VictorJuiz/thesis huggingface dataset:
Cancer Cartography – Three-dimensional Mapping of Tumours to Understand and Improve Nanoparticle Delivery

Nanoparticles offer a flexible platform for delivering therapeutic and diagnostic agents to solid tumours. Researchers have developed the ability to control the physical and chemical properties of nanoparticles enabling them to take on many different shapes, sizes and surface chemistries and carry a broad array of cargos. However, the interactions between the nanoparticles and biological environments form barriers that prevent nanoparticles from reaching their target site within thetumour which reduces their efficacy. A better understanding of these barriers is needed to understand how to improve nanoparticle delivery to solid tumours. Here, I develop a set of tools that utilize tissue clearing, three-dimensional (3D) microscopy and image analysis to study, map, and understand nanoparticle transport to tumours. First, I use these tools to identify a subset of tumour endothelial cells that govern nanoparticle transport into solid tumours. Nanoparticle transport endothelial cells (N-TECs) act as entry gates into the tumour controlling where and how many nanoparticles are allowed into the tumour microenvironment. Second, I use tissue clearing, 3D microscopy and image analysis to map and quantify nanoparticle delivery to metastatic tumours. I show that the delivery of nanoparticles to metastatic tumours is heterogeneous but related to the biological characteristics of the metastasis. I use the imaging data to develop a machine learning-based model to predict nanoparticle delivery given the characteristics of the metastatic tumours. Thirdly, I use 3D images of tumour blood vessel networks as a template to create a microfluidic device of the vessel networks. I use the 3D vessels to create a polydimethylsiloxane (PDMS) device that is seeded with endothelial cells. The devices can be used to study flow, perfusion, and endothelial cell interactions with drugs within the tumour vessel network. Through understanding the interactions between nanoparticles and tumours we will be able to better design and utilize nanoparticles for treating and diagnosing cancer.

Keywords: Cancer
Drug Delivery
Microscopy
Nanotechnology
Advisor: Chan, Warren CW
Theoretical and Experimental Advances in Studying the Ultrafast Dynamics of Atoms and Molecules

Ultrafast science is a rich scientific field with the goal of imaging, understanding and potentially controlling the fastest dynamical phenomena in nature. Due to the underlying complexity of this task the experimental and theoretical studies in this field are multifaceted and often require a diverse base of expertise. Any one experiment in this field relies on the proper functioning of a femtosecond laser source, and, additionally, an electron source for ultrafast electron diffraction. Furthermore, it relies on suitably prepared samples, and on expertise in both executing the experimental work and in carrying out the corresponding theoretical analysis. Through my involvement in a multitude of different projects I was fortunate enough to contribute to various aspects of the field. In this thesis I present the culmination of this work.Initially, a novel design for an electron gun is presented. This design enables producing high-density electron beams with a time resolution below 100 fs, in a table-top setup without relying on high power sources such as klystrons. Secondly, a proposal for a novel experiment, backed by theoretical analysis, is introduced. The theoretical analysis shows that using a specific femtosecond laser pulsing scheme, it is possible to observe, for the first time, a conical intersection signature directly using ultrafast electron diffraction. After that, we introduce a completely novel experimental method that has the potential to achieve two or three orders of magnitude higher time resolution than conventional methods. The method relies on controlling the time variable itself, for the first time in ultrafast science, which is possible through exploiting the relativistic effect of time dilation. A theoretical analysis along with a proposed experimental setup is presented. Following that, we report on experimental progress on the sample preparation side. We present methods for preparing water-soluble samples as well as samples, that are typically unstable under vacuum conditions, for electron diffraction analysis. Lastly, we report on the progress of employing deep learning algorithms to aid with the analysis of electron diffraction patterns. Specifically, we present a neural network architecture that predicts temperature changes in electron diffraction images of bismuth samples triggered by femtosecond laser pulses.

Keywords: Conical Intersection
Machine Learning
Quantum Chemistry
Relativity
Ultrafast Electron Diffraction
Ultrafast Science
Advisor: Miller, R. J. Dwayne
Sexual Competition among Females Leads to Shared Paternity and Female Ornaments: A Tale of Long Tails and Short Tails

When males invest in costly resources important for offspring production, such as paternal care or nuptial feeding, females may compete for access to these direct benefits. This can result in strong sexual selection on female ornaments that are attractive to males. Poorly understood are the conditions in which such sexually selected traits are adaptive in females, and whether these traits honestly or deceptively signal quality to choosy males. Further, female competition for critical resources that males provide may result in intense sperm competition and the potential for biased paternity, an outcome that is costly when investing males sire no offspring. In this thesis, I investigate sexual selection on female ornaments and the outcome of sperm competition (paternity success) using insects from two different orders, New Zealand “short-tailed” ground weta (Orthoptera: Anostostomatidae: Hemiandrus pallitarsis) and an eastern North American species: the long-tailed dance fly (Diptera: Empididae: Rhamphomyia longicauda). Both exhibit valuable male mating gifts and female ornaments, which apparently result from intense sexual selection. Using novel molecular methods to measure female mating success and paternity patterns, I increase understanding of such exceptional systems, which function as valuable tools to test theories of sexual selection and sex differences. In both study species, I find evidence of shared paternity among competing males, suggesting males gain some fitness regardless of mating order and/or the intensity of sperm competition. This may help to explain the evolution of large nuptial gifts when females mate multiply and males have little control over insemination. In the following chapters, I examine female ornaments in both of my study species. In ground weta, I show that females are subject to sexual selection, and those with longer ornaments (accessory organs) experience greater mating success. In dance flies, positive static allometry on female ornaments (tibial scales and abdominal sacs) suggests that these structures exaggerate condition to males, potentially reducing the costs of deception. While my findings are consistent with the basic predictions of sexual selection and parental investment theory, they suggest that the nature of sexual selection may differ in non-conventional systems where females compete for goods and services provided by males.

Keywords: female ornaments
microsatellites
nuptial gifts
polyandry
Sexual selection
sperm competition
Advisor: Gwynne, Darryl T
Systemic Factors Influencing the Remuneration and Utilization of the Surgical Workforce in Ontario, Canada

Background: A salary gap between male and female physicians has been demonstrated in many healthcare systems. A fee-for-service system, however, should theoretically be free of biases that lead to unequal salaries. It is unknown whether sex-based inequities in pay exist within fee-for-service models and how biases in the referral process contribute to inequities. Objective: To determine the magnitude of the sex-based pay gap in surgery and explore disparities in referrals to surgeons. Additionally, this thesis evaluates whether disparities are narrowing over time as more women enter surgery. Methods: We conducted three population based studies in Ontario, Canada using linked administrative databases housed at ICES. First, we used claims for surgical procedures submitted by surgeons (January 1, 2014-December 31, 2016) to compare earnings per hour spent operating to determine whether a sex-based pay gap exists in the fee-for-service system. Second, we analyzed referrals to surgeons over 20 years to examine the existence of and drivers for sex-based inequities in referrals and the influence of physician choice on disparities. Third, we compared the number of referrals to male and female surgeons across the length of their careers to examine whether disparities improved as female surgeons acquired experience, and examined temporal patterns to determine whether inequities were narrowing over time. Results: Within Ontario’s fee-for-service system, female surgeons earned 24% less per hour spent operating than male surgeons and more commonly performed procedures with the lowest hourly earnings. Male physicians demonstrated preferences for referrals to male surgeons, even after adjustment for patient and surgeon characteristics. Disparities did not narrow over time and existed across all levels of experience of female surgeons. Conclusions: Despite assumptions that a fee-for-service system can close the sex-based pay gap and that increasing entry of women into medicine will naturally correct existing inequities, this thesis demonstrates this not to be the case. Female physicians do not receive equal pay for equal time spent working and systemic disparities, such as referral bias, continue to propagate sex-based inequities in medicine. These inequities can have significant financial and career development consequences for women in medicine and require focused efforts for their mitigation.

Advisor: Baxter, Nancy N
Fostering Global Norms of Research Excellence: National Policies and Strategic Responses of Public Universities in Central and Eastern Europe

The history of higher education in Central and Eastern Europe goes back to medieval times when the first universities were established in the early XIV century. During the industrialization period, a wide range of technical universities emerged in the region, while the fall of the communist regimes further fuelled the rise of new regional public universities there. Currently, this region provides a diverse set of public universities that vary in their histories, traditions, foundational rationales, etc. Unprecedented openness of Central and Eastern European countries to external norms and concepts following the collapse of the Soviet Union offers a unique research context to investigate the diffusion and local interpretation of global norms.By examining the national policy interpretations of global research excellence norms in Poland, the Czech Republic and Ukraine, and the role of university organizational identities in shaping their strategic responses to these norms, this study makes an important contribution to our knowledge of universities as organizers of their institutional environments, bridging two fundamental approaches to universities as enactors of broader social norms seeking legitimacy and as strategic actors pursuing unique organizational goals. Theoretically, this study explores how the combination of new institutionalism and resource dependence theory through the lenses of Oliver’s strategic responses framework in conjunction with the literature on organizational culture and identity could explore the phenomenon of university research excellence at three levels: macro (global), meso (national), and micro (organizational). Drawing extensively from 38 interviews with policy experts and university leaders and supplemented by document analysis, my findings provide a richer understanding of the interplay between the diffusion of global norms in national contexts as well as the role of national specificities and organizational attributes in shaping diverse organizational responses across the three national contexts and the nine universities. As the first study of diverse public university types and the repertoire of their strategic responses to research excellence norms in Central and Eastern Europe, my thesis contributes to filling the gap in the mainstream literature by including the universities from the outside of “the global core” in the scholarly discussion on university research excellence.

Keywords: Central and Eastern Europe
organizational change
research excellence
strategic responses
Advisor: Sá, Creso CS
Cortical Gyrification Morphology in Neurodevelopmental and Psychiatric Disorders

The formation of cortical gyrification in early brain development remains a perplexing phenomenon in the field of neuroscience. The important roles of both genetic and environmental factors are evident in cortical gyrification morphology. With the aim of enhancing our knowledge regarding cortical gyrification morphology, we investigate cortical gyrification in neurodevelopmental conditions with largely genetic bases (Autism Spectrum Disorder, ASD, and Attention Deficit Hyperactivity Disorder, ADHD) as well as in a psychiatric condition characterized by a pathological response to traumatic stress (Post-Traumatic Stress Disorder, PTSD). This general aim is achieved through three separate manuscripts including a thorough qualitative (24 ASD and ADHD studies) and quantitative (n=977, from 10 ASD studies) syntheses of ASD and ADHD cortical gyrification literatures, an examination of local degrees of cortical gyrification (local Gyrification Index, lGI) in a large sample of male and female children and adolescents with ASD and ADHD relative to typically developing peers (n=539, 6-17 years of age) and an investigation of local degrees of cortical gyrification (lGI) in stress-exposed adult active service men with and without PTSD (n=44, 26-48 years of age). We found cortical gyrification atypicalities in individuals with PTSD relative to those without PTSD but no significant differences in cortical gyrification between individuals with ASD and ADHD and typically developing controls. The PTSD finding is suggestive of plasticity of cortical gyrification following an environmental risk factor likely in individuals who may have other pre-existing or post-PTSD risk factors. The findings from the study of neurodevelopmental disorders under investigation may be suggestive of either the lack of involvement of the genetic risk factors of ASD and ADHD in cortical gyrification morphology or alternatively that the highly heterogeneous natures of these disorders prohibit the identification of such associations in small and more homogenous subgroups.

Keywords: ADHD
ASD
local Gyrification Index
MRI
Neuroimaging
PTSD
Advisor: Anagnostou, Evdokia
Assessing Frailty Using Sensors and Machine Learning in Home Settings

Frailty is a condition in which the individual is in a vulnerable state at increased risk of adverse health outcomes or dying when exposed to a stressor. Frailty can increase dependence and decrease the quality of life for older adults and family members. Early identification of frailty can reverse or delay the development of frailty. However, it is challenging to identify frailty early in clinical settings due to its hidden and gradually progressing nature, which is more reflected in daily life than during clinic visits. The recent development in sensors and artificial intelligence enables remote health sensing and advanced data analytics, allowing early identification of frailty by monitoring frailty indicators reflected in older adults' daily lives. The overall goal of this thesis is to design, develop and validate a multi-sensor-based system for assessing frailty in home settings. To achieve this goal, we first conducted a systematic review and a focus group study to understand gaps in home-based frailty screening technologies and older adults’ opinions on potential technologies. Guided by the review and focus group findings, a novel multi-sensor-based frailty monitoring system, Frailty Toolkit, was developed. The concurrent validity of the sensor measurements was validated. Additionally, machine learning algorithms were implemented on a large health survey dataset with more than 27,000 samples to classify frailty using the behavioral and physical health features. As a result, the system prototype showed excellent concurrent validity for all ambient sensors but the weight scale in lab tests. The gradient boosting classifier yielded the highest area under the receiver operating characteristic curve (0.95) for classifying frailty. The highest area under the precision-recall curve of 0.70 achieved with the gradient boosting classifier was a significant improvement over a no-skill classifier. In conclusion, this thesis developed and validated a multi-sensor-based system and machine learning models for assessing frailty in home settings. The proposed system is unique because it involves older adults’ voices in the design process and measures a novel set of behavioral and physical health signs of frailty using less invasive ambient sensors. This work has significant implications for home-based frailty assessment.

Keywords: Frailty
Home
Internet of Things
Machine Learning
Sensor
Telehealth
Advisor: Mihailidis, Alex
Diversity, Relative Abundance, and Functional Potential of Viral and Bacterial Communities

Viral and bacterial communities in Hamilton Harbour were explored to discern seasonal and spatial changes in diversity, relative abundance, and functional potentials. The following chapters describe findings derived from metagenomic sequencing and analysis of environmental DNA using a variety of techniques. In the study outlined in Chapter 2, virus diversity and relative abundances were found to be highly variable over small spatial scales. Virophages were often the most abundant group, and discrete virophage taxa were stable despite fluctuations in Mimiviridae community composition. Diverse and distinct Mimiviridae populations were detected, suggesting that Mimiviridae are important algal viruses. The results from Chapter 3 demonstrated that several insights into virus diversity, relative abundances, and host inferences are lost by the common practice of filtering water samples to separate viruses from cells prior to DNA extraction and sequencing. Many viruses of eukaryotes, such as Mimiviridae, Phycodnaviridae, Iridoviridae and Poxviridae, were detected exclusively in the often-disregarded larger size fractions, while higher Caudovirales diversity was captured by the smaller size fractions. Cyanophages were more abundant in the larger size fractions, which may indicate replication within cells during ongoing infections. Analysis of either size fraction alone provides only a partial perspective of dsDNA viruses in the environment, highlighting the need for more comprehensive approaches for metagenomic analyses of aquatic viruses. Unlike the virus communities, the results from Chapter 4 revealed that bacterial communities were similar at different sites within the harbour and demonstrated strong seasonality regarding taxonomy and functional potentials. Some functional categories were highly variable while others were stable, suggesting the presence of generalist gene categories that are always essential versus specialist gene categories that fluctuate based on selective pressures. The results presented in this thesis expand the documented diversity of freshwater viruses and abundant Cyanobacteria in Hamilton Harbour, providing the first observations of highly abundant and potentially ecological important virophage, Mimiviridae, and Limnoraphis robusta populations. Ultimately, this work revealed seasonal and spatial dynamics in microbial community diversity, relative abundances, and functional potentials that can be used to inform ongoing monitoring and remediation efforts in Hamilton Harbour and likely apply broadly to other temperate freshwater lakes.

Keywords: Algal Viruses
Cyanobacteria
Great Lakes
Hamilton Harbour
Metagenomics
Nutrient Metabolism
Advisor: Short, Steven M
Human Papillomavirus (HPV) Vaccination Among Gay, Bisexual, and Other Men Who Have Sex with Men and Men Living with HIV

Gay, bisexual, and other men who have sex with men (GBM) and men living with HIV are disproportionately affected by HPV compared to the general population. The Canadian National Advisory Committee on Immunization recommends HPV vaccination for all GBM and people living with HIV. Starting in 2015, some of the Canadian provinces and territories began introducing publicly-funded HPV vaccination programs for GBM ≤26 years old and people living with HIV. Four research objectives were developed to 1) determine the uptake of vaccination programs and national recommendations, and 2) identify key barriers that need be overcome to increase vaccine coverage. Two data sources were used to address these objectives: a sample of 1677 older men living with HIV from the Ontario HIV Treatment Network Cohort Study (OCS) and a community-recruited sample of 2449 GBM from Vancouver, Toronto, and Montreal from the Engage Study. The first two objectives quantified and determined factors associated with HPV vaccine initiation. The last two objectives explored the association between social and programmatic barriers and facilitators and a multi-stage cascade of vaccine uptake where vaccine awareness and willingness to get vaccinated were considered among unvaccinated men. Only 7% of men living with HIV from the OCS had initiated vaccination. Among GBM from the Engage Study, 26-35% of men ≤26 years old and 7-26% of men ≥27 years old across the cities had initiated vaccination. There were clear social inequities among unvaccinated older men ineligible for publicly-funded vaccine, such as lack of insurance coverage and lower socio-economic status (SES), and lower initiation was seen among Latin American GBM and racialized men living with HIV. Among GBM, accessing sexual healthcare services was associated with vaccine initiation. GBM unaware of the HPV vaccine or undecided/unwilling to get vaccinated faced many barriers to vaccination, such as sexual orientation non-disclosure, not accessing healthcare, and lower SES. The combination of barriers experienced differed across cities and subgroups of men, suggesting the need for tailored interventions. To increase vaccination coverage in these populations, increasing knowledge of the vaccine, and reducing social inequities and barriers introduced by publicly-funded program eligibility requirements should be a priority.

Keywords: Gay bisexual and other men who have sex with men
HIV
Human papillomavirus
Men living with HIV
Vaccination
Advisor: Burchell, Ann N
Deeks, Shelley