VictorJuiz/thesis huggingface dataset:
Site-specific Antibody-Polymer Conjugates Synthesized by Enzymatic Methods
Keywords: antibody conjugates
bioconjugation
drug delivery
enzyme
radioimmunotherapy
site-specific conjugation

Antibody conjugates have typically been prepared by random conjugation to lysine amino groups. However, the effects of antibody conjugation remain unclear and are difficult to predict. Site-specific conjugation methods that control the conjugation site have yielded antibody-polymer conjugates with improved properties compared to their analogue prepared by random lysine conjugation. The preparation of site-specific antibody-polymer conjugates is challenging, as few methods are suited for conjugating large payloads with multiple chemical functionalities. My studies focused on developing a method to prepare site-specific antibody-polymer conjugates using microbial transglutaminase (mTG) and characterizing these conjugates. I also applied an existing method, SiteClick™ conjugation, to prepare conjugates for in vivo studies.In Chapter 3, I describe the synthesis and characterization of 11 polyglutamide-based polymers, including metal-chelating polymers (MCPs) for developing a conjugation method based on mTG, and for use with SiteClick™ conjugation. These polymers also included a series of D-enantiomers to examine the enantiopurity of the polyglutamide MCP. In Chapter 4, I describe a method to site-specifically conjugate polymers to proteins using mTG. I describe the conjugation of an H2N-PEG-oligonucleotide and MCP to two antibody fragments, a VHH fragment that binds to programmed death ligand 1, and a Fab fragment that binds to frizzled-2. For the Fab conjugates, the conjugation site was characterized by mass spectrometry experiments which confirmed that the mTG conjugation was site-specific. In Chapter 5, I examined the properties of conjugates prepared by site-specific mTG conjugation and random lysine conjugation. I analyzed for changes to various properties by differential scanning fluorimetry, biolayer interferometry, and cell-binding assays. The site-specific conjugate showed high affinity to the antigen and ca. 4-fold lower non-specific binding to two cell lines compared to the random conjugate. Site-specific conjugation appeared to reduce non-specific binding associated with random lysine conjugation of the polymer. In Chapter 6, I describe experiments that investigated the SiteClick™ method to conjugate an MCP to a therapeutic antibody, Panitumumab, to test whether biodistribution is improved. I optimized the method and overcame purification issues found in previous attempts to conjugate related polymers. I also analyzed the results obtained with our collaborators and compared them to previous results.
A Search for the H mm Decay and a Measurement of the Mass of the Higgs Boson using H- 4l Events with 139 fb-1 of Proton-proton Collision Data Collected by the ATLAS Experiment
Keywords: ATLAS Detector
Higgs boson
Large Hadron Collider

Using a dataset collected with the ATLAS detector during run-2 of the Large Hadron Collider, a search for the decay of the Higgs boson to two muons and a measurement of its mass are presented. Common to both measurements, an overview of the theoretical background, the Large Hadron Collider, the ATLAS experiment and particle reconstruction algorithms is provided. When the work in this thesis was performed, no evidence for the H ! μμ decay had been observed. The search presented in this thesis uses multivariate classification algorithms to classify events and maximize the expected statistical significance of the result. A signal excess of 2.0 was measured when testing the background-only (no H ! μμ) hypothesis and the signal strength was found to be in agreement with the Standard Model prediction, to within statistical and systematic uncertainties. The measurement of the Higgs boson’s mass was performed using H ! 4l events. Although the measurement of the Higgs boson’s mass has been performed in the same channel by the ATLAS collaboration in the past, the run-2 dataset used in this thesis is approximately four times larger than before, which is expected to reduce the uncertainty by a factor of two. The measurement uses multivariate machine learning techniques to discriminate signal and background events and exploit the inhomogeneous resolution of the ATLAS detector. The measurement is yet to be performed on data, but the expected uncertainty is ± 0.19 (± 0.18 Stat only) GeV.
Colloidal Quantum Dot Surface Modification for Emerging Optoelectronic Applications
Keywords: Materials science
Optoelctronics
Photodetector
Quantum dot
Solar cell
Surface modification

Colloidal quantum dots (CQDs) have received attention for their potential in optoelectronic applications. Their solution-processing and tuning beyond silicon offer an alternative to standard crystalline materials and enable integration with numerous substrates, including flexible ones. In this thesis I seek to modify the CQD surface to improve CQD transport and device performance.I begin by studying the limitations in the best prior PbS CQD solar cells, finding that inefficient charge collection limits performance. I found this is caused by a chemical alteration of the active layer following the deposition of the hole transport layer (HTL) using the standard thiol-based ligand exchange. I then develop a new ligand exchange, obtaining a novel HTL material, chemically orthogonal to the underlying active layer, which minimizes interface defects and improves the charge collection probability at the back interface from 50% to ~100%. Improved transport enables increased fill factor and solar cell efficiency (from 12.2% to 13%). Next, I study the effect of the defects in the HTL: the rapid thiol-based HTL ligand exchange causes agglomeration, defects and incomplete passivation. I develop a kinetically-controlled exchange via solvent engineering, improving passivation and order in the final solid, resulting in 13.3% solar cell efficiency (vs. 12.5% for standard device). Finally, I apply the knowledge gained on surface modification to infrared CQD photodetectors. At the time I started my Ph.D., infrared PbS CQD photodetectors failed to combine quantum efficiency, sensitivity and speed and the external quantum efficiency in the IR was limited to 15%. I found that the CQD shape, determined by synthesis thermodynamic, is responsible for weak coupling, detrimental for device performance. I employed colloidal atomic layer deposition to rationally modify the CQD surface and obtain a shape not achievable with synthesis alone, favoring CQD coupling. The resulting CQD solids show one order of magnitude increase in hole mobility, resulting in 70% external quantum efficiency in the IR (vs. 45% for standard device), and record-performing solution-processed short-wavelength infrared photodetectors. The studies in this thesis improve the understanding of CQD surface, surface modification and its effect on transport, offering routes to improve CQD optoelectronic device performance.
Exploring STEM in a University Outreach Setting
Keywords: constructionist
engineering education
funds of knowledge
outreach
STEM education
third space

STEM literature has proliferated in recent decades. However, few studies consider the setting of university-based STEM outreach programs - programs that negotiate the border of informal and formal learning. In this ethnographic case study, I explore a STEM summer camp at a large Canadian university via two cohorts of learners: (15 elementary school age) campers and (14 undergraduate and graduate student) instructors. The research questions ask: What are the motivations for participating in a university STEM outreach program? How do participants perceive or understand STEM, and its purposes, in a university STEM outreach program? How do participants experience teaching and learning in a university STEM outreach program? Data collection methods included semi-structured interviews, questionnaires, reflections, observations, artifacts, and images. Inductive and deductive analysis are used to identify thematic categories. The findings identify similarities in the interests and aspirations of cohorts that underpin common experiential, preparatory, and learning motivations. Both cohorts are motivated to learn about science and engineering; instructors anticipate teaching. Perceptions of STEM prioritize and conflate science and engineering and view STEM as providing an understanding of the world, affecting change, and serving personal goals. STEM is seen as interdisciplinary, with engineering design informing how it is organized, described, and conveyed. STEM is characterized as hands-on, fun, easy, and broadly transferrable. It is positioned as a reciprocal fund of knowledge; a fund of experience that is built, valued, and leveraged. The facilitation of teaching and learning in the outreach program includes tending to the management of the physical camp space, the relational camp space, and leading hands-on, design-oriented activities. Findings suggest that the outreach program is a site of learning shaped for and by its participants. STEM learning is mediated through engineering design and constructionist approaches that prioritize participant funds of knowledge, in a meaningful third space. This offers a reconceptualization of STEM where engineering is present as content, context, and pedagogy; a perspective that broadens and deepens the connections to be made across practices in outreach, engineering, and education so critical to this work. The thesis concludes with implications and recommendations for theory and practice.
Outcomes and Management of Type 2 Diabetes in India and China
Keywords: cardiovascular disease
China
hospitalization
India
prognosis
type 2 diabetes

Nearly half of all the adults with diabetes worldwide live in India and China. This thesis examines various aspects of the management and outcomes of type 2 diabetes mellitus in these populations. In India, the objective was to examine the associations between diabetes and cardiovascular mortality (due to ischemic heart disease and stroke), and between self-reported medication use and cardiovascular mortality among adults with diabetes (with or without comorbid hypertension), in a nationally representative population of India. In Hong Kong, China, the objectives were to determine how age at diagnosis and modifiable risk factors affect hospitalization rates, glycemic exposure, glycemic deterioration, and responses to oral glucose-lowering drugs. In India, diabetes was associated with double the odds of ischemic heart disease mortality and increased odds of stroke mortality. Medication use was associated with lower odds of ischemic heart disease mortality and stroke mortality in high-burden states among people with diabetes and hypertension, with no significant association among people with diabetes alone. In Hong Kong, people with young-onset type 2 diabetes had the highest hospitalization rates, and that 36.8% of bed-days before age 40 years were attributable to mental illness. The adjusted rate ratio of hospitalization was increased in young- versus usual-onset type 2 diabetes for hospitalizations due to any cause, renal causes, diabetes-related causes, cardiovascular causes, or infection. Based on model estimates, intensified risk factor control in young-onset type 2 diabetes was associated with a one-third reduction in cumulative bed-days from diagnosis until age 75 years. people with young-onset type 2 diabetes had a higher mean A1C throughout the lifespan. The cumulative glycemic exposure was >3 times higher for young-onset versus usual-onset type 2 diabetes. Younger age at diagnosis was associated with faster glycemic deterioration, while age at diagnosis ≥60 years was associated with glycemic improvement. Responses to oral glucose-lowering drugs differed by age at diagnosis. Those with young-onset type 2 diabetes had smaller A1C decrements for metformin-based combinations versus usual-onset type 2 diabetes, but greater responses to other combinations containing sulfonylureas. These findings call for better strategies and further research to improve diabetes management and outcomes in India and China.
Factors Influencing Service Engagement of Youth in Services for Concurrent Disorders: A Mixed-methods Approach
Keywords: concurrent disorders
treatment
youth

Objective. Despite the high prevalence and negative impacts of co-occurring substance use and mental health problems (i.e., concurrent disorders) among youth (ages 14 to 24 years), the dearth of evidence-based and developmentally appropriate services for youth with concurrent disorders, and high rates of discontinuing services early among this population, little research has focused on understanding their service engagement. This dissertation employed a mixed- methods approach to understand a broad range of factors influencing engagement of youth in services for concurrent disorders. Quantitative Study. This investigation examined service engagement, as defined by attending at least five sessions, to understand how engagement changes across service stages and what client-related factors predict engagement. Three hundred and two youth presenting to an outpatient concurrent disorders service completed questionnaires investigating a variety of factors. Those found to be positively associated with service engagement included greater challenges with anxiety, depression, trauma, substance use, and emotion regulation. Identifying alcohol as the only substance of concern was negatively associated with engaging in services. Qualitative Study. This investigation allowed for a broader and more in-depth understanding of service engagement by considering client as well as service-related factors. Qualitative data were gathered from semi-structured interviews with 20 youth who had attended or were attending outpatient services for concurrent disorders. Thematic analysis revealed that youth consider engagement to be expressed in a variety of ways including attendance, participation in sessions, and actions taken between sessions. Factors – including social relationships, mental health and/or substance use challenges, readiness to change, treatment approach, and clinician characteristics – influenced service engagement. Conclusion. Youth engagement in services for concurrent disorders is more complex than just attending sessions. Behaviours during and between sessions are also important. Service engagement among this population is impacted by a variety of factors, including youth’s perspectives of services and their mental health and/or substance use challenges. It is critical that early service delivery efforts seek to understand the needs and preferences of youth in order to individualize services and promote engagement. Continued research should focus on factors influencing service engagement to help establish best practices for youth in services for concurrent disorders.
Origin of Disease Heterogeneity in BCR-ABL1 Lymphoblastic Leukemia
Keywords: Acute lymphoblastic leukemia
BCR-ABL1
Cell-of-origin
Disease heterogeneity
Genomics
Transcriptomics

BCR-ABL1 positive acute lymphoblastic leukemia (ALL) is an aggressive subtype of ALL that commonly appears in adults. Introduction of tyrosine kinase inhibitors into frontline treatments has significantly improved outcomes; however, the disease still frequently relapses and becomes refractory to targeted therapy. To understand this phenomenon, an in-depth genomic investigation, including RNA-sequencing (RNA-seq), single-cell RNA-seq, and whole-genome sequencing (WGS), of BCR-ABL1 ALL was performed. First, RNA-seq analysis identified three distinct molecular subgroups within BCR-ABL1 ALL. The first subgroup expressed higher levels of stem/myeloid genes, phenotypically resembled early-pro-B cells, and was termed ‘Aberrant Stem and Myeloid’ (ASM). The ‘Core B-lymphoid 1 and 2’ (Core-B 1/2) subgroups expressed higher levels of B-lymphoid genes and resembled pre-pro-B/pro-B cells. Clinically, ASM and Core-B 2 patients showed slower rates of achieving remission, higher relapse rates, and worse overall survival than Core-B 1. Single-cell RNA-seq revealed that ASM leukemias are highly heterogeneous and consist mostly of dormant cells, which could contribute to resistance against cytotoxic agents. Second, WGS analysis found that ASM subgroup was enriched for inactivation of HBS1L, RUNX1, and EBF1 genes, whereas Core-B 1/2 were enriched for inactivation of PAX5 and CDKN2A/B. Core-B 2 was uniquely defined by homozygous losses of IKZF1. Most focal deletions in all three subgroups were generated by RAG-mediated recombination. Tracking mutations in hematopoietic precursors and in diagnosis/relapse pairs supported that subgroups arose through secondary, stage-specific inactivation of B-lineage factors. Third, the integrated genomics approach was adapted to detect cryptic genomic lesions in complex karyotype acute myeloid leukemia. While complex karyotype leukemia is often considered a single entity, individual leukemias harboured unique driver events, such as gene fusions. Therefore, genomic analysis can effectively complement conventional cytogenetics in leukemia diagnosis. In summary, transcriptomic and genomic investigations reveal that human leukemias consist of heterogeneous subgroups that arise from acquisition of distinct genetic lesions.
The Making of Urban Knowledge: Ideas, Cities, Gurus
Keywords: Creative Cities
Globalization
Public Art
Science and Technology
Sociology of Ideas
Urban Studies

In the face of severe political, economic and environmental crises at the urban level, cities have been seen in recent decades not only as the place where these problems are created, but also as the location where they could be solved. This construction of cities as sites of both crisis and opportunity is related, at least partly, to the work of urban experts, transnational organizations, professional networks, and local agencies taking part in developing and connecting cities with ‘big ideas’ like Resilient Cities, Smart Cities and Creative Cities. To examine the making of such ideas, this dissertation develops the theoretical model of the Urban Knowledge Making Triangle, joining together three different units of analysis - Ideas, Cities, and Agents. The triangle calls to investigate how the ‘same’ idea varies over time and across places, how cities use the idea to depoliticize and re-politicize local struggles, and how human agents connect cities with the idea. To demonstrate the approach, I focus on the Creative City paradigm, which describes the shift that cities took when adjusting their economic industrial base to the information age. It also offers a formula to recover from the urban decline that many cities experienced during post-industrialization. The Creative City long-life cycle and flexible formula which is applicable to cities of different sizes and geography, make its local translations vary extensively. I use fieldwork methods to examine the making of the Creative City in Jerusalem and Toronto and the role of Richard Florida in connecting the two cities with the idea; I also use Structural Topic Modelling to draw the broader contours of arts and culture discourses using a policy corpus of the largest 26 cities in the Anglo-Saxon world. The findings demonstrate the dialectic relationship between the construction of cities as sites of crises and as sites of opportunities.
Technology to Support Informal Caregivers: Matching the Tools to the Needs from a Sex and Gender Perspective
Keywords: Caregiving
Diversity
Gender
Older Adults
Technology

Caregiving can be highly stressful and associated with poor mental and physical health. Technologies, including mobile and e-health applications, have been developed to address caregiver needs. Yet, although caregiving is a gendered activity, sex and gender considerations have not been incorporated systematically in understanding caregiving experiences and the design of these technologies. As such, this thesis aims to develop a tool to assist in the development of technology interventions to support caregiving by (1) synthesizing evidence on sex and gender distinctions in caregiving experiences and its physical and mental health impacts on informal caregivers, (2) examining caregiver’s knowledge, use, perceived usefulness and feature preferences of technology, and (3) exploring sex and gender influences on technology use and perceptions amongst informal caregivers. Findings from each objective are used to inform tool development. The thesis was based on three studies. The first study, a systematic review on sex and gender distinctions in caregiving experiences and its impact on informal caregivers’ physical and mental well-being, found 13 studies reporting higher caregiving burden among female caregivers. Results from the second study, a secondary analysis of a cross-sectional survey on technology needs and preferences of informal caregivers, revealed that most caregivers did not know much and had never used any technologies to assist with caregiving. Female respondents were more likely to have more knowledge about technology for caregiving while male respondents were more willing to pay higher amounts for these technologies. Findings from the third study involving semi-structured interviews with informal caregivers and technology researchers, highlighted the multi-faceted role technology can play in aiding caregiving, while at the same time draw attention to the pitfalls and drawbacks of these technologies perceived by caregivers. Together, the findings lead to the creation of the CareDATA (Caregiving Diversity and Technology Assessment) tool. It provides key considerations for incorporating sex, gender and diversity when developing technologies for caregiving. Overall, this thesis highlighted the complexities of sex, gender and diversity within the field of both caregiving experiences and technologies and represents a robust step towards the realization of more tailored technological solutions to support informal caregivers.