VictorJuiz/thesis huggingface dataset:
Autophagy’s roles in the activation and ageing of CD4+ T cells
Keywords: Cytokine
Aging
T cell
Autophagy

Autophagy plays an essential role in the differentiation, homeostasis and renewal of various cell types. Though its molecular machinery has been extensively elucidated, what autophagy specifically degrades remains largely unclear. Here, we created the Lc3b-APEX2 transgenic mouse model based on the proximity biotinylation technique, which, for the first time, enables us to directly map the proteinaceous content of autophagosomes in any primary cell. Through inserting APEX2, an engineered ascorbate peroxidase, into the endogenous LC3B allele, proteins residing in the autophagosomes can be specifically labelled with biotin and easily purified. After the systemic validation of the mouse model, next, I utilised it to explore the molecular mechanism of why CD4+ T cells, which orchestrate both humoral and cytotoxic immune responses, rely on autophagy to expand when facing antigen-stimuli. We discovered the interleukin-7 receptor alpha (IL-7Rα) as one of the autophagosomal candidates in proliferating CD4+ T cells. Mechanistically, we confirmed that excessive surface IL-7R sequestrate the common gamma chain, impairing the IL-2R assembly and downstream signalling crucial for T cell proliferation. Moreover, we investigated how CD4+ T cells from aged mice, which mimic some of the phenotypes of autophagy-deficient CD4+ T cells, also show several unique changes related to cellular ageing. This study provides proof of principle that key autophagy substrates can be reliably identified with this model to help mechanistically unravel autophagy’s contribution to healthy physiology and disease.
Another world is possible: reconceptualizing the “safe space”
metaphor at a feminist safer space in New York City
Keywords: safe spaces
feminist anthropology
structural violence
New York City
safety
everyday utopia
counterpublics
hope
feminist bookstore
queer spaces
anthropology of space
cultural critique
anthropology of violence
neoliberal violence
intersectional feminism
anthropology of safety

My thesis seeks to reconceptualize the “safe space” metaphor at a self-described “safer space” in New York City, Pocketbooks. Typically understood as places of comfort, safe spaces are often disparaged for encouraging emotional fragility and stymying intellectual growth. However, the potential of sites like these to offer cultural critique and provoke new ways of thinking about safety (and violence) has been overlooked. Pocketbooks, a feminist bookstore in a hyper-gentrifying neighborhood of Manhattan, is one such place. Although Mayor Giuliani’s “quality of life” laws are often credited for making NYC the safest it has ever been, Pocketbooks positions itself as a “safer space” from a city (and society) that has become increasingly unsafe.
With a view to (re)conceptualizing safe spaces and interrogating the meaning(s) of safety in neoliberal America, my thesis posits the following ethnographic question: How does the Pocketbooks community (re)imagine, negotiate, and enact notions of safety to build a micro-society that is, in their words, “equitable, cooperative, and free?” Integrating fifteen months of fieldwork with a variety of literatures—including but not limited to the anthropologies of violence and counterpublics—I attempt to reconceptualize the safe space metaphor. I argue that Pocketbooks act as a feminist counterpublic whereby people of subordinated and sociospatially-excluded populations can find community and self-expression, acquire skills to reduce the extent of their marginalization elsewhere, develop language to articulate their identities and experiences, and even unlearn violent habitus. Moreover, in an attempt to translate utopian imaginaries into practice, Pocketbooks becomes a place to think from and about safety, and a place to consider how to forge justice in an unequal world. My research challenges the dominant discourse that neglects the structural nature of violence and overlooks safe spaces as creative sites of cultural critique and production, contestation, and hope.
Stratifiers for oxaliplatin outcome in colorectal cancer
Keywords: transcriptomics
genomics
colorectal cancer
cancer
oncology
clinical research

Colorectal cancer (CRC) is the second most common cancer in terms of mortality in the world. Oxaliplatin is the one of the most common approved adjuvant chemotherapeutic drugs for advanced stage II and stage III. Despite the improvement in outcome, a high percentage of cases show lack of response and resistance. Thus, my aim for this thesis is to discover or validate a biomarker of oxaliplatin response with potential use in the clinic to guide therapy decisions. Response has been chosen as the primary end point because it presents a more direct measure of the drug effect. To this aim, I have used multiomic data from two clinical trials of the S:CORT consortium (Focus and Foxtrot) and generated transcriptome from another clinical trial (Coin) for deep bioinformatic interrogation of the clinical question. I first investigated 13 candidate biomarkers known for their prominent role in CRC biology. I have found that KRAS mutation is associated with poor response and survival to 5FUFA, but predicts benefit from the addition of oxaliplatin. Furthermore, DDRD signature positivity is predictive of no benefit of oxaliplatin compared to 5FUFA alone. Secondly, I have investigated 32 candidate biomarkers identified from a systematic literature review that I conducted for oxaliplatin resistance. High CDC6 expression and DNA repair score favours no oxaliplatin and predicts lack of response, while high NFE2L2 expression favours oxaliplatin response. Finally, I generated two signatures from RNA expression data of progressive versus non-progressors patients. From this study, I present predictive biomarkers of response for oxaliplatin, important in neoadjuvant clinical settings.
On top of the city: Rooftops, rights to space, and the fight for St Petersburg’s panoramas

Keywords: Rooftops
Urban Space
Russia
Panorama
St Petersburg
Local Identity

This is a study of St Petersburg’s rooftops. It explores the experience of being on top of the city and demonstrates that, in Russia’s northern capital, the rooftops have become central to the way the city is perceived, both locally and globally. This thesis explores the relationship between built environment and local identity in St Petersburg. Developing from an interest in the urban exploration practice of roofing, the recreational trespass of the city’s rooftops, and hoping to establish why and how the activity has become so popular in St Petersburg, my analysis explores the different uses of the city’s rooftop (and attic) spaces and relates these to social development, urban planning, civic activism, and the local imaginary in St Petersburg.
I argue that the city’s rooftops have captured the local imagination as they connect St Petersburg’s residents to their past. Despite the widespread changes that have taken place across the city, including developments to the skyline, I demonstrate that the roofs, both in their form and use, provide a thread of continuity. As such, this research is interested not only in the contemporary uses of the rooftops, but the cultural processes that have cemented their position within St Petersburg culture. For this reason, this thesis views the city through both a contemporary and historical lens. Based on a multimethod approach, including historiography and ethnographic fieldwork, conducted in St Petersburg in 2019 and early 2020, this thesis explores a range of uses of the city’s rooftops as creative, domestic, commercial, and leisure space.
Pragmatic understanding: comprehension of conversation in individuals with and without communication challenges
Keywords: autism
language
pragmatics
communication

Pragmatic processing of language involves inferring a speaker’s intended meaning by integrating their utterance in context. Pragmatics is thought to be dissociable from “core” aspects of language processing, such as vocabulary and grammar, and to be a specific area of difficulty for some individuals, such as autistic people. As there are limitations in current pragmatic assessments, a new Implicature Comprehension Test was developed to specifically measure a person’s ability to process implied meaning in context. Results supported the hypotheses, showing that processing implied meaning was separable from core language skills, and that the Implicature Comprehension Test was sensitive to cognitive differences between autistic and non-autistic individuals, especially in adults. The situation became more complex when looking at implied meaning in the context of other socio-cognitive-linguistic skills measured through a cognitive test battery, as domain-level differences between autistic and non-autistic people on the battery were subtle at most, even though autistic people were observed and reported themselves as having considerable day-to-day communication difficulties. It is suggested that these subtle differences reflected domain-level information processing differences in judging the meaning of novel communicative stimuli in the context of uncertainty and a preference for explicit information. However, the subtle scale of observed differences supports the view that communication difficulties in autism vary according to the context, with an important contextual factor being the level of structure and uncertainty inherent in the situation. In exploratory analysis, this thesis questions whether difficulties with “theory of mind” account for communication differences in autism. Suggestive evidence is also provided for gender differences in the communication profile in autism and for a selective link between self-reported, but not observed, communication difficulties and mental health challenges.
Metal-organic framework materials for low-k dielectrics and selective sensing applications
Keywords: Interdigitated Electrodes
Impedance Response
Dielectric Response
Metal-Organic Frameworks
Iodine Sensing

Metal-organic frameworks (MOF) are fascinating hybrid materials, gained widespread attention from the scientific community since their emergence about three decades ago. The high porosity and tailorability of MOF structures make them an ideal candidate material for both low-k dielectrics and electrical sensing applications. In this work, an in-depth study on different MOFs was carried out to explore the influence of host-guest interaction and external stimuli including pelleting stress, operating temperature, and frequency, on MOF dielectrics. Additionally, a mechanism was proposed to identify the exceptional MOF materials for target guided electrical sensing and optimise the sensor preparation parameters to enhance its selectivity and sensitivity to revolutionise the conventional electrical sensors. Both polycrystalline (in the form of pellets) and single-crystal MOF samples were studied to gain a deeper insight into both areas.
First, the influence of different external stimuli (temperature, pressure and amorphization) on broadband dielectrics (Hz-MHz and THz) was investigated for both HKUST-1 and MIL-100 MOF systems, to gain a greater understanding of structure-property relation. Secondly, by leveraging the different synthesis approaches, the role of guest molecules was also analyzed for both the polycrystalline powder pellets and single-crystal HKUST-1 MOF systems in the Hz-MHz frequency range. The single-crystal study, which is independent of pelleting pressure and free of grain boundary influence, provided a greater insight into the MOFs intrinsic properties. Thirdly, the impact of host-guest interaction dependent electrical response was materialised in the form of proof-of-concept electrical sensor applications.
Overall, this work consolidates the candidacy of MOFs as an efficient low-k material and also expands its future portfolio to the realm of ultra-trace highly sensitive electrical sensing.
The role of MYB in MLL-AF9 leukaemia
Keywords: promoters
c-MYB
transcription factors
enhancers
MYB
MLL-AF9 leukaemia
miR-196-b

MYB is a DNA-binding transcription factor with a critical role in the establishment of definitive haematopoiesis. In haematological malignancies, MYB is a direct downstream target common to several MLL-fusion proteins (MLL-FP), including MLL-AF9, the most common MLL-FP in acute myeloid leukaemia. MYB is necessary for the maintenance of MLL-AF9 leukaemia, and even partial and transient loss of MYB has been shown to abrogate MLL-AF9 leukaemia in vivo. While MYB inhibition is able to attenuate leukaemogenesis, its specific requirement in the processes of leukaemia initiation and transformation is still unclear. Furthermore, despite its obvious importance in normal and malignant haematopoiesis, much is still unknown regarding its molecular function. Recent evidence from disease models suggests that MYB functions through establishing aberrant enhancer activity, however this hypothesis has yet to be rigorously tested. In this thesis, to investigate the requirement for MYB in leukaemia initiation, we engineered a conditional miRNA mediated Myb repression circuit in a mouse model system, which represses Myb only in the presence of the MLL-AF9 oncoprotein. Myb repression during leukaemia initiation was correlated with a trend in decreased clonogenic potential in vitro, as well as a convincing reduction in leukaemia fitness in vivo, suggesting that a threshold level of Myb is required to propagate an aggressive leukaemia phenotype. Using an artificial chromatin recruitment system, we demonstrated that the MYB transcriptional activation domain was sufficient to generate an enhancer-like element and induce transcription of distal sequences, suggesting that MYB may be competent to initiate enhancer activity in vivo. Further to this, weshowed that MYB dependent gene activation appears to be mediated through its maintenance of enhancer activity, as demonstrated by the loss of H3K27ac, enhancer RNA transcription and chromatin accessibility at the cognate intergenic enhancers of specific MYB sensitive genes with MYB knockdown. Importantly, we found that MYB dependent gene activation can be disrupted with minimal changes in enhancer-promoter interaction frequency, suggesting that these are functionally and temporally separable events.
Linking "good" and "bad" civil society: how local networks promote peace or renewed violence in civil wars
Keywords: peace and conflict studies
complex systems in conflict areas
international aid in conflict areas
peacebuilding and conflict prevention
local civic activism

The notions of “good civil society” and “bad civil society” in early peacebuilding scholarship helpfully challenged prevailing essentialized notions of civil society. This study explored whether international aid to “good civil society” and the marginalization of “bad civil society” has actually helped promote peace in protracted conflicts, as this peacebuilding scholarship has asserted and is largely reflected in international aid practice. Choosing the ability to restrain “own-side violence” as one key measure of influence on peace, the study examines how international aid has impacted civic actors’ ability to restrain violence in protracted conflicts in Kosovo and Georgia. The cases compare pre-war periods marked by locally rooted forms of civic activism with post-war periods when international assistance supported the growth of a large local civil society along the lines of the “good civil society” normative model. The cases examine local civic dynamics on only one side of each conflict, to enable a detailed picture of the broad spectrum of civic actors present and probe the relationships amongst them. The study found little evidence that international support for local “good civil society” helped civic actors gain the legitimacy and influence with domestic constituencies needed to restrain own-side violence. Instead, in Georgia and Kosovo across these time periods, three other interlocking factors appeared to support the ability of civic groups to restrain violence. Applying a complex systems analytical lens illustrates how these multiple factors interacted with each other to support the influence and legitimacy of local civic actors. The study also showed that international certification of local civil society rarely was decisive for civic actors’ efficacy in restraining violence, but their credibility with their own ethnic constituency, or bonding social capital, was an indispensable asset.
What is humility?
Keywords: Applied Ethics
Jesus
Virtue Ethics
Kent Dunnington
Julia Driver
self-sacrifice
Humility

I aim to construct an account of humility which explains and satisfies as many of our pre-theoretical intuitions about the trait as possible, whilst also being internally consistent and otherwise compelling. Starting from a man-on-the-street understanding of what humility involves, I build a secular account of humility which seems coherent and attractive. I then contrast this with a 'radically' Christian understanding of humility drawn from the work of Kent Dunnington, who constructs his account from writings from the early desert monastics and St Augustine, and ultimately on Jesus's willingness to "[humble] himself by becoming obedient to the point of death, even death on a cross" (Philippians 2:8). Having established its distinctiveness, I explain why Christian humility is thought to clash so fundamentally with classical accounts of the virtues, such as those put forward by Aristotle, leading to the oft-cited rift between ‘classical’ and ‘Christian’ virtue ethics. Finally, I investigate whether there are any reasons to consider Dunnington's a more compelling account of humility than its secular counterpart. I compare the two accounts on various grounds including their internal consistency, the viability of their schemes for attaining humility, and their reasons for appraising humility as morally valuable.
Investigating the epigenetic regulation of the eukaryotic centromere by the segregase enzyme p97
Keywords: Centromere
SUMO
SENP6
p97
CENP-A
VCP
segregase

The centromere is a vital locus for mediating chromosome segregation. It defines the location where sister chromatids are joined, and constitutes the foundation of the kinetochore, facilitating microtubule binding in mitosis. The position of the centromere is defined by nucleosomes containing CENP-A, a centromere-specific histone which is a necessary and sufficient locus-specifying seed to facilitate deposition of further CENP-A nucleosomes via an epigenetic self-templating feedback loop. Once incorporated into chromatin, CENP-A is stably maintained across multiple cell divisions with a high degree of retention. No turnover of CENP-A has ever been observed, aside from its replicative halving during passage of the DNA replication fork, prior to deposition of newly synthesised CENP-A in G1 following mitosis.
This thesis explores the roles of recently identified proteins which may actively regulate CENP-A. These factors include SENP6, a SUMO protease found to be vital for stable CENP-A maintenance, and p97, a SUMO/ubiquitin segregase whose depletion was found to increase levels of centromeric CENP-A. The latter finding is unexpected, given that CENP-A turnover has not previously been detected. The experiments described herein confirm these initial observations and investigate mechanistic explanations. The increase in centromeric CENP-A levels in p97 depleted cells was found not to be a consequence of increased CENP-A loading, nor of reduction in cell cycle progression. Therefore, this represents the first observation of a factor capable of physiologically destabilising CENP-A nucleosomes. Simultaneous perturbation of SENP6 and p97 was found to fully rescue defects in CENP-A maintenance otherwise caused by SENP6 depletion. These findings lead to the hypothesis that SUMOylation of centromeric proteins destabilises CENP-A with the aid of the p97 segregase, which is kept in check by SENP6 as it cleaves SUMO chains.
“Where blacks and whites in scorching valleys sweat”: British labouring-class writers and colonial slavery, 1660-1800
Keywords: Seventeenth-century literature
Anti-slavery
Colonisation
Balladry
Eighteenth-century literature
Cultural History
Anticolonial resistance
Poetics
British Empire
Labouring-class writing
Abolition
History from below

This thesis develops the first full-length account of the representation of colonial slavery in British labouring-class writing from 1660 to 1800. It offers a critical reassessment of the diverse social and political significances of slavery across a range of texts and genres — from ballads, plays, romances, portraiture, and pageants, to transportation accounts, periodicals, satires, georgics, narrative poems, and anti-slavery polemics. Recent scholarship has presented labouring-class writing on slavery as an opportunistic response to the nationwide campaign to abolish the slave trade in 1787–88. This suggests that labouring-class authors automatically sympathised with enslaved Africans due to their own subordinate class position, but that they inevitably adopted and echoed prejudicial colonialist views in order to conform to polite expectations. This thesis complicates this paradigm by drawing attention to a much broader range of labouring-class writing on slavery, and argues that over this period: (1) such writing consistently subverted dehumanising portrayals of enslaved Africans, and (2) that these subversions were often in direct response to the representation of enslaved Africans in more elite and canonical texts.
The forced enslavement of Africans was not a subject that was altogether distant from Britons in this period. It not only permeated British culture in terms of the capital’s growing wealth, but was also encountered directly in ports, through forms of work such as seafaring, in the colonies by those transported there as indentured servants, and — most importantly — in print. This thesis explores how a range of anonymous balladeers and labouring-class authors conceptualised and responded to slavery in their written works. The first two chapters consider the response of balladeers during the seventeenth century, respectively, to the increasing presence of Africans in Britain, and to the emergence of forms of forced labour in the New World colonies. The subsequent three chapters concern the writings of Ned Ward, Stephen Duck, and Ann Yearsley, and their responses to the increasing centrality of slavery to British commerce and empire. Slavery was written about in this period by authors from all backgrounds, although most polite, educated writers until the late eighteenth century avoided taking any stance on the issue, even as they often justified the economic basis of slavery. This thesis shows that this was not the case in British labouring-class writing. Overall, it concludes that to fully understand the development of more critical, anti-colonial responses to slavery in this period, it is essential to consider labouring-class writing.