VictorJuiz/thesis huggingface dataset:
The role of MDM2-NBS1 protein interaction in DNA repair in bladder cancer

MDM2 is an E3 ubiquitin ligase that is frequently amplified in human cancers, including muscle-invasive bladder cancer. While it has a firmly established role in negative regulation of the tumour suppressor p53 by proteasomal degradation, the p53-independent functions of MDM2 remain scarcely understood. One of them is the delay of DNA double-strand break repair via a direct binding interaction with NBS1 of the MRE11-RAD50-NBS1 DNA repair complex.
RG7388 is a selective MDM2 inhibitor, a second-generation member of the nutlin family that is currently in early clinical trials for solid and haematological tumours. The inhibition of MDM2-p53 protein interaction by RG7388 has no radiosensitising effect and does not disrupt the MDM2-NBS1 protein interaction in T24 and RT112 cells. However, compared to untreated controls, RG7388 alone and in combination with 5 Gy of ionising radiation (IR) alters the mRNA levels of MDM2 and NBS1 and protein levels of MDM2. NBS1 and MDM2 do not form any foci but co-localise in the nuclei of T24 and RT112 cells four hours after exposure to IR.
In this study, we show that MDM2-NBS1 is an important protein interaction that remains intact in unstressed T24 and RT112 cells and following their exposure to genotoxic ionising radiation alone or in combination with RG7388. Under the same treatment conditions as well as in untreated controls, the pilot western blot experiment suggests that NBS1 is not ubiquitylated either in T24 or RT112 cells. Further experiments are required to verify this finding and to detect and characterise other post-translational modifications that may be involved in regulation of the MDM2-NBS1 protein interaction to determine its impact on DDR.

Keywords: NBS1
MDM2
Bladder
Cancer
Advisor: Kiltie, A
The inter-nation: how international connections shaped Catalan nationhood, 1880-1920 

This thesis examines the shifting debates on Catalan nationhood in the late nineteenth and early twentieth century. Employing a transnational approach, this thesis explores the complex role of international contacts in the making of narratives of Catalan nationhood between 1880 and 1920. It builds on and extends historiography which has explored the connection of internationalism and nationalism. In doing so, it contributes to broader debates on collective identities, particularly in peripheral regions and small nations.

By drawing on extensive archival research from newspaper articles, private correspondence, pamphlets, conference proceedings and unedited manuscripts, this thesis highlights four narratives of how internationalism and nationalism reinforced each other in debates of Catalan nationhood between 1880 and 1920: (i) Nationalism as a trend, (ii) Alliance of the oppressed, (iii) Universal nationhood and (iv) Moral geography. It argues that these narratives were central in discussions of nationhood in Catalonia in the late nineteenth and twentieth century.

International cultural and political connections with scholars, artists and urban planners merged in debates over the form of Catalan nationhood. Catalan nationalists sometimes acted as mediators between the different foreign perceptions of Spain and sometimes as catalysts, sharpening the distinctions made between Europe and Spain in debates over the Spanish nation-state and its empire. Examining the international contacts of Catalan nationalists in the late nineteenth and twentieth century helps to highlight the reciprocal dynamic between local, regional, national and international collective identities.

Keywords: regionalism
Spain
Catalonia
nationalism
Advisor: Zimmer, O
Instruments of identity: Médecins Sans Frontières and humanitarian negotiations for access in the Democratic Republic of the Congo

This thesis examines how humanitarians negotiate access in conflict zones. Drawing on ethnographic fieldwork, interviews and archival analysis, it explores the everyday negotiations between Médecins Sans Frontières and armed groups in North Kivu, in the eastern Democratic Republic of the Congo. I unpack what “negotiating access” looks like on the ground: a social and political process of brokerage, perception management and interest seeking in a complex web of relationships. I focus on people and their interactions, because they determine how abstract humanitarian principles (neutrality, impartiality, and independence) and predesigned interventions are translated into practice on the ground. I describe how humanitarians endeavour to perform humanitarianism and their principles during daily interactions.
The thesis examines how identities become central to maintaining humanitarian access, with ambiguity as their central characteristic. I argue that the personal and collective identities of different humanitarians become instruments for access. Humanitarians negotiate access together in symbiosis as a brokerage “club”: different people in the team play different roles, because they have different perceived identities, access to different networks, have different experiences and savoir faire, as well as different personal histories, and therefore face different risks. The role of identity is central to the process of acquiring and sustaining access, which makes use of factors such as personal history, race, and gender, employing each where it confers particular advantage in performances of humanitarianism. This presents a paradox. Everyday humanitarian practice is shaped by, and reproduces, the very forms of difference that their egalitarian values seek to transcend.

Advisor: Gledhill, J
Scott-Smith, T
Computational methods for light sheet fluorescence microscopy: towards a quantitative analysis of AVE migration in the mouse

Collective migration in epithelial tissues is required for many developmental processes, wound healing, and cancer, and is conserved across vertebrates. It is a process that has been difficult to study for 3D epithelia in vivo as the large timelapse datasets required present significant computational challenges for quantitative analysis. An important example of collective migration in an epithelial context is the migration of Anterior Visceral Endoderm (AVE) cells in the mouse embryo. From E5.5, this subgroup of cells in the visceral endoderm monolayer migrate from the distal tip, specifying the anterior-posterior axis by patterning the underlying epiblast which will later give rise to the embryonic lineage. AVE induction and migration have yet to be fully characterised and understood, and provide an attractive in vivo system to study the biological function of collective migration due to the relatively small cell numbers at this stage and the experimental accessibility of the visceral endoderm tissue. In this thesis, a new computational framework is developed to analyse and extract quantitative information from light sheet fluorescence microscopy (LSFM) 3D timelapse datasets of E5.5 mouse embryos during AVE migration. The proposed framework initially isolates the migratory cell movement, and secondly extracts the apical surface data to simplify the 3D volume to a 2D characterisation problem. Applying this computational framework on LSFM datasets from 3 fluorescent reporter mouse lines, I demonstrate the first comprehensive tracking of individual cells and cell divisions in the entire visceral endoderm, the first study of cell division angles, and the movement of cells in the underlying epiblast. Altogether these results reveal a model of AVE migration as an active process that drives large-scale tissue deformation and changes in morphology independent of cell proliferation in the VE, and presents evidence that suggests the A-P axis could be pre-defined.

Keywords: visceral endoderm
mouse
light sheet fluorescence microscopy
convolutional neural network
CNN
AVE
LSFM
Advisor: Stower, M
Rittscher, J
Srinivas, S
A study of how packaging reveals categorisation and status in the Qianlong Emperor’s collection

This thesis studies the practice of packaging at the imperial court of the Qing dynasty (1644-1911), in particular the agency of packaging in the Qianlong Emperor’s (1711-99) art collection. It discusses the functions of packaging in the imperial collection and provides a new perspective to examine it. It fills an important gap in our understanding of Chinese art history.

The thesis analyses the collection and relevant archives to explore the role of Qianlong’s packaging. It argues that packaging was the way Qianlong handled his collection in order to convey essential information about those items. Applying the existing theory of secrecy to study the imperial collection, it demonstrates that, the emperor used packaging to create a sense of secretiveness to the objects. The thesis also shows that Qianlong made use of the objects’ secretiveness to redefine the objects’ histories (definition), as well as to develop a relationship with his officials. The findings of the thesis call for a reconsideration of the widely accepted view that simply equates owning the imperial collection to having the sovereignty to rule.

A close look at the collection shows that Qianlong utilised different forms of packaging to engage himself with the objects. By doing so, his engagement was materialised and integrated to become part of the objects’ histories. He must have been conscious of the power of packaging as he actively participated with the imperial workshops in the design and production of packaging the imperial collection. Qianlong’s ideas of packaging are best realised in the curio box, an assemblage of many different objects in various packaging devices. It is the packaging, rather than the actual objects, that makes the assemblage a curio item. Much effort was thus made in devising the structure of the curio boxes.

Packaging in the imperial collection comes in a large diversity of forms. Such a diversity indicates the importance of packaging and the necessity to understand it, especially how Qianlong designed it to affect our perception of the collection, and of his sovereignty. Unlike the traditional studies which have long neglected the packaging of the imperial collection or considered it as subsidiary to its contents, this thesis uses a new approach to examine the imperial packaging and objects enclosed.

Keywords: the Qianlong Emperor
secrecy
the imperial collection
packaging
Advisor: Rawson, JM
Harrison, H
Alcohol consumption and health in Chinese adults: the China Kadoorie Biobank (CKB)

Background: Alcohol intake has been associated with poor mental health and increased risks of certain cancers and liver diseases. Evidence is limited from China, where disease rates, drinking patterns, and individuals’ tolerability of alcohol differ importantly from Western populations.

Methods: The prospective China Kadoorie Biobank recruited >512,000 adults (41% men) aged 30-79 years from 10 diverse areas during 2004-2008. Detailed information about alcohol consumption, mental health, and other characteristics were recorded by questionnaire, with follow-up through linkage with death and disease registries and electronic hospital records. Logistic regression yielded adjusted odds ratios relating problem drinking patterns to mental health. Cox regression yielded adjusted hazard ratios (HRs) relating usual alcohol consumption to disease risks.

Results: At baseline, 33% of men drank alcohol regularly (i.e., at least weekly). Among male regular drinkers, the prevalence of heavy episodic drinking (>60g/session) increased between baseline and the second resurvey (30% vs. 35%; 8 years apart), particularly among younger men born in the 1970s (41% vs. 47%). 24% of male regular drinkers reported problem drinking at baseline, which was positively associated with stressful life events, poor mental health (e.g., depression, anxiety, sleep problems), and increased risks for all-cause mortality, hospitalisation, and injuries. Alcohol intake showed positive dose-response associations with risks of incident cancers of the oesophagus (655 events; HR=1.98 [95%CI: 1.79-2.18] per 280g/week higher usual alcohol intake), mouth and throat (236; 1.74 [1.48-2.05]), liver (573; 1.52 [1.31-1.76]), colon and rectum (575; 1.19 [1.00-1.43]), gallbladder (107; 1.60 [1.16-2.22]), and lung (1017; 1.25 [1.10-1.42]), with similar associations among never- and ever-regular smokers. The associations for oesophageal cancer and lung cancer appeared greater among men with low alcohol tolerability. There were also dose-response relationships between alcohol intake and incident liver cirrhosis (408; 1.87 [1.65-2.12]), alcoholic liver disease (ALD) (211; 2.02 [1.79-2.28]), and non-alcoholic fatty liver disease (208; 1.78 [1.42-2.22]). The risks were greater for oesophageal cancer and ALD among daily drinkers, and for liver cancer, liver cirrhosis, and ALD among men usually drinking without meals, compared with their counterparts. Very few women (~2%) drank alcohol regularly which limited the capacity to assess associations with health.

Conclusion: Among Chinese men, alcohol consumption was associated with poor mental health, premature death, cancers at multiple sites, and major chronic liver diseases. Certain drinking patterns may further exacerbate the risks.

Keywords: mental health
drinking patterns
liver disease
alcohol
cancer
Advisor: Yang, L
Chen, Z
Millwood, I
The politics of nonsense: civil unrest, otherness and national mythology in nonsense literature

This study argues that the generative qualities of nonsense literature that foster in the reader a rebellious, anti-authoritarian spirit have been underestimated. At characteristic moments of social unrest the popularity of nonsense literature rises and texts that utilise the mores and tropes of nonsense are enlisted in support of radical causes. Nonsense participates in the genesis of a new political paradigm that is incommensurable with the old, serving as a popular coded representation, and as a vehicle for the propagation, of new concepts, beliefs and ideologies.

These “characteristic moments” of social unrest are akin to the historical situation that Mikhail Bakhtin requires for a flourishing of carnivalesque imagery. Nonsense, like Bakhtin’s carnivalesque, is invigorated by “moments of crisis, of breaking points in… the life of society and man” (Bakhtin, Rabelais 9). Because of its close association with carnivalesque imagery, nonsense is normally situated in a convivial, democratic atmosphere. As Bakhtin posits, this carnivalesque milieu fosters an atmosphere that revels in the expression of political criticism and utopian ideals (ibid 92-3).

Revisiting Elizabeth Sewell’s contention that nonsense rejects magic and superstition (Sewell 171-72), I suggest instead a two-part process. Nonsense first rejects commonly accepted, but arbitrary, systems of authority and then, through subversive allusions to an alien alternative, nonsense subtly advertises the desirability of unofficial belief systems. In nonsense texts, symbols of unofficial belief systems are routinely combined with inexplicable narrative voids and temporal anomalies that tempt the reader to envision a temporary release from constrictive conceptions of society and the self.

Nonsense thus plays a pivotal role in the language, culture and mythology of revolution. This process, which allies nonsense to radical causes in times of social upheaval, is one of the major sources of the popular success of icons of children’s literature such as Mother Goose, Lewis Carroll and Dr. Seuss. Because nonsense is not restricted to texts intended for children, neither is this study. The political aspects of nonsense will be the more holistically examined by inclusion in this discussion of, for example, the political satire of eighteenth century colonial American humorist Francis Hopkinson, the Victorian era libretti of W. S. Gilbert, and the lyrics of 1960s era songwriters John Lennon and Bob Dylan.

Keywords: children's literature
nonsense literature
subversive writing
civil discord
national identity
literary nonsense
popular culture
Advisor: Purkiss, D
New late-stage strategies towards difluoromethylarenes

This thesis consists of the development of novel methodology to access difluoromethylated compounds both in the context of photoredox catalysis and fluorine-18 radiochemistry for Positron Emission Tomography (PET). First a general introduction to late-stage difluoromethylation will be showcased in Chapter I. In Chapter II, a metal-free visible light catalysed synthesis of difluoromethylarenes via a controlled hydrodefluorination of electron-poor trifluoromethylarenes is described. The reaction works both in batch and in flow and proves to be useful in the context of late-stage functionalisation. In Chapter III, a general introduction to PET is provided. General radiochemistry concepts are also introduced. In Chapter IV, a facile and robust radiochemical methodology for PET describing the synthesis of 18F-difluoromethylarenes from aryl boronic acids, ethyl bromofluoroacetate and cyclotron produced [18F]fluoride is presented. The two key steps involve a copper catalysed cross-coupling reaction using bench-stable aryl boronic acids to yield 2-fluoro-2-arylacetic acids in a two-step one-pot reaction followed by a manganese mediated 18F-fluorodecarboxylation to afford 18F-difluoromethylarenes in a streamlined fashion. Chapter V discusses the synthesis of the first 18F-difluorocarbene reagent and its application to react as a difluoromethylating reagent with phenols, thiophenols, N-heterocycles, and boronic acids. Chapter VI provides experimental data for compounds described within this thesis.

Keywords: photoredox catalysis
radiofluorination
difluorocarbene
difluoromethylation
hydrodefluorination
Advisor: Gouverneur, V
Structural studies of trans-synaptic complexes

Neuronal synapses are the functional units of the nervous system, allowing the fast transmission of information between neurons. A plethora of proteins populate the cleft between connecting neurons, and many contribute to the formation of protein complexes than span the synaptic cleft. Such trans-synaptic complexes are of tremendous importance for synaptic function, affecting the neuronal wiring specificity, synaptic plasticity or the differentiation of the pre-and post-synaptic compartments. Two important protein families that form trans-synaptic complexes are ionotropic glutamate receptors (iGluRs) and receptor protein tyrosine phosphatases (RPTPs). In this thesis, I present work conducted on two prototypical protein complexes: the Glutamate Delta 2 (GluD2) receptor, in complex with Cerebellin 1 and b Neurexin 1; and the receptor protein tyrosine phosphatase μ (RPTPμ), which forms a homophilic dimer across cell contacts. Despite previous efforts, it is not well understood how these protein complexes are able to integrate their cell-adhesive properties with their downstream signalling functions. The aim of this thesis is to pave the way towards a mechanistic understanding of the function of these complexes. Using X-ray crystallography and biophysical assays, GluD2-specific nanobodies were identified, leading to the discovery of molecular tools that can stabilize distinct GluD2 conformations. Of particular interest, a nanobody capable of activating the receptor and preventing desensitization was identified, which will be instrumental for unveiling the GluD2 metabotropic signalling mechanism. Single-particle cryo-EM was applied to study the full- length GluD2 receptor, providing the first insights into the general architecture of Delta subtype iGluRs and laying the grounds to obtain a high resolution structure. RPTPμ- mediated cell-cell contacts were analysed by cryo electron tomography, obtaining data from cells thinned by focused ion beam (FIB) milling. The FIB milled sections revealed unprecedented detail of the architecture of insect cells and allowed the analysis of RPTPμ in a native environment. Subtomogram averaging shed light on a potential higher-order organization of RPTPμ at cell-cell contacts. Finally, a protocol for the purification and crystallization of the complete cytoplasmic region of RPTPμ was developed. This data paves the way towards unravelling the structure of the juxtamembrane domain, an essential part for understanding how type IIb RPTPs are regulated.

Keywords: Cryo Electron Microscopy
Receptor Protein Tyrosine Phosphatase
Ionotropic Glutamate Receptors
Nanobodies
X-ray crystallography
Trans-synaptic complexes
Advisor: Aricescu, A
Siebold, C
Grunewald, K
Titus Maccius Plautus Trinummus (1-601, 820-42a): critical edition and commentary with an introduction

My dissertation provides a new critical edition and commentary of Plautus’ Trinummus (ll. 1-601, 820-42a), along with an introductory section. The introduction is divided in six chapters:
Text & Transmission
Date
Staging
Philemon
Language
Metre
They are intended as samples of the issues which a scholar of Plautus has to face, and the outcomes of modern and contemporary scholarship on broad issues such as the intertextual relationship with the Greek model or the linguistic features of each group of speakers are tested on Trinummus.
The critical edition is based on a new collation of the principal mss. (late-antique, Carolingian, and two of the main representatives of the humanistic tradition) and on a collection of the evidence coming from indirect transmission. It follows the criteria set for the most recent critical editions of Plautus, the Editiones Plautinae Sarsinates. Accordingly, it features three apparatuses:
an apparatus for the paratext (rubrics, scene-headings, change of speakers)
an apparatus for the colometry (division of lines in the cantica)
an apparatus for the variant readings and conjectures, the latter attributed with the greatest possible precision to the scholars who first proposed them
Moreover, I provided a summary of the scansion of the commented lines (conspectus metrorum) and an overview of the most important rules of Plautine versification in the introduction.
The line-by-line commentary focusses on issues of transmission, language, metre, and style. Each scene has an introductory section where I discuss general questions related to the characters and the plot of the play.

Keywords: Trinummus
Plautus
Roman comedy
Advisor: Cirilo De Melo, W