VictorJuiz/thesis huggingface dataset:
Novel Roles of GLP-1 and GLP-2 in the Regulation of Hepatic Lipid/Lipoprotein Homeostasis and the Involvement of BAT Activation

Major complications of insulin resistance and type 2 diabetes (T2D) include the development of non-alcoholic fatty liver disease (NAFLD) and an atherogenic fasting dyslipidemic profile, primarily due to increases in hepatic very low density lipoprotein (VLDL) production. Recent studies have implicated neuronal signalling in the control of hepatic lipid metabolism and VLDL production. The gut derived hormones glucagon-like peptide (GLP)-1 and GLP-2 have been shown to signal through neuronal pathways and display postprandial hypolipidemic and hyperlipidemic actions respectively. Furthermore, activation of brown adipose tissue (BAT) through the sympathetic nervous system also displays hypolipidemic actions and has recently been shown to be activated by GLP-1. We hypothesized that GLP-1 and GLP-2 will play opposing roles by decreasing and increasing VLDL production and NAFLD respectively. We further hypothesized that the effects of GLP-1 in modulating lipid metabolism occur through the activation of BAT. Using the Syrian Golden hamster, we showed that the GLP-1 receptor (GLP-1R) agonist exendin-4 decreased body weight, fasting dyslipidemia and VLDL overproduction by enhancing lipid utilization and decreasing hepatic de novo lipogenesis. These effects occurred through a vagal signalling pathway and were independent of changes in food consumption. To assess the involvement of BAT in the hypolipidemic actions of GLP-1, we first characterized the hamster as a novel and effective model of BAT activation. Î˛3-adrenergic receptor (Î˛3-AR) agonism activated hamster BAT, induced browning of WAT and prevented diet-induced NAFLD. The hypolipidemic actions of GLP-1R agonism were partially mediated by BAT as shown in hamsters that underwent BAT removal. Conversely, the sister peptide GLP-2 increased VLDL production and hepatic steatosis in hamsters and mice. Interestingly, GLP-2R knockout (KO) mice were protected against diet-induced dyslipidemia but displayed enhanced hepatic lipid accumulation. An observed reduction in VLDL-TG levels indicated that the enhanced hepatic lipid levels may be due to decreased VLDL production. Taken together, this thesis demonstrates that GLPs play critical but opposing roles in regulating hepatic lipid accumulation and VLDL production. Modulating the balance of GLPs in vivo may be a potential therapeutic approach to correct the dyslipidemia and NAFLD commonly associated with the metabolic syndrome.

Keywords: Brown Adipose Tissue
Diabetes
Dyslipidemia
Fatty Liver
Glucagon-like peptide
Lipoproteins
Advisor: Adeli, Khosrow
Investigating the Signalling Dynamics and Functional Role of FGFR5 in Pancreatic Beta Cells

Loss of glucose homeostasis due to reduced beta cell mass and function are characteristics of the metabolic disorder diabetes. Identifying protein targets that affect beta cell mass and function may lead to better therapeutic strategies to treat this disease. One such family of protein target is the Fibroblast Growth Factor Receptors (FGFRs) of tyrosine kinases. FGFR1, the canonical receptor, influences insulin processing and glucose metabolism by triggering intracellular signalling events upon ligand stimulation. FGFR5, the newest member of this family, exhibits the capacity for extracellular FGF ligand binding yet presents a unique intracellular domain that lacks tyrosine kinase capacity to initiate signalling. Although its structure predicts down-regulation of FGFR1-mediated signalling, FGFR5 signalling and its effects in beta cells were previously unknown. We used a combination of traditional biochemical assays and quantitative live cell fluorescence microscopy to probe the expression, signalling and physiological consequences of FGFR5 in beta cells. We developed a novel microfluidics-based protocol to improve adenoviral transduction of pancreatic islets to deliver genetic material to a majority of cells throughout the tissue and improve the study of protein function in primary ex vivo beta cells. We created a library of fluorescent protein-tagged functional isoforms of FGFR5 and identified receptor localization to insulin secretory granules, association with SHP-1 phosphatase via the receptorâ s unique intracellular region and ligand-independent activation of the MAPK pathway. Furthermore, FGFR5 expression was found to increase total insulin content, cell adhesion, and improve beta cell survival during pro-inflammatory cytokine-induced stress but did not affect beta cell proliferation. Using a combination of co-immunoprecipitation and advanced quantitative fluorescence microscopy, we found that FGFR5 exists as asymmetric trimers at the plasma membrane and forms hetero-complexes with FGFR1, suggesting regulation of canonical receptor signalling. These findings represent advancement in our understanding of FGFR5 biology, specifically in the context of beta cell physiology. The engineered protein constructs and microfluidic device platform provide tools for further characterization of the effects of FGFR5 on insulin processing and signalling dynamics to better understand how the receptor could be targeted to treat diabetes.

Advisor: Rocheleau, Jonathan V
Kilkenny, Dawn M
FPGA-based Real-Time Simulation Platform For Power Grids Including Multiple Converters

This thesis develops an FPGA-based real-time simulation platform for power grids including multiple Power Electronic Converters (PECs) and other classical components, which in contrast to the classical systems do not include long transmission lines for mathematical decoupling of systems for efficient simulation. The presence of short transmission lines creates a large set of network equations that can not be decoupled. Handling the large admittance matrix, representing the large set of network equations, requires floating-point numerical representation which is associated with large latencies and high resource utilization in FPGAs. In addition, the presence of high switching frequency PECs imposes small simulation time-step requirement and therefore high computational burden. Accurate representation of PECs, using two-value resistor model, results in time-variant admittance matrix which also increases computational burden. This thesis proposes Reformulated Modified Nodal Analysis (RMNA) for solution of network equations to enable (i) parallelism between the simulation task of solving network equations and those of other power system component models to achieve small simulation time-steps and (ii) design of a low-latency floating-point matrix-vector multiplication hardware module to efficiently solve relatively large set of network equations associated with systems targeted in this work. An FPGA-based partitioning method is proposed to enable simulation of multiple PECs and representing power switches by two-value resistor model without significantly increasing the computational burden. This overcomes the issues associated with the existing real-time Associate Discrete Circuit (ADC) switch model, i.e., artificial switching loss and numerical oscillation. A new FPGA-based Electrical Machine (EM) Constant-Parameter-Voltage-Behind-Reactance (CPVBR) model is proposed to enable real-time simulation of different types of EMs, i.e., Induction Machine (IM), Synchronous Machine (SM) and Permanent Magnet Synchronous Machine (PMSM), under all test scenarios and regardless of their dynamic saliency and system configuration. Moreover, this thesis develops Inter-Hardware Universal Line Model (IHULM) to enable parallel simulation of distribution system, which includes short transmission lines, in the FPGA-based platform and the rest of the system in commercially available simulation platforms, e.g., RTDS. The platform developed in this work accurately simulates power grids with up to 160 nodes/outputs, four PECs, three EMs and one IHULM using a small real-time time-step of micro-second. Moreover, it features fixed-hardware design to avoid FPGA code compilation time. A model preparation script is developed to calculate the study system parameters based on the modeling approaches devised in this work.

Keywords: Coupled power grid
Electrical Machine
FPGA-based Computing
Power Electronic Converters
Real-time simulation
Transmission Line
Advisor: Iravani, Reza
Damage and Failure of Rocks and Rock-like Materials Subjected to Thermal and Dynamic Loadings

Rocks and rock-like materials may be failed due to high temperatures and inevitable dynamic loading. The understanding of damage and failure of rocks and rock-like materials subjected to thermal and dynamic loadings is thus important in many engineering applications. In this dissertation, the failure parameters (uniaxial compressive strength (UCS), tensile strength and fracture toughness), the failure criterion and the damage evolution of rocks and rock-like materials are investigated over a wide range of loading rates at different heat-treatment temperatures. The influence of thermally induced damage on the dynamic failure parameters of rock-like materials is investigated. The specimens heat-treated at different temperatures were tested using the split Hopkinson pressure bar (SHPB) apparatus. X-ray micro-CT scanning is used to quantify the thermally induced damage of specimens before mechanical loading. The results show that the dynamic failure parameters change with the loading rate and the heat-treatment temperature. The formulas for describing the dependence of the dynamic failure parameters on the thermal effect and the loading rate effect are established using the damage variable. To study the applicability of the dynamic failure criterion, the dynamic punch shear strength and failure parameters of rocks are systematically measured using the SHPB system. A recently developed dynamic Mohr-Coulomb theory is used to interpret the data. The applicability of the dynamic Mohr-Coulomb theory is validated, and the dynamic UCS and the dynamic tensile strength predicted with the dynamic punch shear strength through the dynamic Mohr-Coulomb theory are consistent with those directly measured. The dynamic damage evolution of rocks is studied by using the strain control technique in a modified SHPB system. The stress-strain relations of rocks with the different strain levels are obtained under different compressive loading rates. The recovered specimens, after being subjected to controlled strains, are examined using X-ray micro-CT scanning machine. Three dimensional microcrack networks induced by the different dynamic loading rates are observed and the damage evolution at different loading rates is analyzed.

Advisor: Xia, Kaiwen
Tools for Point-of-Care Digital Microfluidics

Digital microfluidics (DMF) is a liquid handling technology for the manipulation of discrete droplets on a generic array of hydrophobic insulated electrodes. In DMF, protocols are generated through software and are independent of the microfluidic architecture. DMF can be used to miniaturize and automate routine assays. Of interest are miniaturized medical diagnostic assays that could be performed in an automated fashion and can take place close to the point of need. This thesis describes the development of several tools for the realization of this description. The feasibility of performing clinical assays with DMF outside of the laboratory was demonstrated for the first time. DMF immunoassays for anti-measles IgG and anti-rubella IgG were performed in Kakuma, a refugee camp in northwestern Kenya. Custom-built open-source control systems and low-cost inkjet-printed cartridges were used to perform up to four chemiluminescent immunoassays simultaneously. 144 samples were tested and the clinical sensitivities and specificities of the DMF immunoassays were shown to be good (>80%). Having taken DMF out of the laboratory, new tools and detection methods were developed. First, nanostructured microelectrodes (NMEs) for electrochemical analysis were integrated with a DMF device. This was then applied to an immunoassay for anti-rubella IgG. Performance comparable to chemiluminescent methods was achieved. A second tool developed was a method entitled pre-concentration by liquid intake by paper (P-CLIP). Functionalized magnetic microparticles are captured from large (50-300 ÂľL) volumes of liquid and are resuspended in a much smaller volume (1-2 ÂľL). P-CLIP was used with an immunoassay for Pf lactate dehydrogenase and shown to improve signals up to 30-fold. The last tool for DMF clinical assays was the integration of low-cost commercial electrodes. Established methods for integrating sensing electrodes with DMF are costly and have low fabrication throughput. A plastic-based DMF top plate that can receive commercial biosensors and screen-printed electrodes was demonstrated. The sum of the innovations described in this thesis suggest that DMF is a viable platform for point-of-care analysis. Advancement to the tools already described will enable DMF to be used for analysis of a wide range of non-invasive samples such as finger-prick blood samples and saliva samples.

Keywords: diagnostics
microfluidics
point-of-care
Advisor: Wheeler, Aaron R
Processes and Structures of Care for Critically Ill Patients with Acute Brain Injury

Background: Examining the differences in quality and intensity of care within the context of ICU structure is needed to better understand the mortality differences observed between centers, and may help to improve the design of future trials for this neurocritically ill patient population. Methods: This dissertation uses several methods to examine the relationship between processes, organization of care and outcome for critically ill patients with acute brain injury. Results: First in a cohort study, I evaluated the association between centers rendering early decisions to withdraw life-sustaining therapies in severe traumatic brain injury (sTBI), as measured by time until death, and overall risk-adjusted mortality. After adjustment for case mix, care in a center with a preponderance of early deaths (within the first 5 days of ICU admission) was not associated with increased odds of death (adjusted odds ratio (OR) 0.95; 95% confidence interval (CI) 0.83-1.09). Secondly in a meta-analysis, I examined the relationship between the timing of tracheostomy in acutely brain injured patients and mortality. Early tracheostomy was associated with lower long-term mortality (risk ratio [RR] 0.57. 95% CI 0.36-0.90), reduced duration of mechanical ventilation (mean difference [MD] -2.72 days, 95% CI -1.29 to -4.15) and ICU length of stay (MD -2.55 days, 95% CI -0.50 to -4.59), but, was not associated with lower short-term mortality (RR 1.25; 95% CI 0.68-2.30), and, as expected, increased the probability of ever receiving a tracheostomy (RR 1.58, 95% CI 1.24-2.02). Lastly in a cohort study combined with survey data, I examined the association between dedicated neurocritical care units, the presence of standardized management protocols for sTBI, and mortality. Care in a dedicated neurocritical care unit was not associated with a lower risk-adjusted in-hospital mortality (OR 0.97 (95% CI 0.80-1.19), but the utilization of standardized TBI management protocols for these patients was associated with lower risk-adjusted in-hospital mortality (OR 0.77; 95% CI 0.63-0.93). Conclusions: Using several analytical approaches, these findings highlight important opportunities to reduce variability in care negatively impacting on acute brain injury outcomes.

Keywords: Acute brain injury
Critical care structure
Processes of care
Advisor: Nathens, Avery B
The Bioengineering of Annulus Fibrosus Tissues Using Phenotypically Distinct Inner and Outer Annulus Fibrosus Cells on Oriented Nanofibrous Polyurethane Scaffolds

As the current treatments for chronic neck or low back pain do not restore the full functions of degenerated intervertebral discs (IVD), the replacement of degenerate discs with a bioengineered IVD is an approach of great interest. Owing to the complex structure of the IVD, various engineered tissue components of the IVD require proper integration for mechanical functionality. The aim of this thesis is to improve the fieldâ s understanding of tissue engineering strategies necessary for generating a biological IVD replacement. A protocol was developed to generate a multiphasic IVD implant in vitro composed of multilamellated annulus fibrosus (AF) tissues engineered using nanofibrous aligned polycarbonate urethane (PU) scaffolds and nucleus pulposus (NP) tissues engineered on calcium polyphosphate (CPP) bone substitute. The engineered AF tissues were characteristic of the outer annulus fibrosus (OAF) tissues. Integration between different engineered tissues occurred, forming interfaces with mechanical strength. At one month post-implantation, the AF tissue remained adherent to the bone substitute but inadequate graft fixation resulted in the subsidence of the implant. The absence of the inner annulus fibrosus (IAF) component which can lead to inadequate transmission of compressive forces may have contributed to the loss of the NP tissues. It was hypothesized that OAF and IAF cells would generate tissue in vitro that maintained their distinct extracellular matrix (ECM) compositions. A culture protocol restoring the accumulation of appropriate ECM in multilamellated IAF tissues without altering the composition of multilamellated OAF tissues was identified. The restoration of ECM characteristic of IAF was dependent on the activation of glucocorticoid receptor signalling, which also increased the mitochondrial activity. Potential mechanism(s) of the mitochondria in the regulation of proper ECM accumulation for IAF and OAF tissues should be further investigated. Dynamic loading in vitro was explored as a strategy to improve the mechanical functions of these tissues for withstanding in vivo loads after implantation. As OAF and IAF tissues did not show further increase in ECM accumulation when dynamically loaded individually in vitro, the integration of various IVD components may be required for proper load distribution, warranting further studies into the effect of loading on engineered multiphasic tissues.

Keywords: Biomaterials
Intervertebral Discs
Regenerative Medicine
Tissue Engineering
Advisor: Kandel, Rita A
Santerre, J. Paul
The Role of Autophagy in the Pathogenesis and Clinical Course of Abdominal Aortic Aneurysms

Abdominal aortic aneurysm (AAA) is a permanent progressive focal dilation of the aorta that is â Ľ 50% of the normal aortic diameter, due to loss of wall structural integrity. A fatal outcome of the progressive dilation due to the compromised aortic wall integrity is rupture. Mortality associated with rupture is ~88%. While the histopathological characteristics of AAA are well documented, cellular and molecular mechanisms involved in AAA pathogenesis are not entirely understood. Autophagy is a conserved housekeeping basal cellular process for the turnover of organelles and proteins that occur in all eukaryotic cells. It can also be activated as an adaptive response to stressful and pathological conditions to promote cell survival. However, contrary to the classical autophagy pro-survival role, in some circumstances, autophagy can lead to cellular demise. Increasing evidence suggests that autophagy perturbation is associated with the development of multiple age-related and chronic disorders. Also, preclinical studies have identified autophagy as a process that is activated in cardiovascular diseases such as atherosclerosis, which share several pathological features to AAA. Importantly, emerging evidence suggest that vascular cell autophagy is a reparative and protective process in atherosclerosis pathogenesis. While several autophagy-related genes were found to be upregulated in human aneurysmal tissue, the role of autophagy in AAA pathogenesis remains undefined. My research aim was to evaluate the potential role of autophagy in the development, progression and rupture of AAA. To achieve this, we initially sought to define autophagy gene expression in an experimental mouse model of AAA. Then to elucidate the functional role of autophagy in AAA evolution, we utilized both global and cell-specific loss of functional approaches. Our study demonstrated that autophagy was activated in the Ang II-infused ApoE-/- AAA mouse model. Global loss of functional approach via systemic administration of the autophagy inhibitor chloroquine (CQ) did not alter the development, progression or rupture of AAA in mice. However, smooth muscle specific (SMC) ATG7 deficiency enhanced the susceptibility to AAA formation evident by the formation of pre-aneurysmal changes, emphasizing the significance of intact SMC autophagy in impeding the development of pre- aneurysmal changes that otherwise may lead to AAA development.

Advisor: Verma, Subodh
Social Change and Human Population Movements -- Dental Morphology in Holocene Eastern Africa

Millions of Eastern Africans are pastoralists, yet the origins of mobile herding in this region are unclear. Global climate change at the end of the African Humid Period pushed humans and their livestock out of desiccating areas of the Sahara, Sahel, and/or Ethiopian Rift. Herding subsequently entered Eastern Africa through the Turkana Basin, where the earliest domesticated animals coincide with the construction of megalithic â pillar sitesâ between 5200-4200 BP. The appearance of monumentality, along with new ceramic and lithic technologies, is used to argue that the first herders were migrants. Other lines of evidence support diffusion and local adoption. Excavations at three pillar sites have revealed dense cemeteries with zoomorphic artifacts and goat remains, suggesting those interred engaged in herding. This new skeletal sample can be compared to earlier foragers and later pastoralists to determine whether the arrival of herding technologies is associated with a population shift. Tooth size and morphology are often used to study population relationships in the past because they are highly heritable, minimally impacted by natural selection, and preserve well in archaeological contexts. To test the migration hypothesis, dental metric and non-metric traits are compared between the pillar sites (n=25 dentitions) and archaeological skeletons from Holocene Later Stone Age (n=40), early herder (n=53), and Pastoral Neolithic (n=91) sites from Kenya and Tanzania. The results suggest that the transition to food production in Eastern Africa did not involve population replacement. Biological affinity among these archaeological samples indicates that herding likely spread through small-scale population movements with gene flow between herders and foragers. However, there are significant differences between these pre-Iron Age Eastern Africans and contemporary North, sub-Saharan, and Southern Africans, suggesting diachronic changes in African dental complexes. Recent Africans may therefore be poor proxies for genetic relationships in antiquity, particularly in high contact zones like Eastern Africa.

Keywords: Bioarchaeology
Biodistance
Dental Anthropology
Eastern Africa
Monumentality
Pastoralism
Advisor: Pfeiffer, Susan