VictorJuiz/thesis huggingface dataset:
Multidisciplinary design optimisation of aero-engine fan blades

This thesis presents a multidisciplinary and multi-objective design optimisation framework for transonic fan blades of modern high bypass ratio turbofan engines. The optimisation strategy applied is based on a twolevel approach consisting of a Differential Evolution algorithm coupled to a sequentially updated ordinary Kriging metamodel to accelerate the optimisation process. Aerodynamic as well as structural static and dynamic performance criteria are considered by means of high-fidelity threedimensional Computational Fluid Dynamics and Computational Structural Mechanics analysis tools. Multiple key operating points are considered in the optimisation process; aerodynamic performance is evaluated at top-of-climb and cruise conditions, while peak stresses are evaluated at take-off operation, taking into account centrifugal and gas loads. Blade vibration is furthermore assessed over the entire operating range. Aerodynamic performance is separately evaluated for core and bypass flows in order to match the requirements specified by the engine cycle design. The successful application of the optimisation system is demonstrated by example of two complex multi-objective, aerostructural fan blade design problems, including finite element structural models for a full titanium and a composite fan blade made from a carbon-fibre reinforced plastic material.
In addition to aerodynamic and structural considerations, aeroelastic effects are becoming of increasing importance for modern lightweight fan blade designs. Flutter, which is a harmful aeroelastic instability, is of particular relevance. An investigation of computational flutter prediction techniques is presented in this thesis with the goal of assessing their potential applicability in an automated optimisation process, showing that today's most commonly applied method, known as the energy method, might lead to mispredictions of flutter stability for modern lightweight, low-stiffness blade designs.

Advisor: He, L
Verstraete, T
Studies towards squalene synthase inhibitors: total synthesis of 6,7-dideoxysqualestatin h5 via an alkene-protection strategy

The zaragozic acids/squalestatins are a family of bicyclic tricarboxylic acids, isolated from a series of different fungi. Members of this class of highly oxygenated natural products show potent inhibitory activity against squalene synthase at the last stage of cholesterol biosynthesis, and so represent attractive candidates for cholesterol-lowering drugs.
This thesis describes an asymmetric total synthesis of (–)-6,7-dideoxysqualestation H5 (DDSQ), focusing on the use of a bromide substituent to protect the side-chain alkenyl group from electrophilic addition reactions. Specifically, this alkene-protection strategy was used to circumvent an undesired cyclisation reaction during a late-stage acid-catalysed 6,8- to 2,8- dioxabicyclo[3.2.1]octane rearrangement en route to DDSQ.
The synthesis addresses several synthetic challenges, including: efficient construction of the requisite alkenyl bromide functionality in the side-chain; preparation of the crucial β-hydroxy- α-ketoester precursor to the 6,8-cycloadduct; and removal of the bromide substituent through stereoselective methylation cross-coupling in the presence of ester and hydroxyl functionalities.
After the fruitful total synthesis of DDSQ, further work was carried out to extend the scope of Seebach’s alkylation of dimethyl tartrate acetonide, enabling access to enantiopure dialkylated products. Also, conditions have been developed for epimerising the monoalkylated tartrate products that may find application in the synthesis of other natural products. Furthermore, to address a key synthetic challenge in a previous synthesis of DDSQ, a concise route to synthesise α-diazo-ε-ketoesters was also developed that demonstrates the utility of chemoselective alkene ozonolysis in the presence of a diazo functionality.

Advisor: Hodgson, D
Studies towards the total synthesis of an anti-HIV natural product

This thesis primarily concerns progress made towards the total synthesis of the natural product unciaphenol. The first half of Chapter 1 serves as an introduction to the target molecule and closely related enediyne natural products. This includes biological activity, proposed biosynthetic pathways, and previous synthetic efforts on the most closely related natural product to unciaphenol. The second half of Chapter 1 offers a brief historical perspective on the development of iminium ion and enamine organocatalysis. The use of such methods in the preparation of structural motifs similar to the core of unciaphenol is discussed.
Chapter 2 details the proposed strategy for the total synthesis of unciaphenol, including an amine catalysed coupling of an isatin-derived α-keto ester with an α,β-unsaturated aldehyde.
A general protocol for the preparation of such α-keto esters is presented in Chapter 3.
The development of the proposed organocatalysed cyclisation is detailed in Chapter 4. This begins with optimisation of the reaction conditions and is followed by investigation of the substrate scope. A putative mechanism and elucidation of product stereochemistry is offered.
Chapter 5 concerns the use of a model system to probe the proposed route to unciaphenol following the organocatalysed coupling.
Finally, Chapter 6 presents progress made on the total synthesis of unciaphenol using fully functionalised substrates. Included are the preparation of α,β-unsaturated aldehydes for the organocatalysed cyclisation and transformations subsequent to this coupling.
Full experimental details for all compounds prepared are offered further within the thesis.

Keywords: Anti-HIV
Organocatalysis
Total synthesis
Advisor: Burton, J
Uncovering temporal structure in neural data with statistical machine learning models

Methods for analysing neural dynamics have predominantly focussed on resting state activity, typically using unsupervised models to infer the main modes of spontaneous variation in the absence of deliberately controlled experimental stimuli. Analysis of neural task data, on the other hand, overwhelmingly assumes responses that are perfectly aligned in time and synchronised over multiple trials by the onset time of the stimulus. These assumptions contradict widespread evidence for a more dynamic, time-varying structure of neural responses. We here explore methods to relax these assumptions and explicitly model the temporal variability of neural task data, by exploring both supervised and unsupervised extensions of the Hidden Markov Model framework. We establish the importance of this approach by applying an existing model - previously introduced for resting state analysis - to a task-based experiment, demonstrating the existence of distributed patterns of variation over trials that reflect underlying fluctuations of cognitive state and predict behavioural responses. We then develop novel supervised frameworks for analysing faster dynamics directly associated with stimulus processing, and show through simulations how these models improve performance where assumptions of temporal synchrony and alignment over trials are not met. Applying this to a MEG experiment on replay, we prove that these models better extract the successive stages of visual stimulus processing in the data, and then that this improves sensitivity to detecting replay across multiple stages of the visual hierarchy. This allows us to investigate the temporal patterns of activation across the visual hierarchy, and we show that spontaneous replay reverses the original feed-forward direction of information flow, with replayed representations in higher visual areas reactivating ahead of the associated lower level visual areas. Finally, we return to the original unsupervised model to compare how the onset of replay events aligns to whole-brain patterns of activity, and show that replay occurs selectively during periods of default mode network activation. These significant findings advance our understanding of the neural physiology underlying replay, whilst also demonstrating the potential of the novel methodology that we have developed.

Keywords: Resting State Networks
Magnetoencephalography (MEG)
Machine Learning
Replay
Computational Neuroscience
Bayesian Modelling
Advisor: Woolrich, M
Behrens, T
Expressions of Ionianness in the Roman period

The present thesis provides an analysis of expressions of a distinct sense of an Ionian identity (‘Ionianness’) in the Roman period. With the creation of the Roman province of Asia and the ever-increasing degree of incorporation of the Greeks into the Roman Empire, questions of identity gained new relevance and urgency for the Greek provincials. The Ionian cities are thereby a special case, as they, unlike many other cities in Asia Minor, were all old Greek poleis and could look back on a renowned tradition of great antiquity. They also continued to hold common meetings and festivals as members of the Ionian Koinon, which can still be seen as the main focal point of Ionianness in the Roman period. My aim is to complement studies of the extant literary sources – which have traditionally received the greatest share of attention – with analyses of the rich epigraphic and numismatic material from the Ionian cities, which are among the best-attested from the province of Asia. In doing so, I want to achieve a more holistic and nuanced picture, and I hope to contribute to further the understanding of Greek culture under the Roman Empire. The individual chapters are of thematic nature and focus on one aspect of Ionian identity respectively: the perception of Ionia as a cultural region, the Ionian Koinon, myths and cults, ways of time reckoning, and onomastics. The thesis is rounded off by an examination of expressions of Ionianness outside of Ionia, further highlighting its continuing value as a form of cultural capital in the Roman period.

Keywords: Cultural identity
Epigraphy
Ionians
Ionia
Greek culture under the Roman Empire
Koinon of the Ionians
Ionian League
Advisor: Thonemann, P
Halogen- and hydrogen bonding host structures for anion recognition

This thesis describes the utilisation of acyclic and interlocked host molecules for anion recognition and sensing in organic media. Halogen bonding is primarily employed as the intermolecular interaction of choice for anion complexation, often assisted by hydrogen bonding.
Chapter 1 introduces the field of supramolecular chemistry, with a particular emphasis on supramolecular anion recognition and non-covalent interactions, followed by an overview of mechanically interlocked molecules and their applications.
Chapter 2 investigates the construction of amido-(iodo)triazole anion hosts. The synthesis and anion binding properties of a family of cationic and neutral [2]rotaxanes incorporating this motif are reported. In particular, a dramatic increase in iodide affinity upon introducing a halogen bond donor is reported.
Chapter 3 explores the preparation and fine-tuning of (thio)urea-(iodo)triazole acyclic receptors, and the resulting anion binding trends are compared and contrasted. Attempts to construct analogous higher order structures are reported.
Chapter 4 outlines the exploitation of covalently appended perfluoroaryl motifs for enhancing the anion binding properties of novel carbazole-(iodo)triazole structures. Their anion complexation equilibria are quantified through 1H NMR titration experiments and qualitatively assessed through UV-Vis and fluorescence spectroscopy.
Chapter 5 provides a summary of the main conclusions of this thesis.
Chapter 6 details the synthetic protocols employed in this work and includes the characterisation of novel and previously reported compounds in Chapters 2 – 4.

Advisor: Beer, P
On-treatment image-guided radiotherapy for central lung tumours

Central lung tumours are notoriously diﬃcult to treat with conventional or high dose per fraction radiotherapy regimens due to abutting and overlapping radiosensitive organs-at-risk. Using two patient cohorts, this thesis explores the scope of isotoxic dose escalation possible for central lung tumours due to new techniques now technically feasible on magnetic resonance (MR) linear accelerators (linacs), for locally-advanced (LA), and early-stage stereotactic radiotherapy, non-small cell lung cancer patients.
Real-time MR imaging of orthogonal slice pairs or radiographically imaged ﬁducial markers allow target tracking during radiotherapy treatment delivery. In-silico modelling of a tracking technique based on primary tumour centroids was performed, using varying clinical target volume (CTV) to planning target volume (PTV) margins based on ideal, accurate and less accurate tracking. The resulting accumulated dose distributions were assessed for both target coverage and dose to surrounding critical structures, to fully quantify the level of gains that real-time tracked lung radiotherapy on MR-linacs may provide.
A clinically signiﬁcant increase in mean isotoxically prescribed tumour dose of 3.2 - 12.4 Gy was achieved for LA patients, resulting from the increased separation of target volumes and surrounding critical structures through the use of reduced target volume margins.
Whilst reduced target margins resulted in larger reductions in minimum target volume doses compared to the standard internal target volume (ITV) approach when accumulated across the respiratory cycle, due to the large dose escalations achieved during isotoxic planning, an increase in absolute target doses still prevailed. Surrounding critical structures experienced small increases in maximum doses, causing planning tolerance violations. However these were of a similar magnitude (~0.5 Gy) and frequency as measured for the standard technique. Thus the tolerance violations were not clinically relevant, demonstrating the potential for safe implementation of the presented technique.
Assessment of plans produced on images acquired 7 - 22 days prior to treatment delivery demonstrate notably reduced target coverage compared to plans created on the day of treatment, suggesting that daily plan adaption would result in optimal treatment plans. However, for 40% of patients, a higher target dose was achievable using “old” experimental plans compared to the standard ITV technique on up-to-date imaging, demonstrating a beneﬁt of the proposed technique for some patients.
In-silico modelling predicts that tracked delivery of isotoxically dose escalated plans will result in a clinically meaningful increase in two-year disease-free survival for central locally-advanced NSCLC, while respecting current normal tissue dose-limits even allowing for movement eﬀects.

Advisor: Fenwick, J
Hawkins, M
Papiez, B
The KDEL receptor

The integrity of the eukaryotic secretory pathway is maintained through selective export and retrieval of proteins between the endoplasmic reticulum (ER) and Golgi. An essential component of ER protein retrieval is the KDEL receptor (KDELR), an integral membrane protein that recognises a C-terminal KDEL signal sequence (a C-terminal KDEL peptide in mammals and HDEL in plants and Saccharomyces cerevisiae) in a pH-dependent process. However, the evolutionary origin of the KDELR, the mechanism through which it binds and releases cargo, and how it interacts with cellular trafficking machinery, has remained elusive.
This thesis presents high resolution crystal structures of the Gallus gallus KDELR 2, in several states: one apo structure, three peptide-bound structures, and one structure of the KDELR bound to an antagonistic synthetic nanobody (Sybody). These structures are compared and analysed to answer questions about the KDELR’s mechanism of action and likely origin of the KDELR.
In vivo cell localisation and in vitro binding assays were developed to examine different mutants of the KDELR and test hypotheses generated from structural data. Synthesising the data, a model for the retrieval of ER resident proteins from the Golgi, by the KDELR, was developed. The model involves pH sensitive binding to cargo proteins, controlled by the protonation state of a key histidine residue which stabilises a hydrogen bond within the receptor. The stability of this hydrogen bond in the bound-state locks the receptor onto its cargo until the pH changes. The specificity of the KDELR for HDEL or KDEL motifs was also explored, and appears to depend on differential interactions of the HDEL and KDEL signals with a tryptophan residue in the binding pocket. Comparison with other membrane proteins suggests how the KDELR likely evolved from an ancestral secondary active transporter, demonstrating that transporter-like architectures may have been adapted to transmit signals across cell membranes.

Advisor: Newstead, S
Barr, F
Characterization of DnaJB6: a molecular chaperone implicated in LGMD type 1D

To maintain protein homeostasis, life has developed highly conserved networks of molecular chaperones and degradation machinery to assist in protein synthesis, quality control, maintenance, localization and degradation. J-proteins (HSP40s) are a family of co-chaperones that specifically bind misfolded target proteins for the HSP70 chaperone machinery. DnaJB6 is a human J-protein shown to suppress aggregation of misfolded disease-related proteins such as huntingtin, aβ42 and α-synuclein, either through the HSP70 pathway or independently. Mutations in DnaJB6 are associated with limb-girdle muscular dystrophy type 1D (LGMD1D). DnaJB6 contains a substrate binding domain (SBD) with low sequence complexity, especially enriched in S/T/G/F-residues, and possibly a separate C-terminal domain (CTD), but these regions of the protein remain largely structurally uncharacterized. DnaJB6 is also known to form polydisperse oligomers, but the mechanism and func- tion of oligomerization remains unknown. In this work, DnaJB6 was recombinantly expressed, purified and characterized with focus on the properties of oligomerization, the effect of LGMD1D-associated mutations and structural features of the SBD and CTD. Native mass spectrometry indicated that the polydisperse oligomer- distribution is populated from 10-mer to 15-mer with both odd and even oligomers populated, excluding a homodimer as the smallest subunit of oligomerization. The mutation of 6 phenylalanines in the SBD resulted in a significant decrease in oligomerization propensity, while mutation of a positive charge-block of arginines only resulted in a small decrease, as determined by dynamic light scattering. At ionic strength shown to dissociate the DnaJB6 oligomer, holdase chaperone activity for aggregating insulin was lost, indicating that oligomerization is necessary for chaperone function. 1H- 15N correlation NMR spectroscopy of DnaJB6 at oligomeric conditions indicated that regions of the protein remain flexible in the oligomer. Chemical shift perturbations from LGMD1D-associated mutations F89I, F91L and F93L, determined with a DnaJB6 residue 1-130 truncation construct, revealed that these mutations structurally perturb the J-domain of DnaJB6. Helix II and the HPD-motif of the J-domain, known to be important for binding to HSP70 and stimulation of HSP70 ATPase activity, were least structurally perturbed, and stimulation of HSP70 ATPase activity was not significantly affected by LGMD1D- associated mutations.

Keywords: Protein
Molecular chaperone
Advisor: Schnell, J
Benesch, J
Loss, retention, and accretion of inflexional case-marking - diachronic evidence from Italic and Finnic

The development of inflexional case systems has long been of interest to historical linguists. Languages such as Latin, Ancient Greek, and many other Indo-European varieties have lost morphological case distinctions through time. Cross-linguistically, however, we find quite different changes affecting case systems. For instance, Finnish has largely maintained the case system reconstructed for proto-Finnic, whereas the related variety Veps has innovated novel inflexional case-markers.
Although much work has been done to explain the changes that are found in individual varieties, a cross-linguistic comparison of the types of development that are found - that is, the loss, maintenance, or propagation of inflexional case systems - which aims to understand why these particular changes occur has yet to be attempted. This study offers a comparison of several varieties from two unrelated languages families: Italic (Latin and the Romance languages) and Finnic. An understanding of the different morphological structures found in these varieties and how these structures are exploited by language-users in the production of novel inflected forms offers insight not only into what can happen in an inflexional case system diachronically, but why case systems have developed in different ways. Reference to a broader range of languages confirms that there is an implicational relationship between the types of morphological structure found in a language and the size of the inflexional case system.

Advisor: Maiden, M
Forsberg, U
Predict or bridge? Investigating inference making strategies in skilled readers

Inference-making is one of the crucial skills necessary to achieve good reading comprehension. This thesis explored which inference-making strategies are employed by skilled readers when they integrate new information in their mental text representation. Specifically, I examined how context affected readers’ choice of inference-making strategy and its time-course in the word-to-text integration process. Four eye-tracking experiments were carried out to observe inference-making as reading happens. By manipulating the amount of supporting context, the first three experiments studied how different properties of target word referents presented in the previous context influenced generation of bridging inferences. In particular, the effect of having lexically explicit, direct referent as opposed to a contextually-related but indirect referent was examined. The results of the first three experiments conflicted suggesting that readers either used predictive inferences instead of bridging to integrate the target words, or that context offered no advantage for the drawing of bridging inferences. To address this question, Experiment 4 examined whether participants integrated the target words by making predictive inferences even in weakly constraining contexts. Participants were presented with texts where context provided either strong or only weak indication of future text development, which was then confirmed or disconfirmed by the target word. The results suggested that even if context provided only limited indication of future development, skilled readers would generate predictive inferences to integrate new concepts. Only when predictive inferences fail to integrate new words, bridging inferences would be employed.

Keywords: reading comprehension
inference making
Advisor: Nation, K
Joseph, H