VictorJuiz/thesis huggingface dataset:
Defining Delivery Pathways of Nanoparticles
Keywords: Cancer
Drug delivery
Elimination
Kupffer Cells
Liver
Nanoparticles

The goal of nanomedicine is to use nanoparticles to carry drugs to specific target site in the body. For cancer nanomedicine, a recent meta-analysis showed that only 0.7% of the injected nanoparticles reach the tumour. To address this delivery inefficiency, it is important to examine each biological barrier to determine its impact on delivery. In this thesis, first the body was modelled as a series of barriers that nanoparticles need to overcome successively in order to access the target site. The model shows that the number and strength of barriers limits what is available to be delivered. The macrophages of the liver can sequester up to 99% of the injected nanoparticles, and thus are the biggest barrier for targeted delivery. Next, clodronate-liposomes were used to remove the liver macrophages and showed that both nanoparticle tumour delivery and hepatobiliary elimination can be improved. Specifically, nanoparticle tumour delivery can be increased up to 50× and hepatobiliary elimination up to 10×. Removal of the liver macrophages then allowed the exploration of other secondary barriers to delivery such as tumour pathophysiology and the liver sinusoidal endothelium. Together, these studies define concepts and strategies that can improve nanoparticle delivery and reduce unwanted bioaccumulation to pave the way for their clinical translation and regulatory approval.
Control and Operation of the Battery-enabled Direct-current Fast Charging Station for Electric Vehicles
Keywords: DC Fast Charging
DC Microgrids
Discrete-Event Systems
Electric Vehicles
Supervisory Control
Weak AC-grid

This dissertation presents, develops, and evaluates a system architecture and its control structure that mitigates impact of the Electric Vehicles’ (EVs) Direct-Current Fast-Charging (DCFC) station on its host weak Alternating Current (AC) grid. The DCFC station includes multiple DCFC units, a Battery Energy Storage System (BESS), a solar-Photovoltaic (PV) system, and a grid-interface Voltage-Sourced Converter (VSC). The proposed control system, i.e., combination of Local Controllers (LCs) and Supervisory Controller (SC) contains the station dynamics within the station and thus prevents dynamic impact of the DCFC units and other internal sources, such as solar-PV generation, on the host grid. Unlike a conventional station, this enables interfacing the proposed DCFC station to the legacy AC distribution grid, irrespective of the grid weakness and technical limits. A discrete-event control-based Supervisory Controller (SC) for the DCFC station is synthesized, evaluated, and verified to (i) limit the station’s power based on grid-imposed requirements, (ii) coordinate operation of controllable units within the station, (iii) operate the station in either grid-connected mode or islanded mode, and (iv) dynamically adjust power flows inside the station between grid, PV unit, DCFC units, and BESS to satisfy the EVs charging requirements and when applicable charge BESS or export PV power to the grid. Time-domain simulation results, in PLECS software platform, are presented to assess the dynamic performance of the proposed SC subject to various discrete events/transitions. The results demonstrate robustness of the proposed control system to large-signal disturbances and discrete events/transitions. The proposed control system performance, i.e., LCs and SC, is experimentally validated using a two-layer real-time control Hardware-in-the-Loop (HIL) setup. The power circuit of the DCFC station is simulated in real-time in OPAL-RT platform. The LCs and the SC of the DCFC station are implemented in industrial CompactRIO (cRIO) controller and a Programmable Logic Controller (PLC) PLCnext-controller, respectively. The control system performance is tested in case of islanded and grid-connected modes of operation of the station, subject to various disturbances and SC transitions, to verify the functionality of the implemented controls and readiness for final deployment and field tests.
Determinants of Statin Drug Sensitivity in Mevalonate-dependent Cancers
Keywords: Drug repurposing
Mevalonate pathway
Personalized medicine
Statins
Tumour metabolism

Statins are widely prescribed cholesterol-lowering drugs that inhibit HMG-CoA reductase (HMGCR), the rate-limiting enzyme of the mevalonate pathway. Several lines of evidence support that certain tumours depend on the mevalonate pathway for growth and survival and are vulnerable to statins. However, if statins are to be successfully repurposed for the personalized treatment of cancer, we must identify biomarkers that can predict which patients might benefit from the addition of a statin to their treatment regimen, and how best to administer these drugs in combination with other agents to maximize therapeutic responses. Herein, the research objectives were to elucidate novel determinants of statin drug sensitivity in different tumour types, and further characterize the molecular mechanism(s) by which statins induce cancer cell death. To this end, we demonstrated that prostate tumours overexpress HMGCR, and that high HMGCR protein expression is associated with poor prognosis. Interestingly, however, not all prostate cancer cells were sensitive to statin-mediated HMGCR inhibition at physiologically-achievable concentrations. We further identified that statin-sensitive prostate cancer cells were impaired in their ability to activate a sterol-regulated feedback loop in response to statin exposure. Notably, in statin-insensitive prostate cancer cells, where this sterol-regulated feedback loop was intact, the clinically-approved drug dipyridamole was found to inhibit this response and sensitize cells to statin-induced apoptosis. In an independent malignancy, multiple myeloma, we identified that cells positive for the t(4;14) chromosomal translocation were particularly vulnerable to mevalonate pathway inhibition. Statin treatment induced a robust integrated stress response in t(4;14)-positive cells, which was exacerbated by co-treatment with the proteasome inhibitor bortezomib. Moreover, statin treatment synergized with bortezomib to induce apoptosis in t(4;14)-positive cells, providing strong rationale to combine these two clinically-approved agents for the treatment of t(4;14)-positive disease. Taken together, the work presented in this thesis reveals two promising opportunities for the repurposing of statins, as single agents or in combination with additional, clinically-approved drugs, to treat distinct mevalonate-dependent cancers. Since statins are already approved for the prevention of cardiovascular disease, and are available as generic drugs, they offer an immediate, safe and affordable opportunity to improve cancer patient care and treatment outcomes.
Role of microRNA-27B-3P in the Regulation of Key Extracellular Matrix Markers in the Synovium during Osteoarthritis
Keywords: ADAMTS8
Collagen
Extracellular Matrix
microRNA
Osteoarthritis
Synovitis

Synovial fibrosis, characterized by excessive accumulation of extra-cellular matrix (ECM), is a key pathology contributing to joint destruction associated with Osteoarthritis (OA). microRNAs (miRNAs) are small non-coding RNAs that play key roles in various pathophysiological processes. We have previously shown that miR-27b-3p is abundantly expressed in the OA synovium and elevated in the synovial fluid of patients with late-stage knee OA. However, the exact role of miR-27b-3p in the regulation of ECM in the OA synovium is largely unknown. Hence, my PhD thesis project aimed to determine the role of miR-27b-3p in the regulation of ECM components in the synovium during OA. I first show that miR-27b-3p is prominently expressed in the human OA synovial lining and increased in late-stage knee OA compared to early-stage radiographic knee OA. I further show that miR-27b-3p is highly expressed in the synovial lining and fibrocartilage of a surgery-induced mouse model of knee OA. To decipher the role of miR-27b-3p in the regulation of synovial ECM, I transfected primary human OA fibroblast like synoviocytes (FLS, major synovial cells) with miR-27b-3p-mimic and subjected to ECM-specific qPCR array. Profiling the expression of 84 ECM genes in OA-FLS showed that miR-27b-3p-mimic significantly increases the expression of key ECM genes including pro-collagen-Type-I (COL1A1), A-disintegrin-and-metalloproteinase-with-thrombospondin-motifs-8 (ADAMTS8), Thrombospondin-1 (THBS1), Fibronectin-1 (FN1), Collagen-type-V-alpha-1 (COL5A1) and Collagen-type-XIV-alpha-1 (COL14A1). MiR-27b-3p-mimic also markedly increased COL1A1 protein expression as well as migration of OA-FLS. Integrative computational analysis of identified ECM genes predicted a closed relationship between miR-27b-3p signaling and ADAMTS8. To functionally evaluate this, I silenced ADAMTS8 by siRNA in miR-27b-3p-mimic transfected OA-FLS. Results showed that ADAMTS8 silencing attenuated the increased expression of COL14A1, COL5A1 and FN1 without any significant effect on COL1A1 and THSB1 expression in OA-FLS, suggesting that regulation of COL14A1, COL5A1 and FN1 expression by miR-27b-3p may in part be mediated by ADAMTS8. Finally, I performed RNA sequencing on miR-27b-3p-mimic transfected OA-FLS to profile the transcriptome of miR-27b-3p in FLS during OA. Overall, this study provides a crucial evidence on the role of miR-27b-3p in the regulation of key ECM markers in the OA synovium.
Development of Novel Hybrid Silica Aerogels with a Reticulated Structure using New Generation of Marcromolecular Precursors
Keywords: Hybrid Silica Aerogel
Reticulate Structure
Strong
Ultra-insulative

Aerogels (e.g. silica aerogel) have created a prospective market for oil-absorption, insulation and aerospace applications. However, their intrinsic fragility and poor mechanical properties have been a stumbling block to their wider applications. These drawbacks originate from their inherent particulate structure and weak interparticle interactions. For several decades, researchers have been trying to enhance the aerogels’ mechanical properties by improving the particle-to-particle connections. However, the cost was increased processing time, increased density, and increased total thermal conductivity. Therefore, this Ph.D. research aims to find an industrially viable and fast manufacturing technology to produce ultra-light weight and mechanically robust and resilient aerogel while preserving the unique features of the aerogels such as the good thermal insulation properties and high surface area. This dissertation fundamentally addressed the difficulties associated with the improvement of the particle-to-particle connection in the conventional aerogels by inventing a novel non-particulate and reticulate structure, free from the troublesome particles. This new technology relied on the development of a new generation of polymeric silica precursor and a meticulous control of thermodynamics at gelation step. Polymeric precursors with different chemistries and molecular weights were synthesized in the preparatory stage and then through spinodal decomposition, non-particulate and reticulate aerogels were afforded. Thermodynamics variables, molecular weight of the polymeric precursor, solvent, temperature, and the amount of the nonsolvent were systematically studied and correlated to structural parameters and consequently to the final properties. It was found that there is a critical point where a particulate structure transfers to a non-particulate one. The findings have also demonstrated how to tailor the structural factors such as the void fraction, the average pore sizes to optimize the final properties. This study provided an in-depth understanding of processing-structure-property relationship and a novel technology to molecularly engineer the structure and properties of hybrid silica aerogels. Various aerogels’ building blocks assemblies, polymeric precursors, and thermodynamics variables have been investigated to identify the optimal structure and processing methodology to obtain highly robust and super-insulative aerogels.
Spell Checking Nature: Development of a CRISPR- Mediated Gene Editing Approach for the Treatment of Pathogenic Duplications
Keywords: CRISPR/Cas9
Duchenne muscular dystrophy
Duplication
Gene Editing Therapy
Mouse Model Generation
Structural Variants

Duchenne muscular dystrophy (DMD) is a neuromuscular disorder that leads to progressive muscle deterioration, loss of ambulation, and respiratory complications. It is caused by genetic mutations that result in the absence of dystrophin protein expression needed for muscle function. Despite significant advances in our understanding of the pathogenesis of DMD, no curative treatment has been identified to date and the disorder has a life-limiting disease trajectory. Recently, we have pioneered an approach to successfully remove large duplications in patient cells. We first tested this approach in vitro by removing a multi-exon (18-30) duplication of 139 kb in the DMD gene using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated Nuclease (Cas9) with a single guide. To test our treatment approach in vivo, I first generated a mouse model harboring a multiexon duplication of 136.8 kb in Dmd using CRISPR/Cas9. This first multiexon duplication model of DMD specifically mimics a patient duplication of Exons 18-30. Molecular and functional characterization of this model reveals dystrophin deficiency with characteristic markers of dystrophic muscle. Furthermore, using our previously described CRISPR/Cas9 single guide strategy, we have for the first time treated a large genomic duplication in vivo and shown successful removal of the duplication fragment leading to restoration of full-length dystrophin in skeletal and cardiac muscles. Additionally, histopathological analysis shows that treated mice have less indications of dystrophy including fewer centrally localized nuclei as well as significantly improved muscle function. Our findings establish the far-reaching therapeutic utility of CRISPR/Cas9, which can be tailored to target numerous inherited disorders caused by duplications.
Radical Cloud Chemistry: Oxidation of Organic Compounds in Atmospheric Water
Keywords: atmospheric chemistry

Atmospheric aging of organic compounds by photo-chemical oxidation can occur rapidly in the aqueous phase in aerosol particles, cloud droplets, and fog droplets and can result in changes to their chemical composition and absorptivity. Despite their capacity to significantly alter the properties of organic aerosol, aqueous phase reactions have not gained as much attention as other atmospheric aging pathways. The goal of this thesis was to further our understanding of photoreactions of atmospherically-relevant organic compounds in cloud water. This goal was accomplished through three projects, which investigated factors influencing the production of hydroxyl (OH) radicals in aqueous phase reactions and the lifetime, oxidation mechanism, and fate of light absorbing molecules that contribute to brown carbon. In the first project, the impact of dissolved organic compounds, specifically from α-pinene ozonolysis secondary organic aerosol (SOA) material, on the Fenton reaction, a major source of OH radicals in cloud and fog water, was investigated. OH radical production was significantly suppressed in the presence of SOA material, likely due to complexation of the iron involved in the Fenton reaction. In the second project, aqueous photo-oxidation kinetics of three light-absorbing nitrophenol compounds often associated with wildfire smoke were examined and were found to have an in-cloud lifetime on the order of hours. Photo-oxidation initially caused an absorption enhancement that corresponded to products with added oxygenated functional groups. Further photo-oxidation led to products that do not absorb visible light, reducing their contribution to atmospheric warming. In the third project, representative and chemically complex brown carbon was generated in the laboratory from wood smoke. Light absorption increased from aqueous photoreaction and OH oxidation and was linked to oligomerization and functionalization of aromatic compounds, similar to the nitrophenol chemistry. While extended OH oxidation led to a decrease in absorbance, brown carbon in wood smoke is likely to have a longer lifetime than estimated by individual components. Overall, this work demonstrated key outcomes of organic chemical transformations resulting from aqueous atmospheric aging under relevant cloud conditions and provided implications for their effect on the climate system.
Development of Surface-modified Electrodes for Electrochemical Energy Storage Applications
Keywords: Flexible Energy Storage
Multi-functional Devices
Nanostructuring
Smart Textiles
Supercapacitors
Surface Modifications

Recent commercialization efforts made in the fields of flexible sensors, low-energy Bluetooth transmitters, and low-power thin-film electronics have contributed to significant fast-paced growth in the smart wearable industry. This drastic paradigm shift in the flexible electronics component design has fuelled an evolution in the flexible personal electronics, biomedical, athletics, and logistics industries as more flexible, thin-film products are offered. Flexible thin-film electrochemical capacitors (EC) or supercapacitors are energy storage solutions that offer both high energy and power densities resulting from the exceptional high electrode specific surface area and appropriately tuned electrode/electrolyte interface. To meet both the electrochemical and mechanical requirements, several aspects of the electrode design was to be considered in the proposed flexible EC devices: a) Areal- and gravimetric specific capacitance; b) Charge-discharge cycling properties; c) Mechanical bending and flexing behaviours; and d) Environmental stability. In this work, novel facile techniques in fabricating flexible EC electrodes with micro- and nano-structured surface modification have been proposed to produce high-performing flexible EC electrodes with additional intrinsic multi-functionalities, such as piezoresistive sensors and breathing sensors, along with energy storage. Herein, to create facile pathways for fabricating flexible, high-performance EC electrodes, this thesis has been divided into the following studies: The first study focuses on the design of a novel environmental-controlled self-assembly method, where polyaniline (PAni) nanorod structures were grown on polyacrylonitrile (PAN) nanofibers for high-surface-area textile electrochemical capacitor electrodes with intrinsic piezoresistive tactile sensing capabilities. The second study relied on a novel laser-assisted photochemical reduction method to produce reduced graphene oxide micro-ribbon textile electrode directly on a liquid surface, which can be transfer printed onto any substrate for both supercapacitors and breath sensor applications. The third study validated a method for creating hierarchically structured multilayer reduced graphene oxide for flexible intercalated supercapacitor electrodes where simultaneous reduction and nitrogen-doping were successfully achieved. The last study explored the possibility of creating a multi-layered flexible polypyrrole micro-foam/carbon nanotube composite electrodes for flexible supercapacitor devices via the creation of three-dimensional polypyrrole microsphere architecture.
Hybrid Carbon-modified Polymer-based Silica Aerogels with Low Thermal Conductivity and Improved Mechanical Properties
Keywords: Bimodal porosity
Graphene nanoplatelets
Mechanical
Silica aerogel
Spinodal decomposition
Thermal conductivity

Recently, graphene nanoplatelets (GnPs) have attracted a great deal of attention as a multifunctional reinforcing nanofiller in polymer composites, which is due to their unique two-dimensional layer structure with honeycomb characteristics, their excellent mechanical properties and their isotropic reinforcement capability in more than one direction. Here, the effect of the spinodal decomposition process in creating a nonparticulate morphology in the GnPs' orientation and dispersion is investigated. It is also studied how the gelation reaction can participate in the inclusion of GnPs in the aerogel backbone during the sol-gel process to strengthen the body of the gel. Meanwhile, the process of GnP exfoliation and restacking elimination during sol-gel transition is comprehensively studied. The present thesis also analyzes the gelation kinetics and thermodynamics in the presence of GnP and graphene oxide (GO) using in-situ rheology, light scattering (DLS), small-angle X-ray scattering (SAXS) and pore-structure-analyzer. The data collected during the gel network formation obtained with and without GnP or GO are analyzed in which to fully study the kinetics of structure evolution during the gelation. It is confirmed that the use of spinodal decomposition to create a nonparticulate gel network helps to offset the required long aging step during the sol-gel process, which is inevitable to strengthen the particle-to-particle neck using conventional methods such as nucleation and growth. It is also verified that this gelation technique enables the system to take advantage of GnP's full potential through correct exfoliation and elimination of restacking and re-agglomeration. The carbon-modified polymeric silica-based aerogels were first modified to enhance their mechanical properties by the addition of flexible nanofibers and stiff nanosheets into the structurer. The composites assembled homogeneously into the carbon-modified polymeric silica-based aerogel structure to create a uniform network of the solid struts along with the backbone. With such a network, the mechanical properties of the aerogels increased dramatically while preserving/advancing their unique features such as high surface area and thermal stability. The new aerogels could operate a high temperature with a high surface area. Furthermore, such material could resist moisture, which makes this material ideal to be used in high temperatures and humid environments.