VictorJuiz/thesis huggingface dataset:
Paternal age effect mutations in germ cell development: pathological correlates in normal testis and testicular tumours 
Keywords: normal testis
testicular tumours
paternal age effect mutations

Pathogenic gain-of-function mutations associated with increased paternal age, albeit harmful to embryonic development, are paradoxically enriched in the normal testis. Evidence from previous studies indicates that these so-called paternal age-effect mutations confer a proliferative advantage to the spermatogonia in which they arise, leading to clonal expansion within the normal testis over time. Recently, spermatocytic seminoma (SS; a rare testicular germ cell tumour that occurs mainly in older men) has emerged as a key link between the processes of somatic and germline mutation (Goriely et al, Nat Genet. 41:1247-52, 2009), suggesting that the proposed clonal expansion events can in some cases lead to testicular tumourigenesis.
In this thesis, I have used immunohistochemistry to seek evidence for putative clones of cells in the normal adult testis. To address this, a screening approach was developed using markers chosen from analysis of normal testicular tissues and SS. The ontogeny of OCT2 and SSX expression in human testis, from embryonic development to adulthood, identified distinct subpopulations of spermatogonia at different maturation stages. Together, these data reveal the potential of OCT2 as a novel marker of Adark spermatogonia (human reserve spermatogonial stem cells). In parallel with these observations, two distinct types of SS characterised by differential OCT2 and SSX immunoexpression were identified, providing new evidence for heterogeneity of this tumour.
This work provided the backdrop to the detailed immunohistochemical study of normal adult testis by characterising in serial sections the expression of five spermatogonial markers, MAGEA4, SSX, FGFR3, OCT2 and SAGE1, and a proliferation marker, Ki67. Independent sections were screened with predetermined criteria set to identify unusual positively-stained cellular clusters within the seminiferous tubules. Several antigenic combinations previously described in SS were observed in a subset of these clones, suggesting differing genetic origins and a possible link with early events of testicular tumourigenesis. The size (minimum number of cells) of each clonal event was estimated and its correlation with the staining pattern of the molecular markers was investigated.
In summary, the data presented in this thesis convincingly identify for the first time the previously hypothesised clonal events in the testis using immunohistochemical markers. My research will pave the way for future work involving genetic analysis of microdissected cells from these putative clones, aimed at identifying the underlying mutational events thought to be present.
A pure world: moral cognition and spiritual experiences in Chinese World of Warcraft
Keywords: Moral cognition
China
spiritual experiences
World of Warcraft

This dissertation is about moral cognition and the production of spiritual experiences in the Chinese version of the massively multiplayer online game, World of Warcraft (CWoW). Chapter 1 introduces the game, field sites, data collection methods, and the questions and paradigms that structure the dissertation's narrative. This chapter explains that during fieldwork CWoW players frequently described gameplay as yielding positive moral and spiritual experiences. Chapter 2 outlines the cognitive mechanisms – Haidt and Joseph's 'moral foundations' (2004; 2007) – that are hypothesised to inform the in-game experiences to which players attributed moral significance. Chapter 3 argues that some aspects of the WoW gameworld are high in cognitive 'relevance' (following Sperber & Wilson, 1986) for Haidt and Joseph's moral foundations. This relevance yields the game a capacity for cross-cultural appeal. Chapter 4 argues that social agencies operant in the lives of CWoW players motivated players to utilise these morally relevant aspects of gameplay as a 'religion-like tool for group cohesion' (following Sosis & Alcorta, 2008). These extra-game agencies help explain why these aspects of gameplay were cultivated in lieu of, or as superordinate to, aspects that may be 'relevant' to other cognitive mechanisms. Chapter 5 argues that reports of soul merger experiences obtained in CWoW resemble Durkheim’s 'collective effervescence' (Durkheim, 1995 [1912]) and may be understood at the cognitive level as 'flow' (Csikszentmihalyi, 1990) experiences conjoined with affective outputs from Haidt and Joseph's moral foundations. Chapter 6 summarises the key points made in the preceding chapters and concludes that in the contexts sampled here, high-contingency aspects of CWoW gameplay may be viewed as Durkheimian religious rituals.
Dysregulation of cholesterol homeostasis
Keywords: Cholesterol
NPC
Smith-Lemli-Opitz

Cholesterol plays a critical role in the health and normal function of every mammalian cell. Cholesterol has multiple cellular functions including maintenance of cell membrane stability and fluidity, steroid hormone and bile acid synthesis, and membrane receptor signaling. As with any critical metabolite, cholesterol is highly regulated. I will detail my research focusing on the two prevalent disorders of cholesterol homeostasis. The first is a disorder of cholesterol biosynthesis, Smith-Lemli-Opitz syndrome (SLOS), and the second a disorder of cholesterol trafficking, Niemann-Pick disease, type C1 (NPC). I have identified a unique cellular phenotypic overlap between these two previously unrelated disorders. Specifically, increasing concentrations of the precursor sterol present in SLOS, 7-dehydrocholesterol, leads to the induction of an NPC-like cellular phenotype. Aspects of the NPC cellular phenotype that can be induced in SLOS fibroblasts include lysosomal storage of unesterified cholesterol, sphingosine, and glycosphingolipids. Also, similar to what is observed in NPC, dysregulation of acidic calcium stores is present in SLOS. Further research indicates that this cellular phenotype extends into both the mouse models of SLOS and the patients. The dysregulation of cholesterol trafficking in SLOS cells likely decreases cellular cholesterol bioavailabilty and thus potentially limits the therapeutic efficacy of dietary cholesterol supplementation in SLOS patients. I also show that treatment of SLOS cells with miglustat, an established therapy for NPC, ameliorates the NPC-like cellular phenotype and thus may have therapeutic benefit in SLOS. The incidence of both SLOS and NPC has been the subject of debate. Thus, using data generated from massively parallel sequencing of the human exome, I demonstrate that the previously predicted incidence of SLOS of 1:40,000 births is likely correct, but call into question the predicted NPC rate of 1:120,000 . In fact, NPC maybe closer to a rate of 1:40,000. The role of oxysterols in the teratogenicity of SLOS and the underlying secondary storage of lipids in the phenotypic presentation of SLOS has been investigated.
A fourdimensional microscope for single molecule studies in living cells using astigmatic axial resolution enhancement
Keywords: Astigmatic Microscopy
Single molecule tracking
Biological Physics
Super-resolution Microscopy

An important part of life is to react to the environment and adapt to it. All living cells rely on chemical cascades that form signal pathways, from stimulus to transcription events at the DNA. To know more about these pathways we need tools to visualise the signals.
Here is outlined developmental and experimental work on a bespoke microscope system primarily for fast single molecule tracing of proteins in living eukaryote cells. Both hardware and software has been developed. Frame rates and exposure times have been pushed to match the speed of freely diffusing particles in living cells. An EMCCD camera with an electronic gain of 300x and a 5 ms exposure time at 200 frames per second enables this.
An astigmatic axial resolution enhancement approach has been implemented to allow tracking with high precision of single fluorescent proteins in real-time in three dimensions in a comparatively large volume. The high resolution in three spatial dimensions and one temporal aim to meet these demands. Software to extract the additional axial information has been developed that can determine axial displacement with 38 nm precision.
The microscope system has proven it can find and track small clusters of YPet fluorescent protein in E. coli at short exposure times.
Development of biochemical tools to characterise human H3K27 histone demethylase JmjD3
Keywords: JmjD3
epigenetics
histone demethylase
chromatin

Covalent modifications of histone tails play essential roles in mediating chromatin structure and epigenetic regulation. JmjD3 is a JumonjiC domain containing histone demethylase, belongs to the KDM6 subfamily, and catalyses the removal of methyl groups on methylated lysine 27 on histone 3 (H3K27), a critical mark to promote polycomb mediated repression and gene silencing. The importance of JmjD3 has been implicated in development, cancer biology and immunology.
In this thesis, I report the recombinant production of active human JmjD3, development of two in vitro screening assays, a cell-based assay, and structural determination of JmjD3 in complex with the inhibitor 8-hydroxy-5-carboxyquinoline (8HQ). A highly selective and potent small molecule inhibitor GSK-J1 was subsequently identified. The inhibitor is active in HeLa cells and promotes a dose-dependent increase of global H3K27 methylation.
The inhibitor GSK-J1 was used in two different cell assay systems related to inflammation and differentiation, to understand how H3K27 demethylation controls cellular functions.
By inhibiting H3K27me3 demethylation, it is demonstrated that tumor necrosis factor (TNF) and other pro-inflammatory cytokines are regulated by H3K27 demethylase inhibition in M1- type macrophages derived from healthy volunteers and rheumatoid arthritis patients. It is also shown that inhibition of H3K27me3 demethylation abrogates cellular fusion of M2- type macrophages.
During RANKL induced osteoclast differentiation, JmjD3 is up-regulated and promotes the expression of the key transcription factor NFATc1. By inhibiting JmjD3, NFATc1 expression is reduced and osteoclastogenesis is inhibited. This mechanism demonstrates a novel anti-resorptive principle of potential utility in conditions of excess bone resorption such as osteoporosis, bone erosion in inflammatory arthritis or cancer of the bone.
These experiments further resolve the ambiguity between scaffold and catalytic function associ- ated with the H3K27 demethylase in these biological systems, and demonstrate that its enzymatic activity is crucial for epigenetic regulation of macrophage and osteoclast function.
The particularisation of error within the 'culture of fact', 1600-1650
Keywords: history of fact
early modern english literature
History of error seventeenth-century
early modern english drama

Barbara Shapiro's A Culture of Fact argued that a fact-orientated culture emerged in seventeenth-century England. Fact, formerly a legal category, was absorbed by a range of other discourses and became a crucial component of the epistemological shifts of the period. The question of how the culture of fact altered the articulation of the related concept of error has not been investigated.
This thesis analyses the changing concept of error against the emergence of the culture of fact, arguing for a shift from the personified and allegorised representation of error to a status as the particularised counterpart and opposite to the establishment of fact. The epistemological, religious, and cultural contexts informing notions of error and its particularisation are established. This particularisation is exemplified in the introduction by an account of the incorporation of the language of fact into the titles of texts concerning error. The chapters build on the critically established narrative of the permeation of evidential concerns surrounding matters of fact into drama, pioneered by Lorna Hutson, to examine plays and non-dramatic literary texts which offer perspectives on error as a mistake in matter of fact. Plays engage with the contexts of error, the conventions of fact, and stage how mishandling these conventions results in error. Poems by Spenser and Fletcher, and masques by Middleton and Campion reflect the shifting status of Protestant Truth, a key context of error, and its consequences for the representation of error. Jonson addresses error in forms scrutinised by seventeenth-century cultura animi authors and considers how they engender factual errors; whilst Ford and Brome, reacting to specific medical subgenres of error writing, conceived of error’s utility in a curative theatre. These playwrights unite a cultural concern with error as a specific sense of being mistaken in matters of fact with drama’s historical prerogative to exploit error in plots which may reflect a seventeenth-century recognition of error’s utility in the pursuit of fact.
Gestational age estimation in resource poor settings
Keywords: Image Processing
Epidemiology
Machine Learning
Gestational Age
Resource-poor Setting
Fetal Medicine

Background and objectives: The incidence of preterm birth (PTB), and the extent to which it results in perinatal mortality in sub-Saharan Africa (sSA) is unclear, partly because reliable estimates of gestational age (GA) at birth are lacking. This research: 1) Describes how clinical and ultrasound (US) estimates of gestational age (GA) influence PTB rates and perinatal mortality amongst a population in Kilifi, Kenya; 2) Implements a novel PTB classification system as proof of concept that such systems are feasible in low-income settings, and 3) Presents two novel approaches for estimating GA for women presenting >24 weeks’ gestation.
Methods: Objectives 1) and 2) used a perinatal surveillance platform developed at the KEMRI/Wellcome Trust Research Programme in Kilifi, Kenya. Ultrasound (US) was offered for GA estimation in women ≤24 weeks’ gestation clinically. To achieve objective 3), two candidate US dating equations were derived by combining a machine learning algorithm with polynomial regression analyses. Lastly, an entirely automated model with the capacity to estimate GA using computational image analysis of the fetal cerebral cortex was developed and tested.
Results: 1) Between November 2011 and July 2013, 3630 women presented for antenatal care, 1107 women had US and data were available for 950 (86%) of these. The PTB rate by US (US-GA) was 10.0% compared to 17.1% by a best clinical estimate of GA (C-GA), although the number of perinatal deaths that were preterm by US and C-GA were similar; 2) Implementation of a novel PTB classification system is feasible, and 3) New dating equations and an automated model provide estimates in the 3rd trimester with a prediction error at 34 weeks of 12.4 and 14.2 days, respectively.
Conclusion: Clinical estimates of GA significantly overestimate the rate of PTBs. Despite this, the proportion of perinatal deaths in those identified as preterm by clinical and US methods was similar, suggesting that US may be a better predictor of PTB and its associated mortality. Novel dating methods can estimate GA at 34 weeks’ gestation with an error equivalent to that provided by routine clinical methods at 22 weeks’. This has important implications and may extend capacity to provide GA estimates amongst a large group of women whose birth phenotypes remain poorly described.
The construction of Zi Zhi Tong Jian's imperial vision: Sima Guang on the Southern and Northern Dynasties
Keywords: historiography
Zizhi tongjian
Sima Guang

The great drama of China has been the repeated attempts to bring under single control and preserve the unity of its vast territories, so varied ethnically, socially, and geographically. Han Chinese confidence in the integrity of their own identity has been lastingly unsettled by long periods of fragmentation into regional states, and even in times of political unity the heart-searching has continued: what went wrong? What lessons could be learned for the future? The Southern and Northern Dynasties’ era (317-589 AD) was the longest period of political fragmentation in the imperial era. Its political and social confusion gave rise to differences in later accounts of it. In the eleventh century, scholar-officials intensively debated the issue of imperial rule during this period. At stake was the integrity of the Han Chinese state. On one side were historians who accorded legitimacy to the barbarian dynasties of the north; on the other were those who favoured the southern Han Chinese-ruled dynasties. By the time Song’s power base transferred south in 1127, a strong sense of a Han Chinese identity had developed and pro-Southern opinion predominated. This study approaches the Southern and Northern Dynasties’s era indirectly. It examines it through the most prominent work of eleventh-century historiography, the keystone written history of early imperial China, Sima Guang’s 司馬光 Zi zhi tong jian 資治通鑑 – the main focus of this study. That text has played a central role in shaping later understanding of imperial China’s political traditions and, as a corollary, has contributed to the formation of a Han Chinese self-identity. Yet Sima Guang’s representation of China’s past, though well-researched and written, was inevitably coloured by personal political and social experiences, and by his current commitments – by spin, in fact. This study will argue that at the heart of Sima Guang’s representation of the Southern and Northern Dynasties was a concern for the political survival of the eleventh-century state under which he served. He needed to understand and explicate the political and moral lessons of the earlier period in order to present an imperial vision that would avoid its frailties. This study therefore investigates and demonstrates the previously unexplored extent to which contemporary political concerns informed Sima Guang’s account. By developing a reading of Zi zhi tong jian as an ideological and textual construct, and more than just a simple account of the past, this study affords insights into the composition of historical writing in imperial China, as well as the complexities of the political environment that spawned it. It shows that works of historiography like Zi zhi tong jian served a more nuanced function than later scholarship suggests, and it brings into focus important questions of historical and literary authority.
Studies towards the nucleophilic dearomatisation of electron-deficient heteroaromatics and hydrogen borrowing reactions of methanol
Keywords: transition metal catalysis
catalysis
chemistry
chiral counterions
asymmetric catalysis
heterocyclic chemistry
organic chemistry
phase-transfer catalysis
hydrogen autotransfer
transition metal chemistry
hydrogen borrowing

Introduction – Dearomatisation of Heteroaromatic Compounds
The introduction provides a survey of dearomatisation reaction of heteroaromatics, with a particular focus on pyridines/pyridinium salts and furans. The mechanism, scope, and limitations of various approaches are covered, along with the goals of this project.
Results and Discussion – Dearomatisation of Electron-Deficient Heteroaromatics
This chapter initially explores the asymmetric addition of organometallic nucleophiles to pyridinium salts bearing a chiral counterion. Unfortunately, this approach ultimately proved unsuccessful, due to low observed enantioselectivities, and the low solubility of such salts. The second part of this chapter concerns the attempted asymmetric addition of dicarbonyl nucleophiles to electron-deficient furans, under conditions of chiral phase-transfer catalysts, affording bicyclic products in moderate enantioselectivity. Various alternative routes were also explored for the dearomatisation of furans and benzenoid systems.
Introduction – Hydrogen Borrowing Alkylation Reactions with Alcohols
The introduction surveys the range of methods available for the alkylation of various nucleophiles with alcohols under transition metal-catalysed conditions. Related methodologies are also explored, along with methods for the dehydrogenation of methanol.
Results and Discussion - Rhodium-catalysed Methylation of Ketones Using Methanol
This chapter describes the development of a novel ketone α-methylation using methanol. The development of reaction conditions is explored, followed by expansion of the substrate scope, including limitations of the methylation reaction. Mechanistic investigations support a methanol oxidation, aldol reaction/elimination, conjugate reduction pathway. Investigations into the role of O2 in the methylation reaction proved inconclusive. The utility of the reaction was also expanded via one-pot dialkylation reactions (work by Di Shen), Baeyer-Villiger oxidation of the products, and an attempted asymmetric transfer-hydrogenation.
Results and Discussion - Interrupted Hydrogen Borrowing Reactions of Methanol
This chapter looks to intercept intermediates from the α-methylation reaction. The selective methylenation of ketones is described, and a range of nucleophiles are screened for further functionalisation of ketones. Finally, a number of nucleophiles, including nitroalkanes, amines, peroxides and boronic acids are applied to one pot methylenation/conjugate addition protocols, affording complex products after two steps in one reaction vessel.
Experimental
Full experimental procedures and spectroscopic characterisation of compounds are provided.
Neutrality in political decision making
Keywords: neutrality
Rawls
Dworkin
Liberalism
multiculturalism

Liberal neutrality – as understood in current legal and political debates – has two underlying intuitions and therefore two distinct elements. On the one hand it refers to the intuition that there are matters the state has no business getting involved in (hands-off element). On the other hand it is motivated by the idea that the state ought to treat citizens as equals and show equal respect and for their different conceptions of the good life (equality element). This thesis defends this two-fold understanding of neutrality with reference to Rawls’ conception of society as a fair system of cooperation and the idea of citizens as free and equal persons. In particular, the idea that citizens are to be treated as free justifies the hands-off element and argues that the state must be involved in nothing but justice. In the context of political decision making this requires the state to be justificatorily neutral. Treating citizens as equals requires the state to grant its citizens equal political rights and also to ensure that these rights have “fair value.” Given the danger that cultural bias undermines the equal standing of citizens the state has to ensure procedures of political decision making that are able to take citizens’ different conceptions into account. Treating citizens as free and equal therefore requires that the state bans all considerations of the good from being part of the justification of state action while at the same time taking these considerations into account when deliberating the way how these regulations are to be implemented.