VictorJuiz/thesis huggingface dataset:
Continuity of care and clinical outcomes in the community care of patients with psychosis
Keywords: Psychosis
Community Mental Health
Psychiatry
Continutiy of Care

Continuity of care in mental health care is considered both an important objective of NHS policy and vital to clinical practice. However, it remains poorly defined and there is little research into its association with outcomes. Mental health services are unique in their ability to legally compel patients to adhere to treatment in the community and there has been no research into how this may affect continuity. My thesis aims to critically appraise the definition of continuity of care and systematically review the literature on its association with outcomes. It also measures its association with readmission by conducting a longitudinal study, and measures the association between community compulsion and continuity of care.
The literature review confirmed that continuity of care is best understood as the process of care of an individual patient over time. This is perceived by both the patient and providers of care as comprehensive, consistent, and connected. The systematic review found little evidence for an association between continuity of care and outcomes but that this may be due to persisting variation in both measures and outcomes.
Results from the longitudinal study suggested that better continuity was associated with both better and worse hospital outcomes. Community compulsion had no association with continuity of care.
My findings suggest that patient follow-up has improved considerably in the last three decades and, because of this, some traditional measures of continuity may be redundant. Measures of frequency of contact do not accurately measure the flexible, assertive practice that is a feature of current services. Continuity of care is useful as an indicator of the process of care but for it to be an effective research tool there needs to be a radical change in the way it is measured. Current mental health services are characterised by separation and specialisation into different components of care. Therefore, the most useful measures of continuity of care may be ones which successfully measure how it can be maintained between these services.
Life is in the manuscript: Virginia Woolf, historiography, and the "mythical method"
Keywords: Historiography
"Mythical Method"
Modernism
Creative Nonfiction
Virginia Woolf

Virginia Woolf's writing is aesthetically complex, politically engaged, and remains relevant today—an astonishing achievement. This thesis begins by asking how and why this is the case, and thinks through Woolf's relationship to history as a means of suggesting some answers. References to the past abound in Woolf's fiction in the form of meaningful names, stories, myths, and national histories. I am especially interested in allusions that are not immediately obvious, but still work to convey something about human nature. These were sometimes inspired by artifacts in museums, or by articles in magazines or newspapers, or literature she owned, or borrowed, or was being written by her contemporaries—sources that a careful researcher can track down. Other references are more difficult to prove; for example, they may have come from travel experiences related by friends, or personal experiences not recorded in her diary. In this case we need to balance circumstantial evidence, common sense, and an understanding of the spirit and concerns of the age.
In the first chapter I highlight Woolf's early interest in the tension between fact and fiction as it is expressed in her 1906 short story, "The Journal of Mistress Joan Martyn". The chapter serves as way of demonstrating my process. I point out the interplay between form, content, and autobiography that is in her other work. In short, a good deal of what is imagined may have been inspired by personal experience and real historical material. The next three chapters reveal new character types and source material for Jacob's Room, To the Lighthouse, and The Waves—the novels in which Woolf worked out what I have called her "mythical method". I end by inviting scholars to reconsider tensions in her work such as fact and fiction, self and other, art and politics from a new angle: not only as thematic preoccupations but also as crucial to thinking of—to borrow from Gertrude Stein—composition as a form of explanation. Woolf's project in fiction was to figure out what modernism can and should do.
Although it is not necessary for all readers to do the kind of research demonstrated here in order to understand the novels, having an awareness of this work is important. This new way of looking at how and why Woolf wrote both in and outside of time as part of the process of composition makes us think again about the reasons that we should care so much about "Mrs. Brown". It helps us appreciate that the project of conveying both the ephemeral and temporal qualities of human experience is what makes the study of literary modernism (and its current global, transnational forms) a dynamic, political, and expanding phenomenon today.
The role of autophagy in intestinal T cell homeostasis
Keywords: Autophagy
T cells
IBD
Mucosal immunology

A polymorphism in the essential autophagy gene ATG16L1 is associated with susceptibility to inflammatory bowel disease. However, the role of autophagy in maintenance of intestinal immune homeostasis remains unclear. Using targeted deletion of Atg16l1 in T cells, we demonstrate critical requirement for autophagy in generation of appropriate adaptive immune cell responses within the mucosa. Selective deletion of Atg16l1 in T cells resulted in spontaneous intestinal inflammation, characterized by accumulation of Th2 cells and aberrant antibody responses towards dietary and microbiota antigens. Foxp3+ Treg cells were dependent on autophagy for their survival and function within the intestinal lamina propria, where they acted to limit Th2 cell accumulation. In addition, we demonstrate a novel role for autophagy in limiting Th2 cell survival in a cell-intrinsic manner. The distinct requirements for autophagy in the survival of different intestinal CD4+ T cell subsets reveals a novel role for autophagy in mucosal T cell homeostasis, with potential implications for understanding and treatment of chronic inflammatory disorders.
Pyrrhic progress - antibiotics and western food production (1949-2013)
Keywords: Agricultural intensification
Antibiotic regulation
Bacterial resistance
Non-human antibiotic use
Agricultural antibiotic use
Risk Management

This dissertation addresses the history of antibiotic use in British and US food production between 1950 and 2013. Introduced to agriculture in the 1950s, antibiotics underpinned the 20th-century revolution in Western food production. However, from the late 1950s onwards, controversies over antibiotic resistance, residues and animal welfare began to tarnish antibiotics' image.
By mapping both the enthusiasm and the controversies surrounding antibiotic use, this dissertation shows how distinct civic epistemologies of risk influenced consumers', producers' and officials' attitudes towards antibiotics. These differing risk perceptions did not emerge by chance: in Britain, popular animal welfare concerns fused with new scenarios of antibiotic resistance and drove reform. Following 1969, Britain pioneered antibiotic resistance regulation by banning certain feed antibiotics. However, subsequent reforms were only partially implemented, and total antibiotic consumption failed to sink. Meanwhile, scandals and public pressure forced the American FDA to install the first comprehensive monitoring program for antibiotic residues. However, differing public priorities and industrial opposition meant that the FDA failed to convince Congress of resistance-inspired bans. The transatlantic regulatory gap has since widened: following the BSE crisis, the EU phased out growth-promoting antibiotic feeds in 2006. The US proclaimed only a voluntary and partial ban of antibiotic feeds in December 2013.
In the face of contemporary warnings about failing antibiotics, the dissertation shows how one group of substances acquired different meanings for different communities. It also reveals that the dilemma of antibiotic regulation is hardly new. Despite knowing about antibiotic allergies and resistance since the 1940s, no country has managed to solve the dilemma of preserving antibiotics' economic benefits whilst containing their medical risks. Historically, effective antibiotic regulation emerged only when differing perceptions of antibiotics were broken down either by sustained regulatory reform or large crises.
Ameliorating β-thalassaemia by manipulating expression of the α-globin gene
Keywords: genome editing
alpha-globin
epigenetic drug targetting
thalassaemia

β-Thalassaemia is a disorder of haemoglobin production characterised by severe anaemia requiring life-long blood transfusions. The common genetic defects are predominantly based in and around the β-globin gene resulting in reduced or absent β-globin chain synthesis. The resultant excess of free α-globin chains, which precipitates in red blood cells and their precursors and causes ineffective erythropoiesis, is the main pathophysiological mechanism of anaemia in these patients. Clinical and genetic data accumulated over the last 30 years have indicated that reduction of α-globin expression is clinically beneficial to patients with β-thalassaemia, and in the subset of patients with HbE β-thalassaemia it could be transformational. Attention has been centred on pathways that increase γ-globin expression and hence the production of foetal haemoglobin, but I have explored avenues that down regulate the α-globin gene expression without affecting the β-like globin expression, to equalise globin chain imbalance and could have potential clinical applications.
Initially, an in vitro erythroid differentiation system in serum-free medium was optimised and characterised. This generates a large number of erythroid cells from human CD34+ cells with minimal non-erythroid contamination. This system appears to be a faithful recapitulation of normal erythropoiesis and was validated with newly developed assays. A library of epigenetically active small molecules and licenced drugs was then screened and this identified a number of interesting compounds including IOX1, a histone demethylase inhibitor. Secondary assays confirmed IOX1 as a selective down regulator of α-globin expression, with no significant adverse effects on β-like globin expression, erythroid cell viability, erythroid differentiation or global erythroid transcriptome.
Next, CRISPR/Cas9 genome editing technique was used to introduce targeted deletions of multispecies conserved sequences (MCS) R2 region, the most critical distant cis-acting regulatory element enhancing α-globin expression in humans. High transfection and mutation efficiencies were achieved in human CD34+ cells and single cell assays confirmed high frequency of homozygous and heterozygous deletion events. More importantly, and analogous to patients with an identical mutation, the deletion of MCS-R2 element resulted in selective knockdown of α-globin expression without altering β-globin expression or erythroid differentiation. In conclusion, I have demonstrated that selective down regulation of α-globin expression is plausible through pharmacological and genome engineering approaches and these findings unveil new pathways of therapy for β-thalassaemia.
Post-translational modifications of BRAF and MITF
Keywords: drug screening
BRAF
MITF
nuclear export signal

Malignant melanoma is the deadliest and most aggressive form of skin cancer. Despite the development of targeted molecular therapies which specifically target oncogenic pathways in melanoma, melanoma remains highly refractory to treatment and prone to relapse. In order to develop more effective therapies, there is a need to investigate additional ways of manipulating aberrant molecular pathways in melanoma. To this end, we have identified novel sites of post-translational modifications in two oncogenic proteins that are known to play pivotal roles in driving melanoma tumorigenesis. We showed that BRAF, the most commonly mutated oncoprotein in melanoma, can be acetylated at K473 and K475 by the p300/CBP acetyltransferases. Importantly, acetylation of BRAF reduced its activity regardless of its mutational status at the commonly mutated V600 residue. We also identified a novel phosphorylation site targeted by GSK3 in microphthalmia-associated transcription factor (MITF), the melanocyte master regulator. GSK3 phosphorylation of S69, together with ERK-mediated phosphorylation of the nearby S73 residue, was found to promote MITF nuclear export via a previously undescribed nuclear export signal comprising of the S69, S73, M75, L78 and L80 residues. Importantly, phosphorylation-induced nuclear export was associated with reduced MITF activity, which may have important functional implications for melanocyte development and melanoma oncogenesis. In addition, we showed that the cyclin-dependent kinases CDK1 and CDK2 can also phosphorylate MITF at S73.
Dynamic nuclear polarisation as a probe of metabolism in pathophysiology
Keywords: MRI
Metabolic imaging
Hyperpolarized 13C
DNP
Metabolic data analysis
Hyperpolarized Carbon
Pulse-sequences
Dynamic Nuclear Polarisation
MRS

Spin-half nuclei in a magnetic field possessing a population difference in excess of that expected at thermal equilibrium are said to be hyperpolarised. Dynamic Nuclear Polarisation (DNP) is a method to generate hyperpolarised systems, pumping nuclear spins into a given state at low temperature. Hyperpolarised samples can be rapidly dissolved in a hot solvent, and maintain a highly polarised spin population that relaxes to the new thermal equilibrium over several minutes. It is possible to inject hyperpolarised molecules into an organism, sample the population difference through NMR spectroscopy, and obtain spectra with a large (&GT; 104) increase in their signal-to-noise ratio compared to thermal equilibrium. The use of hyperpolarised [1-13C]pyruvate allows for the quantification of the rate of [1-13C]lactate production, increases of which are a defining characteristic of cancer; or the rate of 13C-bicarbonate production, which is altered in heart disease.
This thesis describes the development of magnetisation-efficient sequences of spectrally-and-spatially selective radiofrequency pulses and rapid imaging readouts that are able to image the metabolism of hyperpolarised [1-13C]pyruvate in three dimensional space, with a reconstructed resolution of 1 × 1 × 2 mm3. The technique’s sensitivity to metabolism is demonstrated, and attempts are made to image cancer that has metastasised to the brain prior to the point of conventional detection through its metabolic phenotype. It is also used to image metabolism in the post ischæmic myocardium, where it reports on regions of non-viable tissue.
Additionally, hyperpolarised 13C-urea is used as a 'metabolically inert' probe of perfusion in the myocardium. Flow-sensitisation gradients and a spiral readout allow 13C-urea to be resolved in the myocardium. The ability to 'co-polarise' [1-13C]pyruvate and 13C-urea is demonstrated. This technique could simultaneously resolve perfusion deficits and metabolic changes in the acutely damaged heart, with several potential advantages over current clinical methods.
Finally, several methods for analysing data generated by hyperpolarised experiments are proposed: weighted averaging for combining spectroscopic data of varying quality; novel Bayesian approaches to quantifying metabolic rate constants of interest following the injection of hyperpolarised [1-13C]pyruvate; and the Fast Padé Transformation as an improved method for the reconstruction of truncated hyperpolarised spectral data.
DNP is a technique that, following its development for particle physics experiments in the 1970s, is transitioning to clinical practice as a safe, novel molecular imaging modality. It is hoped that the techniques proposed in this text ultimately find wide utility in the assessment of cancer and heart disease, which combined are responsible for approximately 50% of deaths occurring in the developed world.
Tethered flurophore motion studies of DNA segregation machinery
Keywords: Site-specific recombination
XerCD-dif-FtsK
Single-molecule
Total internal reflection fluorescence microscopy

Tethered fluorophore motion (TFM) is a single-molecule fluorescence technique, used to monitor an effective length along a biopolymer, such as DNA. In this work, I start by characterising TFM, focussing on the theoretical basis and potential applications, and then use TFM to study the bacterial site specific recombination system, XerCD-dif. I present a description of the sources of noise in TFM and derive an analytical expression for the resolution, which is compared to simulations and experiments. The work demonstrates that length changes as low as 100 bp of double-stranded DNA are distinguishable using TFM. The optimum pixel size for TFM is derived and validated experimentally.
XerCD-dif recombination is responsible for chromosome decatenation in most bacteria with circular chromosomes. It is activated by the DNA translocase FtsK. I describe the application of TFM, in combination with Förster resonance energy transfer (FRET) and protein induced fluorescence enhancement, to observe the formation and activation of XerCD-dif synaptic complexes. The work followed the reaction, as Holliday junctions formed by XerD-mediated strand exchange isomerised and were resolved to product by XerC, and measured the lifetimes of all the intermediates observed.
To analyse the role of FtsK in the activation of recombination, and to monitor its assembly, translocation and behaviour when encountering XerCD-dif, TFM was extended with the use of two spectrally distinct fluorophores, allowing simultaneous monitoring of two effective lengths along the same DNA. FtsK was observed to assemble on DNA, stepwise, into a single hexamer, and begin translocation rapidly (&Tilde;0.25 s). Single hexamers approached XerCD-dif, and resided for 0.5s to 1s before dissociating, irrespective of whether XerCD-dif was synapsed or recombination was activated.
The final section of this thesis details the design, construction and evaluation of a three colour microscope. Alternating laser excitation was implemented in the green, red and near-infrared spectral channels with three laser sources, and an inexpensive automatic focus system was implemented using the back reflection of the excitation lasers and a complementary metal oxide semiconductor camera.
En d'autres mots. L'écriture translingue de soi
Keywords: translingual
Literature
Alexakis
Huston
Molnár
French
Kristof
life writing
Makine
Bianciotti

For several reasons, translingual writers, defined here as authors who write in a language that is not their native one, have gained increased visibility in recent years. This is particularly true in the context of French literature where, more frequently than before, and with a more explicit recognition of their particular status, translingual writers have received important literary prizes and have been welcomed into the French Academy. Central to this recognition is their rich and diverse mobilisation of life writing, a corpus curiously neglected in the study of the phenomenon of literary translingualism. This thesis focuses on the writers Andreï Makine, Hector Bianciotti, Vassilis Alexakis, Nancy Huston, Agota Kristof and Katalin Molnár. It demonstrates that the translingual experience, in its capacity to question one's sense of self and provide novel tools for the exploration of one's personal history and subjectivity (conceived as an experience in language), appears eminently suited to the genre of life writing and that, in the current configuration of the French literary space, life writing is demanded from translingual authors. It proposes an original cartography of contemporary translingual literature in French, suggesting that more than any similarities in the conditions of their literary adoption of French, what creates family resemblance between translingual writers is the types of relation with their adopted language that are constructed in their autobiographical texts.
Biologically inspired de novo protein structure prediction
Keywords: Bionformatics
Protein Informatics
Protein Structure Prediction
Cotranslational Protein Folding

Fragment-based approaches are the current standard for de novo protein structure prediction. These approaches rely on accurate and reliable fragment libraries to generate good structural models. We demonstrate that fragments presenting different predominant predicted secondary structures should be treated differently during fragment library generation. Using this information, we developed Flib and shown that it generates fragment libraries with higher precision and coverage than two other methods.
We explored co-evolution to identify pairs of residues that are in contact, which were then used to improve model generation. We performed a comparative analysis of nine methods in terms of their precision and their usefulness to de novo structure prediction. Our results show that metaPSICOV stage 2 produces the most accurate predictions and that metaPSICOV stage 1 generates the best modelling results. In general, contact predictors are good at identifying contacts between β-strands and bad at identifying contacts between α-helices. We also show that the ratio of satisfied predicted contacts can be used to assess whether correct models were generated for a given target.
We also investigated whether the biological process of cotranslational protein folding, the notion that proteins fold as they are being synthesized, can be used to improve de novo protein structure prediction. Our tool for this investigation is SAINT2. SAINT2 differs from conventional fragment-assembly approaches as it is able to perform predictions sequentially from N to C-terminus, starting with a small peptide that is extended as the simulation progresses (SAINT2 Cotranslational). SAINT2 is also able to generate decoys in a standard non-sequential fashion (SAINT2 In Vitro). We compared SAINT2 Cotranslational to SAINT2 In Vitro and shown that SAINT2 Cotranslational generally produces better answers, generating an individual decoy between 1.5 to 2.5 times faster than SAINT2 In Vitro. Our results suggest that biologically inspired structure prediction can improve search heuristics and final model quality.