VictorJuiz/thesis huggingface dataset:
Targeting IgV-like Domain Immune Checkpoint Receptors with Novel Nucleic Acid and Protein-Based Therapeutics
Keywords: Aptamer
Autoimmunity
Immunomodulation
Immunotherapy
Inflammation
Oncology

The immune system is heavily regulated by negative checkpoint pathways; a network of cell signaling events governed by immune inhibitory ligand-receptor interactions. Physiologically, these negative checkpoint pathways are crucial for maintenance of self-tolerance in peripheral tissues. These pathways are often usurped by tumors as a mechanism to dampen anti-tumor immune responses. Clinically, the targeted blockade of PD-1:PD-L1 and CTLA-4:CD80/86 checkpoint ligand-receptor interactions using monoclonal antibodies has proved to be a viable means to provoke effective and durable anti-tumor responses. Conversely, agonists that stimulate these natural immunoinhibitory signaling pathways could potentially serve as immune-suppressants for treating patients with inflammatory and autoimmune disorders. The central theme of this thesis was to derive novel biotherapeutics that agonize or antagonize clinically-relevant checkpoint receptors. Specifically, the thesis focuses largely on targeting checkpoint receptors with short, single-stranded oligonucleotides, termed DNA aptamers, which bind molecular targets with affinity and specificity rivalling that of monoclonal antibodies. As a proof-of-principle, I first describe the derivation of DNA aptamers which bind to murine PD-1 and antagonize the PD-1:PD-L1 pathway to release anti-tumor immune responses and suppress the growth of a murine colon carcinoma tumor implant in-vivo. Second, I report the development of aptamers that bind to CD200R1 and agonize this inhibitory receptor. Strikingly, these anti-CD200R1 agonists were found to act as strong immunosuppressant’s in mouse models of transplant rejection and allergy. Lastly, I described the engineering of a novel multimeric fusion protein, consisting of the extracellular IgV-like domain of the checkpoint ligand VISTA, fused to a short helical pentamerization domain derived from the cartilage oligomeric matrix protein. This soluble agonist readily inhibited T-cell activation in-vitro, and suppressed inflammation in models of transplant rejection and autoimmune hepatitis. Notably, this construct represents the first agonist targeting the as-of-yet discovered VISTA-receptor to stimulate immunoinhibitory signaling in-vivo.
Examining host specificity of Chrysochus spp. (Coleoptera: Chrysomelidae) to inform management of invasive dog strangling vine Vincetoxicum rossicum (Apocynaceae)
Keywords: biological control
Chrysochus spp.
invasive species
novel associations
Vincetoxicum rossicum

Native insects have the capacity to form novel associations with invasive plants, which in some cases may allow them to exploit the invaders as hosts. To date, little work has been done to predict these novel associations and their outcomes before they occur. By conducting host-specificity tests on native North American Chrysochus spp. (C. auratus, C. cobaltinus, and their hybrid) with the European invasive vine, Vincetoxicum rossicum and North American Apocynaceae plants, this thesis: (1) addresses the question as to whether native Chrysochus spp. will form a novel association with the vine; (2) predicts the outcomes of such an association; (3) suggests ways to improve the potential biotic resistance of these beetles to reduce the spread of this vine; (4) compares host specificity results of these North American beetles with their European congener C. asclepiadeus, in order to enhance predictions of its ecological host range. Feeding, survival, oviposition, and development tests with North American Chrysochus at all life stages demonstrate: (1) V. rossicum may act as an ovipositional sink for eastern C. auratus; (2) the vine could be a source of food for C. cobaltinus when the plant expands its range westward; and (3) Chrysochus hybridization will not increase use of this invasive vine. In addition, host-specificity tests conducted here show that C. auratus, which does not feed or develop on Asclepias spp. in its natural ecological host range, will complete development on plants in this genus when exposed under lab conditions. This false positive for host plant specificity suggests that, in this genus, the predicted ecological host range of the European congener (C. asclepiadeus) of the two North American species may have been overestimated. Overall, my findings highlight: (1) the importance of predicting novel associations before they occur in the field; (2) demonstrate how the testing of native relatives of biological control candidates can enhance ecological host-range predictions for classical agents; and (3) increase our knowledge about the potential outcomes of novel associations between introduced V. rossicum and North American Chrysochus spp.
Coexistence in a warm and patchy world
Keywords: Climate change
Dispersal
Metacommunity
Milkweed
Priority effects
Warming

For the many species that rely on patchily distributed resources, patterns of coexistence and diversity are the product of local abiotic and biotic interactions and inter-patch dispersal. Understanding the multi-scale drivers of coexistence in patchy landscapes has become increasingly pressing, as habitat fragmentation makes the world patchier, and warming threatens to disrupt biological processes across spatial scales. In my thesis, I use meta-analytic, observational and experimental approaches to understand how local species interactions and dispersal shape diversity in patchy landscapes, and how warming disrupts these dynamics. In Chapter 1, I review metacommunity experiments to identify when common experimental approaches that homogenize metacommunities fail to test existing theory, and outline how emerging theory on the invasion criterion, food webs and priority effects could be used to help reveal the mechanisms underlying observed responses. In Chapter 2, I use dispersal and anti-predator traits of specialist milkweed herbivores to predict species’ distributions across a patchy landscape and test the importance of local top-down pressure in mediating classic biogeographic relationships. In Chapter 3, I test predictions about the impact of warming on plant-herbivore interactions and the importance of species’ arrival order and demonstrate how warming strengthens trophic interactions, amplifies priority effects and alters the interspecific differences in dispersal that determine arrival order. In Chapter 4, I test the combined impact of warming-induced changes to local competitive interactions and dispersal on metacommunity diversity, and show that positive local effects of warming, combined with the risk of moving across the matrix, can produce unexpected interactive effects of temperature and connectivity on metacommunity diversity. By describing and implementing novel approaches that provide better tests of metacommunity theory, and applying a multi-scale approach to climate change research, my thesis informs our understanding of how natural and anthropogenic processes shape diversity in patchy landscapes.
Optimization of Wireless Power Transfer Systems with Multiple Transmitters and Receivers
Keywords: Magnetic Fields
Multiple Transmitters
Optimization Techniques
Semidefinite Relaxation
Wireless Charging
Wireless Power Transfer

Wireless Power Transfer (WPT) has undergone a revolution, being transformed from a somewhat fantastical technology of the future to reality, encompassing a large variety of applications and forming a billion-dollar industry. Wireless charging of devices, ranging from mobile phones to biomedical implants and electric vehicles has been long imagined. Over the past few years, thousands of these products and solutions have been developed and reached a customer base of dozens of million users. Despite the impressive advancements and practical implementations in the field, the physical limitations of WPT have not been rigorously explored, apart from simple systems consisting of a single transmitter-receiver pair. A universal all-encompassing framework from which general WPT systems can be optimized, analyzed and compared remains elusive all the same. Such a framework, from which these fundamental limits could be obtained, would be invaluable to the community, setting an absolute upper bound on performance to which any and all specific implementations could be compared and contrasted. Moreover, the framework could allow a deeper understanding of the underlying physics of such systems, resulting in improved design guidelines and optimal design rules. This work aims to bridge this gap by providing optimization methods for general WPT systems, consisting of an arbitrary number of transmitters and receivers, in order to determine the absolute maximum achievable performance of said systems. The methods are based on convex optimization, which effectively guarantees to find global maxima. Furthermore, implementations of maximally efficient systems are presented and investigated, to gain insight into how these limits may be achieved. Practical examples and related applications, including antenna arrays and magnetically mediated hyperthermia for cancer treatment, illustrate the usefulness and capabilities of these findings.
Exploring Music-based Cognitive Rehabilitation Following Acquired Brain Injury: A Randomized Control Trail Comparing Attention Process Training and Musical Attention Control Training
Keywords: acquired brain injury
attention
Attention Process Training
cognitive impairment
Musical Attention Control Training
music-based cognitive rehabilitation

Cognitive impairment is the most common sequelae following an acquired brain injury (ABI) and results in significant impact on the individual’s potential for rehabilitation, functional independence, and on their quality of life. Because of the recently emerging evidence of the influence of music on brain function, music may serve as a unique and powerful cognitive rehabilitation tool following ABI. Although the research literature supports a rationale for music-based cognitive rehabilitation, there is a limited number of experimental studies investigating the clinical benefits of music-based cognitive rehabilitation. This study used a Randomized Control Trial. The control group participated in three standardized attention training sessions: Attention Process Training (APT) (Sohlberg Mateer, 2001). The experimental group participated in three Neurologic Music Therapy (Thaut Hoemberg, 2014) sessions using a standardized intervention: Music Attention Control Training (MACT). Pre-and post- testing used standard neuropsychological tests included Trail Making A B, Digit Symbol, and the Brown-Peterson Task. No significant difference was found within or between the groups for Trail A Test, Digit Symbol, or Brown-Peterson Task. The MACT group showed a statistically significant improvement (p=0.4) on the Trail B in contrast to the APT group when using paired t-tests to compare pre- versus post-test. However, a repeated measures ANOVA analysis for Trail B did not support statistically significant findings between the two conditions (p=0.051). The mean difference time between pre- and post-test showed no significant difference between APT and MACT using a two-sample t-test. However, a non-parametric follow-up test (Mann Whitney) (p=0.029) indicated significant differences in favor of MACT. Therefore, close significance values and partial evidence from nonparametric testing suggest only mixed support or potential trends in favor of MACT over APT. Although MACT outcomes performed comparable to the well established attention training technique of APT, further research with a larger sample size and more statistical power is needed to investigate specific benefits of MACT to improve attention.
Fast and Robust Transaction Processing on Emerging Hardware
Keywords: databases
hardware
systems
transaction processing

Database engines must adapt to the underlying hardware for high-performance transaction execution. Conventional database engines are built on the storage-centric architecture assuming small DRAM, limited parallelism, and slow network. Emerging hardware, including byte-addressable non-volatile memory (NVRAM), massively parallel processors, and ultra-fast interconnect, has lead to significant changes in the design and implementation of modern database engines. Modern database engines, despite being optimized for multicore hardware, still have unscalable components and unnecessary data redundancy that hinder performance on future servers with large core counts (up to 1000). Database engines should also be robust against various workloads, including traditional short, write-intensive transactions and emerging long, read-mostly, and high-conflict transactions. Existing database engines fail to address these problems, leaving the vast opportunity of accommodating heterogeneous, read-mostly and high-conflict workloads that are enabled by emerging hardware largely unexplored. These problems must be tackled to make database engines perform fast and robustly on modern high-end and future hardware. In this thesis, we first remove the unscalable logging bottleneck by utilizing NVRAM. NVRAM allows us to revive distributed logging, a once prohibitive but effective solution to centralized logging bottlenecks. Avoiding unscalable logging is crucial in building fast main-memory databases that can potentially scale up to 1000 cores in future servers, but is not enough for handling the inconvenient workloads robustly. We continue on devising concurrency control mechanisms that handle a wide spectrum of workloads robustly. Finally, we demonstrate how high availability solutions can be built to guarantee both data safety and freshness using emerging hardware and by eliminating unnecessary data redundancy through indirection. This thesis serves as a toolbox and provides the guidelines for the design and implementation of high-performance and robust database engines and other concurrent systems. The solutions have been evaluated on both mainstream high-end servers and precursors of future hardware that could feature as many as 1000 cores and NVRAM. The techniques are applicable to both modern and future hardware that is yet to come.
Observations of Exoplanet Atmospheres
Keywords: eclipses
planet
spectrocopy
transits

The focus of this thesis is the observation of extrasolar planet atmospheres. Our research utilizes a variety of telescopes and analysis techniques to observe planets with a variety of properties. In Chapter 1, we present a brief overview of the current state of exoplanet detections. In Chapter 2 is a comprehensive analysis of hot-Jupiter phase curves observed by the Kepler Space Telescope, where planetary properties including albedo, temperature, radius and mass are reported. In Chapter 3, a larger sample of Kepler phase curves are analyzed, including that of an ultra-short period rocky planet. Unlike in Chapter 2, the analysis of this sample also includes a measurement of the phase curve peak brightness offset, which it then used to infer brightness variations across the planet's surface. In Chapter 4, high-resolution Doppler spectroscopy is used to search for water absorption in the transmission spectrum of 55 Cancri e and in Chapter 5 ground-based differential spectrophotometry is used to search for the water absorption signature of HD189733 b in transit observations at K and H band wavelengths. In the final Chapter, future exoplanet discovery missions, and follow-up observing instruments, are described and predictions are made about the success of future exoplanet atmospheric studies.
Studies on DNA Replication Repair and Cancer: Insights from Biallelic Mismatch Repair Deficiency Syndrome
Keywords: Cancer
CMMRD
DNA repair
Glioblastoma Multiforme
Mismatch repair
Replication repair

Biallelic Mismatch Repair Deficiency Syndrome (bMMRD) is an aggressive childhood inherited cancer predisposition syndrome. Individuals harboring biallelic germline mutations in the mismatch repair genes (MSH2, MSH6, MLH1, or PMS2) develop a myriad of cancers in all tissues; predominantly brain tumors, hematological malignancies and gastrointestinal cancers. Due to the rarity of the syndrome, the origin and progression of bMMRD cancers is not yet clearly understood. The focus of this thesis work is to elucidate the clinical and biological aspects of bMMRD cancers and to apply these findings across other tumors with replication repair deficiency. Chapter 1 delivers an overview of various aspects of DNA replication repair and their implications to cancer development and therapies. Chapter 2 describes recent advances in our understanding of both clinical and biological aspects of bMMRD, including prevalence of the syndrome, techniques for diagnosis, tumor spectrum and onset, and surveillance recommendations. Chapter 3 focuses on genomic profiling of tumors arising from bMMRD, including the discovery of the first pediatric ultrahypermutant tumors, secondary somatic driving mutations unique to bMMRD tumors, and the implications of the genomic findings as they pertain to tumor onset and progression. Chapter 4 expands the discovery of hypermutant tumors beyond the syndrome to a wide variety of pediatric and adult tumor types, thereby revealing the greater role that replication repair deficiency plays in tumor onset and progression across cancers in general. In Chapter 5, the hypermutant phenotype in bMMRD tumors is used to justify the administration of a novel immune-based therapy. The aim of this thesis is to utilize bMMRD as a model system for replication repair deficiency as it pertains to cancer in general, while also applying the findings to improve patient care.
"Things Are Changing": Police Mental Health and Psychotherapeutic Help-seeking Within an Evolving Police Culture
Keywords: help-seeking
mental health
operational stress injury
police
police culture
workplace culture

Due to repeated trauma exposure and significant ongoing sources of operational and organizational stress, police officers are vulnerable to mental health problems, including PTSD, depression, and other Operational Stress Injuries (OSIs). In recent years, police organizations have made efforts to build awareness and the address mental health needs of their membership, and Ontario legislation has attempted to address gaps in access to services among first responders. As such, aspects of traditional police culture which may be incompatible with psychotherapeutic help-seeking, such as norms of hegemonic masculinity, authoritarianism, and emotional control have been challenged. The current study aimed to explore the lived experiences of Ontario police officers with regard to job-related psychological distress and help-seeking, and to elucidate the complex role of contemporary police cultural norms in shaping help-seeking behaviours. In-depth research interviews were conducted with 18 police officers of various occupational ranks and roles. A constructivist grounded theory approach was utilized toward the development a model of psychological help-seeking within the contemporary police culture. Results demonstrated that although most officers reported that “things are changing” within the police cultural and institutional context, themes of weakness versus strength, us versus other, safety and suitability for the job, and co-constructed silence continue to pervade many of their experiences and perceptions of psychological difficulties, constraining help-seeking behaviours and often delaying help-seeking. Specific factors interfering with help-seeking included issues with accessibility, education, and awareness, but more prominently, identity issues, a fear of work-related consequences, and skepticism and mistrust, especially of mental health treatment providers. Establishing trust and reducing stigma via leadership and peer access points to community service providers were important facilitating factors. Psychotherapeutic service engagement often resulted in a shift away from policing as a fundamental component of identity, as well as a greater level of comfort with help-seeking, challenges to previously-held stigmas, and most powerfully, an inclination to share these experiences with one’s peers and thereby challenge the culture of silence. A model of the influence of the police culture on psychotherapeutic help-seeking among police is presented, and theoretical implications, as well as implications for prevention and intervention with police are outlined.
Inter-limb Coordination in Balance Control: Implications for understanding Balance after Traumatic Brain Injury
Keywords: Asymmetry
Coordination
Motor recovery
Postural balance
Traumatic brain injury

Coordination of forces generated in the lower extremities is essential for maintaining balance and recovery from postural instability. Temporal synchronization of force amplitude from each limb in upright stance illustrates the importance of the integrity of the central nervous system (CNS) and its contribution to the regulation of the centre of mass within its base of support in producing appropriate coordination between both limbs. Weight-bearing symmetry is also important to postural control and the maintenance of balance in response to upcoming perturbations. Therefore, inter-limb coordination in balance control is critical when the integrity of the CNS has been compromised as a result of a traumatic brain injury (TBI), and its compromise can lead to increased risk of falling. Balance impairments after TBI are common and result from multiple TBI-related sequelae, which includes cognitive deficits and sensorimotor and coordination impairments. Impaired balance performance is typically seen after TBI; however, the motor contributions that influence postural control are not well understood in this population. The overall purpose of this dissertation was to further understand the role of inter-limb coordination in postural control and to determine the extent to which inter-limb coordination is altered in individuals following moderate-to-severe TBI. The decoupling of inter-limb synchronization was particularly important in preparation for balance perturbations that were less predictable and required stepping responses. Balance asymmetry and poor static balance control were found in individuals with TBI. There was no change in inter-limb synchronization and as a result of large within-group variability, inter-limb synchrony post-TBI did not fall outside healthy control norms. Additionally, anticipatory and reactive balance control mechanisms were also impaired after injury. Although there were improvements in some balance measures, balance impairments persist one year after injury. The findings of this dissertation are the first to quantify balance asymmetry after TBI and provide further evidence that asymmetry and inter-limb coordination are essential components of balance control after TBI. Furthermore, these findings suggest that future rehabilitation intervention may benefit from balance training with a focus on asymmetry to reduce of risk of falling and that other TBI-related sequelae may also be impeding on the recovery of balance outcomes.