VictorJuiz/thesis huggingface dataset:
Proteomic-based Signature of Brain-related Proteins as Novel Candidate Biomarkers for Alzheimer’s Disease Diagnosis
Keywords: Alzheimer's disease
Biomarkers
Cerebrospinal fluid
Mass spectrometry
Selected reaction monitoring

Alzheimer’s disease (AD) is the most common type of dementia characterized by the progressive memory loss and cognitive decline, with typical age of onset after 65 years. The main disease hallmarks include extracellular amyloid beta deposits and intracellular neurofibrillary tangles. Brain pathology is reflected in cerebrospinal fluid (CSF) where core biomarkers amyloid beta 1-42, total tau, and phosphorylated tau protein levels are changed relative to cognitively normal elderly. There is a need for novel disease-specific biomarkers that will capture disease more accurately and at an earlier stage, predict disease severity, and be used in research and clinical trial settings for patients’ enrichment and stratification or to monitor drug efficacy. The aim of the present dissertation is to evaluate diagnostic potential of brain-related proteins in CSF of AD patients. The study was focused on proteins with high specificity for brain tissue. Only proteins expressed predominantly in the brain and reliably identified in the human CSF proteome were selected for development of multiplex mass spectrometry-based assay. Candidate biomarkers were then evaluated in AD patients with different spectrum of disease severity and cognitively healthy individuals (in total 154 subjects). This exploratory study suggests APLP1 protein as a promising biomarker for early AD detection. Specifically, the protein was elevated in mild cognitive impairment compared to cognitively healthy individuals (p
The Immune Impact of Common Sexually Transmitted Viruses and the Vaginal Microbiota: Implications for HIV Susceptibility in African, Caribbean, and other Black Women from Toronto
Keywords: Female Genital Tract
HIV
Infectious Diseases
Mucosal Immunology
STI

Genital inflammation is a key determinant of human immunodeficiency virus (HIV) transmission and may increase the availability of HIV-susceptible target cells at sites of exposure. The African, Carribean, and other black (ACB) community is at increased risk of HIV acquisition in Toronto and several genital conditions that increase HIV risk are also more prevalent, including bacterial vaginosis, herpes simplex virus type-2 (HSV-2) and human papillomavirus (HPV) infection. Therefore, we assessed the impact of these three genital conditions on mucosal immune cells and cytokines in the female genital tract of ACB women. Endocervical cells and cervicovaginal secretions were collected by cytobrush and Instead Softcup, respectively. T cells and dendritic cells were assessed by flow cytometry, proinflammatory cytokines and chemokines by multiplex enzyme-linked immunosorbent assay (ELISA), and the microbiota by 16S ribosomal ribonucleic acid gene sequencing. HSV-2 infection was associated with elevated levels of endocervical HIV target cells (CCR5+ CD4 T cells), Lactobacillus-deficient microbiota was associated with elevated proinflammatory cytokines, prevalent HPV infection was associated with Lactobacillus-deficient microbiota, and HPV clearance was associated with higher numbers of Langerhans cells in the female genital tract. These results suggest multiple ways in which genital conditions are associated with factors that have been shown to influence HIV susceptibility and provides novel targets for future HIV prevention strategies.
Modeling and Analysis of Optical Blur for Everyday Photography
Keywords: aberration
calibration
depth from defocus
image restoration
optical blur

Optical blur obscures image detail due to the camera's optics. The blur appearance depends on the scene's depth, wavelength, as well as the camera. The inference of such information --- optical calibration, image deblurring, and depth estimation -- is of great interest to computer vision. Existing approaches make impractical assumptions about the camera and the scene, and are therefore restricted to lab settings. In this thesis, we propose novel optical blur models towards solving the above inference problems in everyday settings. First, we propose a practical model for lenses with monochromatic optical aberrations, assuming the aberrations can be fully described by Seidel aberrations. Although the model produces realistic 2D blur kernels of complicated appearance, it has very few parameters and thus can be estimated using very limited data. We show specifically that just three blur kernels contain enough information to estimate the lens parameters up to an aperture-dependent scale factor. Second, we study image deblurring for RGB-Infrared imaging. This problem is especially challenging since RGB-Infrared cameras suffer from inevitable chromatic aberration, channel crosstalk, and pixel multiplexing due to the color-filter-array. The coupling of the distortions are critical to deblurring quality but is non-trivial to invert efficiently. We propose a practical image formation model that captures all three distortions while enables fast restoration. Third, we develop an approach to two-frame Depth from Defocus (DFD) in everyday settings. The main challenge here is that the inter-frame motion needs to be estimated in addition to depth from just two images. We propose conditions to control the camera focus to guarantee near-optimal DFD estimation and a method to estimate depth and the motion jointly in local 9x9 patches. This allows us to capture sparse depth map even in non-rigid scenes. Fourth, we propose a method to fuse local DFD results into dense depth and flow maps. The noise, sparsity and ambiguities inherent in DFD makes this problem particularly difficult. We introduce a splined-based prior to enable fusion over great image distances and irregular shaped regions, and to allow explicit reasoning about figure-ground relationships. Our final results exhibits high quality results with crisp boundaries.
Trends and Outcomes of Carotid Artery Revascularization in Ontario, Canada: A Population-Based Analysis
Keywords: carotid revascularization
carotid stenosis
clinical epidemiology
health services research
stroke
vascular surgery

Introduction: Evidence for the safety and efficacy of carotid-artery stenting compared with endarterectomy is accumulating from randomized controlled trials. However, data on utilization trends and long-term outcomes of carotid revascularization strategies in real world practice are lacking. Methods: We first conducted a multicenter validation study to assess the accuracy of carotid-artery revascularization coding in Ontario health administrative databases. We then identified a retrospective population-based cohort of individuals who underwent carotid endarterectomy or stenting in Ontario, Canada (2002-2015). We used time-series analyses to examine temporal changes in the utilization rates of carotid revascularization procedures, and compared long-term (up to 13 years) and 30-day outcomes of carotid endarterectomy versus stenting overall and by operator specialty. Results: Carotid-artery revascularization procedures were coded with high accuracy in administrative databases (positive predictive value, 87-99%; sensitivity, 90-93%). Overall, 86% of patients underwent endarterectomy and 14% stenting. The rate of endarterectomy decreased by 36%, whereas carotid-artery stenting increased by 72% during the study period. Rate of the composite outcome of 30-day death, stroke or myocardial infarction plus any stroke during 13-year follow-up was higher with stenting (16.3%) compared with endarterectomy (9.7%) (adjusted hazard ratio, 1.57; 95% confidence interval, 1.43-1.73). In the endarterectomy group, the risk of 30-day stroke or death was higher among patients treated by non-vascular surgeons (4.0%) compared with vascular surgeons (2.9%) (adjusted odds ratio, 1.32; 95% confidence interval, 1.08-1.62). Operator specialty was not associated with adverse outcomes after carotid-artery stenting. Conclusions: Although the utilization of carotid-artery stenting has increased, stenting carries a 1.5-fold higher risk of long-term events compared to endarterectomy. Vascular surgeons appear to perform endarterectomy at the lowest event rates. While non-randomized, these results raise potential concerns about the interchangeability of carotid endarterectomy and stenting in the context of actual clinical practice, and may have implications for local referral practices and policies.
Promoting Financial Management Activities After An Acquired Brain Injury: Enhancing Assessment Evidence
Keywords: assessment
brain injury
cognitive impairment
finanial management
instrumental activities of daily living
measurement

The purpose of my dissertation was to provide guidance for evidence-based financial management assessment in acquired brain injury rehabilitation. The objectives were to (1) synthesize current financial management assessment instrument literature, and (2) qualitatively examine the real-world financial management actions and behaviours of adults with brain injury. I conducted three studies. In the first study I used systematic search and instrument content analysis methods to identify 88 different instruments that include financial management items. Of these, eight instruments were identified as being potentially advantageous to the comprehensive observation- based assessment of financial management. However, two areas of financial management were missing from these eight measures: budgeting and monitoring of spending. In the second study I used systematic assessment instrument review methods, including an evidence critical appraisal, to critique the eight select instruments identified in the previous review and content analysis. Five of the eight measures had moderate volumes of low-risk of bias evidence for construct validity (hypothesis testing); two instruments had limited evidence for test-retest reliability; and all instruments lacked content validity and responsiveness evidence. In the third study I used qualitative inquiry and grounded-theory methodology to develop the Financial Management Activity Process conceptual framework. This framework was created from interviews with adults with brain injury and close-others who help with financial activities. It highlights the use of personalized financial management strategies that account for the person, activity, and environment factors facilitating or limiting activity completion. Together, the studies highlight that current financial management instruments require more investigation prior to endorsement. Also, instruments’ need refinement to address all current relevant areas of financial management. Strategy use may be a salient consideration in developing new instruments, as it was relevant to the everyday financial management actions and behaviours of adults living with acquired brain injury. Further instrument development and research is needed.
Tablet Technology for Neuropsychological Testing and fMRI
Keywords: fMRI
Neuropsychological tests
pen-and-paper test
visual feedback of hand position

Abnormal behaviour may be a warning sign of underlying brain disease. Neuropsychological (NP) tests - behavioural tasks that very commonly involve handwriting and drawing - are widely used in the clinic to detect abnormal brain function in a variety of brain diseases. Task-based functional magnetic resonance imaging (fMRI), a method for noninvasively mapping the brain activity that underlies specific behaviours, can possibly help to inform use of NP tests, and to improve their sensitivity and specificity. Task-based fMRI typically involves peripheral devices that are used to present sensory stimuli and record behavioural responses. Such devices (e.g. video projectors, key pads for detecting button presses) must be designed for compatibility with fMRI procedures, including operation at the very high magnetic field of the MRI system without introducing electromagnetic interference. The common fMRI-compatible devices are insufficient for evaluating many NP tests, however. Consequently, an fMRI-compatible tablet, including a touch-sensitive surface, was developed in the Graham laboratory to enable fMRI studies of NP tests that involve writing and drawing responses. In its original prototype, the tablet did not enable individuals to see their hand while performing writing and drawing actions. This missing feature, termed “visual feedback of hand position” (VFHP), may make it difficult for certain patient populations to interact easily with the tablet during task-based fMRI. The interactivity of the tablet thus should be improved before proceeding to map the brain activity of specific NP tests. This thesis focuses on developing a real-time system to integrate VFHP with the tablet in an augmented reality display, including simple computer graphics to present visual stimuli and tablet responses, and merged streaming video of the hand as it manipulates a stylus during writing and drawing behaviour. First, the new tablet prototype is developed and validated in the context of a writing task that involves copying sentences, showing that tablet interactivity is enhanced when VFHP is included. Second, the prototype is used to perform the first characterization of the brain activity in a control population of young healthy adults as they perform a novel NP test that was specially designed to detect and evaluate writing impairments in patients with Mild Cognitive Impairment and Alzheimer’s Disease. Third, the impact of adopting the tablet with and without VFHP is studied for a group of young healthy adults as they undergo fMRI while performing the trail making test (TMT), an NP test that is commonly used to assess the frontal lobes of the brain. Finally, future directions of this research are discussed, including use of this new tablet technology to assess patients with brain diseases in task-based fMRI trials.
Ontology-based Context in Visualizations to Facilitate Sensemaking: Case Studies of Phenotype Comparisons
Keywords: Analytical Abstraction
Case Study
Collaborative Design
Hierarchy Comparison
Human Phenotype Ontology
Visualization

Visualization can help domain experts make sense of their data, but determining appropriate visual representations can be challenging because interpretation relies on tacit domain knowledge. Terminological ontologies explicitly formalize domain knowledge as concepts, entities, and relations that can be represented as a directed-acyclic graph (DAG). This DAG topology could aid sensemaking by visualizing data in the context of domain knowledge. Ontologies were developed to support computational analyses and their application to visualize ontology-annotated data for sensemaking has not been systematically explored. Ontologies define complex relationships between entities and the resulting DAG topology must be simplified to visually represent data. Since the relationships encode domain semantics, they could be leveraged to directly address analysis goals through visualizations that support comparisons and interpretation of patterns and trends. This work contributes Ontology-based Analytical Abstraction for Visualization (OAAV), an approach that uses a DAG representation to fuse ontology-annotated data with the relationships defined by a terminological ontology. OAAV supports existing ontology-based computational analyses, while also enabling transformations into a variety of structured representations for visualization (e.g., hierarchies, matrices, scatterplots, charts). OAAV contributes methods to unify disparate data observations (e.g., quantitative, non-quantifiable, timeseries), to simplify the DAG topology (e.g., breadth, depth), and to compute measures for analysis on data observations (e.g., similarity, relevance). These approaches were developed and refined through three case studies with medical domain experts studying phenotypes in genetic diseases. Resulting prototypes demonstrated that visualizations created with OAAV aligned with the mental models of domain experts, and helped them to perform visual comparisons and interpret patterns and trends. The prototypes developed using OAAV have helped medical domain experts characterize disease subtypes, identify anomalies in their data, and suggest terminological ontology improvements. The prototypes continue to be used by the domain experts, and one has contributed to a scientific publication in the medical domain. OAAV was designed based on a systematic exploration of applying ontology relationships to organize and encode ontology-annotated data for visualization in the biomedical domain. This unified approach could be applied to ontology-annotated data in other domains.
On the Generation of Rapid Eye Movement Sleep and the Reversal of Sleep-Related Hypotonia in Muscles of the Upper Airway
Keywords: acetylcholine
in-vivo
microdialysis
Pons
REM sleep
sleep apnea

Rapid eye movement (REM) sleep - characterized by vivid dreaming, motor paralysis, and heightened neural activity - is one of the fundamental states of the mammalian central nervous system. One of the major consequences of REM sleep is an augmentation of the muscle hypotonia that occurs throughout sleep. Hypotonia in muscles of the upper airway is a precipitating cause of obstructive sleep apnea (OSA): a prevalent syndrome characterized by repeated episodes of upper airway narrowing and closure that occur only during sleep. The studies described in this thesis aimed to: (i) identify the role of cholinergic input to the pontine subcoeruleus (SubC) region in the generation of REM sleep, (ii) determine the involvement of the ventrolateral periaqueductal gray (vlPAG) and deep mesencephalic reticular nucleus (DpMe) in the bistability of sleep, and (iii) identify pharmacological targets for the reactivation of the upper airway musculature throughout sleep. The data reported here will show that contrary to the prevailing hypothesis of cholinergic involvement in REM sleep, cholinergic input to the SubC does not induce transitioning into REM sleep but rather reinforces transitions after their initiation, making them quicker and less likely to fail. In a separate study, evidence is presented indicating that vlPAG/DpMe neurons, namely the REM sleep-inactive subpopulation, are not critical regulators of non-REM (NREM)-to-REM sleep transitioning. In contrast, the results of vlPAG/DpMe inactivation instead support a major involvement of REM sleep-active neurons in preventing breakdowns in sleep bistability specifically during REM sleep. Lastly, proof-of-principle is established that targeted blockade of certain potassium channels at the hypoglossal motor pool is an effective strategy for reversing upper airway hypotonia and causing sustained reactivation of upper airway muscles throughout NREM and REM sleep. These findings identify an important new direction for translational approaches to the pharmacological treatment of OSA.
THE ROLE OF KAT7-DEPENDENT INTRAGENIC HISTONE ACETYLATION ON ENDOTHELIAL CELL GENE REGULATION
Keywords: Chromatin
Endothelial Cells
Epigenetics
Intragenic Histone Acetylation
KAT7
Vascular Biology

Cellular identity is largely defined by a cell’s gene expression profile. Epigenetic mechanisms figure prominently in establishing endothelial cell (EC) gene expression profiles. Although their functional importance in EC-enriched gene regulation has been well characterized at their promoters, their role at the intragenic regions is not clear. Moreover, little is known of the epigenetic modifiers that are critical for EC gene expression. Here, we determined the histone acetylation profiles of select EC-enriched genes and identified a histone acetyltransferase (HAT) that establish these profiles. Specifically, we characterized the histone H3 and H4 acetylation profiles of 19 genes with EC-enriched expression via loci-wide chromatin immunoprecipitation followed by ultra high resolution (5 bp) tiling array analysis in ECs versus non-ECs throughout their genomic loci. Aside from observing differential EC enrichment of H3 and H4 acetylation at the most EC-enriched gene promoters, broad differential intragenic histone acetylation enrichment was surprisingly observed at select EC genes, especially VEGFR-1 and VEGFR-2. Importantly, VEGFR-2 and VEGFR-1 were upregulated in non-ECs by histone deacetylase inhibition. To determine the role of broad intragenic histone acetylation in determining the EC phenotype, we characterized the histone acetyltransferase KAT7. KAT7 was expressed ubiquitously and its protein level decreased in ECs subjected to fluid shear stress. Fluid shear stress may reduce KAT7 expression to promote an anti-inflammatory and vasodilatory state in ECs. Upon depleting KAT7 in human ECs, VEGFR-2 expression was reduced and their angiogenic potential was perturbed. Furthermore, microarray analysis of human KAT7-depleted ECs identified 279 differentially regulated genes (fold change ≥ 2, p ≤ 0.05), many of which are key for growth and angiogenesis. KAT7 depletion in zebrafish embryos disrupted vessel formation and caused loss of circulatory integrity, especially hemorrhage, all of which were rescued with human KAT7. Notably, EC-enriched gene expression, especially VEGFR-1 and VEGFR-2 homologs, was perturbed in these zebrafish embryos. Mechanistically, KAT7 localized to the human VEGFR-2 genomic locus and participated in its transcription by mediating Pol II binding, H3K14, and H4 acetylation in its intragenic region. Collectively, our findings reveal a previously uncharacteried role of intragenic histone acetylation and KAT7 in regulating EC gene expression and function.
Investigating the Role of EphrinB1 in the Control of Xenopus laevis Gastrulation
Keywords: Cadherin
Collective migration
EphrinB1
Fibronectin
Gastrulation
Xenopus

During animal development, the early embryo undergoes gastrulation to bring the primary germ layers into their definitive positions. The ancestral mode of vertebrate gastrulation can be studied using the African clawed frog Xenopus laevis. A core function of gastrulation is the movement of prospective endoderm from the surface to the embryo interior. In X. laevis, endoderm internalization is achieved through vegetal rotation, a tissue morphogenetic process that has only been characterized at the tissue level. I have investigated the cell and molecular basis of endoderm morphogenesis in X. laevis gastrulae to connect vegetal rotation with common mechanisms of germ layer internalization in other organisms. I characterized the arrangement, shape change, and migration of cells in the endoderm, and found that movement of vegetal endoderm cells located deep to the embryo surface represents an adaptation of mechanisms of monolayer internalization (namely, invagination and cell ingression) to the multilayer structure of the vegetal cell mass. Thus, this movement was termed “deep cell ingression”. Deep cell ingression integrates an amoeboid-type motility whereby cells propel themselves forward using strategic cell shape changes to move, but with different rates, a unique mode of intercellular migration where cells move with a common direction but at different velocities with respect to neighbouring cells to drive cell rearrangement during vegetal rotation. Despite their collective movement, endoderm cells are separated by a vast network of extracellular material. Cells are interconnected by stitch-like contacts, and cell migration requires the adhesion molecule C-cadherin, and the matrix protein fibronectin. A basic requirement for migration is that cells must detach to complete rearrangement, and in this regard, the leading cell resolves its contact with the following cell through trailing edge retraction involving ephrinB1-dependent macropinocytosis and trans-endocytosis. Beyond the endoderm, ephrinB1 is also required for the modulation of ecto- and mesoderm tissue cohesion.