, RB1 and CDK4, is found in a majority of cancers. The transcription factor E2F1 is able to activate genes involved in proliferation as well as apoptosis, but the mechanisms that govern these opposing biological effects remain poorly understood. In this study, I would describe how E2F1 activity can be regulated by two novel post-translational modifications which result in different functional consequences. It was found that PRMT1 asymmetrically methylates E2F1 at R109, while PRMT5 symmetrically methylates R111 and R113. The symmetric dimethyl marks on E2F1 promoted the recruitment of Skp2, a component of the E3 ubiquitin ligase complex, which coincided with decreased protein stability and transcriptional activity, as well as enhanced cell proliferation and reduced apoptosis. The asymmetric dimethyl marks on E2F1 was found to hinder symmetric dimethylation, leading to reduced cell proliferation and enhanced apoptosis. The competition between PRMT1 and PRMT5 at the E2F1 RG-rich motif was found to be regulated by the adjacent cyclin A binding site. Induction of DNA damage, which resulted in decreased cyclin A level, corresponded to an increase in PRMT1 and decrease in PRMT5 binding. This study uncovers a new mechanism in E2F1 regulation and establishes the importance of arginine methylation in cell proliferation and apoptosis.
Role of HR23B, HDAC6 and Myd88 and their interplay in response to HDAC inhibitor treatment
Keywords: Myd88
HDAC6
biomarker
HDAC
HR23B

Abnormal epigenetic control is a common early event in tumour progression, and aberrant acetylation in particular has been implicated in tumourigenesis. Histone deacetylases (HDACs) are enzymes that regulate acetylation of chromatin and a variety of other non-histone substrates. Significantly, HDAC inhibitors are potent anti-proliferative agents and exhibit clinical activity in lymphoproliferative and haematological maligancy. However, the mechanistic details by which HDAC inhibitors affect proliferation remain to be elucidated. I have explored the cellular processes affected by HDAC inhibitors, and begun to illuminate a new pathway, regulated by HDAC, which impinges on the cellular effect of HDAC inhibitors. My results suggest that the proteins HR23B and Myd88 are important sensitivity determinants for HDAC inhibitor treatment, and that their interplay with HDAC6 dictates cell fate choice between survival by autophagy or apoptosis.
Actuation of DNA cages and their potential biological applications
Keywords: DNA cages
DNA nanotechnology

DNA cages are polyhedra self-assembled from synthetic oligonucleotides in a one-pot process. The main system described in this thesis is a reconfigurable, wire-framed DNA tetrahedron in nanometre-scale. On one of its vertices this tetrahedron has an overhang that can hybridise with a specific sequence of nucleic acids and open the cage.
We describe the design of a reconfigurable cage that remained closed under physiological conditions and only opened in the presence of an appropriate signal in solution. Fluorescence techniques were employed to distinguish the open and closed states of the cage.
We used flow cytometry and confocal microscopy to successfully established the open and closed states of the cage inside live cultured mammalian cells. Further experiments revealed that the DNA cage could be opened by a separately transfected signalling strand. Hybridisation between two separately transfected systems was possible. The DNA cage was then simplified to a DNA duplex so that the intracellular interactions between the two nucleic acids systems could be studied more efficiently. Microscopy images showed that the interaction occurred in membrane-bound compartments.
We describe an investigation into the use of various cellular RNAs, including full-length mRNA and tRNA-RNA fusion, to actuate the DNA cages. Choosing an appropriate cellular opening signal remains a challenge. Analysis showed that bulky cellular RNA experienced steric hindrance with the rigid DNA cage. Finally, other potential biological applications of DNA cages, such as using DNA nanostructures as the carriers for genetic therapeutic agents, were also presented.
Applications of the Heck reaction for the syntheses of substituted pyridines and β,β-disubstituted vinyl Weinreb amides: studies towards the syntheses of inthomycin B and inthomycin C
Keywords: Heck reaction
Pyridines

The Heck reaction has become a fundamental reaction for synthetic organic chemists over the last half century and is utilised heavily in the fine chemical industry and for natural product synthesis. This thesis describes some of the applications of the Heck reaction to modern day organic synthesis.
Introduction: This section presents an overview of the Heck reaction starting from its conception during the late 1960s to present day understanding. A variety of ligand classes are described along with commonly accepted catalytic cycles for their activity during the reaction.
Results and Discussion: In the first part of the thesis, the use of a cross-metathesis/Heck reaction protocol to synthesise a range of 2,4,6-trisubstituted pyridines is described. Attempts were made to expand the scope of the methodology by employing vinyl Weinreb amides, but this proved unsuccessful for the synthesis of pyridines. Nevertheless, the Heck reaction on vinyl Weinreb amides worked efficiently and the scope of this arylation was explored. Following on, the functionalisation of the Weinreb amide products was studied to generate a range of enone products, some of which would be difficult to synthesise via direct Heck reaction on the respective precursor enone.
In the second part of the thesis, previous syntheses of inthomycin B and inthomycin C are described. The synthesis of inthomycin B and inthomycin C were then attempted using an unprecedented Mukaiyama aldol/cross-metathesis based approach to generate the triene core of both natural products.
Superconductors and high magnetic fields
Keywords: superconductors
thermal stability
pulsed magnetic fields
high tensile fibre
magnetic fields
magnet design
superconducting magnets
high magnetic fields
bulk superconductors
pulsed field magnetisation
flux trapping
Superconductivity
finite element analysis

This thesis describes a portfolio of work aimed at the high field applications of superconductors and can be split into four main topics:
The thermal stability of technical superconductors. This section investigates the effects of thermal perturbations on technical superconducting wire used in MRI scanner construction. The ultimate aim of this section is to predict how the architecture of the wire may affect its thermal stability. To this end a detailed finite element analysis model was constructed, verified by detailed experimental data, which could then be used to quickly and easily vary the wire’s parameters. Design of a high field pulsed electromagnetic coil for flux trapping in superconductors. This section details the design, construction and testing of a novel pulsed high field magnet. The design uses finite element analysis to predict the electromagnetic, thermal and structural properties of the coil.
Explosive testing of high tensile fibres used in the construction of the high field coil. This section describes the refinement and use of a novel method for testing the mechanical properties of high tensile fibres in cylindrical geometries by using highly pressurized copper vessels.
Pulsed field magnetization of bulk high temperature superconductors. This section discusses the process of magnetizing bulks of high temperature superconductors by using pulsed magnetic fields. It investigates how the trapped field varies with the magnitude and rise-time of the magnetizing field, sample temperature and time after magnetization.
Viscous fingering and liquid crystals in confinement
Keywords: viscous fingering
Lattice Boltzmann method
complex fluids
Saffman-Taylor instability
multi-phase flow
liquid crystals

This thesis focuses on two problems lying within the field of soft condensed matter: the viscous fingering or Saffman-Taylor instability and nematic liquid crystals in confinement.
Whenever a low viscosity fluid displaces a high viscosity fluid in a porous medium, for example water pushing oil out of oil reservoirs, the interface between the two fluids is rendered unstable. Viscous fingers develop, grow and compete until a single finger spans all the way from inlet to outlet. Here, using a free energy lattice Boltzmann algorithm, we examine the Saffman-Taylor instability for two different wetting situations: (a) when neither of the two fluids wet the walls of the channel and (b) when the displacing fluids completely wets the walls. We demonstrate that curvature effects in the third dimension, which arise because of the wetting boundary conditions, can lead to a novel suppression of the instability. Recent experiments in microchannels using colloid-polymer mixtures support our findings.
In the second part of the thesis we examine nematic liquid crystals confined in wedge-structured geometries. In these systems the final stable configuration of the liquid crystal system is controlled by the complex interplay between confinement, elasticity and surface anchoring. Varying the wedge opening angle this competition leads to a splay to bend transition mediated by a defect in the bulk of the wedge. Using a hybrid lattice Boltzmann algorithm we study the splay-bend transition and compare to recent experiments on {em fd} virus particles in microchannels. Our numerical results, in quantitative agreement with the experiments, enable us to predict the position of the defect as a function of opening angle, and elucidate its role in the change of director structure. This has relevance to novel energy saving, liquid crystal devices which rely on defect motion and pinning to create bistable director configurations.
The electronic spectrum of selenium dioxide
Keywords: selenium dioxide
electronic spectrum

The C͂¹B₂ ←　X͂¹A₁ electronic transition of SeO₂ has been investigated under high resolution, at a rotational temperature of around 10 K, using the technique of Laser Excitation Spectroscopy. The vibrationally-resolved survey spectrum contained around 100 new bands in addition to the bands which had been reported in a previous study of the same region (G.W. King and P.R. McLean, J. Mol. Spec. 51, 1974). In the light of this new spectrum a number of bands have been reassigned, most significantly the O⁰₀ band, and a number of progressions have been extended. This led to a revised determination of the vibrational constants of the excited state, and a more acceptable estimate of v'₃ than was suggested in the previous work. These reassignments and extensions of existing assignments accounted for only a small fraction of the newly observed bands; those remaining are thought to be due to a different electronic transition which lies in the same region as the C͂¹B₂ ←　X͂¹A₁ transition. The 1³₀, 1²₀ and 1¹₀ bands of the C͂¹B₂ ←　X͂¹A₁ transition were also recorded at rotational resolution and analysed using the method of ground state combination differences. The 1³₀ band was found to be perturbed, which was one of the major factors which prompted the survey study described above. From the analysis of these bands the rotational constants of the excited state were determined and hence the geometry of the SeO₂ molecule in the given vibrational levels of the ¹B₂ excited state was calculated. This in turn enabled the rotational constants and the geometry of the (00) vibrational level of the excited state to be estimated. This work confirms that the symmetry of the excited state is ¹B₂ and the transition studied is C͂¹B₂ ←　X͂¹A₁. An additional band around 31957 cm⁻¹ was also recorded at rotational resolution, which was initially though to be the O⁰₀ band, on the basis of King and McLean's assignments. However in the light of the reassignments the nature of this band is not known, and attempts to assign it as vibrationally cold band of the C͂¹B₂ ←　X͂¹A₁ transition were unsuccessful, implying that it is probably either a hot band of the C͂¹B₂ ←　X͂¹A₁ transition or a band belonging to different electronic transition.
Tet2 and relevant potential intervention in cancer
Keywords: epigenetic
drug
cancer
Tet2
nucelotides
Paf
metabolism

5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxycytosine (5caC) are products of TET enzyme activity, which initiates at 5-methylcytosine (5mC) in DNA. 5hmC has been found to be globally depleted in cancer, while TET2 is highly mutated. The first objective of this work was the investigation of the fate of the associated nucleosides in the context of nucleotide metabolism. Moreover, since many nucleoside analogs are used in cancer therapy to induce replication arrest and DNA demethylation, the effects on proliferation induced by the administration of nucleosides with bases, which are implicated in DNA demethylation, were evaluated. Finally, the TET2 protein interaction network was investigated to elucidate its lost function in cancer and shed light on possible means of intervention. It is demonstrated that DNA polymerase is capable of accepting modified cytidine triphosphates for polymerization. However triphosphate generation is impaired by substrate selectivity of CMPK1. 5hmdC and 5fdC given as media supplements to a number of cancer cell lines caused selective inhibition of proliferation without obvious defects in DNA methylation. By analyzing gene expression datasets, cytidine deaminase (CDA) overexpression was identified in sensitive cell lines. Overexpression and knockdown experiments demonstrated that CDA is necessary and sufficient to confer sensitivity to 5hmdC. Furthermore, CDA was able to deaminate in vitro 5hmdC and 5fdC, but not 5cadC, and a deaminated version (5hmU) was detected in the DNA of treated cells. 5hmU and 5fU in the DNA correlated with S/G2 phase arrest and increased levels of γH2AX at 72 h, suggesting that defects in proliferation relate to DNA damage. 5hmdC and 5fdC administration to mice (IP route) resulted in no overt toxicity and some degree of antitumor activity. Furthermore, TET2 was found to interact with WDR61, a member of the PAF complex (involved in transcriptional elongation), possibly explaining its role in 5hmC deposition over gene bodies and in oncogenesis, given the documented role of PAF in leukaemia. In conclusion, this study identifies the salvage route of new biological cytidine variants, a new avenue with which to target CDA overexpressing cancers, and a possible mechanism to explain the role of TET2 in leukemogenesis.