VictorJuiz/thesis huggingface dataset:
Dissecting mechanisms involved in the aetiological overlap between Type 2 diabetes and cancer

The advent of large scale genome wide association studies (GWAS) have uncovered a plethora of proposed susceptibility loci, most previously not connected to T2D pathogenesis. One of the most intriguing GWAS discoveries is the frequency with which T2D susceptibility loci map close to genes with roles in cell-cycle regulation. This previously unsuspected link between genes known for being dysregulated in cancer and T2D pathogenesis is supported by epidemiological evidence linking T2D and cancer. The aims of this thesis were to gain insight into T2D pathogenesis by studying specific examples involved in the complex interplay between T2D and cancer.
I investigated two loci already known for their roles in cancer pathogenesis: the tumour suppressor PTEN locus on chromosome 10 and the CDKN2A and CDKN2B locus at chromosome 9p21 (Chr9p21). PTEN is known to negatively regulate the phosphatidylinositol-3-kinase/AKT (PI3K-AKT) pathway which mediates many of the metabolic downstream effects of insulin signalling. Rodent data supports a role for PTEN in insulin action: tissue-specific Pten knockout and Pten haploinsufficient mice display improved glucose tolerance and insulin sensitivity. I recruited individuals with a rare cancer predisposition syndrome, Cowden syndrome, due to PTEN mutations and assessed their glucose homeostasis. Using oral glucose tolerance tests, euglycaemic hyperinsulinaemic clamp studies and adipose/muscle tissue biopsies, I have demonstrated that these PTEN haploinsufficient individuals display heightened insulin sensitivity and that this is via amplified signalling through the PI3K-AKT pathway.
The Chr9p21 T2D susceptibility loci are proximal to the tumour suppressors CDKN2A and CDKN2B. A noncoding RNA, ANRIL, is transcribed close to the regions of T2D association and a hypothesised mechanism for the T2D association is that the T2D variants affect ANRIL expression leading to altered CDKN2A/CDKN2B expression. Through a series of molecular studies I have demonstrated that ANRIL may have regulatory effects upon CDKN2A/CDKN2B expression in human islets. Although there is some rodent evidence suggesting a role for CDKN2A in regulation of beta-cell mass and glucose homeostasis, there is no direct evidence linking CDKN2A/B to glucose homeostasis in humans. I recruited individuals with rare CDKN2A mutations and performed oral and intravenous glucose tolerance tests to assess beta-cell function. The sample size precluded definitive conclusions but interesting trends were observed and further studies are planned. Collectively, the data presented in this thesis illustrate some mechanisms that may contribute to the aetiological overlap between T2D and cancer.

Advisor: McCarthy, M
Gloyn, A
Utopia and civilisation in the Arab Nahda

This doctoral thesis explores the contexts of utopian writing and thinking in the Nahda, the Arab 'Awakening' of the long nineteenth century. Utopian forms of social imagination were responses to fundamental changes in the societies of the Arab-Ottoman world brought about by integration into a capitalist world economy and a European-dominated political system. Much Nahda writing was permeated by a sense of a 'New Age' opening and of wide horizons for future change – and this was not simply illusory, but a direct response to actual and massive changes being wrought in the writers' social world. My study focusses on Egypt and Bil&amacr;d al-Sh&amacr;m in the middle decades of the nineteenth century, from the early 1830s to the mid-1870s. An initial chapter offers a definition of the social classes and groups which contributed to the Nahda in these years – such as the Beiruti bourgeoisie and the Egyptian-Ottoman official class – drawing on the work of Arab Marxists such as Mahd&imacr; '&Amacr;mil and social historians such as Bruce Masters. The following chapters deal in detail with writings produced by three distinct cultural formations within the Nahda movement, and with different aspects of their social imagination. Chapter 2 examines the discourse of civilisation (tamaddun) through the work of the Beiruti writers Khal&imacr;l al-Kh&umacr;r&imacr; and Buṭrus al-Bust&amacr;n&imacr; in the 1850s and 1860s. Chapter 3 deals with Nahda writers' sense of their place within the European-dominated world, mainly through translations of geography books made by Rif&amacr;'a al-Ṭahṭ&amacr;w&imacr; in Mehmed Ali's Egypt in the 1830s and 1840s. Chapter 4 examines the utopian aspirations of the Nahda, through a close study of the major utopian literary work of the period, Frans&imacr;s Marr&amacr;sh's Gh&amacr;bat al-Ḥaqq (The Forest of Justice, 1865). Finally, a conclusion places my study in relation to other recent work in the field of 'Nahda studies'.

Keywords: Civilisation
Nahda
Utopia
Butrus al-Bustani
Fransis Marrash
Rifa'a al-Tahtawi
Advisor: Omri, M
Chemical composition and oxidation study of nitrogen doped carbon nanotubes

In this work, carbon nanotubes (CNTs) and nitrogen doped carbon nanotubes (N-CNTs) were synthesized by aerosol chemical vapour deposition and the synthesis parameters such as temperature, catalyst concentration, precursor concentration, gas flow rate and reaction time were studied. N incorporation was extensively investigated on the basis of N bonding configurations detected by X-ray photoelectron spectroscopy (XPS), N concentration distribution measured by electron energy loss spectroscopy (EELS) and N spatial distribution by aberration corrected scanning transmission electron microscopy coupled with EELS (STEM-EELS). Pyridinic, graphitic, gaseous and N-oxide configurations were detected. EELS revealed N concentration differed from nanotube to nanotube within a given sample and also differed from region to region on a given nanotube. N is mostly concentrated regions of high curvature such as dome of repetitive compartments occurring within the inner channel of nanotubes. N was also found towards the innermost graphitic shells. The effects of N incorporation on nanotube outer and inner diameter distributions, wall thickness, morphology types, and morphology distributions are demonstrated. Correlations were found between nanotube morphology and chemical composition. Gaseous N tends to occur in thin-walled N-CNTs with large inner diameters and to be found in hollow and incomplete compartments morphologies. Si occurrence was also detected in CNT and N-CNT samples.
Oxidation resistance of CNTs and N-CNTs synthesized from a variety of C/N ratios were studied by thermogravimetric analysis. Undoped CNTs and N-CNTs were classified into three groups of oxidation in terms of the number of oxidation steps they followed. CNTs showed single step oxidation whereas N-CNTs showed two or three steps, indicating the non-uniform chemical composition of N-CNTs. This might result from the N concentration differing from nanotube to nanotube within a given sample and the N concentration differing from region to region in a given nanotube. Partially oxidised CNTs and N-CNTs were characterised by aberration corrected STEM-EELS to map their elemental compositions and understand the chemical changes they undergo during oxidation, which revealed that oxidation starts at specific sites in CNTs and N-CNTs.

Keywords: spectroscopy
STEM
microscopy
carbon nanotube
scanning transmission electron microscopy
EELS
electron energy loss spectroscopy
nanotube
nitrogen doped carbon nanotube
nanomaterials
Advisor: Grobert, N
Dissecting the inflammatory response in melanoma

While the immune system can control tumour growth, regulatory mechanisms, necessary in preventing immunopathology & autoimmunity, contribute to tumour progression impeding elimination of immunogenic tumours such as melanoma. To identify how the inflammatory response can influence tumour biology & be targeted in immunotherapy it is necessary to understand how expression of inflammatory molecules involved in regulatory mechanisms is controlled, which aspects of the inflammatory response are associated with accumulation of immune-regulatory populations & how these impact on frequency & activity of cells involved in tumour control.
Tumour-associated macrophages & regulatory T cells possess key tumour-promoting functions, including production of the suppressive cytokine, interleukin 10 (IL-10). I have analysed IL-10 regulation in myeloid cells by disrupting a putative enhancer.
The tumour inflammatory environment can influence neutrophil biology, leading to accumulation of low-density granulocytes, suggested to have immunosuppressive functions. I investigated the nature & frequency of low-density granulocytes in melanoma & their correlation with the inflammatory response & disease outcome. I identified low-density cells with an activated phenotype & cells with an immature phenotype enriched in the peripheral blood of stage IV melanoma patients. Marked inter-patient variation in the frequency of these subsets that correlated with accumulation of distinct cytokines, suggested the existence of distinct inflammatory axes. Analysis of patients undergoing anti-CTLA-4 treatment revealed that a lower frequency of activated neutrophils before treatment & an increase in frequency during treatment were associated with better response to anti-CTLA-4.
To establish whether accumulation of distinct neutrophil subsets was linked to wider inflammatory changes, the frequency of other immune cell subsets was determined. An enrichment of immature neutrophils was associated with TH2 cell enrichment, whereas an enrichment of activated neutrophils associated with inflammatory monocytes & activated TCR-γδ T cells, further supporting the existence of distinct inflammatory axes. The frequency of activated neutrophils negatively correlated with CCR4+ CXCR3+ CD8+ effector memory T cells, perhaps reflecting greater tumour infiltration of this population. Given the association of this subset with a neutrophil population linked to anti-CTLA-4 response, the importance of CD8+ T cells in anti-tumour responses, & the fact this population had not previously been described, I attempted further characterisation, as well as characterisation of intratumoural CD8+ T cells.

Advisor: Cerundolo, V
Middleton, M
Exploring the moon in the thermal infrared: the space environment goniometer

Measurements of the light scattering behaviour of the regolith of airless bodies in the Solar System, across wavelengths from the visible to the far infrared are essential to understanding their physical properties. This thesis describes the design, build and calibration of a novel instrument to measure the angular directionality of thermal infrared emission from surfaces (direction emissivity, DE). This work was originally motivated by the need for new DE measurements to support analysis of data collected by the thermal and far infrared Diviner Lunar Radiometer instrument (8 – 400 μm) currently in orbit around the Moon.
To fully interpret the brightness temperatures measured by the Diviner instrument a three dimensional thermal physical model is required. These models typically assume that infrared radiation is scattered isotropically from the lunar surface. Although generally the models are in very good agreement with Diviners measured brightness temperatures, there are some discrepancies particularly in permanently shadowed regions near the lunar poles. One possible reason for these discrepancies is that the thermal infrared DE of the lunar surface is not isotropic as is typically assumed by many of these models. The "Oxford Space Environment Goniometer" (OSEG) was developed to measure the DE of surface across wavelengths from the visible to the thermal and far infrared.
Analysis and modelling of initial DE measurements made with the OSEG show that the DE is dependent on the optical properties and roughness of the surface. DE measurements of the lunar regolith analogue material JSC-1AF have been incorporated into a three dimensional thermal physical model to show that the predicted surface temperatures of a polar lunar-like permanently shadowed region can differ by 10 K compared to assuming an isotropic DE.

Advisor: Bowles, N
The philosopher masked as literary theorist: 'cunning intelligence' (metis) instantiated in Bakhtin's rhetorical style

This dissertation discusses and analyses Mikhail Mikhailovich Bakhtin's conscious strategy of self-fashioning and reinvention, which is realised in his life and supported by the theoretical constructs contained in his Collected Works. It addresses the ambiguities and uncertainties in Bakhtin's life and work and uses two aspects of his philosophical approach and constructs to explicate these inconsistencies: his theory of identity and his theory of language.
The analytical tools used to arrive at this conclusion include the notion of reflexivity (using Bakhtin's own theoretical constructs to analyse incidents in his life, and in turn, using those incidents to illustrate the concepts he developed). Theoretical support for Bakhtin's self-fashioning is provided by Fitzpatrick’s theory of reinvention through impersonation and imposture in Revolutionary Russia. Bakhtin's theory of identity (expressed in his Nietzsche-influenced concept of the mask and its associated concept of travesty) supports this reinvention. Bakhtin's notion of double-voicedness, supported by his linguistic theories of interdiscursivity, heteroglossia and the utterance reinforce these two lines of thought. Bakhtin’s two figures of speech: the word with a 'backward glance' «слово с оглядкой» and the word with a 'loophole' «слово с лазейкой» encapsulate this convergence of theory and life. These two constructs are brought into sharp relief when illuminated by Wittgenstein's theory of language-games, Austin's concept of performativity and Benveniste’s formulation of deixis.
The overarching metaphor for this dissertation is the Classical Greek concept of metis, or 'cunning intelligence', a concept that is instantiated in the way in which Bakhtin framed the narrative of his life and the manner in which he performed his work. The dissertation concludes that Bakhtin evolved a multi-threaded philosophy which was self-consistent in the way in which it addressed the creation of identity, the expression of language and the performance of life and work through the metaphor of metis.

Keywords: consistency of life and theory
reflexive analysis
metis
narrative identity
revolutionary reinvention of persona
philosophy of  language
cunning intelligence
philosophy of identity
Advisor: Zorin, A
Treatment of Plasmodium falciparum malaria in the Democratic Republic of the Congo

Despite international efforts, the malaria burden remains high worldwide with half of all malaria-attributable deaths occurring in the Democratic Republic of Congo and Nigeria. Children under five and pregnant women bear the heaviest burden. New treatment options for falciparum malaria are urgently needed due to potential wide spreading plasmodium resistance to artemisinin derivatives.
In the first study, amodiaquine-artesunate, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DHA-PQ) were assessed in 684 Congolese children under 5. The efficacy was good and comparable for all combinations. The short parasitaemia clearance half-life suggested that the local parasite populations are still susceptible to the artemisinin derivatives. DHA-PQ provided the greatest prophylactic effect making it a good candidate for Intermittent Preventive Treatment in pregnancy. Plasma level of piperaquine and lumefantrine in small children at day 7 was however suboptimal indicating the necessity of adjusting the current dosage.
Artemether-lumefantrine is the most recommended ACT for malaria treatment in pregnancy although its pharmacokinetics properties are altered in this group. In the second study, the PK, efficacy, safety and tolerability of a 5 days regimen of AL were tested in a group of 48 pregnant women and a control group of 48 non-pregnant women with uncomplicated falciparum malaria versus the standard 3 day regimen. The day 42 PCR corrected efficacy was 100% in both treatment arms. Pregnancy was associated with reduced exposure to both lumefantrine and dihydroartemisinin. The extended regimen improved the exposure to lumefantrine, artemether and DHA in pregnancy. The QTc duration remained normal, but transient hematological or biochemical changes were observed in both groups. Babies born from the women treated in the study displayed a normal physical and neurological development in the first 12 months of life. At delivery 38% of women had placental malaria. The extended AL regimen is a promising option for those areas with emerging artemisinin resistance.

Advisor: Day, N
Fanello, C
Visions of China, Korea, and Japan in the East Asian War 1592-1598

Readings of contemporary accounts of the Japanese invasion of Chosŏn Korea and Ming China's intervention, by Japanese, Korean, and Chinese writers; analysis of the writers' disparate world-views and how they each envision their country and its neighbours.
This thesis uses contemporary writings from across the region to study the significance of the East Asian War of 1592-1598 for Chinese, Korean, and Japanese senses of identity, and argues that the war was a crucial moment in the development of those identities.
Despite the 1592-1598 conflict affecting millions of people, and resulting in almost unprecedented cross-border flows of people and information, most previous considerations of its effect on identity have focused on court documents. In the first dedicated study of identities in the East Asian War, this thesis shifts from the hitherto emphasis on politicians and commanders to prioritize individuals at the frontiers of cross-border contact. This shift of focus from centre to periphery contributes to our understanding of two areas of history. In terms of the East Asian War as a historical event, it provides a far more nuanced picture of what this momentous conflict signified for people at the time. In terms of the history of Chinese, Korean, and Japanese identities, it demonstrates persuasively that the sense of belonging to a country held real meaning for people across society, influencing the actions even of those totally removed from the state. Tracing the legacy of frontier writings again contributes to both the history of the war and of identity, by revealing how peripheral insights and central biases combined to give birth to the orthodox narratives of the war, some of which remain influential to this day.
Personal writings show how first-hand encounters in the war modified but also re-inforced already well-established identities, making national identities of immediate significance for an immeasurably wider group than in peace time. The late sixteenth-century growth in printing and literacy subsequently greatly amplified the impact of the East Asian War by allowing real-life interaction to be endlessly re-told as a dramatic clash between China, Korea, and Japan.
This study restores the war to its proper place as a key moment in the longer development of national identities in East Asia. It also calls for a primary-source based, East-Asia centred reconsideration of theories on the historical development of collective identity, which remain overly influenced by later European experience.

Keywords: National identity
Imjin War
Advisor: Lewis, J
Haar, B
Physiological patterns in pregnancy

The Confidential Enquiries into Maternal Deaths in the UK have highlighted an urgent need for development of a national Modified Early Obstetric Warning System (MEOWS) to aid the more timely recognition and treatment of complications in pregnancy. Six vital signs are used to assess the clinical status of women presenting acutely during and immediately after pregnancy: heart rate, oxygen saturation, systolic and diastolic blood pressure, temperature and respiratory rate. In the case of MEOWS, these define the thresholds that determine if a woman requires further medical review. Dynamic changes in maternal vital sign physiology associated with pregnancy complicate the use of vital signs to detect physiological deterioration. These changes are currently poorly described in the literature.
The aim of this work is to establish the normal physiological response to pregnancy in low-risk pregnant women, in terms of expected changes in vital signs. Using this knowledge, we will propose the first evidence-based, gestation-specific MEOWS chart.
To achieve this, we have set up the Prediction of Physiological Patterns in Pregnancy (4P) study. Using a custom-designed digital health system, healthcare professionals and women self-monitoring at home collect large numbers of vital sign measurements electronically. In particular, as respiratory rate currently is the only vital sign measured manually in routine clinical care, we propose two methods for electronic measurement of respiratory rate: using the in-built accelerometer of a smartphone and using the photoplethysmogram signal output by a pulse oximeter. These methods are validated against the current reference standard derived from a 15-second nurse count of breaths.
This thesis uses a dataset of 2,645 sets of vital sign measurements, collected from 439 women during pregnancy, in the 4P study. Using the electronic methods for measurement of respiratory rate, we obtain respiratory rate estimates with a mean absolute error of 2.9 respirations per minute compared to the reference measurement. From these data, we design reference ranges for changes in all six vital signs conditional on gestational age. Using a centile-based approach, we propose gestation-specific thresholds of normality for each vital sign, which will form the basis of a new MEOWS score to alert for physiological deterioration. Defining normality is the first step in recognising abnormality.

Keywords: Pregnancy
Vital signs
Patient monitoring
Advisor: Tarassenko, L