VictorJuiz/thesis huggingface dataset:
Advances in Knowledge-based Planning for Radiotherapy with an Open Framework

Automated radiotherapy planning is on the verge of transforming personalized cancer treatment, and it will likely help address the growing global cancer burden. The most common type of automated planning is knowledge-based planning (KBP), which can generate treatment plans for radiotherapy without human intervention. In general, KBP is implemented as a two-stage pipeline that first predicts the dose that should be delivered to a patient, and then an optimization model converts that prediction into a treatment plan. Although KBP research is flourishing, it is largely limited to institution-specific datasets and evaluation metrics, which makes comparing competing approaches difficult. The purpose of this thesis is to develop state-of-the-art KBP methods and an open framework for the KBP research community to benchmark new contributions. In this thesis, we developed the first generative adversarial network for KBP dose prediction, which outperformed several baselines. Next, we launched the OpenKBP Grand Challenge, which was the first platform that enabled researchers to compare KBP prediction methods fairly, and helped democratize KBP research by making it accessible to everyone. Next, we found that there were interaction effects between the two stages in KBP and that the choice of both stages can contribute to considerable variations in plan quality. To explore this further, we developed new plan optimization methods using open data and the dose predictions from the OpenKBP Grand Challenge. Overall, we improved KBP methods and promoted more collaboration within the KBP research community.

Keywords: Computer vision
Generative models
Inverse optimization
Knowledge-based planning
Open data
Radiotherapy
Advisor: Chan, Timothy C. Y.
Development of a Next-generation Rechargeable Aluminum Battery Technology

This dissertation is focused on the development of next-generation rechargeable aluminum batteries. Two approaches are taken to achieve the main objective: i) development of new electrolytes chemistries that are more environmentally sustainable and economic than the state-of-the-art, and ii) comprehensive investigation of electrolyte properties and charge storage mechanisms to gain fundamental insights into designing/engineering high-performance electrode materials. Dialkylimidazolium chloride-based chloroaluminate ionic liquids have been highly popular in the research and development of room-temperature rechargeable aluminum batteries due to their high conductivity, high ionicity, and wide liquidus range. However, their high cost associated with small-scale production and potential environmental concerns, greatly diminish the practicability of resulting battery systems. On the other hand, chloroaluminate ionic liquids are known to function simultaneously both as a medium for ion transportation and as electroactive materials (anolytes) in many existing chemistries. This unique dual functionality fundamentally governs several key battery performance metrics including capacity, energy- and power densities. In this dissertation, first, a rechargeable aluminum battery employing natural graphite cathode and an ionic liquid analog made of aluminum chloride-urea anolyte is developed. Fundamental investigations reveal a new aluminum electrodeposition/stripping mechanism. The achievable capacity and energy density of aluminum chloride-urea|graphite battery are assessed and in-depth characterizations are performed to gain insights into the physicochemical properties of aluminum chloride-urea ionic liquid analog. In the subsequent work, the research focus is extended to Lewis organic bases beyond urea. A novel chloroaluminate ionic liquid made of aluminum chloride and low-cost trimethylamine hydrochloride is identified. In addition to the cost advantage of trimethylamine hydrochloride over existing dialkylimidazolium chlorides, the resulting ionic liquid electrolyte/anolyte also demonstrates improved electrochemical stability window, specific- and volumetric anodic capacities. To investigate the limitations of existing chloroaluminate ionic liquids, electrical and transport properties of trimethylamine hydrochloride-based and dialkylimidazolium chloride-based ionic liquids are investigated. In addition, the research is further expanded to understanding of fundamental properties and charge-storage mechanisms of graphitic- and organic cathode materials in chloroaluminate melts. Lastly, critical assessments of concepts, proposed mechanisms, performance metrics, and key challenges of existing rechargeable aluminum batteries are conducted to provide future guidance for the research community.

Keywords: Aluminum-ion battery
Chloroaluminate ionic liquid
Electrical and transport properties
Rechargeable aluminum battery
trimethylamine hydrochloride
urea
Advisor: Azimi, Gisele
Peripheral Skeletal Muscle Structure and Contractile Function in Adults with Cystic Fibrosis

Genetic mutations in cystic fibrosis (CF) result in dysfunction of the CF transmembrane conductance regulator (CFTR) protein. As people with CF are living longer, issues regarding skeletal muscle performance have become more prominent. Limb muscle structure and contractile function in adults with CF are not well characterized and their associations with patient demographics and clinical features have not been adequately evaluated. CFTR protein is expressed in human skeletal muscle, but its role is unknown. This thesis was undertaken to characterize limb muscle structure and contractile function in people with CF, to examine their associations with demographic and clinical variables in people with CF, and to delineate the impact of abnormalities of CFTR protein on skeletal muscle structure and contractile function in people with CF. A systematic review and meta-analysis (Study 1) found adults with CF to have thigh muscle atrophy, and a subgroup had quadriceps weakness. Also, adults with CF had lower handgrip strength, especially in females, and it was associated with lower lung function. A prospective study designed to investigate the association between CFTR protein dysfunction and muscle structure (Study 2) demonstrated no differential impact of the extent of diminished CFTR protein activity on quadriceps size or muscle quality, as determined by ultrasound measures. Upper and lower limb muscle strength, determined by dynamometry, and leg muscle power assessed with stair climb power test (Study 3) showed no relationships between CFTR protein dysfunction and impairment in muscle strength or muscle power. Nevertheless, quadriceps muscle contractility was found to be lower in people with severe CFTR protein dysfunction. In conclusion, adults with CF are confirmed to have impairment in their limb muscle size and muscle strength, and CFTR protein plays a role in muscle contractility, which needs to be confirmed with cellular and molecular studies in humans with CF. Future studies are needed to examine the implications of these results on ventilatory muscle contractility, and how CFTR modulator therapies affect muscle contractility in adults with CF. Furthermore, upper limb muscle structure and contractile function, and other aspects of muscles, e.g. muscle architecture, need further exploration in adults with CF.

Keywords: Cystic fibrosis
Muscle composition
Muscle Contractile function
Muscle Contractility
Muscle size
Skeletal muscle
Advisor: Mathur, Sunita
Convergence of Molecular, Nanoscale, and Data-driven Technologies for Therapeutics and Diagnostics

The next revolution in healthcare will require the convergence of many traditional healthcare sectors to create therapeutic drugs and diagnostics tools that can target challenging diseases. Solutions which utilize molecular processes of cells and proteins, devices which use nanoscale physical principles for precision operation, and data-driven solutions which provide insights beyond current knowledge will all significantly impact clinical practices. In this thesis we aim to explore three main convergent fields: microfluidics for therapeutics research, machine learning for drug discovery, and biosensors for wearable disease management. With microfluidics, we develop a label-free cell sorting platform to sort whole populations of cells from the eye to isolate retinal stem cells, a potential therapeutic target that could reverse blindness. Deterministic lateral displacement cell sorting is implemented with notched microstructures, increasing sorting resolution by limiting cell deformation. Retinal stem cells are sorted and profiled based on size, purifying the population for downstream photoreceptor differentiation experiments. Next with machine learning, we develop an in silico pipeline, kCellect, for therapeutic antibody candidate selection from in vitro phage display biopanning against proteins associated with various cancers. We utilize k-means clustering for motif-based selection of antibody candidate sequences and identify cluster correlations with in vitro sequence frequency data. We discover novel antibodies against CD151 and FZD7 with similar or greater affinity to first-in-class antibodies, and doing so more time and computationally efficiently compared to previous methods. Finally, with biosensors, we design molecular pendulum sensors which consist of rigid DNA, an antibody recognition element to target proteins, and a redox reporter. Under an applied electric field, the pendulums fall, and the kinetics of motion between bound and unbound probes are measured through a surrogate redox electron transfer. We demonstrate the detection of multiple biomarkers of chronic disease in numerous biological fluids, and the continuous monitoring of biomarkers in situ in a mouse’s mouth. The three projects described in this thesis showcase biomedical convergence for the development of advanced therapeutics and diagnostics. The strategies utilized are sensitive to small quantities of biologicals, rapid in processing and development time, and versatile to many challenging disease targets.

Keywords: Biosensors
Cell Sorting
Drug Discovery
Electrochemistry
Machine Learning
Microfluidics
Advisor: Sargent, Edward
Design of Organic Carbonyl Materials for Lithium-ion Batteries

Redox-active organic compounds have great potential as electrodes for lithium-ion batteries due to their structural tunability, high natural abundance, and ability to attain high capacity. Among others, carbonyl-containing organic cathode materials have demonstrated promising results, since they have fast redox kinetics and structural diversity in design. However, these electrodes still exhibit intrinsic drawbacks, such as solubility in battery electrolytes, low conductivity or poor cycling stability. In this thesis, I present the design of new carbonyl compounds to address specific challenges of organic electrode materials. In chapters 2 and 3, I explored triptycene-based small molecules and frameworks that can produce multi-redox reactions. Triptycene-based quinones have unique rigid structures that impart high stability in electrolytes, which practically provide a high specific capacity and cycling performance. Chapter 2 explores a unique synthetic route to prepare triptycene-based frameworks and small molecules consisting of dual redox-active units at both the core building blocks and linkers. This work provides a direction for new design in developing highly stable cathode materials for lithium-ion batteries. Chapter 3 describes synthetic strategies to produce triptycene-based small molecules for organic electrodes. Series of triptycene ortho-quinones and triptycene dimers with sulfides are explored. Importantly, this work emphasizes the advantage of using a rigid triptycene scaffold in the design of lithium-ion batteries; the scaffold offers a new molecular platform with minimal non-active mass for achieving high performing organic cathode materials. Chapter 4 studied the rational molecular design of redox-active and ionically conducting oxanorbornene pendant polymers that can increase Li-ion mobility. The additional oxygen contained within the repeat unit of poly(oxanorbornene) serves as an ionic-conducting functionality that facilitates the transport of Li-ions into the bulk materials. Poly (oxanorbornene) results in superior electrochemical performance, including a high rate capability, cycling stability and ionic conductivity. Lastly, Chapter 5 summarizes the thesis and potential future works of the above projects, and provide an overview of carbonyl-based electrodes.

Keywords: batteries
organic electrodes
organic rechargeable batteries
redox materials
Advisor: Seferos, Dwight
A General Interfacial Capacitance Model for Nanomaterial Supercapacitors: Insights from Computational Quantum Mechanics

Electrochemical energy storage devices play a crucial role in the drive towards a sustainable energy future. They are ubiquitously utilized in electric vehicles, distributed renewable energy systems, and are increasingly considered for utility-scale power applications. High-power operation, however, present unique challenges to these devices at the physical and chemical level. Despite decades of experimentally driven research progress, theoretical and computational models of energy storage devices, such as batteries and supercapacitors, are built upon a foundation that was laid more than 150 years ago. The electrode/electrolyte interface is the region of most interest. This is where charge transfer reactions take place in batteries and ion adsorption/polarization take place in supercapacitors. The physicochemical phenomena occurring at the interface depend on a wide variety of quantum mechanical effects which are not accounted for within traditional continuum models based on partial differential equations. While there have been many efforts to address this knowledge gap through traditional methods, they are either limited in applicability or entail simplifying assumptions which exclude whole classes of devices such as those based on low-dimensional nanomaterials. Graphene- based supercapacitors are especially sensitive to quantum interactions since the electrode’s capacitance can be influenced by the presence of substrates, dopants, and/or electrolyte species. Conventional quantum-capacitance-based series models of graphene capacitors assume no electronic interaction between graphene and its interfacial neighbours, which leads to an overestimation of electrode capacitance by an order of magnitude. To address these limitations, we have developed a General Interfacial Capacitance Model (GICM) for nanomaterial-based supercapacitors. The GICM is based on first-principles computational quantum mechanics in the frameworks of Density Functional Theory (DFT) and Ab-Initio Molecular Dynamics (AIMD) combined with the principles of microscopic polarization theory. Three case studies for graphene-based interfaces are presented as applications of the GICM: bilayer graphene on a silica substrate, nitrogen-doped graphene on a copper substrate, and an interface between water and copper-supported graphene. The aim of this work is to improve current understanding of the performance of nanomaterial-based electrochemical supercapacitors and guide their design at the atomic level.

Keywords: density functional theory
energy storage
graphene
molecular dynamics
nanomaterial
supercapacitor
Advisor: Dawson, Francis
Huzayyin, Ahmed
Single-cell Profiling of Molecular and Cellular Features that Underlie Myeloma Disease Progression

Multiple myeloma (MM) is an incurable cancer of bone marrow (BM) plasma cells, consistently preceded by a premalignant disease stage. However, the drivers of progression are incompletely understood owing to extensive genomic heterogeneity and a complex microenvironmental ecosystem. To address this gap, I profiled the malignant and non-malignant tumour compartment of a transgenic mouse model of myeloma progression throughout disease evolution using a longitudinal single cell RNA-sequencing (scRNA-seq) approach. This included 104,880 cells isolated from 18 mice at 3 separate time points. Using scRNA-seq data from 7,160 plasma cells, I found that while the malignant compartment contains copy number-driven subclones at all disease stages, transcriptional divergence emerges late. Importantly, I showed that certain late-stage subclones reflect previously dominant molecular programs from early disease, which represents a novel concept in precursor myeloma evolution. This notably included a stress response-related subclonal program universally present in MM mice that I subsequently implicated in precursor progression using publicly-available patient data and established as a novel therapeutic vulnerability in myeloma. Turning to the non-malignant population, I next analyzed 97,720 BM cells and found that immune-related changes occurred prior to the development of active MM. This notably included early emergence of a dysfunctional T cell population that co-expressed LAG3 and PD-1. I then demonstrated that early combinatorial blockade of these proteins delays progression, supporting that immune dysregulation plays a causal role in precursor progression. Finally, to understand the mechanisms underlying response to this regimen, I performed paired scRNA-seq and TCR-profiling on 41,705 cells isolated from the BM of mice with varying responses to LAG3/PD-1 blockade. In doing so, I found that response variability is associated with differential enrichment of expanded T cells along a continuous dysfunctional gradient, which may be related to underlying differences in the TCR repertoire. Moreover, I determined that these expanded T cells derive from a TCF1+ progenitor exhausted T cell subset. Collectively, this work advances our understanding of molecular processes that underlie myeloma progression and nominates novel mechanisms associated with transition from precursor to active MM that may inform new approaches to the identification and treatment of high-risk precursor patients.

Keywords: myeloma
single cell RNA-sequencing
Advisor: Trudel, Suzanne
Pugh, Trevor J
The ATRX Chromatin Remodelling/Helicase Protein Maintains Telomere Integrity Through its Protein Associations

Telomeres are repetitive genetic elements at chromosomal ends that span up to 14 kb and protect subtelomeric genes from degradation and damage. Due to the inherent nature of DNA replication, telomeres shorten with each cell division, with short telomeres ultimately triggering senescence. Cancer cells subsequently elongate telomeres to achieve replicative immortality. Typically, this is achieved through reactivation of the telomere-extension enzyme, telomerase. However, a subset of cancers instead utilizes the alternative lengthening of telomeres (ALT) pathway. ALT strongly correlates with a loss of the ATRX protein. ATRX is an ATP-dependent chromatin remodeller/helicase that associates with the DAXX histone chaperone to deposit histones at repetitive DNA elements, including telomeres. This maintains nucleosome density and transcriptional silencing. Because the ATRX-DAXX interaction imparts the histone deposition capabilities of ATRX, I hypothesized that other ATRX protein interactions confer additional molecular functions, and that these are needed to maintain telomere stability. Using proximity-dependent biotinylation (BioID), I identified 36 proximal ATRX associations, including known interactors such as DAXX. To assess the breadth of their roles, I centered on the proteins that remained enriched over the most stringent controls, with a particular focus on the novel DNA damage response association, SLF2. The ATRX and SLF2 proteins together play roles in telomeric stability by suppressing aberrant telomeric exchanges and influencing proteins at telomeres. Together, these functions may inhibit or prevent ALT. Altogether, I have expanded the known ATRX protein associations, thereby expanding its functions beyond histone deposition.

Keywords: ALT
ATRX
chromatin
chromatin remodelling
proteomics
telomeres
Advisor: Campos, Eric I
Unification Educators and the Enactment of Educational Policy for North Korean Refugee Students in South Korea

Educational injustice is prevalent in the education of North Korean Refugee Students (NKRSs) in South Korean schools. This qualitative study critically examines the policies regarding the education of NKRSs, and elicits the views of 18 paraeducators, known as Unification Educators (UEs), who are also North Korean refugees and former NK teachers. They are appointed at schools with more than ten NKRSs to assist NKRSs to ensure a more just education. This thesis concerns the students known as North Korean Defector Students, herein NKRSs. Based on Freire’s (2007) pedagogy of oppression, the NKRSs are viewed as individuals oppressed within the South Korean educational system. The work of Levinson, Sutton, and Winsted (2009) contextualizes the UEs as policy actors who must implement their mandates within the oppressive system. The Ministry of Education policies are reviewed along with prior research on the education of the NKRSs. The present research adopts a qualitative research design founded on Ball, Maguire, and Braun (2011) using in-depth interviews with the UEs to inquire about their practices in relation to the policy stakeholder, i.e., NKRSs and their parents, school administrators, and teachers, and their lived experiences as the primary policy enactors. Through the voices of the UEs, this study confirms that the educational well-being of the NKRSs has been threatened due to the lack of economic, social, and cultural capitals from their family and support within the school system. Likewise, UEs suffer from oppression, and their role as policy actors is limited by bureaucracy and prejudice. The thesis offers recommendations to include UEs in the drafting of educational policy, to improve relationships with the Ministry of Education and with educational staff to achieve educational equity.

Keywords: Education Policy enactment
North Korean refugee students
North Korean youth education in South Korea
Refugee education
South Korea education policy
Unification Educators
Advisor: Portelli, John