VictorJuiz/thesis huggingface dataset:
Structural Studies of Membrane-tethered KRAS4B Interaction with RAF and Inhibitors, and RIT1 Disease Mutants

For more than three decades, RAS genes have been recognized as among the most important cancer-causing genes. RAS mutations are found in some of the most aggressive and deadly cancers, and are generally associated with poor prognosis. However decades of research have yet to yield a drug that can effectively inhibit RAS. Failed attempts to develop RAS inhibitors, including GTP-competitive analogs and farnesyltransferase inhibitors, have driven researchers from this field and led pharmaceutical companies to abandon RAS projects. However, in the last few years, researchers have started returning to this field, recognizing that RAS is still one of the most important targets in oncology. Although now armed with improved technology and a better understanding of RAS, researchers are mindful that there are still many hurdles, including the knowledge gap in understanding bilayer-anchored KRAS. RAF is one of the most important effectors of RAS and membrane anchoring of KRAS is critical for RAF activation. The RAS-binding domain (RBD) and Cysteine-rich domain (CRD) of RAF are key elements coupling RAS GTP loading and RAF activity. Their engagement with KRAS-GTP and membrane relieves the auto-inhibition of RAF kinase domain. This proposal aims to improve understanding of structure and function of KRAS in complex with CRAF RBD-CRD on biological membranes, and develop novel approaches towards inhibiting RAS in its membrane-tethered form by exploiting its tendancy to adopt an ‘occluded’ orientation on the bilayer surface. The discovery of RAS oncogene in human cancer marked the beginning of decades' journey of exploring the structure and function of RAS superfamily members. Recently, the RAS-like wildly expressed in many tissues (RIT1) came to researchers' spotlight because of its etiologic role in Noonan Syndrome and cancer. Using a real-time NMR-based GTPase assay, we characterized the GTP hydrolysis and nucleotide exchange of RIT1 WT and five disease-associated mutants including S35T, A57G, Y89H, F82V and T83P. This characterization will facilitate understanding of the biophysical properties and disease role of RIT1 and its mutants.

Keywords: Cancer
Drug discovery
NMR
Protein membrane interactions
RAF
RAS
Advisor: Ikura, Mitsu
The Divinity of Conscience: Forgiveness, Religion, and the Politics of Secularity in Hegel’s Phenomenology of Spirit

This dissertation explores the intersection of forgiveness and religion in G.W.F. Hegel’s Phenomenology of Spirit. I argue that religion and forgiveness can be profitably understood as parallel communicative practices through which a community affirms its sense of that which has “absolute” value. Religion, as Hegel conceives of it, is a communicative practice that gives expression to the basic “terms of membership” through which individuals both affirm and are affirmed with respect to their fundamental belonging to a community. Such terms are likewise invoked in the practice of forgiveness, for Hegel, insofar as forgiveness activates a community’s infinite capacity to acknowledge and incorporate the irreducibly finite nature of human individuality and agency. In view of this similarity, Hegel’s philosophy of religion offers productive resources for theorizing religions as “socio-cultural idioms of forgiving,” and, by extension, for rethinking the nature of interreligious dialogue in the public sphere. Just as no single act of forgiveness could ever wholly or finally resolve the inherently transgressive potential of human action, so too is religious expression subject to ongoing critique and transformation, owing to the necessarily determinate and particular ways in which the idiomatic language of religion expresses “the absolute.” This “absolutely idiomatic” nature of religious discourse, I argue, offers a promising starting point for addressing the political challenge surrounding religious differences. In their intersection with the norm of forgiveness, particular religious idioms not only are exposed to the demand to forgive their religious “others,” but also (and for this reason) contain within themselves the self-critical resources for the promotion of democratic ideals such as tolerance, reasoning in public, and respect for difference.

Keywords: conscience
forgiveness
G. W. F. Hegel
phenomenology
religion
secularism
Advisor: DiCenso, James
Iminium Ions and Imines: Application in an Alumino-Mannich, a Domino Condensation/Ring-opening/Electrocyclization, and Strategies towards the Total Synthesis of Nagelamide J and Agelamadin B

Iminium ions and imines have been important for the synthesis of various organic molecules. The aim of the dissertation was to use iminium ions or imines as reactive intermediates for the development of novel methodologies in organic synthesis and for the application towards the total synthesis of natural products. In Chapter 2, the focus is on the development of a multicomponent reaction with an organoaluminum reagent to synthesize a variety of tertiary amines. It was hypothesized that, in a one-pot method, an amine and aldehyde would form the corresponding iminium ion. This electrophilic iminium ion would then react with a nucleophilic organoaluminum reagent. After screening various reaction conditions, it was found that the trifluoromethanesulfonate counterion and trimethylsilyl amines were required to form the nucleophilic organoaluminum ‘ate’ species. This reaction provides an alternative for the synthesis of amines in a multicomponent manner. In addition, it expands the current application of organoaluminum reagents in multicomponent reactions. Secondly, Chapter 3 depicts the investigation to form unsymmetrical trans-diaminocyclopentenones, a common building block in marine natural products. Previous work in this area failed to form the unsymmetrical trans-diaminocyclopentenones through a lanthanide-catalyzed domino condensation/ring-opening/electrocyclization. Mechanistic insights showed that the iminium ion intermediate was too reactive and, it was therefore proposed that stable imines could react selectively. With an imine and a Lewis acid catalyst, the unsymmetrical trans-diaminocyclopentenones product was observed, however could not be isolated. Various strategies were explored and, based on these experiments, this chapter discusses future directions for this project to obtain these valuable products. Finally, the first total syntheses of dimeric pyrrole-2-aminoimidazole (P2AI) natural products, nagelamide J and agelamadin B, were explored in Chapter 4. Based on previous work, a divergent strategy was proposed and relied on forming a common intermediate. The key-step to form the common intermediate was the dysprosium-catalyzed domino condensation/ring-opening/electrocyclization reaction, which is based on an iminium ion intermediate. Various selective reactions were developed, such as imidazole lithiation, N-acylation, and guanylation. During the development of this chemistry, an analogue of these natural products was isolated and validated the structural identity of agelamadin B.

Keywords: Alumino-Mannich
Electrocyclization
Imines
Iminium Ions
Marine Alkaloids
Total Synthesis
Advisor: Batey, Robert A
For King and What Country? Chinggisid-Timurid Conceptions of Rulership and Political Community in Relation to Territory, 1370–1530

This thesis investigates Chinggisid-Timurid conceptions of rulership and political community in relation to territory, focusing on Perso-Islamic Central Asia and Iran during the period 1370–1530. It also discusses the thirteenth-century Mongol-ruled world for backdrop, and highlights the distinctiveness of the said conceptions through comparisons with contemporaneous European and East Asian/Ming Chinese conceptions of the same. This is a study of a chapter in the history of “international states system” before the European model of international states system became the global standard. The political culture of the Chaghatayids, Ilkhanids, and Timurids included conceptions of rulership and political community vis-à-vis territory that were rooted in a mix of Mongol and Perso-Islamic traditions. In the early thirteenth century, the Mongols conceived of a qan (khan) as leading an ulus, that is, a mobile demographic entity not defined by specific territory. Tājīk historians in Mongol service appeared to have understood this, though a number of them also attributed certain territorial characteristics to ulus. The matter becomes more complicated when Chinggisid-Timurid chancellery documents/diplomatic letters are considered, as unlike their European and East Asian counterparts, these documents lacked straightforward claims of rulership over politico-administrative territory. At the same time, a certain representation of rulership over territories, in the form of “pādeshāhs of wilāyats,” can be found in the histories, but this was evidently neither a formal nor a pronounced representation. By 1402, the Timurids no longer recognized a Chinggisid khan as their overlord, but they also did not clearly articulate what this meant in terms of the political community to which they belonged—especially, did they still belong to the ulus of Chaghatay? This study seeks answers to a basic question concerning the Chaghatayids, the Ilkhanids, and especially the fifteenth-century Timurids: “What was their country?”

Keywords: Babur
Chaghatay
Chinggisid
Ilkhanid
Mongol
Timurid
Advisor: Subtelny, Maria E
Pseudo-Anosov Homeomorphisms Constructed using Positive Dehn Twists

The mapping class group is the group orientation preserving homeomorphisms of a surface up to isotopy. The mapping class group encodes information about the symmetries of a surface. We focus on studying the pseudo-Anosov mapping classes, which are the elements of the group that mix the underlying surface in a complex way. These maps have applications in physics, notably in fluid dynamics, since we can stir a disk of fluid to create topological chaos, and in the study of magnetic fields since pseudo-Anosov maps create odd magnetic fields. Pseudo-Anosov maps also appear in industrial applications such as food engineering and polymer processing. We introduce a construction of pseudo-Anosov homeomorphisms on n-times punctured spheres and surfaces with higher genus using only sufficiently many positive half-twists. These constructions can produce explicit examples of pseudo-Anosov maps with various number-theoretic properties associated to the stretch factors, including examples where the trace field is not totally real and the Galois conjugates of the stretch factor are on the unit circle. We construct explicit examples of geodesics in the mapping class group and show that the shadow of a geodesic in mapping class group to the curve graph does not have to be a quasi-geodesic. We also show that the quasi-axis of a pseudo-Anosov element of the mapping class group may not have the strong contractibility property. Specifically, we show that, after choosing a generating set carefully, one can find a pseudo-Anosov homeomorphism f, a sequence of points wk and a sequence of radii rk so that the ball B(wk, rk) is disjoint from a quasi-axis a of f, but for any projection map from mapping class group to a, the diameter of the image of B(wk, rk) grows like log(rk).

Keywords: Algebra
Geometric group theory
Geometry
Mapping class groups
Pseudo-Anosov
Topology
Advisor: Rafi, Kasra
Digital Landscape: An Annotated List of Works for Solo Cello and Electronics

In the late 1940s, composers began to experiment with the integration of sound and recording technology within their compositions. As technology advanced, the integration of electronics into classical music compositions became a widespread practice. There have been well over one hundred works written for solo cello and electronics, and many hundreds more that feature the cello in a chamber music or orchestral setting with electronics. This annotated list will catalogue and review published works for solo cello and electronics written between 1950 and 2019, with the intent of providing a vital resource for cellists seeking out alternative and rarely performed repertoire. Many schools, universities, colleges, and examination centres list repertoire selections within four main eras or categories: Baroque, Classical, Romantic, and Contemporary, also referred to as twentieth or twenty-first century, the Modern era, or another combination of similar terms. The Contemporary era now stretches over 100 years and includes composers such as Schoenberg, Berg, and Stravinsky beside mid-century masters such as Shostakovich, Prokofiev, and Britten, and more recently, the pioneers of electronic works such as Stockhausen, Reich, and Saariaho. Unfortunately, much of the electronic repertoire takes a backseat to repertoire from these established composers that have already stood the test of time. As a result, there is no central database or catalogue of works that cellists can reference in their search for repertoire featuring electronics. This dissertation will fill that gap and allow teachers, students, and performers to identify pieces that fall within the body of work for solo cello and electronics. Each work is listed in this thesis with basic information such as date, composer, nationality, duration, publisher, and availability. This list also includes information about the equipment needed to perform each piece, technical characteristics (including excerpts where applicable), a musical and an electronic difficulty rating, other pertinent notes, as well as details regarding the commission, premiere, and recordings, as available. The goal of this research is to promote music for solo cello and electronics, ultimately resulting in more frequent performances of these pieces, while encouraging composers to continue to write music for this genre.

Keywords: Annotated Bibliography
Cello
Composition
Electronics
Strings
Violoncello
Advisor: Elliott, Robin
A Lewis Acidic Stroll Through the p-Block

Since the inception of frustrated Lewis pair (FLP) chemistry more than a decade ago, the development of an assortment of main group Lewis acids in the literature has contributed to the enrichment and diversification of FLP reactivity to achieve transition metal-like chemistry. While most of the employed Lewis acids were initially boron-based, exploration of the remainder of the p-block has led to the expansion of the boundaries of reactivity. The present work focuses on the exploration of Lewis acids based on the scantly explored p-block elements in the context of FLP and Lewis acid chemistry. Fluorosulfoxonium cations containing a Lewis acidic sulfur(VI) center were prepared from sulfoxides in an analogous fashion to previously reported fluorophosphonium cations. These cations were shown to enact Lewis acid catalysis via a S-F σ*-orbital and are among the first sulfur-based Lewis acids to be employed in such chemistry. Azophosphonium cations were prepared from the reaction between diazonium cations and phosphines. Their Lewis acidity is derived from the masked nitrenium character of one of the nitrogen centers. The azophosphonium cations act as one-electron acceptors to form paramagnetic species, and a combination of the bulky phosphine PtBu3 and one of the azophosphonium cations acted as an FLP to effect the cleavage of disulfides. Phosphorus(V) dications containing both an ortho-quinone and terpyridine backbone were prepared and shown to effect the Lewis acid-mediated hydrodefluorination (HDF) of fluoroalkanes with silanes, despite the phosphorus center being coordinately saturated. Computational data support the notion that these dications are in fact Lewis acidic at the para-carbon of the central ring of the terpyridine ligand, with the phosphorus center not directly participating in the chemistry. Following these results, ethylene-bridged bipyridinium dications were prepared to verify their reactivity without a phosphorus center. Indeed, these dications also displayed similar Lewis acidic behavior, acting as one-electron acceptors and effecting the same HDF catalysis, further supporting the notion of the para-carbon center acting as the electrophilic site of reactivity.

Keywords: acid
catalysis
FLP
group
lewis
main
Advisor: Stephan, Douglas W
Learned Improvements to the Visual Egomotion Pipeline

The ability to estimate egomotion is at the heart of safe and reliable mobile autonomy. By inferring pose changes from sequential sensor measurements, egomotion estimation forms the basis of mapping and navigation pipelines, and permits mobile robots to self-localize within environments where external localization information may be intermittent or unavailable. Visual egomotion estimation, also known as visual odometry, has become ubiquitous in mobile robotics due to the availability of high-quality, compact, and inexpensive cameras that capture rich representations of the world. Classical visual odometry pipelines make simplifying assumptions that, while permitting reliable operation in ideal conditions, often lead to systematic error. In this dissertation, we present four ways in which conventional pipelines can be improved through the addition of a learned hyper-parametric model. By combining traditional pipelines with learning, we retain the performance of conventional techniques in nominal conditions while leveraging modern high-capacity data-driven models to improve uncertainty quantification, correct for systematic bias, and improve robustness to deleterious effects by extracting latent information in existing visual data. We demonstrate the improvements derived from our approach on data collected in sundry settings such as urban roads, indoor labs, and planetary analogue sites in the Canadian High Arctic.

Keywords: computer vision
deep learning
machine learning
mobile autonomy
SLAM
visual odometry
Advisor: Kelly, Jonathan S
Assessing Immunological and Microbiome Determinants of HIV Susceptibility in the Male Genital Tract

Penile circumcision (PC) is a one-time, cost-effective HIV prevention strategy. A deeper understanding of its protection-mechanisms may inform novel prevention methods for vulnerable men declining PC. PC eliminates the foreskin, a preferential HIV acquisition site, and underlying subpreputial space resulting in reduced penile anaerobe density and diversity. In my thesis, I hypothesize that penile anaerobes on the prepuce induce proinflammatory cytokines that mediate HIV-target cell recruitment to the adjacent inner foreskin tissue, thus enhancing HIV susceptibility. The inner foreskin may be more HIV susceptible and I first assessed differential HIV susceptibility in CD4+ T cells derived from inner versus outer foreskin. Inner foreskin CD4+T cell density was >two-fold higher, with more Th17 cells and higher levels of proinflammatory cytokines, despite an unexpectedly higher per-cell HIV susceptibility in outer foreskin-derived CD4+ T cells. . Although our research suggests that HIV is acquired directly in foreskin tissue, other groups have hypothesized that PC actually reduces HIV acquisition risk in the urethra. To test this, I established a protocol to assess the impact of PC on the urethral immune milieu and microbiota in Ugandan men. PC did not change urethral immune parameters and had minor transient microbiota effects versus dramatic coronal sulcus changes, suggesting that PC does not mediate HIV protection through effects at the urethra. Additional prevention tools are needed for vulnerable men declining PC. I hypothesized that one way to reduce their risk would be via non-surgical microbiome alteration, specifically treatments to reduce penile anaerobes and associated immune activation. Low-cost, commonly available antibacterial agents may be one approach, and a clinical trial protocol is presented with preliminary analysis showing that oral tinidazole intake reduces viral entry in inner foreskin-derived CD4+ T cells by 30% compared to the control group. This may lead to novel non-surgical HIV prevention strategies suitable for uncircumcised men.

Keywords: antibacterials
foreskin immunology
Human Immunodeficiency virus
penile HIV prevention
penile microbiome
urethra
Advisor: Kaul, Rupert
Efficacy of β-amyloid Attenuation Depends on Regional and Temporal Progression of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common cause of dementia. Progressive loss of memory, executive function and activities of daily living defines the decline in cognition and quality of life in AD patients. To date there are no effective disease modifying therapies that slow cognitive decline. AD is defined neuropathologically by the presence of β-amyloid (Aβ) plaques and neurofibrillary tangles composed of hyperphosphorylated tau. Current models propose that disease progresses in a cascade, with Aβ triggering accumulation of tau, followed by neurodegeneration and cognitive impairment. However, Aβ-targeted therapeutics fail to exhibit disease modifying effects or cognitive improvement in the clinic. I hypothesize that progression of AD neuropathologies are driven by Aβ-dependent and Aβ-independent pathways that ultimately contribute to cognitive presentation. In my first aim, I assessed the efficacy of Aβ attenuation to improve hippocampal neurogenesis in TgCRND8 mice with developed Aβ-driven pathology. In contrast to an early AD-like phenotype, Aβ attenuation with scyllo-inositol did not rescue deficits in hippocampal neurogenesis in late AD-like pathology. Combination of Aβ attenuation with neotrofin treatment, to supplement neurotrophins, had no effect on hippocampal proliferation, but enhanced neuronal maturation and survival in late AD-like pathology, over both single treatments alone. To understand the contribution of Aβ, tau and neurodegeneration to cognitive function, I utilized TgF344-AD rats in my second aim, which recapitulate the salient hallmarks of AD, including frank neuronal loss and tau pathology from endogenous rat tau. I treated disease-bearing TgF344-AD rats with scyllo-inositol to attenuate Aβ and observed a rescue of behavioural deficits in pattern separation and executive function, but persistent impairments in activities of daily living and spatial memory. Rescue in hippocampal neurogenesis, neuronal function and reduced plaque-associated tau inclusions underlie improvements in pattern separation and executive function. Persistent entorhinal cortical tau pathology and entorhinal-hippocampal hypoconnectivity underlie lack of rescue in spatial memory. Therefore, regional and temporal variability in the efficacy of Aβ attenuation to improve cognitive function may explain failure of Aβ-targeted therapeutics in AD patients, and suggest the use of combinatorial therapeutics to halt cognitive decline.

Keywords: Alzheimer's disease
Aβ attenuation
cognition
hippocampal neurogenesis
TgCRND8 mice
TgF344-AD rats
Advisor: McLaurin, JoAnne