VictorJuiz/thesis huggingface dataset:
Development of molecular targeted imaging methods for detection of lung metastasis and angiogenesis
Keywords: Micrometastasis
Angiogenesis
MPIO
Lungs
RGD
PET

The focus of this thesis is the development of two molecularly targeted imaging methods, in both cases based on contrast agents encompassing micron-sized microparticles of iron oxide (MPIO). MPIO are obligate intravascular agents and as presented in this thesis the half-life in the blood circulation is < 1min.
In the first approach described in the thesis, the overall goal was to detect metastasis in mouse lungs, very early in metastatic development, by targeting vascular cell adhesion molecule 1 (VCAM-1) using conjugates of an anti-VCAM-1 antibody and 1 μm MPIO (VCAM-MPIO). In Chapter 3, I demonstrate specific retention of VCAM-MPIO in the vasculature of a lung metastasis model, and also the very short blood half-life of the contrast agent; both of which suggest the potential for in vivo detection. In Chapter 4, I show that whilst the bound VCAM-MPIO do not sufficiently dephase the signal obtained with the bright lung MRI approaches used (hyperpolarized 3He/129Xe or 19F MRI), it is possible to sensitively detect the presence of lung metastases in vivo using radiolabelled VCAM-MPIO (89Zr-DFO-VCAM-MPIO) in combination with PET imaging.
The overall goal of the second approach described, was to detect and characterize tumour angiogenesis by targeting αvβ3-expressing endothelium in vivo, using a conjugate of cyclic penta-peptides c(RGDyK) and 2.8 μm MPIO [c(RGDyK)-MPIO]. To this end, I demonstrate in Chapter 5 that c(RGDyK)-MPIO specifically binds to αvβ3-expressing endothelium in subcutaneous tumours and yields quantifiable contrast effects on T2&ast;-weighted MRI. Furthermore, I have implemented in this approach gadolinium DCE imaging, providing dynamic vascular information.
To date there is no reported detection method for pulmonary metastasis at the micrometastastic stage, as presented in this thesis. Translation of this method into clinic could allow for earlier therapeutic intervention and, thus, more effective treatment. The angiogenesis characterization imaging method presented here may provide a sensitive approach for the characterization of heterogeneity in tumour angiogenesis/vascularity and monitoring of anti-angiogenic therapies.
Between two worlds: Baroque spectacle and enlightenment thought in the autos sacramentales by Sor Juana Inés de la Cruz (1648-1695)
Keywords: Sor Juana
auto sacramental

This thesis is the first book-length study of the three autos sacramentales by Sor Juana Inés de la Cruz. Sor Juana’s religious drama has received little attention, despite her status as one of the greatest figures of Mexican literature. She was also writing during a particularly significant period in Hispanic literary history: at the end of the Spanish Golden Age, and at the rise of a new class of intellectual élites in the New World, the criollos. I contend that Sor Juana’s autos sacramentales are crucial to understanding how she contributed to the formation of a criollo identity. In doing so, she engaged with the mentalities of two continents and two historical periods: Europe and the Americas, and the Baroque and the Enlightenment.
To demonstrate this, I provide a study of each of Sor Juana’s sacramental plays, alongside the loa which was written to accompany them. My method combines close-text reading with a historical approach, and I pay particular attention to the theological function of the plays. In each chapter, I focus on the concurrent strands of thought in her works. I consider how the plays demonstrate the Catholic doctrine of transubstantiation, and how they engage with the aesthetic and theological mindset of the Spanish Baroque. I study how they incorporate indigenous Nahuatl theatrical traditions, and ask how they engage with the scientific developments of the Enlightenment. I conclude that in her autos sacramentales Sor Juana expresses a mindset that is both geographically and historically “between two worlds.”
The influence of Nahuatl theatre on Sor Juana’s dramaturgy has never before been studied. The influence of Enlightenment thought on her works has been noted by a few scholars, but never considered in relation to her religious works. The demonstration of the interaction of Enlightenment and Catholic ideas challenges our notion of the Enlightenment as a secularising movement, and has potential implications for scholars of the period beyond the sphere of Sor Juana studies.
Identification of the transneuronal homeostatic machinery at a central synapse
Keywords: Synapse
Homeostatic Compensation
Drosophila melanogaster

Two different kinds of stabilising homeostatic behaviour have been observed in neurons. The first type involves the cell-autonomous maintenance of a cell-identity-based level of electrical activity. Neurons continually monitor their own electrical activity and can adjust many intracellular parameters, such as membrane ion channel densities, to keep this activity within a tight physiological range. The second type of homeostatic behaviour shares the same goal, to maintain a fixed level of electrical activity, but instead of adjusting intracellular parameters, the neuron recruits its synaptic partners to assist in maintaining a genetically prescribed activity level. This behaviour is most easily observed when a neuron is either electrically silenced by expressing an inwardly-rectifying potassium channel or rendered less sensitive to neurotransmitter through mutation of its postsynaptic receptors. Both of these perturbations result in increased synaptic drive from the presynaptic cells, either through increasing the number of neurotransmitter release sites or increasing the probability of release from single release sites.
Many genes that are instrumental in the second type of homeostatic behaviour have been identified, mainly at the neuromuscular junction in the peripheral nervous system. However, studies on transsynaptic homeostatic compensation in an intact central nervous system have been few and far between. Also, which, if any, of the homeostatic genes are transcriptionally regulated in the nucleus after the onset of transsynaptic homeostatic adjustment, has not been adequately addressed. This thesis has developed a system to measure transcriptome-wide gene expression levels in presynaptic circuit elements after altering the firing properties of the downstream circuit in the CNS. Many transcriptionally regulated genes have been identified and are now being tested for their potential use as reporters for transsynaptic transcriptional regulation. It might be possible to capitalise on endogenous homeostatic signalling pathways to gain genetic access to synaptically connected neurons.
The ritualistic child: imitation, affiliation, and the ritual stance in human development
Keywords: imitation
cultural transmission
affiliation
social groups
ostracism
ritual

Researchers have long argued that ritual plays a crucial role in marking social identities and binding individuals together in a system of shared actions and beliefs. The psychological processes underlying how and why ritual promotes group bonding and influences in- and out-group biases have not yet been fully elucidated. The research presented in this thesis was designed to examine the social and cognitive developmental underpinnings of conventional/ ritualistic behavior. Because learning cultural conventions is essential for participation in group behavior and for signaling group membership and commitment, I propose that conventional/ ritualistic learning is motivated by a drive to affiliate. Experiment 1 investigated the affiliative nature of ritualistic learning by examining the effects of third-party ostracism on imitation of an instrumental versus ritual action sequence and prosocial behavior. Individuals who do not participate in shared group conventions often face the threat of ostracism from the group. Given that attempting re-inclusion is an established response to ostracism, I predicted that the threat of ostracism increases affiliative motivations and thus will increase imitative fidelity, especially in the context of conventional learning. Experiment 2 examined the effects of first-person ostracism in the context of in- and out-groups on children’s imitation of a ritualistic action sequence and pro-social behavior. I predicted that the experience of ostracism by an in-group versus an out-group has important implications for the construal of social exclusion and affiliative behavior. I hypothesized that children would be motivated to re-affiliate by imitating the model and acting pro-socially towards the group, especially when ostracized by in-group members. Based on the findings of this research and insight from anthropology, and social and developmental psychology, I will present a picture of how children acquire the conventions of their group and how these conventions influence social group cognition.
Refocusing antibody responses by chemical modification of vaccine antigens
Keywords: Immunogenicity
Neutralizing Antibody
Antigenicity
Chemical Cross-linking
Glycosylation
Protein Modifications
Envelope Glycoproteins
HIV-1
Vaccine Design
Glycoconjugates

The envelope glycoprotein (Env) of Human Immunodeficiency Virus 1 (HIV-1) has developed several immune-evasion mechanisms to avoid the induction of neutralising antibodies, including immunodominant non-neutralising epitopes, conformational flexibility of conserved epitopes, and spontaneous subunit dissociation, thus impeding vaccine development. Here, chemical modification of Env-based vaccine antigens is explored to overcome these obstacles.
Firstly, covalent fixation of Env by chemical cross-linking was used to stabilise the conformationally flexible structure and prevent subunit dissociation. Cross-linked Env constructs showed reduced binding of many non-neutralising antibodies whilst largely maintaining antibody recognition by broadly neutralising antibodies. Compared to unmodified material, immunisation with some of these cross-linked proteins led to the induction of significantly increased antibody titres targeting the conserved CD4 binding site of Env despite similar overall antibody titres. These refocused antibody responses resulted in increased serum neutralising titres compared to animals receiving unmodified protein.
Secondly, an epitope masking strategy was developed to reduce or eliminate the immunogenicity of neutralisation-irrelevant surfaces. This was achieved using site-selective addition of theoretically immunosilent glycoconjugates to lysine residues. Masking of model protein hen egg lysozyme (HEL) led to site-selective loss of antibody binding to the modification sites in vitro, which translated into refocusing of antibody responses from masked to unmasked epitopes in vivo. Mutant HIV-1 and influenza virus surface glycoproteins were designed that had lysine residues removed from close proximity to the respective broadly neutralising epitopes, but added throughout the remaining surface. Masking of these mutant proteins with second-generation glycoconjugates led to predictable perturbations of antibody binding in vitro. However, administration of these modified glycoproteins revealed unexpectedly that the masking glycans were highly immunogenic in vivo. Thus, this strategy may well prove useful if truly non-immunogenic glycoconjugates can be identified.
Taken together, these chemical modifications of vaccine antigens may allow focused targeting of specific antigenic regions for increased B cell recognition, and may thus be a valuable tool for vaccine antigen design.
The development of WTO law in light of transnational influences: the merits of a causal approach
Keywords: international trade law
WTO law
international economic law

The WTO is one piece in a complex network of international, regional and domestic legal systems and regulatory frameworks. The influences on the development of WTO law extend far beyond its own Members and institutions: domestic legal instruments have provided the inspiration for numerous WTO obligations while the rights and obligations under the covered agreements are frequently incorporated into the legal systems of the Membership. The WTO is home to numerous committees and working groups that also engage with other international bodies and their domestic counterparts. Transnational actors seek to take advantage of these networks, encouraging WTO law to develop in their favour. The interactions involved, however, are highly complex and unpredictable. By drawing on different models of causal explanation, it is possible to offer a perspective on the development of WTO law that accepts its role as part of a larger globalized process. Three different causal influences are identified: instrumental, systemic and constitutive. Together, they offer a prism through which to examine the development of WTO law as it responds to the behaviour of transnational actors, bridging gaps between international relations and law and, it is hoped, offering a convincing explanatory rationale for the way in which WTO law develops.
Communal riots, sexual violence and Hindu nationalism in post-independence Gujarat (1969-2002)
Keywords: sexual violence
Ahmedabad
gender
India
Gujarat
communal riots
inter-religious violence
Hindu nationalism

In much existing literature the incidence of sexual violence during Hindu-Muslim conflict has been attributed to the militant ideology of Hindu nationalism. This thesis interrogates this view. It first examines the ideological framework laid down by the founding ideologues of the Hindu nationalist movement with respect to sexual violence. I argue that a justification of sexual violence against Muslim women is at the core of their ideology. In order to examine how this ideology has contributed to the actual incidents, this thesis studies the episodes of Hindu-Muslim violence that occurred in 1969, 1985, 1992 and 2002 in the western Indian city of Ahmedabad, Gujarat. An examination of these episodes shows that sexual violence against Muslim women, in both extreme and less extreme forms, were significantly motivated by Hindu nationalist ideology. However, in addition to this ideology, patriarchal ideas that serve to normalize sexual violence as ‘sex’ and sanction its infliction to maintain gendered hierarchies also motivated such crimes. Moreover, this thesis argues that the manifestation of Hindu nationalist and patriarchal motivations in acts of sexual violence was enabled by the breakdown of neighbourhood ties between Hindus and Muslims in 1969 and 2002. By contrast, during the 1985 and 1992 riots Hindus and Muslims strengthened neighbourhood ties despite extensive communal mobilization, which seems to have prevented the perpetration of extreme sexual violence against Muslim women. Thus, by providing a comprehensive analysis of the contribution of Hindu nationalist ideology, and arguing for the significance of the patriarchal ideas and neighbourhood ties in the infliction of sexual violence during conflict, this study contributes to and departs from the existing literature.
Functional genomics of severe sepsis and septic shock
Keywords: faecal peritonitis
functional genomics
sepsis
community-acquired pneumonia
microarray
septic shock

Sepsis is the systemic inflammatory response to an infection. Severe sepsis with multi organ failure is one of the commonest causes of admission to intensive care units, and is associated with poor early and late outcomes. The pathophysiology of sepsis is complex, and poorly understood. This is reflected in the limited and contentious treatment options for sepsis.
Genetic factors have been shown to be associated with the risk of and subsequent outcomes from infection. However, clear associations with bacterial sepsis are rare, and even when associations are present their functional effects are often unknown.
Gene expression signatures in sepsis are investigated in this project using serial samples obtained from patients admitted to intensive care units with community-acquired pneumonia or faecal peritonitis.
The evolving gene expression signatures that define the response to sepsis were identified with large changes seen in genes coding for ribosomal proteins RPS4Y1 and RPS26P54. The differences in the sepsis response between the two diagnostic classes were examined. The gene expression predictors of mortality in sepsis were determined and include genes from the class II MHC HLA-DRB4, HLA-DRB5 and the T cell differentiation protein MAL. The effects of important covariates on gene expression were investigated and their impact on survival related expression determined. The findings were confirmed in a validation cohort. A novel clustering of samples representing distinct inflammatory patterns in a clinically homogeneous population of sepsis patients was identified and related to differences in clinical behaviour. The biological relevance of the differentially expressed genes was ascertained by identifying enriched gene sets.
The gene expression changes in sepsis were examined in the context of related clinically relevant immune phenomena: the sterile systemic inflammatory response in patients undergoing elective cardiac surgery and the phenomenon of endotoxin tolerance in PBMCs derived from healthy volunteers.
The results highlight the complexities of clinical sepsis and identify hypotheses for future investigations.
One-pot nitro-Mannich cascade reactions: new methodologies and synthetic applications
Keywords: enantioselective
cascade
methodology
Slaframine
diastereoselective
multi-component reaction
nitro-Mannich

Pyrrolidine and pyrrolidinone rings are common motifs found in many biologically active natural products and drugs. Accordingly, our work focuses on the development of new methodologies for their one-pot synthesis.
An efficient diastereoselective nitro-Mannich / lactamisation reaction cascade of methyl 3-nitropropanoate with cyclic and acyclic imines for the direct preparation of trans-monocyclic and fused tricyclic pyrrolidinone derivatives was developed. The reaction is easy to perform, broad in scope and tolerates a wide variety of functional groups. For the monocyclic methodology, 28 examples with a very good average yield of 72% and excellent diastereocontrol (typical dr >98:2) were obtained using optimized conditions and varying the amine and the aldehyde reagents.
The methodology has been extended to the synthesis of 1,3,5-trisubstituted 4-nitropyrrolidinone derivatives using α-substituted 3-nitropropanoate. Using a one-pot protocol, 22 derivatives were synthesised in good yields (65% average) and diastereomeric ratios ranging from 3:1 to 30:1 in favor of the trans/trans diastereoisomer.
In addition, the nitro-Mannich / lactamisation cascade of methyl 3-nitropropanoate was developed further to allow the rapid synthesis of 5-isopropyl-4-nitropyrrolidin-2-one from reaction with ammonium acetate and 1-butyl-4-nitropyrrolidin-2-one from reaction with formaldehyde. Also, the synthetic utility of the nitro-pyrrolidinones formed was exemplified through various functional group modifications: the selective reduction of the lactam carbonyl, the reduction of the nitro group in the presence or absence of a carbonyl group and the reductive removal of the nitro group.
The development of an enantioselective version of the cascade under chiral Brönsted acid catalysis provided promising results (up to 90% ee). Moreover, various studies were undertaken to understand the mechanism of the reaction and the nitro-Mannich / latamisation cascade is now well understood. Furthermore, a formal synthesis of rac-Slaframine in 8 steps and 15% overall yield was achieved and it inspired additional work towards a nitro-Mannich / epoxide ring opening cascade.
Investigating rare genetic variants in common migraine
Keywords: Stem cells
Migraine

Migraine is a highly prevalent headache disorder imposing a significant burden of disability on human health worldwide. The headache is believed to arise from activation of trigeminal pain pathways, with CNS regions also playing an integral role in attack initiation and progression. Recent genetic associations have been made, but there is a need to convert these into relevant experimental models to study underlying disease mechanisms. Herein, I detail functional analysis of two deleterious variants in the genes KCNK18 and SLC12A3, that segregate with migraine with aura in one large pedigree. Gene function has been studied in a range of cell models, from heterologous expression systems and primary neuronal cultures, to Induced Pluripotent Stem (iPS) cell-derived nociceptors. In this context, the protein products of KCNK18 and SLC12A3 have been shown to modulate parameters of neuronal excitability, including baseline membrane properties and firing patterns. Migraine attacks are not wholly attributable to perturbations in peripheral pathways. I have shown that these genes are also expressed within the CNS in a small number of discreet regions, suggesting a possible role in central processing. Utilizing recently defined genetic variants and physiological cell- based models, will provide a platform for mechanistic insights into migraine pathogenesis and allow for the development of drug screening assays for new migraine therapies.