VictorJuiz/thesis huggingface dataset:
Dearomative reductive functionalisation reactions of azaarenes
Keywords: pyridine
isoquinoline
reductive functionalisation
quinoline
dearomatisation chemistry
annulation reactions
N-heterocycles

Chapter 1: Introduction
The introduction gives an overview of the different strategies for the reduction of azaarenes, with a particular focus on transfer hydrogenation approaches for the synthesis of aliphatic N-heterocycles. The second half of the introduction presents a brief overview of relevant dearomative reductive functionalisation reactions of azaarenes published in recent years.
Chapter 2: Single-point activation strategy for the reductive hydroxymethylation of pyridines.
In this chapter a single-point activation strategy of pyridines is described that allows for the use of a more electronically diverse range of substrates to undergo the dearomative reductive hydroxymethylation reaction. Additionally, a total synthesis of ()-paroxetine is described, the target was prepared from a key dearomatized intermediate in 3 synthetic steps.
Chapter 3: Expending the scope of electrophiles in the dearomative reductive functionalisation reactions of quinolines
In this chapter the dearomative reductive functionalisation of quinolinium salts to their tetrahydroquinoline analogues is described. Two sets of new reaction conditions are developed with formic acid acting as the terminal reductant under transition-metal-free conditions or rhodium catalysis with very low catalyst loadings. The scope of electrophiles was expanded from just formaldehyde to a wide range of electrophiles, including enones, imides, unsaturated esters and sulfones.
Chapter 4: Expending the scope of electrophiles in the dearomative reductive functionalisation reactions of isoquinolines
In this chapter the dearomative reductive functionalisation of isoquinolinium salts to their tetrahydroisoquinoline counterparts is described. Analogously to the quinoline system, formic acid was used as the source of hydride and the reaction was possible under transition-metal-free conditions or rhodium catalysis with very low catalyst loadings. The scope of electrophiles that were intercepted by the enamine species generated in situ was further expanded to include enones, imides, unsaturated esters and sulfones, β-nitrostyrenes and aldehydes.
Chapter 5: Dearomative annulation reactions of isoquinolines
In this chapter various dearomative annulation reactions of activated isoquinolines are presented. The reactivity of in situ generated intermediates is exploited further to assemble complex tricyclic frameworks in a single step with excellent diastereoselectivities. The formal [3+3] annulation with methyl vinyl ketone is explored in greater detail including model studies towards the synthesis of the natural products in the crinane-alkaloid family.
Chapter 6: Experimental
This Chapter contains the experimental procedures and spectroscopic data for all the compounds described in this thesis.
Chapter 7: References
The references cited in the thesis can be found in this chapter.
Jerica Radez - Thesis submitted in partial fulfilment of the degree of Doctor of Clinical Psychology (DClinPsych)
Keywords: thematic analysis
youth mental health
schools
general practitioner
at-risk mental state
primary care
early intervention
screening
adolescence
barriers and facilitators

Identifying individuals at risk of developing psychosis: A systematic review of the literature in primary care services.
Aim: Psychosis and related disorders are a major public health issue. Early identification and prevention for those at high risk (at-risk-mental-state, ARMS) is important. General practitioners (GPs) are often the first point of contact for health services. In this review we aim to identify 1) the most common methods for identifying individuals with an ARMS in primary care, 2) the methods for improving identification of individuals with an ARMS in primary care, and 3) the most common barriers that prevent GPs from screening for individuals with an ARMS.
Methods: We conducted a systematic review (PROSPERO CRD42021245095) of quantitative and qualitative studies with no date restriction. Searches were performed in September 2021. Studies’ quality was appraised using Mixed Methods Appraisal tool (MMAT).
Results: We identified 16 eligible studies, and all but one provided quantitative data. Nearly two-thirds of studies were classified as ‘medium’ quality. Employing narrative synthesis, we identified three themes relating to 1) improving GP knowledge and confidence in identifying individuals with an ARMS, 2) balancing the over- and under-identification of individuals with an ARMS in primary care, and 3) supporting GPs as significant stakeholders in early diagnosis and treatment of individuals with an ARMS.
Conclusions: Improved identification of individuals with an ARMS is needed. We identified various strategies, including development and implementation of identification methods (e.g., screening measures), educational interventions for GPs (e.g., workshops), and systemic interventions (e.g., simplifying referrals to secondary care, developing integrated services). When implemented successfully, these interventions may help facilitate the access to appropriate care for individuals with an ARMS.
Active targeting of rhabdomyosarcoma cells using helenalin-loaded functionalised cubosomes
Keywords: cancer therapy
active targeting
cubosome
nanomedicine

Rhabdomyosarcoma (RMS) is the most frequent paediatric soft tissue sarcoma and affects ~55 young patients in the UK every year. Even though multidisciplinary treatments such as chemotherapy, surgical resection and radiation therapy can be employed, the clinical outcomes for patients with metastatic or released/refractory RMS remains poor. In this study, helenalin was chosen as a candidate anti-tumour compound for RMS treatment, since it showed the highest anti-tumour efficacy towards paediatric tumour cells among numerous natural products from a previous high-throughput assessment. Nanoparticle encapsulation of drugs can improve the pharmacokinetics and anti-tumour potency of cargos, while at the same time decreasing off-target impact on healthy cells. Herein, helenalin was designed to be loaded into next-generation lipid nanoparticles, i.e., cubosomes. These cubic phase nanoparticles are self-assembled liquid crystalline nanoparticles possessing a honey-combed structure and have been reported to have high drug-loading capacity, biocompatibility, bio-adhesive and permeation capacity, and thermodynamic stability. The aim of this thesis was to evaluate the anti-tumour potential and mechanism of action of helenalin towards RMS cells and then to target the tumour cells in an active manner using multifunctional cubosomes carrying helenalin. It was found that helenalin suppressed the proliferation, cell cycle, migration, and colony formation of RMS cells, while inducing a relatively lower toxicity towards healthy control cells. The pivotal mechanism of anticancer action of helenalin was revealed to be ROS generation and oxidative stress in RMS cell death, while mitochondrial depolarisation, endoplasmic reticulum stress, and NF-𝛋B deactivation might also contribute to the cytotoxicity on a small scale. The cubosomes were fabricated using a top-down approach and further functionalised with hyaluronic acid, antibodies, and/or iron oxide nanoparticles. CD44 and CD221-directed magnetic cubosomes carrying helenalin showed active targeting towards RMS cells in vitro by enhancing the anti-tumour capacity of helenalin without causing additional side-effects.
'If I could be equall with Solomon...' - Ecclesiastes and English practical divinity c.1590, with particular reference to Henry Smith & George Gifford
Keywords: prayers
Ecclesiastes
Qoheleth
Jean de Serres
George Gifford
Henry Smith
sermons
Solomon
koheleth

The book of Ecclesiastes is a scripture that has been notoriously vexing and endlessly inspiring to Christians and students of Christianity through the ages, and it has been a standout text in the diachronic study of biblical reception. Nevertheless, there is no dearth of problems, questions, potential advances, and needful correctives that remain outstanding.
One such set of issues relates to the reception of the scripture in sixteenth century England. When the Tudor dynasty began, interest in Ecclesiastes was limited, mainly to humanist scholars and the upper echelons of English society. By the end of Elizabeth’s reign, it had emerged as a focus of engagement, worldly application, and personal emulation for all, from puritan and conformist divines to London liverymen and independent craftswomen, from governing intellectuals like Francis Bacon to social outliers like the author(s) of Hæc-Vir. To date, the relevant historiographies have largely bypassed this arc of change.
The present thesis is an interdisciplinary study that identifies bands added to this arc of change by the generation of certain scripted prayers and sermons delivered c.1590 by the puritan ministers Henry Smith and George Gifford. Treating these materials as events of the imagination as well as texts, it also ascertains specific modes of their enduring influences, and argues that they were the vanguard of historically significant evolutions in the reception of Ecclesiastes that both deepened the scripture’s role in English practical divinity and had wider, abiding effects on English thought and expression well into the seventeenth century. Refinements to current scholarship are also offered, such as further pruning to the origins of the Victorine (Hugh of St Victor) influence on Reformed exegesis of vanitas. Certain bibliographical correctives are suggested as well, such as the place and importance of The Books of Homilies in the pre-1590 reception of Ecclesiastes.
The WEAVE fibre positioner: calibration, commissioning, and first-light
Keywords: WEAVE
fibre positioner
calibration
astronomical instrumentation
metrology

This thesis details the final assembly and calibration procedures for the WEAVE fibre positioner, from October 2019 to first-light in September 2022. The positioner was successfully mounted to the William Herschel Telescope (WHT) in May 2022. I present the first-light results of WEAVE for each of its three observing modes and discuss whether the positioner has met its design expectations.
Chapter one describes the evolution of astronomical spectroscopy and the scientific motivations behind the construction of WEAVE. This is followed by the instrument design specification and sub-systems required to meet them. Chapter two will focus on the positioner in detail and include the evolution of our quality control methods.
An account of the calibration procedures, in both the lab environment and on the elevation testing rig, is given in chapter three. The test rig revealed flexure behaviour in the positioner's structure, which was modified to correct for this. The calibration work was repeated with improved techniques, to predict changes in the positioner's metrology with elevation. This chapter then presents the results of the fibre movement testing, including the current placement timings
To maximise the scientific output from WEAVE, I applied a series of adjustments to a subset of target fields, identifying methods that will improve the survey output using the fibre assignment program, Configure, and highlight potential selection effects.
Chapter five presents the first-light results and the steps taken to achieve this. It required extensive measurements of the optical distortion map across the FoV, which were carefully mapped using astrometry of the night-sky across our focal plane. I then compare these results with the observational requirements from WEAVE's conception, to define its overall success. Chapter 6 provides an overview of the work completed in this thesis and describes potential upgrades to the instrument in the future.
Mapping the evolving landscape of child-computer interaction research: structures and processes of knowledge (re)production
Keywords: literature review
child-computer interaction
thematic analysis
human-computer interaction
innovation
correlated topic model
word2vec
sociology of knowledge
publication strategies
mixed methods research
research practices
negative binomial regression

Implementing an iterative sequential mixed methods design (Quantitative → Qualitative → Quantitative) framed within a sociology of knowledge approach to discourse, this study offers an account of the structure of the field of Child-Computer Interaction (CCI), its development over time, and the practices through which researchers have (re)structured knowledge comprising the field.
Thematic structure of knowledge within the field, and its evolution over time, is quantified through implementation of a Correlated Topic Model (CTM), an automated inductive content analysis method, in analysing 4,771 CCI research papers published between 2003 and 2021. Detailed understanding of practices through which researchers (re)structure knowledge within the field, including factors influencing these practices, is obtained through thematic analysis of online workshops involving prominent contributors to the field (n=7). Strategic practices utilised by researchers in negotiating tensions impeding integration of novel concepts in the field are investigated through analysis of semantic features of retrieved papers using linear and negative binomial regression models.
Contributing an extensive mapping, results portray the field of CCI as a varied research landscape, comprising 48 major themes of study, which has evolved dynamically over time. Research priorities throughout the field have been subject to influence from a range of endogenous and exogenous factors which researchers actively negotiate through research and publication practices. Tacitly structuring research practices, these factors have broadly sustained a technology-driven, novelty-dominated paradigm throughout the field which has failed to substantively progress cumulative knowledge. Through strategic negotiation of persistent tensions arising as consequence of these factors, researchers have nonetheless affected structural change within the field, contributing to a shift towards a user needs-driven agenda and progression of knowledge therein. Findings demonstrate that the field of CCI is proceeding through an intermediary phase in maturation, forming an increasingly distinct disciplinary shape and identity through the cumulative structuring effect of community members’ continued negotiation of tensions.
Design, characterisation and testing of organic semiconductors in the production of solar fuels
Keywords: solar energy
solar fuels
photocatalysis
carbon dioxide
organic semiconductors
porous polymers

Carbon dioxide emissions from burning fossil fuels is one of the key underlying causes of global warming. The removal of carbon dioxide from the atmosphere, as well as the mitigation of the use of fossil fuels is of growing concern with carbon dioxide levels approaching non-reversible amounts, and addressing the issue is becoming imperative. Solar fuels offer an elegant solution and merit research and understanding. Solar fuels store solar energy in chemical bonds and offer a synthetic, carbon neutral and renewable alternative to fossil fuels. They directly address issues of the intermittency of solar energy and its transport and storage.Carbon dioxide photocatalysis also offers the possibility of a carbon negative process, via synthetic formation of chemicals such as methanol or higher hydrocarbons for use as feed-stock or solvents in chemical industries. This thesis focuses on the use of organic semiconductors for solar fuels applications. The processability of organic materials, tuneable energetics, and functionalities as well as their inexpensive starting supplies and scalability make them an ideal candidate as materials in the formation of solar fuels. This work initially focused on photoelectrochemical water splitting. Specifically, it was found that the presence of an organic overlayer with glycol chains and anchor groups showed an increase coverage of TiO2 ALD at low cycle numbers, and showed an increased stability compared to the same device with no overlayer. This study highlighted the potential of organic functionalities in addressing the issues of adhesion and stability in photocathodes. Principles from photoelectrochemistry were adapted when looking into photochemistry for carbon dioxide reduction. Firstly, a set up was designed, built, and optimised for gas phase photoreduction of carbon dioxide. In conjunction a series of conjugated, solution processable polymers of intrinsic microporosity were designed and adjusted for use as materials catalysing carbon dioxide photoreduction in the presence of hydrogen. The structure-performance relationship was interpreted, and it was found that increasing pore sizes and higher photoluminescence decay times were related to increased CO production. The polymers were also tested as heterojunctions and with the presence of a copper-based co-catalyst which enhanced activity significantly. Learning from the design of this iptycene based series, another series based on spirobifluorene compounds, with higher yields and fewer synthetic steps was designed to further investigate pore sizes and taking advantage of the structure's known fluorescent properties. These studies paved the way for solution processable polymers for this application. This work outlines the interdisciplinary nature of photocatalysis and emphasizes the multitude of factors to be reconsidered in this application, in an attempt to lead to intelligent material and testing design
CRISPR interference-based functional genetic interaction mapping in FTD/ALS and PD
Keywords: FTD
neurobiology
CRISPRi
CRISPR interference
lysosome
neurogenetics
neurodegeneration
neuroscience
ALS
iPSC
genetic interaction mapping
iPSC-derived neuron
i3Neuron
Parkinson's

Parkinson’s disease (PD) and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis (FTD/ALS) are progressive neurodegenerative diseases that are neuropathologically defined by the presence of protein aggregates and the loss of specific subsets of neurons. Both diseases are associated with variants in genes that are implicated in lysosome function and proteostasis. Therefore, it is likely that converging disease pathways exist across these subsets of neurodegeneration, and the interrogation of these pathways can be used both to enhance our understanding of these disorders and lead to innovative therapeutic interventions.
Utilizing a modified i3Neuron platform to facilitate systematic single and pairwise knockdown (KD) of large panels of PD and FTD/ALS-associated genes through CRISPR interference (CRISPRi) to interrogate gene-gene interactions. My efforts focus on generating the first genetic interaction maps between the major genetic causes and risk factors of PD and FTD/ALS. Most notably, our interaction screen has identified several top gene-gene interaction candidates: TARDBP-TMEM106B, CLN8-NBR1, ATP13A2-CLN8, GRN-TMEM106B, and CTSL-GRN.
TMEM106B was a component of multiple hits, and a recent study has demonstra- ted that it modifies TDP-43 pathology [1], while overexpression induces cell death and causes the cleavage of TDP-43 [2]. Additionally, it has been implicated as an interactor of GRN in the clinic [3, 4], and as a regulator of lysosomal function and acidification in mice [4, 5]. A remarkable trend was apparent across all interactions with TMEM106B, where the pH is significantly lower than the non-targeting comparison, indicating a postive overall effect on lysosomal function with knockdown.
Strikingly, there is no significant phenotype between CTSL-GRN and non-targeting controls across DQ-BSA assays or the Magic Red assay, despite the severe deficits seen in GRN single KD. Lysosomal pH, however, is decreased significantly, which indicates a potential rescue across all assays. It is known that CTSL cleaves GRN [5], but no current studies exist showing an interaction beyond that, certainly not to the degree of rescue shown by the data in this thesis. This may be an ideal target for follow-up studies as a priority interaction. These promising initial results demonstrate that identifying common pathogenic changes elicited by disease genes can help us understand the underlying converging mechanisms in PD and FTD/ALS. Through these efforts, I hope to help lay the groundwork for improved molecular understanding and therapeutic discovery.
Externalist internalism: essays on hybrid theories in the philosophy of mind and epistemology
Keywords: epistemic internalism
consistency
privileged access
hybrid theories
equal justification thesis
externalism about mental states

This thesis collects four chapters connected by the theme of hybridity across theories in the philosophy of mind and epistemology. More precisely, this thesis assesses the consistency of hybrid epistemic internalism, a view that combines externalism about mental states with epistemic internalism.
I begin in chapter 1 by motivating both views. I distinguish between two variants of epistemic internalism, access internalism and mentalism, that are motivated by two considerations, the access motivation and the Equal Justification Thesis. I defend a non-standard version of access internalism that focusses on the permissive notion of “ready access”. I identify two challenges to the consistency of hybrid epistemic internalism: the access problem and the equal justification problem.
In chapter 2, I turn to the equal justification problem. State externalism undercuts the Equal Justification Thesis which states that individuals in the bad case have justification to believe the same things as their internal duplicates in the good case. I argue that a weak variant of the thesis, the Indiscriminable Justification Thesis, solves the equal justification problem if certain results of chapter 3 and 4 are established.
In chapter 3, I discuss the access problem in the form of the discrimination argument against ready access to one’s external states. I defend the discrimination argument against a compatibilist strategy that argues either that the discrimination argument is not sound, or that its application conditions are not relevant to us. I conclude that state externalism leads to an access problem.
In chapter 4, I defend a novel epistemic definition of the internalism/externalism debate about mind, the categorical epistemic definition. According to this view, state internalists and externalists disagree about the possibility of “mental state switching”. The view implies that state externalism leads to an access problem by definition. Further, by emphasising the difference between an epistemic definition of the debate and metaphysically committing accounts within the debate, the proposed view avoids common objections.