VictorJuiz/thesis huggingface dataset:
Redirecting the cellular information flow with programmable dCas9-based chimeric receptors
Keywords: SYNTHETIC BIOLOGY
CRISPR
GENOME ENGINEERING
SYNTHETIC RECEPTORS

Signal integration and transduction by cell-surface receptors is a complex, multi-layered process resulting in tight regulation of downstream mediators, which in turn elicit pre-defined native cellular responses. The modular architecture of transmembrane receptors provides a unique opportunity for engineering de novo sensor/effector circuits, enabling the development of custom cellular functions for research and therapeutic applications.
The signal transduction module of most existing chimeric receptors consists of either native intracellular domains or effectors domains fused to non-programmable DNA binding proteins. Therefore, these receptors can only engage in natural signalling pathways or drive the expression of artificial, pre-integrated transgenes. By harnessing the programmability of a nuclease deficient CRISPR/Cas9 (dCas9) signal transduction module and leveraging the evolutionarily optimised ligand-sensing capacity of native receptors, I have created a novel class of dCas9-based synthetic receptors (dCas9-synR).
I demonstrate that an optimised split dCas9-based core architecture and custom protease-based signal release mechanism can be standardised across multiple classes of extracellular domains to engineer receptor tyrosine kinase (RTK)-based and G-protein-coupled receptor (GPCR)-based chimeric receptors. dCas9-synRTK and dCas9-synGPCR integrate a broad variety of input signals (peptides, proteins, lipids, sugars) with highly specific and robust activation of any custom output transcriptional programme in an agonist dose-dependent manner. Finally, to showcase the therapeutic potential of dCas9-synRs, I used them to convert a pro-angiogenic signal into an anti-angiogenic response, deploy a chemokine/cytokine programme in response to tumour-enriched biomolecules, and induce insulin expression following glucose stimulation. The performance of dCas9-synRs and their unique versatility in redirecting the information flow makes them ideally suited to engineer designer cells capable of sensing specific disease markers and in turn drive various therapeutic programmes.
Bimetallic alloy catalysts for green methanol production via CO2 and renewable hydrogen
Keywords: renewable hydrogen
nanocomposite photocatalysts
heterogeneous catalysts
bimetallic alloy

Recently, the increasing level of atmospheric CO2 has been widely noticed due to its association with global warming, provoking a growth in environmental concerns toward the continued use of fossil fuels. To mitigate the concentration of atmospheric CO2, various strategies have been implemented. Among options to turn waste CO2 into useful fuels and chemicals, carbon capture and utilisation along with renewable hydrogen production as the source materials for methanol production is more preferable. In the 1960s, the highly active and economic Cu/ZnO/Al2O3 catalyst was developed for CO2 hydrogenation reaction to methanol, since then, metal nanoparticles and nanocomposites have been extensively investigated and applied. Especially, bimetallic catalysts have emerged as an important class of catalysts due to their unique properties and superior catalytic performances compared to their monometallic counterparts. This thesis presents the evolution of the catalyst development for CO2 hydrogenation to methanol: Firstly, we introduced the CuZn-based catalysts with Zn content increased in the bimetallic CuZn system via a heterojunction synthesis approach. Secondly, we increased the active CuZn sites via introducing ultra-thin layered double hydroxide as the catalyst precursor for methanol production from CO2 and H2. Thirdly, a new class of Rh-In bimetallic catalysts were studied, which shows high methanol yield and selectivity under thermodynamically unfavourable methanol synthesis conditions owing to the strong synergies of Rh-In bimetallic system. Fourthly, for the renewable methanol production from H2 and CO2, the hydrogen source must come from the green production routes. Therefore, an in-depth study of a nanocomposite system, CdS-carbon nanotubes-MoS2, for photocatalytic hydrogen production from water has been demonstrated. Finally, the conclusion of this thesis is given and an outlook is presented for the future development in this research area.
Operator splitting methods for convex optimization: analysis and implementation
Keywords: Convex optimization
Linear convergence
Infeasibility detection
Operator splitting methods

Convex optimization problems are a class of mathematical problems which arise in numerous applications. Although interior-point methods can in principle solve these problems efficiently, they may become intractable for solving large-scale problems or be unsuitable for real-time embedded applications.
Iterations of operator splitting methods are relatively simple and computationally inexpensive, which makes them suitable for these applications. However, some of their known limitations are slow asymptotic convergence, sensitivity to ill-conditioning, and inability to detect infeasible problems.
The aim of this thesis is to better understand operator splitting methods and to develop reliable software tools for convex optimization. The main analytical tool in our investigation of these methods is their characterization as the fixed-point iteration of a nonexpansive operator. The fixed-point theory of nonexpansive operators has been studied for several decades.
By exploiting the properties of such an operator, it is possible to show that the alternating direction method of multipliers (ADMM) can detect infeasible problems. Although ADMM iterates diverge when the problem at hand is unsolvable, the differences between subsequent iterates converge to a constant vector which is also a certificate of primal and/or dual infeasibility. Reliable termination criteria for detecting infeasibility are proposed based on this result.
Similar ideas are used to derive necessary and sufficient conditions for linear (geometric) convergence of an operator splitting method and a bound on the achievable convergence rate. The new bound turns out to be tight for the class of averaged operators.
Next, the OSQP solver is presented. OSQP is a novel general-purpose solver for quadratic programs (QPs) based on ADMM. The solver is very robust, is able to detect infeasible problems, and has been extensively tested on many problem instances from a wide variety of application areas.
Finally, operator splitting methods can also be effective in nonconvex optimization. The developed algorithm significantly outperforms a common approach based on convex relaxation of the original nonconvex problem.
Informal mandates &amp; judicial power
Keywords: COURTS IN LATIN AMERICA
JUDGES IN LATIN AMERICA
CONSTITUTIONAL COURTS
JUDICIALIZATION, JUDICIAL POWER, COMPARATIVE CONSTITUTIONAL LAW
JUDICIAL POLITICS

Standard explanations of judicial behaviour (i.e. legal, rational-choice, attitudinal, and institutional models) are overly static and exogenous, interested in instances of sudden change in judicial behaviour, as triggered by appointments, legal reforms, or shifts in the political context. While these models are useful in understanding the external incentives affecting judicial behaviour, they are unsuitable for explaining sustained judicial empowerment beyond temporary strategic calculations. In response, recent 'ideational' approaches, especially studying constitutional courts, highlight the importance of judges' ideas about their role – not their ideologies or policy preferences – in instilling a mission, rather than an incentive-oriented view of the judicial function. Yet, despite their more dynamic approaches, those methods have overlooked how ideational change in the 'outside' world translates into change 'inside' this type of courts. Due to those limitations, this study proposes a complementary explanation of judicial empowerment: a theory of informal mandates and endogenous empowerment. Viewed through this lens, change and variation in judicial empowerment within and across cases are explained by the construction, expansion, and endurance – or absence and collapse – of collective internal understandings of the court's role and mission. Such understandings are developed as legal doctrines and articulated under broader informal mandates by 'mission leaders'. Gradually, these informal mandates can expand and gather majority support from strategic partnerships formed between 'mission leaders' and 'supporting leaders' – usually justices with high seniority. The more these informal mandates expand and endure inside the court, the less exogenous factors and strategic incentives over-determine its behaviour in the long-run. Judicial empowerment, thus, is better understood as a process that develops and expands gradually, endogenously, and informally, with a mission-oriented purpose. The theory is applied in the constitutional tribunals of Costa Rica, Chile, and Uruguay from 1990 to 2016. These countries have similar rule-of-law conditions, but their constitutional tribunals differ considerably in the strength and endurance of their informal mandates and, as a result, have attained different levels of judicial empowerment.
Controls on the distribution of gas hydrates in sedimentary basins
Keywords: sedimentary basins
gas hydrates
seismic interpretation
Fluid flow
petrophysics

Natural gas hydrates store a substantial portion of the Earth’s organic carbon, although their occurrence is restricted by thermobaric boundaries and the availability of methane-rich fluids. The complexity of geological systems and the multiphase flow processes promoting hydrate formation can result in a mismatch between the predicted and the observed hydrate distribution.
The purpose of this research is to achieve a better comprehension of the factors that influence the distribution of gas hydrates and the mechanism of fluid movements beneath and across the gas hydrate stability zone (GHSZ). Therefore, this study integrates seismic, petrophysical and geochemical data from different gas hydrate provinces.
This work provides evidence that hydrates can occur below bottom-simulating reflectors, in the presence of sourcing thermogenic hydrocarbons. The relationship between fluid-escape pipes and gas hydrates is further explored, and pipe-like features are suggested to host a significant volume of hydrates. The host lithology also represents a critical factor influencing hydrate and free gas distribution and, in evaluating a natural gas hydrate system, needs to be considered in conjunction with the spatial variability in the methane supply.
The three-dimensional distribution of gas hydrate deposits in coarse-grained sediments, representing the current target for hydrate exploration, is shown to be correlated with that of the underlying free gas zone, reflecting sourcing mechanisms dominated by a long-range advection. In such systems, the free gas invasion into the GHSZ appears controlled by the competition between overpressure and sealing capacity of the gas hydrate-bearing sediments.
Globally, the thickness of the free gas zones is regulated by the methane supply and by different multi-phase flow processes, including fracturing, capillary invasion and possibly diffusion.
In conclusion, this research indicates that geological, fluid flow and stability factors interweave at multiple scales in natural gas hydrate systems.
The clinical epidemiology of acute ischaemic stroke and its long term health economic outcomes
Keywords: Mortality
Ordinal Analysis
Sex differences
Recovery
Disability
Quality of Life
Stroke
Institutionalization
Dichotomous Analysis
Dementia
Lacunar stroke
Modified Rankin Scale

This thesis examines 5-year clinical and health-economic outcomes of ischaemic stroke, and their relationship to short-term post-stroke disability, as captured by the 3-month modified Rankin Scale (mRS) – the favoured primary outcome measure in acute stroke trials. I use data from the Oxford Vascular Study (recruited 2002-2014), a population-based prospective cohort for which I followed patients in-person and via medical records until 15-May-2017.
I demonstrate that 3-month mRS strongly predicts 5-year post-stroke disability and mortality, including in clinically-relevant groups (treatable major strokes, atrial fibrillation-related strokes, and lacunar strokes), reaffirming its use as a trial outcome measure. About one in four patients experience functional recovery between 3-12 months post-stroke, and mortality follow-up beyond 1-year by stroke trials can show translation of early disability gains into lower mortality. Contrary to previously reported apparent sex-differences, I find no evidence of worse outcomes in women after accounting for differences in age and pre-stroke mRS. I find that late recovery between 3-12 months occurs more often in lacunar strokes, supporting the focus of restorative therapies in this group, but highlighting that uncontrolled studies cannot assume that improvements after 3-months are treatment-related.
In addition, I demonstrate that like death/disability, outcomes of institutionalization, post-stroke dementia, health/social-care costs, and quality-adjusted life expectancy (QALE) also show meaningful differences with each step up the mRS ladder. Consequently, ordinal analysis of the 3-month mRS (capturing transitions across the scale’s range) better predicts long-term outcomes than dichotomous approaches, which also foster high exclusion rates of relevant patient segments from trials owing to their pre-morbid disability. However, the mRS should be weighted in ordinal analyses, as different state transitions carry different implications for long-term outcomes. Using 3-month mRS-stratified data for clinical endpoints, care costs, and QALE, I derive mRS weights that could be used for meaningful ordinal analyses, clinical prognostication, and cost-effectiveness analyses of stroke therapies.
Remotely detecting submarine volcanic activity at Monowai: insights from International Monitoring System hydroacoustic data
Keywords: CTBTO
Submarine volcanism
Monowai
IMS

Monowai is an active submarine volcanic center in the Kermadec Arc, Southwest Pacific Ocean. We show, using cross-correlation and time-difference-of-arrival techniques, that low-frequency underwater sound waves from the volcano travel in the Sound Fixing and Ranging (SOFAR) channel and can be detected by bottom-moored hydrophone arrays of the International Monitoring System (IMS), a global sensor network maintained by the Comprehensive Nuclear-Test-Ban Treaty Organization. Hydroacoustic phases associated with the May 2011 eruption at Monowai are identified in the record of the IMS station at Ascension Island, Equatorial Atlantic Ocean. The source-receiver distance of ~15,800 km is the furthest documented range of any naturally occurring underwater signal ever observed. Our observations are consistent with results from transmission loss modeling, which suggest that acoustic propagation at southern latitudes is facilitated by the anomalous temperature regime of the Antarctic Circumpolar Current. Subsequently, we examine the 3.5-year record of the IMS hydrophone station near Juan Fernández Islands, Southeast Pacific Ocean, for volcanic activity at Monowai. Density-based clustering of arrivals during the time periods when data is available, i.e. from July 2003 to March 2004, and between April 2014 and January 2017, reveals 82 discrete episodes that are spaced days to weeks apart, typically ranging from a few hours to days in length. The resolution of the hydrophone data for seismic events at the volcano is estimated at 2.2 mb and exceeds regional broadband networks by one order of magnitude. Considering the results and techniques developed in the study of Monowai, we investigate the 2014 submarine eruption of Ahyi volcano in the Northern Mariana Islands. Acoustic phases of the 15-day episode are identified in the record of an IMS hydrophone array located at Wake Island in the northwestern Pacific Ocean. Explosive volcanic activity occurred in two bursts, accompanied by a decrease in low-frequency arrivals that is interpreted as a shift in signal source parameters. Acoustic energy released during the event is on the order of 9.7 1013 J.
The integration of Spanish and Portuguese organ music within the liturgy from the latter half of the sixteenth to the eighteenth century
Keywords: sixteenth
liturgy
music
organ
Portuguese
18th
eighteenth
Spanish
seventeenth
16th
17th

Spanish and Portuguese organ music still remains a relatively unchartered area escaping the attention of most general assessments of European musical history. The work which has been done in this field has tended towards stylistic appreciations of the published large-scale compositions and the compilation of short biographies of prominent musicians. No extensive investigation has yet been undertaken which deals with such fundamental issues as the role of the organist and the origins and function of the extant organ repertory, of which a large proportion lies dormant in manuscripts, within the liturgy. Indeed, there is no monograph about organists and organ music in the Iberian peninsula as a whole.
The overall aim of this thesis is to provide a musical background and liturgical context for short organ pieces called versos which were thoroughly integrated within a musical celebration of the Offices. For this end, a variety of musical and documentary material has been examined: practical sources of organ music; plainchant manuals; ceremonials and musical treatises. To an enormous extent this organ music was subject to long-standing liturgical customs and legislation, as well as to strongly defined traditions of musical composition.
The prescriptions to the organist given in the ecclesiastical constitutions and how these may have been realized in the Canonical Hours and in the Mass constitutes the essence of part two of this thesis. This interpretation of musico-liturgical practices has entailed an examination of the relationship between plainchant and the organ verset and the technicalities of mode and tranposition which were involved when alternating the organ with choral plainchant. An analysis is also made of the musical development of versets based on the psalm-tones, organ hymns (the Pange lingua in particular) and the 'organ mass'. An anthology of transcriptions complementing this discussion is contained in a separate volume.
As a counterbalance to the analytical discussion in part two, part one provides an historical and cultural background to the subject. An assessment is made of the contribution made by individual organists and organ 'schools' and some consideration is made of the extent to which both royal and ecclesiastical patronage was responsible for the livelihood of music and the arts.
Inflammasome regulation and activation in the intestinal epithelium
Keywords: Citrobacter rodentium
Pattern recognition receptors
Organoids
Intestinal epithelium
Inflammasome
Pyroptosis

Microbiota colonisation of the intestinal tract makes it difficult for pattern recognition receptors (PRR) to discriminate between beneficial microbes and harmful pathogens. We aim to define the roles of cytosolic Nod-like receptors (NLR) in intestinal immunity and homeostasis. Upon activation, some NLR form inflammasomes that mediate the release of inflammatory cytokines and pyroptosis, an inflammatory form of cell death. NLR activation in the non-hematopoietic compartment was shown to be protective during acute intestinal infection. To identify the cell type responsible for this protection, we generated transgenic mice in which the key inflammasome adaptor molecule Asc is selectively ablated in intestinal epithelial cells (IEC) (AscΔVC) and observed that inflammasomes are important for controlling Citrobacter rodentium clearance in these mice. To further dissect the importance of pathogen clearance by IEC inflammasome, ex vivo cultures of primary IEC organoids were established. Thus far this system has revealed profound differences in inflammasome regulation between IEC organoids and bone marrow-derived macrophages (BMDM). This research will inform our understanding of cell type-specific regulation of inflammasomes.
Micro- and macro-mechanical testing of grain boundary sliding in a Sn-Bi alloy
Keywords: Superplasticity
Grain boundary sliding
Micromechanics

This project explores the fundamental mechanisms of grain boundary sliding (GBS) with an emphasis on its role in superplasticity, using both micro- and macro-mechanical testing methods. GBS plays an important role in the deformation of polycrystalline materials, especially at high homologous temperatures (above half of the melting point). Classical models for GBS (Rachinger sliding and Lifshitz sliding) assume that all grains and grain boundaries undergo the same process, but recent research has shown this is not true. Individual grain boundaries differ in their ability to participate in sliding and diffusion. Therefore, it is important to investigate the response of individual grain boundaries to stress. This project uses microcantilevers, loaded using a nanoindenter, to investigate the response to stress of individual grain boundaries in Sn-1%Bi, which is expected to exhibit GBS at room temperature. The response of individual grain boundaries are correlated with grain boundary characters determined using electron backscattered diffraction (EBSD). On the macroscopic scale, both in-situ and ex-situ shear tests are conducted to investigate the superplastic behaviour of this material. The strain rate sensitivity index of the material with a grain size of 8.5 μm is found to be around 0.45. Surface marker lines have quantitatively revealed grain boundary sliding. The investigation from surface studies is expanded to the interior of bulk material in 3D by conducting an in-situ tensile test coupled with diffraction contrast tomography (DCT) at a synchrotron facility.
The microcantilever tests enable grain boundary sliding and diffusion creep to be investigated separately by varying the normal and shear stresses on the grain boundary plane. GBS is dependent on grain boundary structure (misorientation angle, rotation axis and grain boundary plane orientation). The microcantilever size is similar to the grain size used in the macro-mechanical tests. It is demonstrated that the shear stress for steady-state GBS is comparable in micro- and macro-tests. Grain neighbour switching events have been identified in the interior of bulk material in 3D for the first time.