VictorJuiz/thesis huggingface dataset:
Structure and inhibition of novel cyclin-dependent kinases
Keywords: Rebastinib
CDK12
Cancer
Cyclin-dependent kinase
THZ531
CDK16 (PCTAIRE1/PCTK1)
Kinase
Transcriptional CDKs

Protein phosphorylation by members of the cyclin-dependent kinase (CDK) family determines the cell cycle and regulates gene transcription. CDK12 and CDK16 are relatively poorly characterised family members containing atypical domain extensions and represent novel targets for structural studies, as well as cancer drug discovery. In this thesis, I developed protocols to express and purify the human CDK12 kinase domain in complex with its obligate partner, CycK. I solved three distinct crystal structures of the complex providing insights into the structural mechanisms determining CycK assembly and kinase activation. These structures revealed a C-terminal kinase extension that folded flexibly across the active site of CDK12 to potentially gate the binding of the substrate ATP. My structures also identified Cys1039 in the C-terminal extension as the binding site for the first selective covalent inhibitor of CDK12, which has enormous potential as a pharmacological probe to investigate the functions of CDK12 in the DNA damage response and cancer. I also identified rebastinib and dabrafenib as potent, clinically-relevant inhibitors of CDK16 and solved a co-crystal structure that defined the extended type II binding mode of rebastinib. Preliminary trials using these relatively non-selective compounds to inhibit CDK16 in melanoma and medulloblastoma cancer cell lines revealed rebastinib as the more efficacious drug causing loss of cell proliferation in the 1-2 micromolar range. Use of the co-crystal structure to design more selective derivatives would be advantageous to further explore the specific role of CDK16. Finally, I identified a D-type viral cyclin from Kaposi’s sarcoma-associated herpesvirus that could bind to the CDK16 kinase domain and interfere with its functional complex with human CycY causing loss of CDK16 activity. These studies provide novel insights into the structural and regulatory mechanisms of two underexplored CDK family subgroups and establish new opportunities for cancer drug development.
Holistic image understanding with deep learning and dense random fields
Keywords: Probabilistic Graphical Model
Deep Learning
Conditional Random Fields
Dense Random Fields

One aim of holistic image understanding is not only to recognise the things and stuff in images but also to localise where they are exactly. Semantic image segmentation is set up to achieve this goal. The purpose of this task is to recognise and delineate the visual objects. The solution to this task provides detailed information to understand images and is central to applications such as content-based image search, autonomous vehicles, image-editing, and smart glasses for partially-sighted people. This task is challenging to address not only because the visual objects from the same category could have a variety of appearances but also because of the need to account for contextual information across images such as edges and appearance consistency. The objective of this thesis is to bridge the gap between the pixel-based image representation in computer devices and the meaning extracted by humans.
Our primary contributions are fourfold. Firstly, we propose a factorial fully-connected conditional random field that addresses the problem of jointly estimating the segmentation for both object class and visual attributes. Secondly, we embed the proposed factorial fully-connected conditional random fields framework in an interactive image segmentation system. This system allows users to refine the semantic image segmentation with verbal instructions. Thirdly, we formulate filter-based mean-field approximate inference for fully-connected conditional random fields with Gaussian pairwise potentials as a recurrent neural network. This formulation allows us to integrate fully convolutional neural networks and conditional random fields in an end-to-end trainable system. Fourthly, we show the relationship between fully-connected conditional random fields with Gaussian pairwise potentials and iterative Graph-cut: We found that fully-connected conditional random fields with Gaussian Pairwise potential implicitly model the unnormalised global colour models for foreground and background.
Optimisation of vessel-selective magnetic resonance perfusion imaging and angiography
Keywords: Perfusion imaging
Angiography

The diagnosis and treatment of cerebrovascular disease, such as stroke and vascular lesions in the brain, requires knowledge of the status of brain tissue and cerebral arteries. Perfusion imaging and angiography offer information on blood flow to the tissue and through the brain-feeding arteries. A variety of imaging modalities exist to assess brain haemodynamics, including measures of cerebral blood flow and other parameters, however many of these are invasive and/or involve the use of contrast agents toxic to certain patient populations.
One non-invasive magnetic resonance imaging alternative for perfusion imaging and angiography, which also provides vessel specific blood flow information, is vessel-encoded pseudocontinuous arterial spin labelling (VEPCASL). VEPCASL uses the blood as an endogenous tracer and can magnetically label the blood from different arteries of interest. The combination of VEPCASL with different imaging strategies can provide a map of the vascular perfusion territories in the brain, or dynamic information on blood flow through the cerebral arteries.
The work in this thesis seeks to optimise and develop the encoding process of VEPCASL and accompanying angiographic readouts. Firstly, a rapid and automated method for calculating a minimal number of signal-to-noise ratio (SNR) efficient encodings, for any number and arrangement of vessels, was developed. Its use resulted in improved SNR in perfusion territories fed by more complicated vessel arrangements in the labelling plane. The labelling efficiency of VEPCASL, and its non-vessel-selective equivalent, PCASL, is affected by the presence of magnetic field inhomogeneities in the labelling plane. Consequently, a correction for phase offsets was introduced into the calculation of the optimised encodings. These encodings enabled the recovery of SNR in perfusion territories for PCASL and VEPCASL when phase offsets were present at the labelled arteries.
As current VEPCASL angiography methods are relatively slow to acquire, an accelerated readout was developed to acquire two-dimensional vessel-selective dynamic angiograms in approximately one minute. A radial k-space trajectory was found to offer the best vessel definition and SNR. Three-dimensional (3D) angiograms provide the most detailed view of the cerebral vasculature for use in diagnosis and treatment of cerebrovascular disease. A 3D radial readout was optimised to acquire vessel-selective dynamic angiograms. These angiograms offer information on the structure of the vascular tree and how it is fed by the major arteries in the neck.
The techniques developed here aim to increase the clinical viability and applicability of VEPCASL perfusion imaging and angiography. It is hoped that the techniques herein could be used in patient populations to add to and improve the diagnostic information available.
Probing the cohesin loading reaction using forward genetics and quantitative ChIP-sequencing
Keywords: Calibrated ChIP-seq
Smc1
RSC complex
Scc2

Cohesion between sister chromatids that are newly formed in S-phase is crucial to ensure the fidelity of chromosome segregation. The cohesin complex mediates cohesion and is comprised of two SMC proteins, Smc1 and Smc3, with a kleisin subunit, Scc1. The SMCs interact via their hinge domains to form a v-shaped heterodimer, with Scc1 forming a bridge between their head domains to produce a ring structure that topologically entraps sister chromatids. In order to confer cohesion, cohesin needs to be loaded onto DNA, a process that is poorly understood. It is known that cohesin loading depends on a loading complex comprised of Scc2 and Scc4, ATP hydrolysis and presumably opening of at least one of the interfaces of the cohesin ring.
Using the recently developed technique, quantitative ChIP-seq, we show that Pds5, a cohesin-associated protein, is displaced at centromeres from the cohesin ring during the loading reaction. This event is accompanied by the engagement of SMC ATPase heads in the presence of ATP. Upon ATP hydrolysis, the loading reaction completes with DNA entrapment, translocation to the pericentromeric sequences and the displacement of Scc2 by Pds5.
We also describe mutations in Scc2, Smc1 and histone proteins H2A and H2B that enable loading in the absence of Scc4. The mutations in Scc2 alter the dynamics of the association between the loading complex and cohesin, reducing dissociation during the translocation step. All of the mutations are able to restore loading along chromosome arms but not at centromeres where Scc4 has a particular role. However, the Smc1 mutation hinders loading at the centromere, even in the presence of Scc4, due to a defect in the second step of the loading reaction, namely translocation driven by ATP hydrolysis. We suggest that this discrepancy in functionality at the arms and centromere is due to changes in the hinge accompanying both the first and second steps. The rate limiting reaction is the first step at arms and the second at the centromeres. The histone mutants show that nucleosome occupancy plays an important role, at least on chromosome arms, but we find no evidence that this involves the RSC complex.
Security in next generation air traffic communication networks
Keywords: wireless security
air traffic communication security
air traffic control safety

A multitude of wireless technologies are used by air traffic communication systems during different flight phases. From a conceptual perspective, all of them are insecure as security was never part of their design and the evolution of wireless security in aviation did not keep up with the state of the art.
Recent contributions from academic and hacking communities have exploited this inherent vulnerability and demonstrated attacks on some of these technologies. However, these inputs revealed that a large discrepancy between the security perspective and the point of view of the aviation community exists.
In this thesis, we aim to bridge this gap and combine wireless security knowledge with the perspective of aviation professionals to improve the safety of air traffic communication networks. To achieve this, we develop a comprehensive new threat model and analyse potential vulnerabilities, attacks, and countermeasures. Since not all of the required aviation knowledge is codified in academic publications, we examine the relevant aviation standards and also survey 242 international aviation experts. Besides extracting their domain knowledge, we analyse the awareness of the aviation community concerning the security of their wireless systems and collect expert opinions on the potential impact of concrete attack scenarios using insecure technologies.
Based on our analysis, we propose countermeasures to secure air traffic communication that work transparently alongside existing technologies. We discuss, implement, and evaluate three different approaches based on physical and data link layer information obtained from live aircraft. We show that our countermeasures are able to defend against the injection of false data into air traffic control systems and can significantly and immediately improve the security of air traffic communication networks under the existing real-world constraints.
Finally, we analyse the privacy consequences of open air traffic control protocols. We examine sensitive aircraft movements to detect large-scale events in the real world and illustrate the futility of current attempts to maintain privacy for aircraft owners.
Greek declamation in context
Keywords: Aelius Aristides
Greek and Latin Declamation
Hermogenes of Tarsus
Ancient Rhetorical Theory
Greek Imperial Literature
Philostratus
Ancient Rhetoric
Second Sophistic
Polemo of Laodicea
Ancient Greek Rhetoric
Lucian of Samosata
Greek Declamation
Ancient Greek Rhetorical Theory

This thesis looks at the genre of Greek declamation in the second and third centuries of the Common Era. Communis opinio sees the genre as 'nostalgic', a chance for Greeks dissatisfied with their political powerlessness under Rome to 'escape' to the glorious classical past of a free Greece. I argue, by contrast, that despite its famous classicism of language and theme, Greek declamation remains firmly anchored in the present of the Roman empire, and has much to say to that present. The thesis explores in three sections three contemporary contexts in which to read the genre. Each section is made up of two chapters, the first of which examines the context in question and reconstructs the sort of reading process it requires, while the second illustrates and explores that reading process through extended examples. In the first section (chapters one and two), Greek declamation is read in the context of the extraordinary developments in rhetorical theory that were taking place in this period: I argue that the reading of declamation through rhetorical theory was more widespread than has hitherto been appreciated, and that the relationship between theory and practice in declamation should ultimately be seen as dialogic. In the second and third sections (chapters three to six), the genre is read in its contemporary context more broadly. In the second section (chapters three to four), I explore how we might read declamation as 'mythology', that is, as a sort of safe space for exploring major contemporary concerns. In the third section, I make the case for 'metalepsis' in declamation, which I define as a breaking of the boundaries between a declamation and its immediate performance context, used above all by declaimers to talk about themselves and their careers, and also frequently to make reference to their audience.
Numerical investigations of single bunch collective instabilities in synchrotron storage ring
Keywords: beam instability

Electron beam traversing in vacuum chamber can be severely affected by collective instabilities generated from an interaction of beam with its surrounding, geometric wakefield, and the synchrotron radiation emitted, radiation wakefield. The beam dynamics is significantly influenced by such beam-wakefield interactions eventually limiting the maximum stored current. Especially in short bunch consideration which is a primary criterion for the generation of coherent synchrotron radiation (CSR), the beam instability is strongly amplified by an enhanced wakefield. The understanding of beam intensity limitation mechanism has still been underdeveloped. Therefore, the dynamical development of a bunch with a presence of collective instability needs to be scrutinized.
A numerical evaluation tool, sbtrack, is developed to be able to calculate the collective effects due to both radiation and geometric wakefields. The impedance characterization with Haissinski equation is also proposed and evidently shows that a broad-band impedance model is able to reproduce most features of intensity dependent bunch development under particular wakefield. Evaluation of longitudinal beam dynamic verifies that each kind of wakefield contributes characteristic effect to the bunch development and essentially influences resulting CSR bursting behaviour. In positive alpha, the bunch transforms from a confined barred-spiral shape to sawtooth behaviour while in negative alpha, spur-like local fluctuation is induced on the bunch phase space and enhancing the semi-chaotic fluctuation of the entire bunch when the chaotic threshold is exceeded. Beyond the chaotic threshold, bunch profile of both alpha cases are found to evolve with similar systematic development. However, such mechanism in negative alpha seems to be able to consistently occurred at higher current than positive alpha. Unexpectedly, the temporal occurrence of chaotic-harmonic evolution of a bunch is numerically discovered in negative alpha. The bunch appears to be recovered to the state of steady CSR bursting even when it has already exceeded the chaotic threshold. This phenomenon is likely suggesting a novel technique on the generation of THz CSR at much higher current than any conventional methods.
Electron selective contact in perovskite solar cells
Keywords: Condensed Matter Physics
Perovskite Solar Cells
Photovoltaics
Renewable Energy

Over the last 4 years, perovskite solar cells emerged as an attractive, highly efficient, and low-cost alternative to established, conventional photovoltaic technologies. The power conversion efficiency of these devices recorded an unprecedented rise, currently exceeding certified values of 20%. This thesis covers a number of technological advancements which lead to improved photovoltaic performance, as well as vital insight into some more fundamental aspects of the perovskite device operation. The focus of this body of work is primarily directed towards the electric contact in the PV stack which is responsible for electron collection.
The motivation of the study presented here is given in Chapter 1, and includes a brief summary of the current energy landscape. Chapter 2 introduces the theoretical background of photovoltaic technology, starting from the basics of semiconductor physics, through to the principles of solar cell operation, as well as some characteristic properties of the perovskite materials. Details of the experimental methods used in this study are reported in Chapter 3.
Chapter 4 reports the development of a low temperature process (sub-150 °C) for the manufacture of perovskite solar cells. Dispersions of pre-synthesised, highly crystalline TiO2 nanoparticles were used as an electron selective contact, which eliminated the high temperature sintering step.
Chapters 5, 6 and 7, report the interface modification of an n-type contact, resulting in a substantially improved device operation and suppression of hysteresis phenomenon which is characteristic of perovskite photovoltaics. Fullerene-based materials have been found to make excellent electronic contact with halide perovskite materials, and are shown to be far superior to commonly used metal oxides. The facilitated electron collection allows enhancements in the photovoltaic performance of these devices. Furthermore, the organic layers used in this study can be processed at low temperatures.
Finally, the development of transparent conductive electrodes based on silver nanowires is presented in Chapter 8. The fabricated electrodes exhibit low sheet resistance, high degree of transparency, and can be processed at low temperatures, allowing them to be compatible with processing on flexible substrates and multi-junction architectures. The application of silver nanowires in different perovskite solar cell architectures is also reported.
The rise of a manuscript culture and the textualization of discourse in early China
Keywords: Manuscript Studies
Early China
Warring States
Manuscript Culture

This thesis analyses a change in the ways people composed and engaged with texts during the Warring States (481-221 BCE) period in Early China. It examines changes in the textual sphere as a result of an emergent manuscript culture, that is to say, the increased spread and reliance on manuscript texts for the communication of ideas. This shift moved away from the predominantly oral, commemorative, and ritual use of text in earlier periods, and provided key elements that would function in the text based discourse of the early empires. It influenced the way text across a variety of genres of writing was used and understood, structured and composed, and how it was collected and combined to form new arguments.
I focus on texts from the Documents 書, and Odes 詩 genres, in addition to philosophical texts dealing with the past, and collections of sayings and arguments dealing with questions from cosmological to ethical issues. These materials form the mainstay of Warring States intellectual discourse, and exemplify the following textual developments: 1) the rise of collecting materials into compilations; 2) the emergence of genre classification; 3) the development of new authorship functions, 3) an increase in textual structuring and the integration of lore about the past, 4) the development of commentarial traditions, 5) the emergence of an explicit, self-reflexive understanding of writing and transmission, 6) advances in material structuring of manuscript-texts that interrelate form and content.
The analysis is based primarily on excavated materials not edited during the early empires, and engages with comparative and interdisciplinary theory. It argues against models solely based on transmitted sources, which explained Warring States developments as a response to socio-political contexts. Instead, it posits developments in the textual culture itself as a necessary condition to explain the changes in intellectual discourse of the period.
An action research investigation into peer and self-assessment strategies and their effectiveness in enhancing student learning in GCSE Geography
Keywords: MLT
Geography
MLT2016

The aim of the research is to examine the use of peer and self-assessment strategies (PASA) within the Geography classroom. It adopts a broad definition of PASA which considers any student-led reflections about work quality to be examples of PASA.
PASA strategies are frequently heralded in the literature as having the potential to have significant long term impacts on student learning and student agency. Despite this, there is very little use of such strategies within the school in this study and very little understanding of teacher and student perspectives of such an approach to formative assessment.
This study begins with a literature review to critically evaluate the evidence for the effects of PASA on student learning. It examines the conditions under which such practices can enhance student learning and explores some of the subject-specific issues concerning the use of PASA in Geography.
The study took the form of two action cycles; working collaboratively with two other Geography teachers over a term to introduce Year 9 students to PASA activities. The student and teacher responses to these action cycles were interpreted, allowing short term implications for the action research to be acted upon as well as identifying longer term implications for my understanding of the issue and subsequent practice.
The study’s findings indicate that the improvement purpose of the feedback provided in PASA was not valued by the students in the study. However, it appeared that PASA did enhance students understanding of the anatomy of quality in Geography with the result that they had a clearer picture of progression. It seemed that this anatomy of quality was found to be more effective when it was subject-specific rather than specific to the actual phenomena being taught. The research also reflected the dynamic interconnection between the personal and school-related level and policy-level factors. In this study students' personal experiences of assessment had not taught them that their own views or opinions on their work are valid. Whilst incorporation of PASA at a classroom level is possible, the findings indicate that unless this is supported by wider school and policy level factors, it is unlikely that students would be receptive to their use.