VictorJuiz/thesis huggingface dataset:
Enhancing Parental Role in Managing Pain in Neonates
Keywords: infant pain
infant pain management strategies
parental education

Infants are exposed to a variety of painful procedures in the first year of life. Infants admitted to NICUs are exposed to repeated painful procedures. Repeated and prolonged exposure to pain is known to have detrimental neurodevelopmental side effects. Therefore, reducing pain in these infants is of key importance. Evidence supports a variety of non-pharmacological pain reducing strategies that are still not consistently used. Parents are a potential untapped resource for helping to improve infant pain management. This program of research was designed to investigate the facilitators and barriers to parental participation in infant pain management, determine the impact of parental education on utilization of pain management strategies, explore parents’¬ experience with pain care, and describe perceptions of an educational bundle to increase parental involvement. The Parental Involvement in Neonatal Pain Management conceptual model guided this research and additional, the COM-B model was utilized in the third study. The first study, a metasynthesis of qualitative literature, demonstrated parents have the desire to learn and participate in their infant’s pain management but their lack of knowledge, the NICU environment and health care providers’ behaviours impact their ability to participate. The second study, a systematic review and meta-analysis, demonstrated parental education provided improved utilization of pain management strategies for the infants but it was unclear how to best educate parents. The third study, an exploratory descriptive qualitative study, supported parental beliefs, information/support, and parent-infant proximity as important factors in parents’ participation in their infant’s pain management. Parents desire to be involved; however, they require knowledge and support from health care providers (HCPs) to attain this involvement. HCPs were both facilitators and barriers to parent participation. The educational bundle developed for the study, including a book, videos, and posters, was well received by parents. Parents reported learning new knowledge and self-efficacy regarding future participation. Educating and supporting parents to provide pain management strategies for their infants has the potential to improve pain management in their infants and potentially improve their long-term outcomes.
Absorption-Dominant Electromagnetic Interference Shielding Polymer Composites and Foams
Keywords: Advanced Manufacturing
Conductive Polymer Composite
EMI Shielding
MXene
Polymer Foam

The development of conductive polymer composites (CPCs) and foams offers a promising solution for achieving absorption-dominant electromagnetic interference (EMI) shielding while mitigating secondary electromagnetic pollution. Despite the significance of structural and geometrical factors in creating high-performance absorption-dominant EMI shielding materials, systematic structure-property (i.e., EM wave reflection efficiency) relationships have rarely been reported for these materials. Therefore, this dissertation aims to demonstrate how theoretical computation and experimental design can be integrated to overcome the challenges of structural design and optimization of absorption-dominant EMI shielding CPCs for cutting-edge applications.The first part of the thesis includes an in-depth understanding of the effects of cellular structure and geometry on the EMI shielding properties of single-layer EMI shielding CPCs and foams. An input impedance model was applied to explore the thickness dependency of reflectivity (R) in microcellular CPC foams and then decouple the effect of thickness on the R-value from other structural variables, such as the void fraction and cellular morphology. In particular, the presence of microcellular structure can effectively tune the input impedance matching while maintaining a satisfactory EMI shielding effectiveness, resulting in a reduced R and enhanced absorption-to-reflection ratio at optimal thickness. The second part of this thesis demonstrates a theoretically guided approach to designing and fabricating bilayer gradient CPC systems that offer advanced absorption characteristics for EMI shielding. These systems comprise an absorption layer that dissipates the EMI energy and a shielding layer that reflects and shields the remaining energy. Heterostructured SiC nanowire/MXene (Ti3C2Tx) nanosheet hybrids were developed in the absorption layer via interface engineering, which revealed an improved EM energy dissipation capability and satisfactory impedance matching in theoretical results. Moreover, the input impedance of the bilayer CPC systems can be effectively tuned by optimizing the microstructure and geometry of both absorption and shielding layers via theoretical computations, achieving absorption-dominant EMI shielding performance with broadband ultralow reflectivity and a controlled sample thickness. This dissertation developed a fundamental understanding of structure-property relationships and proposed new methods to develop and fabricate CPCs and foams for achieving high-performance absorption-dominant EMI shielding.
Emerton-Gee Stacks, Serre Weights, and Breuil-Mézard Conjectures for GSp_4
Keywords: automorphic representation
Galois representation
Generalized Serre weight conjectures
Langlands Program

We construct a moduli stack of rank 4 symplectic projective étale (phi,Gamma)-modules and prove its geometric properties for any prime p>2 and finite extension K/Q_p. When K/Q_p is unramified, we adapt the theory of local models recently developed by Le-Le Hung-Levin-Morra to study the geometry of potentially crystalline substacks in this stack. In particular, we prove the unibranch property at torus fixed points of local models and deduce that tamely potentially crystalline deformation rings are domain under genericity conditions. As applications, we prove, under appropriate genericity conditions, an GSp_4-analogue of the Breuil-Mézard conjecture for tamely potentially crystalline deformation rings, the weight part of Serre's conjecture formulated by Gee-Herzig-Savitt for global Galois representations valued in GSp_4 satisfying Taylor--Wiles conditions, and a modularity lifting result for tamely potentially crystalline representations.
The Structural and Functional Connectivity of the Cerebellum in Autism Spectrum Disorder
Keywords: autism
cerebellum
connectivity
fMRI
MRI

The cerebellum coordinates motor, cognitive, and affective function in the brain, largely via its connectivity to the cerebral cortex. Perinatal injury to the cerebellum and mutations to genes integral for cerebellar development are strongly associated with Autism Spectrum Disorder (ASD), a highly prevalent neurodevelopmental disorder with an unclear etiology and heterogeneous behaviour presentation. Disrupted cerebellar development results in changes to its coordinated growth and neurophysiological activity with other brain regions, heretofore referred to as structural and functional connectivity. Recurrent patterns in cerebellar-cerebral connectivity in the context of atypical neurodevelopment have been observed. However, much is still unknown regarding the extent to which these patterns correspond to particular ASD-related behaviours and genetic mutations. In chapter 2, behaviour-correlated functional connectivity profiles - measured using resting-state functional magnetic resonance imaging (MRI) - were identified using a neurodevelopmental disorder (NDD) imaging and behaviour dataset. The findings were then assessed for replication using an independent dataset from a second consortium. Two functional connectivity components were observed in the original and replication dataset: a first component maximally correlated to obsessive-compulsive behaviour and a second component characterized by social communication deficit contrasted against attention deficit. Statistically stable features of these components mainly included nodes pertaining to the attentional, central executive, and default mode networks. Having identified functional connectivity profiles correlated to ASD-related behaviours, structural connectivity profiles were then characterized and compared to those of clustered mouse models, where each model bore a genetic mutation associated with ASD. Structural connectivity was defined as correlations between regional brain volumes measured via MRI. Two mouse model clusters were significantly similar to human clusters following False Discovery Rate correction: the cluster with elevated protein product expression in the cerebellum versus the cerebrum, and the cluster with genes implicated mTOR pathway biomolecule synthesis. Structural correlations were most similar between mice and humans for correlations between cerebellar Crus II or vermal lobule VI and all cerebral regions. Similar to the findings of chapter 2, large structural correlation differences mainly involved regions pertaining to the attentional, central executive, and default-mode networks.
Reduction of Manganese Ore by Methane
Keywords: Manganese
Methane
Reduction

Manganese is a critical element in steelmaking and most manganese ores mined today are consumed as some form of ferromanganese (FeMn) or silicomanganese (SiMn) alloying material for steel. The production of FeMn and SiMn is energy and carbon intensive, typically requiring thousands of kilowatt-hours of electrical energy and hundreds of kilograms of coke per tonne of alloy produced in the conventional submerged arc furnace (SAF) process, resulting in substantial CO2 emissions. As demand for these FeMn and SiMn materials is expected to grow significantly with the widespread adoption of next generation high-manganese steel grades, a less energy- and carbon-intensive processing strategy is required. A methane-based gas-solid reaction scheme has previously been proposed for the reduction of manganese oxides and ores. Using this approach, a combination of methane and hydrogen gases are used to develop a high activity adsorbed carbon phase on the surface of the manganese oxide, enabling the reduction of the oxide at high temperatures. The basic feasibility of this approach has been demonstrated for manganese oxide and ore powders in systems not limited by bulk diffusion of the gases. The present work considered the reduction of manganese ore briquettes with the intent of informing the scale-up of this methane-based reaction scheme. The reaction rate was observed to be sensitive to the partial pressure of methane in the system, consistent with prior investigations. However, a significant impact of gas diffusion within the ore briquette was observed, resulting in a ten-fold decrease in the apparent rate of reaction under the conditions assessed. This decreased rate of reaction is in part attributed to the sintering of the oxide phase and partial melting of metallic phases, both of which present a critical limitation on the reaction temperature. Additional technical barriers include challenges associated with the thermal decomposition of methane in the temperature range of interest for this reduction scheme and a strong sensitivity to the partial pressure of carbon monoxide in the system. As a result of these barriers, it is unlikely that a methane-based reduction scheme will be a technically or economically viable alternative to the conventional SAF processing route.
Exploring the Role that SR Kinases Play in Controlling Viral Infections with a Focus on HIV-1
Keywords: Coronaviruses
HIV
RNA processing
SR kinases
Therapeutics

RNA processing plays a critical role in gene expression, enhancing protein diversity. SR proteins are essential components of this regulation whose activity and localization are modulated by their phosphorylation by SR kinases (CLK1-4, DYRK1A, SRPKs). HIV-1 relies on host RNA processing for viral protein production/replication, making the modulation of this process a potential target to regulate HIV-1 replication. This thesis examines the discrete roles of SR kinases in controlling HIV-1 gene expression. Depleting CLK1 enhanced HIV-1 gene expression, while CLK2 or SRPK1 depletion reduced it. CLK3 or DYRK1A depletion had no impact on HIV-1 expression. The opposing effects of CLK1 vs CLK2 depletion were due to action at distinct steps; CLK1 depletion increased HIV-1 promoter activity while depletion of CLK2 affected steps post-transcript initiation. RNA-Seq on cells depleted of each SR kinase revealed moderate but very discrete roles of the kinases in regulating host gene expression. While >80% DYRK1A depletion had the least impact on the host transcriptome, a two-fold reduction in CLK2 impacted the greatest number of genes at all levels. In most instances, CLK1 or CLK2 depletion had opposite effects on splicing indicating antagonistic roles of the two kinases. BioID-mass spectrometry (MS) of the CLKs identified a total of 287 potential interacting partners common and unique to each enzyme, many previously identified as affecting HIV-1 expression. Besides the known substrates of CLKs (SRs and related proteins), BioID-MS also detected factors that function at the level of transcription initiation, elongation, polyadenylation, splicing, and export. The demonstration that modulating SR kinase levels/activity can be used to alter HIV-1 expression, led me to identify small molecule SR kinase inhibitors, 1H3, 2E3, and Harmine with potent anti-HIV-1 activity. The compounds also modulated CLK1 and CLK2 function and altered their abundance. Harmine was unique among the SR kinase inhibitors tested in suppressing coronavirus replication, including SARS-CoV-2. At doses required to suppress HIV-1, Harmine had limited impact on the host gene expression as assessed by RNA-Seq. Together, my studies demonstrate the feasibility of targeting host RNA processing to inhibit a range of viruses with minimal impact on the host cell.
Physical Mechanisms Behind the Midlatitude Atmospheric Energy Transport Response to Imposed Arctic sea ice loss
Keywords: Atmospheric energy transport
Sea ice loss
Storm tracks

The extratropical storm tracks play a major role in shaping midlatitude climate and account for most of the atmospheric heat transport (AHT) in the extratropics. The storm tracks are expected to intensify and shift poleward, in part due to a tug-of-war between low-latitude warming and strong Arctic warming. In this thesis, we focus on the role of Arctic warming through sea ice loss on the midlatitude storm tracks and on AHT. We present a multi-model analysis of the AHT responses to Arctic sea ice loss and low-latitude warming, employing numerical experiments from the Polar Amplification Model Intercomparison Project (PAMIP). A moist isentropic circulation framework allows separation of the contributions of mass transport from those of stratification driving changes in AHT. In PAMIP's atmospheric general circulation model experiments, prescribed sea ice loss reduces high-latitude AHT by warming the returning moist isentropic circulation, while prescribed warming of the ocean surface increases AHT by strengthening eddy mass transport. Ocean-atmosphere coupling has been shown to contribute significantly to the response to Arctic sea ice. To assess the role of ocean coupling on the storm tracks and AHT, we carry out the centennial coupled sea ice loss experiments from. We present a novel sea ice constraining method that grants better control over the partitioning of sea ice concentration and sea ice thickness, in comparison with existing methods, while conserving total water. The development of a novel technique is required because of the relatively weak sea ice melt in the PAMIP targets. Using the coupled PAMIP simulations, we build an ocean-atmosphere coupling hierarchy in order to characterize the role of ocean-atmosphere interactions on the storm-track response to Arctic sea ice. These simulations reveal that ocean-atmosphere coupling is necessary to capture the weakening of the storm tracks in response to Arctic sea ice loss, and that surface turbulent heat flux and ocean dynamics have complementary effects on the response. From the isentropic diagnostic perspective, most of the weakening of the storm tracks and its associated changes in AHT arise from a weakening of the transient eddy mass flux.
Affinity-Based Approaches for Controlling Release of Therapeutic Proteins from Biopolymer Hydrogels
Keywords: affibodies
affinity-based release
biopolymer hydrogels
controlled release
directed evolution

Proteins are powerful therapeutic agents but are challenging to effectively administer to the body. Their fragile 3D structures enable them to interact with other molecules in precise ways to regulate biochemical pathways. Most are administered parenterally, but natural clearance mechanisms limit the duration of their effect. Conventional controlled-release strategies typically used for small-molecule drugs often require harsh processing conditions that can cause irreversible protein denaturation. Affinity-based release systems incorporate therapeutic proteins into delivery vehicles under mild conditions, enabling higher bioactive drug loading. The rate of release is governed by diffusion and non-covalent interactions with the delivery vehicle. We designed a series of release strategies enabling flexible delivery from biopolymer-based hydrogels. Src homology 3 (SH3) binding peptides enabled the sustained release of rod-derived cone viability factor long (RdCVFL) fused with an SH3 domain from a hyaluronan methylcellulose-based hydrogel. Using finite element analysis, we modelled drug distribution to inform the delivery vehicle formulation. We learned that higher excess concentrations of binding peptide led to subtherapeutic levels of protein in the tissue, while lower concentrations did not extend the effective time of release. This strategy could enable effective concentrations of RdCVFL-SH3 for 35 days. To enable multifactor release, we developed unique affibody binding partners through directed evolution that specifically bound to insulin-like growth factor 1 (IGF-1) and pigment epithelium-derived factor (PEDF). By varying the concentration of these protein binding partners, tunable and simultaneous release of both IGF-1 and PEDF from biopolymer hydrogels were achieved over the course of 7 days. This strategy enables the delivery of multicomponent therapies that are vital to the clinic. To streamline the process of developing binding partners, we utilized ROSETTA to create a binding peptide for vascular endothelial derived growth factor (VEGF). We isolated a 10 amino acid sequence within the complementarity-determining region by analyzing the crystal structure of the complex between bevacizumab and VEGF. We further validated the interaction using biolayer interferometry. This approach enables the rapid discovery of binding peptides for affinity-based release. Overall, we demonstrated that affinity-based release systems effectively sustain the delivery of therapeutic proteins, and specific binding partners enable multicomponent controlled release strategies.
Validation of Existing Methods for Determining Protein and Amino Acid Requirements
Keywords: Amino acid
Glutathione
Oxidation
Protein
Requirements

The validity of protein and amino acid (AA) requirement estimates obtained using the minimally invasive 1-day indicator amino acid oxidation (IAAO) method have been questioned. Critics argue that there is no evidence linking 1-day IAAO-derived protein requirements to beneficial health outcomes in humans. Another concern is that the 1-day IAAO protocol is too short, potentially leading to inaccurate estimates of AA requirements due to incomplete adaptation. To address these concerns, this thesis conducted the following research: 1) a randomized cross-over trial measuring erythrocyte glutathione (GSH) kinetics in healthy adults receiving graded proteins intakes (0.6 to 1.5 gkg-1d-1) for 3 days; 2) a scoping review on adaptation and AA oxidation methods, identifying knowledge gaps to inform the planning of study 3 and; 3) a repeated measures design using IAAO to determine whether 1, 3, or 7 days of adaptation to experimental diets altered the threonine requirement in adult men. The first study found that a protein intake of 1.0 gkg-1d-1 (95% CI= 0.63, 1.39) maximized GSH fractional synthesis rates in healthy adults. The scoping review indicated that adaptation periods exceeding 7 days violate the conditions of successful adaptation, but further research is needed to directly compare 1-day and 7-day adaptations in AA requirement studies. This led to the purpose of study 3. In study 3, the mean threonine requirements (95% CI) for days 1, 3, and 7 were 10.5 (5.7, 15.9), 10.6 (7.5, 13.7), and 12.1 (9.2, 15.0 mgkg-1d-1), respectively. These requirements were not statistically different. In healthy young adults, maximum antioxidant synthesis was achieved at a protein intake of 1.0gkg-1d-1, which closely aligns with the 1-day IAAO-derived requirement of 0.93 gkg-1d-1. This suggests that 1-day IAAO-derived protein requirements are indeed reflective of favourable health outcomes. Furthermore, the short 1-day IAAO protocol allows for reliable estimation of AA requirements, as it was not different from those obtained after 3 or 7 days of adaptation. Overall, the 1-day IAAO method proves suitable for studying protein and AA requirements in humans. Moreover, its minimally invasive nature makes it particularly appropriate for investigating the nutritional needs of vulnerable populations that have been scarcely studied.
VEPH1 Modulation of the BMP Signaling Pathway: Effects on Cadherin Levels and Cell Migration
Keywords: BMP4
Cadherin
Cancer
EMT
SMAD1/5
VEPH1

VEPH1 is an 833-amino acid adaptor protein containing a conserved C-terminal PH domain. It has been implicated in the modulation of the TGF-β and mTOR signaling pathways, which are heavily involved in cancer progression through the promotion of EMT. EMT is a program of steps cancer cells undergo to metastasize to secondary sites, involving the downregulation of epithelial polarity and cell-cell adhesion, and upregulation of mesenchymal characteristics. A key event is the repression of the cell adhesion molecule E-cadherin by the SNAI1/2 family of transcription factors, which are, in turn, regulated post-translationally by GSK3β-mediated degradation. VEPH1 was previously shown to interact with the TGF-β type I receptor (TβRI), ALK5, and inhibit downstream SMAD2/3 signaling. VEPH1 was also predicted to interact with BMP signaling pathway members SMAD1, ALK2 and ALK6. The TGF-β/BMP superfamily regulate development, immunity and tumorigenesis through SMAD and non-SMAD pathways. The objective of my study was to investigate the impact of VEPH1 on BMP-SMAD signaling and BMP-induced changes in proliferation and migration. I hypothesized that VEPH1 modifies BMP4 canonical signaling via a physical interaction with SMAD1 and/or type 1 receptors ALK3 or ALK6. VEPH1 inhibited BMP4-induced SMAD1/5 phosphorylation and SMAD1 nuclear accumulation in HepG2, SKOV3 and ES2 cells. A positive effect on basal nuclear SMAD1 levels in SKOV3 cells suggests VEPH1 could modulate SMAD1 distribution. Cell line-specific effects of VEPH1 were observed on BMP gene target transcript and protein levels. VEPH1 decreased SNAI1 protein levels in HepG2 cells, which was consistent with N-cadherin-to-Ecadherin switching, resembling MET, and reduced migration and increased aggregation, as well as decreased GSK3β phosphorylation levels. In SKOV3 cells, VEPH1 increased AKT phosphorylation levels and SNAI2 protein levels, which correlated with a decrease in E-cadherin and augmented migration. VEPH1 also decreased basal and BMP4-induced cell culture growth in HepG2 and SKOV3 cells. Although a physical interaction of VEPH1 was not observed with either SMAD1 or ALK3, novel ALK5-mediated BMP4-SMAD1 signaling was identified for SKOV3 cells, along with ALK3 signaling. This study provided cell-specific models for a VEPH1 effect on BMP-dependent and –independent cancer progression, further highlighting its role as a modulator of cancer signaling pathways.