VictorJuiz/thesis huggingface dataset:
Investigating the molecular role of transcription factor MAFG in circadian rhythm regulation
Keywords: luciferase reporter assay
photoentrainment
molecular neuroscience
circadian rhythms
chromatin accessibility

The molecular mechanisms underlying circadian photoentrainment are complex, comprising several regulatory factors. There is evidence to suggest differential chromatin accessibility in the master clock, SCN, in response to light at different times of the day. Several genes identified close to differential regions of chromatin accessibility are already known to play an important role within the molecular clock and are recognized to be important for entrainment. Previous studies in the lab using ATAC-seq (Assay for Transposase Accessible Chromatin) showed that chromatin near the gene Mafg (MAF BZIP Transcription Factor G) closed following a nocturnal light pulse (LP), indicating repression of the gene. Additionally, the response element to which MAFG binds, which is the AP-1 motif, was highly over-represented in the light regulated accessible chromatin profile, leading us to hypothesise that MAFG, that is part of the AP-1 transcription factor family, regulates photoentrainment through the regulation of AP-1.
To investigate this, I conducted in vitro and in vivo analyses to evaluate MAFG function in circadian entrainment. Sections of the Mafg promoter that responded by closing in response to light were cloned into a luciferase reporter plasmid and transfected into U2OS cells. Forskolin (which simulates a LP via the AP-1 pathway) reduced reporter expression, and this was further reduced in cells with siRNA- mediated Mafg knockdown. Furthermore, knockdown of Mafg in BMAL1:Luc U2OS circadian reporter cells showed a reduction in amplitude. In vivo, the baseline circadian phenotype, and photic entrainment phenotype of Mafg knockout mice was studied by housing Mafg+/+ and Mafg-/- mice in strict light/dark cycles. Periodogram analysis showed reduced amplitude of circadian period in knockout mice, suggesting that they have weak & fragmented rhythms. Mafg knockouts also showed slower re- entrainment in a 6-hour phase-advancing jetlag study and reduced phase shifting in response to a nocturnal LP (CT 16), indicating reduced photic responses in Mafg -/- animals. However, qPCR analysis of gene expression in the SCN isolated from CT16 light pulsed Mafg+/+ and Mafg-/- mice shows very little difference in a subset of the light regulated genes assessed between the genotypes. In summary, a novel role for MAFG in regulating circadian photoentrainment was shown, however discrepancies in the mechanism of action remain to be addressed.
Novel capabilities for gas-phase laser-induced gratings
Keywords: laser-induced grating spectroscopy
LIGS
temperature
optical diagnostics

Laser-Induced Grating Spectroscopy (LIGS) is a non-intrusive optical diagnostic primarily used for temperature measurements in the gas phase. The technique boasts excellent accuracy and precision, achieved at relatively low cost and complexity, compared to similar diagnostics.
A drawback of the technique is its temporal resolution, which has generally been limited to 10 Hz without compromising the accessibility of the technique (through the use of toxic tracer species or expensive lasers). The discovery of a new LIGS tracer species, biacetyl, which enables the use of accessible high repetition rate lasers is presented. Temperature measurements, obtained at a rate of 1 kHz, and the application of the technique to study thermoacoustic instabilities, have been demonstrated.
A significant problem for LIGS is an inherently poor spatial resolution due to an elongated (in the axial direction) measurement region. A novel approach enabling simultaneous 1-D spatially-resolved LIGS measurements in the axial direction is presented. This capability can be incorporated into standard LIGS experiments with a negligible increase in cost or complexity, thus preserving the accessibility of the technique. A computational model for the approach was developed and validated. A preliminary experiment demonstrated a 93% improvement in axial spatial resolution, as well as a three-fold increase in the number of single-shot measurements obtained, when compared to a standard LIGS configuration.
To exploit the significant advantages of the technique by enhancing its accessibility, a unique transportable LIGS system (named PILOT) was designed, manufactured and characterised. The mobile, self-contained system is capable of collecting tracer-free LIGS measurements at a rate of 400 Hz. An accuracy of less than 0.37% and precision of +/-0.7% was demonstrated for temperature measurements in room air. Characterisation experiments showed that the use of an avalanche photodetector for signal detection would permit the use of the system in scattering environments. A novel systematic investigation of tracer-free LIGS in different gases highlighted the polarisability of a gas as a key indicator for performance of the technique. These findings will inform experimental design for future applications. Finally, the deployment of PILOT in a research facility was demonstrated.
New cation-mediated enantioselective transformations and catalytic enantioselective photocyclization
Keywords: dearomatisation
atropisomerism
photocyclisation
catalysis
photochemistry
phase transfer catalysis

This thesis describes the development of novel catalytic enantioselective reactions. Chapter 1 describes the development of transformations mediated by chiral ammonium salts. The historical context of enantioselective phase transfer catalysis is provided and the key fundamental advances are detailed. The development of a cation-mediated kinetic resolution of atropisomeric biaryls is described as well as the synthesis and resolution of a range of substituted BINOLs.
The extension of the chiral cation mediated approach to the dearomatization of 2-naphthols by electrophilic amination and of indoles by C3 alkylation is also described. In both cases, good reactivity and moderate enantioselectivity were achieved.
Chapter 2 focuses on the development of a Lewis acid mediated approach to the catalytic enantioselective [6π] photocyclization of acrylanilides. The work is contextualized by a discussion of the previous approaches to enantioselective photochemical reactions covering direct irradiation, triplet energy transfer and photoredox strategies. The elucidation of competing triplet energy transfer and photoredox pathways to the same product is described alongside an account of the design and development of a photocatalyst that engages predominantly in the photoredox pathway. The reaction was tested on a range of substrates to determine the scope and limitations of the method.
Mechanistic studies of H2 oxidation and evolution catalysed by NiFe hydrogenase enzymes
Keywords: hydrogenase
IR spectroscopy
spectroelectrochemistry

The complexity of metalloenzyme catalysis has led to the development of a range of techniques, broadly separated into those that probe activity, and those that provide structural information. However, reconciling data from each of these approaches is challenging due to the differences in the physical form of samples, and that most methods cannot simultaneously provide both structural insight and information on catalytic activity.
Two IR spectroelectrochemical techniques are utilised in this Thesis to provide insight into the catalytic mechanism of [NiFe]-hydrogenases.
In situ protein film infra electrochemistry bridges the gap between activity- and spectroscopic-based measurements and has revealed that the rate determining step in H+/H2 catalysis is different for the O2-tolerant Hyd-1 and O2-sensitive Hyd-2.
A technique is developed which combines single crystal IR spectroscopy with electrochemical control to unify structural and spectroscopic information of metalloenzymes. With this technique, a complete redox characterisation of single crystals of E. coli Hyd-1 is described, demonstrating that proton transfer equilibria and electron transfer redox equilibria are maintained in crystallo. Thus the crystalline state can be thought of as a dynamic system, much like in solution.
Studies on single crystals of E. coli Hyd-2 provide evidence of the Nia-L species which was not conclusively identified before for Hyd-2. The observation of the Nia-C species in frozen solution converting into Nia-L upon illumination confirms the assignment of the Nia-L species in Hyd-2.
Overall this work highlights the necessity for utilising a variety of techniques when investigating metalloenzyme catalysis. The single crystal IR microspectroscopicelectrochemical technique developed in this Thesis will provide valuable opportunities for unifying the structural and spectroscopic insights on the catalytic mechanisms of hydrogenases and other metalloenzymes in the future.
Numerical methods for unsteady film cooling in gas turbine
Keywords: gas turbine
scaling law
LES
Reynolds stress budgets
high order scheme
discharge coefficient
Film cooling
turbulence
self-similarity
turbulent heat flux
eigenmode decomposition
inflow generator
conjugate heat transfer
Reynolds stress
turbulent heat flux budgets
fan-shaped
boundary layer
hexahedral mesh

Large eddy simulation (LES) of film cooling flows are focused on, not only because the complexity of film cooling flows brings challenges to accurate numerical simulations, but also because to improve the RANS model which is the main source of inaccuracies of RANS, a systematic set of Reynolds stress and turbulent heat flux data are needed. Achieving high accuracy of prediction for the film cooling flows mandates the exploitation of all the available elements of numerical modelling and computation methods. These methods as a whole should be able to result in reliable budgets of Reynolds-stress tensor and heat flux tensor in scale-resolving simulations. The LES framework for this flowfield is designed by including key ingredients of accuracy -- i) a meshing system (automatic hexahedral mesh generator) resolving small scales and representing complex geometries, ii)a high-resolution scheme (a thrid-order limiter), handling unwanted oscillations while retaining high order accuracy; iii)an efficient inflow generation (synthetic generator based on eigen-decoposition from realistic approximations of the covariance tensor ) minimizing the required inlet development length. Results reveal that the set of modelling methodologies is valid for calculating film-cooling performance in terms of velocity, turbulence, heat flux profiles, and discharge coefficient for fan-shaped and cylindrical holes. The energy-carrying turbulence structures in and near the cooling holes are illustrated from a standpoint of turbulent Reynolds stresses. The mechanisms by which energy is extracted from the mean flow and distributed among the normal Reynolds stresses are highlighted. A qualitative summary of the structure of the film in terms of jet edge, potential core, the lower edge of the jet, and confined region is proposed on the basis of their positions and relative magnitudes of the mean temperature, turbulent heat fluxes, and temperature variance in each region. A scaling law for the outer part of a three-dimensional wall jet has been proposed. Similarity patterns of velocity, turbulent heat fluxes, non-dimensional temperature, Reynolds stresses, and budget profiles are discussed. Far downstream of the cooling films, the Reynolds stress budgets near the wall present similarities with the Reynolds stress budgets in a boundary layer, while the Reynolds stress budgets further away from the wall resemble budgets in a free-shear flow. Results show that the dynamic balance of all budget terms is significantly influenced by the cooling hole shape, while each budget term may scale with the velocity defect, temperature deficit, and the normalized streamwise distance to the power of an exponent dependent on the hole shape.
Endothelial colony-forming cells as a platform for early cardiovascular risk assessment
Keywords: exercise
proteomics
pulse wave velocity
retinal microvasculature
endothelial colony-forming cells
hypertension

The human endothelial colony-forming cells (ECFCs), a subpopulation of endothelial progenitor cells (EPCs), offer a potential platform for cellular assessment due to their remarkable angiogenic expansion, regenerative, and self-renewable potentials in vitro. This thesis investigated how ECFC function and proteome profiles are altered in young adults with elevated cardiovascular disease (CVD) risk factors, including increased blood pressure (BP). It also demonstrated the effect of an exercise intervention on ECFC function and the potential to use ECFC to predict response to exercise intervention.
The main investigations of this thesis were based on a cohort of young adult participants aged 18 to 35 years, recruited through the Trial of Exercise to Prevent HypeRtension in young Adults (TEPHRA). Detailed clinical measurements, including BP measurements, retinal micro-vascular imaging, pulse wave velocity, blood biochemistry and lipid profiles, as well as ECFC culture and cellular assessments, were performed at baseline pre-exercise intervention. Measurements were repeated following a 16-week exercise intervention training period in a subgroup of participants. Our data presented a distinct proteomic signature with altered angiogenic mechanisms in dysfunctional ECFCs. An increase in CVD risks, including higher BP, body mass index and impaired lipid profile, were associated with a reduction in expansion and vasculogenic capacity in dysfunctional ECFCs. Further analysis revealed that the young adults with elevated BP had significantly reduced ECFC functionality and presented a potentially adverse retinal micro-vascular structure and greater macro-vascular resistance. Although no significant changes were observed in the ECFCs after exercise intervention, we demonstrated that baseline ECFC functional characteristics might positively affect aerobic training response. In addition, baseline ECFC functional characteristics may predict response to exercise, suggesting that mechanisms or substances modulating ECFC colony formation and function may be essential factors that affect an individual’s response to exercise.
Criss-crossing creativity: on creativity, Wittgenstein, and artificial intelligence
Keywords: creativity
artificial intelligence
Wittgenstein
generative AI
AI

Until lately, the view prevailed that creativity is the last stronghold of human supremacy, unconquerable by even the most intelligent machines. Yet, recent advances in artificial intelligence (AI) cast doubt on this cherished conviction: there are now programmes that generate music in the style of famous composers or produce paintings that are displayed in renowned galleries. In the face of these awe-inspiring algorithmic achievements, this thesis pursues two main goals. First, it devises a new set of conceptual tools for analysing human creativity. It presents a novel practice-based account of creativity which captures the multifacetedness and distributed character of this phenomenon. Ludwig Wittgenstein’s later philosophy, especially his remarks on rule-following, serve as a crucial source of inspiration in this context. The framework that will be developed overcomes the shortcomings of existing definitions and theories that pervade the philosophical and scientific literature on creativity. Secondly, this thesis examines whether and to what extent creativity can legitimately be attributed to machines in the era of AI. It engages critically with influential objections to the notion of computational creativity and assesses the creative potential and limitations of state-of-the-art AI systems. The proposed approach challenges strong forms of anthropocentrism as well as the hyperbole evoked by recent developments in deep learning. So, the present work is not just a contribution to the emerging philosophy of creativity, but also to the blossoming philosophy of AI. The thesis concludes with a speculative exploration of possible conceptual futures for “creativity” in the face of potential future machines with superhuman creative powers.
Weird music: reading John Ireland and Arthur Machen in tandem
Keywords: Arthur Machen
John Ireland

John Ireland’s music divulges a more sophisticated relationship to literary influences than has traditionally been explored. Despite broad recognition of his literary interests, this thesis argues that Ireland’s enthusiasm for and engagement with the work of his professed favourite writer, Arthur Machen (1863-1947), is at best fractionally understood. This thesis submits that Ireland’s music is entwined preternaturally with a literary figure whose defining characteristic, ‘weirdness’, grants his music and life a comparable quality, thriving off a complex and ambiguous language of interdisciplinary systems and symbols, and contributing a singular body of work to the repertoire of early twentieth-century music.
Providing contextual frames for works by both artists, this study takes as its point of departure the concept of ‘weirdness’ as it pertains to Machen’s post hoc classification by S.T. Joshi as a progenitor of ‘weird fiction’. Reconstructing the worldview that inspired and sustained Machen’s writings through literary criticism, socio-cultural movements, and aesthetic and philosophical systems, it is demonstrated that Ireland’s subsequent compositions and artist-persona emerged from an absorption of the defining principles of Machen’s work with an emphasis on schematizations of weirdness. As such, it is argued that Ireland’s life and work can only be properly perceived within the context of Machen’s own writings; they must be read in tandem.
By placing Machen’s writings within concurrent aesthetic and cultural contexts animating notions of weirdness, this thesis establishes a discourse between these elements and representative compositions by Ireland that were composed after his discovery of Machen’s work in 1906. This analysis evinces that a sympathetic understanding of Ireland’s work and character benefits substantially from a dissection of the intricate interaction between his and Machen’s works; between assorted cultural and aesthetic elements of English music, literature, and landscape; between the reception of his works by contemporaneous and contemporary critics; and by contemplating further the aesthetic and philosophical implications of his music for English musicology, musical ontology, and notions of weirdness in art and artists.
Automated analysis of heterogeneous catalyst materials using deep learning
Keywords: HRTEM
deep learning
nanoparticle
heterogeneous catalysis
machine learning
electron microscopy
computer vision
image analysis

Heterogeneous catalyst materials play a key role in modern society, as many processes in the chemical and energy industry rely on them. Optimising their performance is directly connected to a large potential of reductions in energy consumption, and thus to a more sustainable future. A fundamental part in the optimisation process is represented by materials characterisation. This is often done using in situ (Scanning) Transmission Electron Microscopy ((S)TEM) imaging in order to obtain a full understanding of the catalyst performance in different environments and temperatures at high resolution. However, the analysis of corresponding dynamical datasets is often time-consuming and requires manual intervention alongside tailored post-processing routines. At the same time, the emergence of direct electron detectors allowing for the acquisition of datasets at kiloHertz frame rates, as well as novel imaging techniques raised data generation rates significantly and created a need for new, reliable and automated data processing techniques.
This work introduces nNPipe as Deep Learning based method for the automated analysis of morphologically diverse heterogeneous catalyst systems. The method is based on two Covolutional Neural Networks (CNNs) that were exclusively trained on computationally generated HRTEM image simulations and allow for rapid and precise analysis of raw 2048 x 2048 experimental HRTEM images. The performance of nNPipe is demonstrated in a realistic automated imaging scenario where statistically significant material properties are inferred accurately. Moreover, time-efficient and reproducible retraining methods based small experimental datasets are described for both, further performance improvements and adaption to new imaging scenarios. In this context, a potentially new pathway for the generation of suitable training datasets obtained by thousands of mostly non-expert annotations is highlighted. Finally, the analytical capacities of the nNPipe method are showcased on time-resolved datasets in two advanced applications scenarios: i) Live image analysis during sample acquisition and ii) Analysis of the particle coalescence of an in situ heated Pd/C catalyst.
Additive manufacturing of ni-based superalloys: effects of composition
Keywords: metallurgy
superalloys
3D Printing
cracking
additive manufacturing
alloy design

Additive manufacturing (AM) is now reaching maturity as a method for processing metal alloys. It promises to bring about multifunctional component design integrating fully digital manufacturing. However, preventing cracking during processing remains a key challenge to overcome. This is of particular importance for the Ni-based superalloys used in high temperature applications such as aeronautics and power generation. In this work the effects of alloy composition on the cracking tendencies and performance of Ni-based superalloys are investigated. This study is motivated by the need to develop a better understanding of how to design new alloys specifically tailored for AM. A set of fifteen different compositions – some heritage and some novel – are studied in order to elucidate composition-microstructure-property relationships in 3D-printed Ni-based superalloys. Quantitative characterisation procedures are here developed to distinguish the two dominant cracking types that occur during AM: solidification and solid-state cracks. Experiments are carried out to explore the effects of alloy composition on the thermophyiscal, thermo-mechanical, and microstructural properties of the alloys and how these relate to the cracking phenomena observed. The magnitude of the ductility- dip (exacerbated by increasing amounts of solid solution strengthening elements) and the solidification path (widened by greater interstitial content) are unambiguously proven to be the critical factors giving rise to solid-state and solidification type cracks respectively. A model for solid-state cracking is proposed, based on an incapacity to relax the thermal stress and withstand the thermal strain arising from differential thermal contraction. This is supported by the development of novel methods for measuring the stress development during constrained cooling using electro-thermal mechanical testing. Stress relaxation by creep was found to be inconsequential during constrained bar cooling given the rapid cooling conditions of AM. This suggests that the development of highly creep resistant yet readily processable alloys is possible. The influence of the (Nb+Ta)/Al ratio is studied to tailor the properties of the novel alloys. This ratio is determined to dictate the trade-off of strength in the athermal regime, creep resistance, oxidation assisted cracking resistance, and oxidation resistance at high temperatures via alumina scale formation. The novel alloys print to γ phase and following sub-solvus heat treatment (with no solutionizing step) generate desirable γ/γ′ microstructures tied to good properties. Further assessment of the high temperature oxidation behaviour of all fifteen alloys provides alloy design guidelines for developing oxidation-resistant alloys for AM. In summary, this work highlights the potential to develop new alloys specifically for AM with properties matching those of the heritage ones designed for investment casting.