VictorJuiz/thesis huggingface dataset:
Therapeutic Potential of Protein Kinases and Their Downstream Targets Following Traumatic Cervical Spinal Cord Injury

Despite recent advances in the management and characterization of traumatic spinal cord injury (SCI), the current therapeutic options for patients remain limited. The SCI-induced cellular response is mediated through series of protein kinases, which are a group of globular proteins that reversibly phosphorylate downstream substrates to alter the transcriptional patterns of local and surrounding cells. While these altered kinase activities at the cellular level represent compelling targets for therapeutic intervention, the specific function of different kinase pathways is yet to be investigated. The objective of this doctoral thesis is to elucidate the role of protein kinases in injury progression and explore their therapeutic potential following traumatic cervical SCI. First, a comparative cross-species transcriptional and genomic analysis identified molecular pathways with great therapeutic potential and translational relevance. As these molecular targets were predominantly kinase-related, the subsequent experiments were aimed to assess the efficacy of a clinically approved protein kinase inhibitor—midostaurin—to alleviate secondary pathogenesis. While the results showed great promise, more targeted strategies would be necessary to minimize off-target effects and enhance effectiveness. Hence, gene therapy was used to modulate a downstream target of protein kinases, which demonstrated that restoring KCC2 activity can enhance functional recovery. This work demonstrates the importance of targeted kinome-based therapeutics to alter the secondary response following traumatic SCI.

Keywords: Cross-Species Comparison
KCC2
Kinome
Spinal Cord Injury
Advisor: Fehlings, Michael G
Insulin Recepto Loss Impairs Mammary Tumourigenesis in Mice

Breast cancer (BC) prognosis and outcome are adversely affected by increased body weight, obesity, and the obesity-associated type 2 diabetes. Hyperinsulinemia, common in the obese state, has been associated with higher risk of death and recurrence in BC. Up to 80% of breast cancers overexpress the insulin receptor (INSR), which correlates with worse prognosis. To directly probe the role of insulin signaling in mammary tumorigenesis, we generated the MMTV-driven polyoma middle T (PyMT) and ErbB2/Her2 BC mouse models, respectively, with coordinate mammary epithelium-restricted deletion of the INSR. In both models, deletion of either one or both copies of the INSR in the mammary gland led to a marked delay in tumor onset and burden, including in mice fed to mimic conditions of human obesity. Phenotypic characterization and longitudinal monitoring of mouse tumours, and ex vivo analysis of mammary cells from the generated mouse models revealed that tumor initiation, rather than progression and metastasis, were impacted by INSR deletion. The similarity of phenotypes elicited by the deletion of one or both copies of INSR indicates that there is a dose-dependent threshold for the contribution of INSR to mammary tumorigenesis, with major implications for primary and secondary prevention of breast cancer in the obese.

Keywords: bioenergetic fitness
breast cancer
insulin receptor
mouse models
obesity
Advisor: Stambolic, Vuk
Energy Harvesting Information Systems and Design in the Energy Transition

Design is a historically informed, future-facing activity. Transitioning to a low carbon, sustainable society will require many new objects, processes and systems to harvest sustainable energy. Developing a historically informed approach to the design of energy harvesting information systems is the central rationale for this study. The dissertation explores this research question in four activities: the first is a collection of energy harvesting information objects and media of photovoltaic design history -- for the descriptive study of material form, use, function and durability, informed by the practices of museums and collections scholarship, for a gathering and interpretation of texts. The second is a technical history of the design of these devices -- how they were created, came to market, function, and persist, from a socially oriented, material perspective. The third discusses the design history from foci which characterized their historical development and are significant concerns of the energy transition: colonialism / nation building, environmental impact and social justice. The fourth presents speculative design-experiments that reflect and reimagine, a "response" to this newly assembled collection of historical objects as hybrid transitions designs. The four activities enact complementary methods addressing specific challenges of historical context, analysis methodology and micro-macro readings of the domain, while reflecting on how social issues of colonialism or nation-building, the environment and social justice have changed. The broad intellectual contribution is to the corpus of science and technology studies, STS writings about energy history, a persistent and significant interest of this field. The more specific contribution is to energy transition design techniques as related to information studies, where responses to planetary warming levels of critical and exigent concern are urgently required.

Advisor: Ratto, Matt
Mapping the Genesis of Malignant Gliomas at Single-Cell Resolution

Malignant gliomas and glioblastomas are genetically diverse brain malignancies of both children and adults. Despite the remarkable progress in deciphering the genomic architecture of these tumours, the cellular programmes and mechanisms that give rise to the mostly incurable late-stage tumours remain unresolved. In this thesis, I aimed to explore the roots of gliomagenesis and map the process of tumour initiation and development. First, I used the transgenic Sox2eGFP mice to explore the heterogeneity of mouse cerebral precursor cells and downstream lineages across the developmental time-course, from embryonic day 12.5 to postnatal day 365, by performing single-cell transcriptomics on >100,000 cells to generate an atlas of cerebrum development. I used this atlas as a reference to explore single-cell data from human malignant gliomas and identified the acquisition of developmentally restricted radial glial-like precursor cell states in both paediatric and adult tumours. Next, I traced the origins of tumour development from the earliest stages of initiation by combining glioma mouse modeling with serial magnetic resonance imaging (MRI) and single-cell profiling. I was able to track the process of tumour formation across four MRI-defined time points from the preneoplastic to the endpoint stage of gliomagenesis. My findings revealed entire developmental-like lineages that dominate the various stages of tumourigenesis. Importantly, I identified a malignant cell state with a strong neural crest-like gene expression signature that showed high abundance in the early stages, but was relatively diminished in the late-stage of tumourigenesis. Genomic analysis based on the presence of copy number alterations revealed that these neural crest-like cells exist as part of a heterogenous clonal hierarchy that governs tumour growth. Further, by exploring the injury response in the wounded normal mouse brain, I identified cells with a similar signature that emerge following injury and then disappear over time. Surprisingly, my experiments uncovered an injury-like microenvironment that is initiated in the brain following oncogene activation in cerebral precursor cells, suggesting that tumour initiation involves the activation of an injury-like response programme. Collectively, my results present a roadmap of glioma initiation and development, and raise exciting new possibilities for early disease diagnosis and prevention.

Keywords: Brain injury
Cancer biology
Glioblastoma
Mouse brain development
Neural crest cells
Single-cell sequencing
Advisor: Dirks, Peter
Investigations on soot and flow field characteristics of blended liquid and gaseous fuels in turbulent swirl-stabilized non-premixed flames

Combustion of fossil/carbon-based fuels in both ground and aviation-based transportation devices produce emissions such as NOx, CO2 and soot. Among these, soot formation is a complex process and their characteristics have not been understood completely. Hence, it has been the subject of recent studies in an effort to reduce its footprint in atmospheric pollution. The current work explores the possibility of adding different fuel additives to existing carbon-based fuels in aviation-type gas turbine combustors to understand their effect on soot formation. This study involves understanding the various hydrodynamic and chemical effects on soot formation through controlled lab-scale experiments with well-defined boundary conditions in both liquid and gaseous swirl-stabilized turbulent flames. Particle image velocimetry, laser diffraction and laser induced incandescence are utilized to experimentally characterize the flow-field, spray and soot characteristics respectively within the combustor. Various biofuels and oxygenated compounds are blended in small amounts to base Jet A-1 fuel in liquid spray combustors, whereas hydrogen/helium is used as an additive to ethylene base fuel in gaseous combustor. The overall effectiveness of a certain fuel additive along with the effect of various blending ratios, flow rates and spray characteristics on soot in different combustor configurations are discussed in detail. The changes in spray characteristics was noticeable for lower alcohols, but diminished with higher alcohols as their physical properties do not deviate largely from neat Jet A-1. The measurements revealed that even though the hydrodynamic effects such as flow-field and turbulence can influence the soot formation regions, spatial soot distribution and soot intermittency, the global changes in the magnitudes of soot volume fractions were mostly affected by local fuel chemistry. Higher alcohols were found to be highly effective in reducing soot concentrations when added to neat Jet A-1, whereas addition of hydrogen in small concentrations to ethylene resulted in an increase in soot loading, opposite to that observed in atmospheric laminar flames. In addition to this, high speed planar measurements in gaseous flames revealed that apart from the effect of swirl, bulk flow unsteadiness and local flow fluctuations contributed immensely to the growth and transport of soot from formation to oxidation regions.

Keywords: Biofuels
Combustion
Emissions
Laser Diagnostics
Soot
Advisor: Gulder, Omer L
An Arithmetic-geometric Reciprocity between Theta Functions Attached to Real and Imaginary Quadratic Fields

We use the theta correspondence to construct classical holomorphic modular forms associated to ideal classes in quadratic number fields. These modular forms are theta functions that were originally introduced by Hecke in the 1920s andhave been investigated by several authors since. Our framework allows us to prove old and new results concerning the periods of these modular forms over certain geometric cycles defined by arithmetic data. In particular, we establish a reciprocity relationship between the periods of theta functions attached to ideal classes in real and imaginary quadratic fields. This provides an analogue of (and context for) Hecke’s discovery that certain periods of his imaginary quadratic theta functions are special values of classical Eisenstein series at CM points.

Keywords: modular forms
number theory
theta correspondence
theta functions
Advisor: Kudla, Stephen
Ready for Action! When the Brain Learns, Yet Memory-Guided Behavior Does Not Follow

The ability to use memory for action is critical for everyday life, such as for remembering which alarm signals danger. Although research suggests that memory for past events influences how we respond to events in the present, the magnitude of behavioral benefit varies and can even be absent. How is it that the brain learns, yet the learning does not influence memory-guided action? In this thesis, I show that 1) not all learned memory representations are usable for behavior and 2) those that are usable for behavior are supported by distinct neural mechanisms during retrieval. Study 1 demonstrates that learning and behavioral expression of learning are separable and differentially affected by attention. Studies 2 and 3 provide further evidence that memory-guided behavior is supported by distinct neural substrates. Specifically, Study 1 leveraged high-density electroencephalography (EEG) and revealed a striking brain-behavior dissociation. Learning was observed neurally in two attention conditions. However, only one condition, in which attention was directed to the task-relevant object at learning, led to a memory-guided behavioral benefit at retrieval. Further, these behaviorally accessible memories were accompanied by an implicit neural memory component that correlated with the degree of response preparation, but not with response execution. In Study 2, I conducted a systematic review and a meta-analysis and demonstrated that fronto-parietal attention and control networks are critical for memory-guided behavior. Study 3 empirically validated this working model, using time-frequency source localization. Specifically, I showed that, in addition to fronto-parietal networks, memory-guided behavior is accompanied by anterior temporal lobe activity that scales with the magnitude of behavioral benefit. Together, the results of the presented studies suggest that 1) attention at learning affects memory accessibility and guided behavior at retrieval and 2) accessible memories that guide behavior are supported by distinct temporal and fronto-parietal networks and implicit neural memory that triggers response preparation.

Keywords: Attention
Electroencephalography
Lateralized readiness potential
Long-term memory
Memory-guided attention
Response preparation
Advisor: Alain, Claude
Moscovitch, Morris
Rejection-Free and Partial Neighbor Search MCMC Algorithms

The Metropolis algorithm involves producing a Markov chain to converge in distribution to a specified target density $\pi$. To improve its efficiency, we can use the Rejection-Free version of the Metropolis algorithm, which avoids the inefficiency of rejections by evaluating all neighbors. Rejection-Free can be made more efficient through parallel hardware. However, for some specialized hardware, such as Digital Annealing Unit, the number of neighbors being considered at each step is limited. Hence, we propose an enhanced version of Rejection-Free known as Partial Neighbor Search, which only considers a portion of the neighbors. Partial Neighbor Search can be applied efficiently despite the number of neighbors. Especially for continuous cases with uncountable many neighbors, Partial Neighbor Search can be applied easily and samples efficiently while Rejection-Free is not feasible, and the Metropolis algorithm is slow. Both algorithms can be used in many other circumstances as well, such as the optimization question. In combinatorial optimization, Simulated Annealing using Metropolis steps at decreasing temperatures are widely used to solve complex problems. In order to improve its efficiency, we can also use the Rejection-Free version of the Metropolis algorithm, which avoids the inefficiency of rejections by considering all the neighbors at every step. In addition, in optimization questions, Partial Neighbor Search can not only be helpful when being applied on parallel hardware, but it can also avoid the algorithm from becoming stuck in local extreme areas, and thus Partial Neighbor Search for optimization finds the optimal solution much faster than the other two algorithms. For both sampling and optimization, we demonstrate the superior performance of the Rejection-Free and Partial Neighbor Search algorithms by applying these methods to several examples, such as the Ising mode, the QUBO question, the Knapsack problem, the 3R3XOR problem, the quadratic programming, etc.

Keywords: MCMC
Metropolis Algorithm
Partial Neighbor Search
QUBO
Rejection-Free
Unbiased PNS
Advisor: Rosenthal, Jeffrey
Sulphur Amino Acid Requirements and Metabolism in Healthy Adults ≥60 Years

Current protein and indispensable amino acid (AA) recommendations for older adults are based on young adult data. The protein requirement based on nitrogen balance studies is lower than our indicator amino acid oxidation (IAAO) derived estimate in older adults. Physiological studies suggest that protein intakes similar to our IAAO-derived estimates result in better physiological outcomes. Glutathione (GSH) is a functional marker of cellular antioxidant capacity, and its synthesis rate depends on protein and sulphur AA (SAA) intakes. Recommendations for increased plant-protein consumption necessitate determining the indispensable AA needs directly in older adults, particularly the SAA, which are limiting in plant proteins. The goal of the current thesis was to assess the protein and SAA requirements of healthy adults 360 years by 1) measuring GSH synthesis as a functional marker of protein adequacy using a precursor-product method; 2) deriving the total SAA (methionine devoid of cysteine) requirement and 3) the minimum methionine (methionine with excess cysteine) requirement using the IAAO method. GSH fractional synthesis rate (FSR) was maximized at a protein intake of 0.96 g·kg-1·d-1 (95% CI: 0.74,1.18). Total SAA requirements for older males and females were 26.2 and 17.1 mg×kg- 1×d-1 respectively, which were statistically different (Difference in 95% CI: 9.1 ± 8.85). The minimum methionine requirement for older males and females was 5.1 mg×kg-1×d-1 (95% CI: 3.67, 6.53). Our lab's IAAO protein requirement estimates in healthy adults 360 years are comparable to the level of protein intake that maximized GSH synthesis. This suggests that the IAAO method measures a protein requirement higher than that needed for nitrogen balance. Additionally, considering the observed sex and age effect of total SAA requirement, young adults indispensable AA requirements do not apply to older adults. Therefore, all remaining indispensable AA requirements of older adults should be urgently assessed to properly assess the effectiveness of dietary intakes and plant-based diets to meet their specific needs.

Keywords: Glutathione
Older adults
Protein
Requirement
Stable isotopes
Sulphur amino acids
Advisor: Courtney-Martin, Glenda
Pottery Production at Seh Gabi in the Central Zagros of Iran during the Dalma and Seh Gabi Periods (Middle Chalcolithic Period)

The concept of pottery manufacturing technology extends beyond a series of activities that result in the production of vessels. It also has a social dimension. A comprehensive examination of pottery production technology, therefore, helps to better understand the social and cultural settings of a society in which pottery was produced. This study investigates the pottery manufacturing technology and organization of production at Seh Gabi, a Chalcolithic site in the east Central Zagros.In this research, I used a chaîne opératoire approach to investigate the choices that the potters made throughout the manufacturing process to learn about the people who were involved in production during the Dalma and Seh Gabi periods (5th millennium BC). The results show that pottery production was organized at a household level during both periods. This research also demonstrates that individuals could express themselves through the technological activities and the choices they made in production and through these activities form their own identity. Despite some diversities in technological practices resulting from household production, the general uniformity in the style of the Dalma pottery suggests that the Dalma potters belonged to a distinct social group with the same identity who had a rather uniform skill level in making desirable products, while the Seh Gabi period potters possessed different levels of skill in manufacturing pottery and making technological choices. The difference in skill levels was particularly prominent among the Seh Gabi Painted wares. The degree of knowledge and skill, reflected in pottery production, could define their identities as skilled or ordinary producers. The skill in production could give the potters a social status or prestige in society that distinguished them from the others. Finally, comparing the pottery technology of both periods provided a better understanding of the technological continuity and change through time. While the Seh Gabi period potters made changes in some aspects of the production of the red slipped and impressed wares to meet their own requirements, the general manufacturing technology of these wares continued through time. However, the manufacturing technology of the painted wares in these periods were so different that they represented distinct cultures.

Advisor: Reichel, Clemens
From Evolution to Potential Revolution: Explaining the Reform of the Global Corporate Tax Regime from 2008 to 2021

The two-pillar framework for the taxation of multinational business profits contained in the landmark October 2021 international tax agreement was a major and potentially revolutionary step toward a new Global Corporate Tax Regime (GCTR). The two pillars introduced a rare and substantial departure from long-established and salient norms governing source-based taxation and methods of preventing corporate tax avoidance. It also proposed unprecedented constraints on state sovereignty through new methods of coordinating inter-nation taxing rights. Why was there an abrupt shift to the enduring status quo causing this potentially revolutionary change? How and why has the GCTR evolved from 2008 to 2021, and what is its likely evolution and impact in the future? This study argues that multilateral cooperation on international tax law and policy reform coordinated by the G-20 and OECD was catalyzed by the shocks of the Global Financial Crisis in 2008 and the COVID-19 pandemic in 2020, each of which disrupted the status quo and set in motion a multi-phase causal process and international institution-building that provided a new governance framework, which facilitated this potentially revolutionary change. The original empirical, comparative, and meta-historical analysis in this study demonstrates that the OECD-centered Transnational Tax Policy Community (TTPC) was the primary cause of the regime’s normative development, its influence was strengthened after the 2008 Global Financial Crisis, and it acted as a powerful agenda-setter, adviser, gatekeeper, veto-player, and interlocutor. Yet despite the TTPC’s influential role, this study argues that the international politics of distribution are highly correlated with the implementation of domestic legislative outcomes and enforcement. Thus, considering the significant distributional implications of the two-pillar framework and the proposed constraints on state sovereignty, it is an open question whether the agreement will be comprehensively implemented by the 136 countries that endorsed the October 2021 agreement. This dissertation uses a mixed methods approach and synthetic middle-range analytical framework to develop a Dynamic Model of Corporate Tax Governance that describes and predicts the causes of norm and rule changes in the GCTR. It provides a useful basis for estimating future global tax governance “hard” and “soft” law outcomes.

Keywords: Base Erosion and Profit Shifting
Global tax governance
Group of 20
International corporate taxation
Organization for Economic Co-operation and Development
Tax avoidance
Advisor: Kirton, John J