Background: It is well established throughout the literature that regularly engaging in physical activity throughout pregnancy is associated with optimized health outcomes for both the mother and the fetus. The mediators and mechanistic pathways through which these observed exercise-induced outcomes are achieved are largely unknown. This thesis attempts to address this gap in knowledge. Methods: The objective of the first study was to develop an exercise protocol based on the recommendations from the ‘2019 Canadian guideline for physical activity throughout pregnancy’ and to subsequently evaluate the myokine response post-exercise. Pregnant (n=13) and non-pregnant (n=17) women performed a moderate-intensity bout of treadmill walking following which pre- and post-exercise serum for a panel of ten well-characterized myokines was analyzed. The objective of the second study was to evaluate whether acute and/or chronic exercise elicited changes in metrics of placental growth and development – thereby proposing possible mechanisms through which physical activity may be conferring health benefits to the fetus. Serum (pre- and post-exercise) collected from the first study was used to treat placental cell lines to assess the effect of acute exercise on cellular proliferation as well as nutrient transporter (GLUT1, SNAT1, FATP4) expression and localization. Term placental tissue collected from active (n=10) and non-active (n=10) participants in the PLACENTA study were used to evaluate the role of chronic exercise on changes in nutrient transporter (GLUT1, SNAT1, FATP4) expression and localization. Results: Pregnant women from the first study exhibited higher levels of four myokines post- versus pre-exercise: FGF21, EPO, BDNF and IL-15. As for the second study, BeWo cell lines treated with serum collected from pregnant women yielded higher GLUT1 expression compared to non-pregnant serum, independently of exercise. Lastly, FATP4 expression was found to be higher in term placentas of active compared to non-active pregnant women. Conclusion: This thesis identified four myokines that are elevated in the serum of pregnant women following a bout of acute exercise. The role of these myokines in pregnancy remains to be elucidated. Further, chronic and acute exercise are shown to alter expression of key placental macronutrient transporters.

This dissertation research involved investigations into possible drug-nutrient or disease-nutrient transport interactions in the nursing mother-neonate dyad. The overall hypothesis was that cefepime would inhibit L-carnitine transport at the lactating mammary gland and in developing neonates. Additionally, inflammation would alter energy substrate transporter expression in mammary tissue.<p> The first objective was to investigate the potential for drug-nutrient transport interactions at the lactating mammary gland. A continuous cefepime infusion to lactating rats reduced L-carnitine transfer into milk at early but not mid lactation. In conjunction with higher milk L-carnitine and cefepime concentrations and higher expression levels of Octn2, the data suggests cefepime competitively inhibited Octn2-mediated L-carnitine transport into milk.<p> The second objective was to assess the influence of lactation stage on milk-to-serum ratios (M/S) for an actively transported drug, cefepime, and its impact on the calculation of neonatal exposure indices. Higher cefepime M/S on day 4 lactation versus day 10 coupled with lower systemic clearance values for cefepime in postnatal day 4 versus day 10 pups resulted in >7-fold higher exposure index values at postnatal day 4. These data confirm the need to determine M/S at different lactation stages for actively transported drugs to avoid over- or underestimation of neonatal exposure risk.<p> The third objective was to examine a drug-nutrient transporter interaction in neonates. Cefepime administered twice daily according to different dosing schedules (postnatal days 1-4, 1-8, 8-11, 8-20 and 1-20) caused significant alterations in the ontogenesis of several mechanisms involved in the L-carnitine homeostasis. These alterations likely represented adaptive responses to cefepime inhibition of L-carnitine transport. Furthermore, these changes seemed to depend on duration and timing of exposure relative to postnatal maturation.<p> The fourth objective was to examine the effects of inflammatory stimuli on energy substrate transporter expression in mammary tissue. Inflammatory stimuli altered expression of glucose, fatty acid and L-carnitine transporters in mammary tissue <i>in vitro</i> and <i>in vivo</i>.<p> Collectively, this research provided experimental evidence for significant disease- or drug-nutrient transport interactions in the nursing mother-neonate dyad. Further research may identify a need for dietary modification during pharmacological management of disease in the nursing mother-neonate dyad.

This dissertation research involved investigations into possible drug-nutrient or disease-nutrient transport interactions in the nursing mother-neonate dyad. The overall hypothesis was that cefepime would inhibit L-carnitine transport at the lactating mammary gland and in developing neonates. Additionally, inflammation would alter energy substrate transporter expression in mammary tissue.<p> The first objective was to investigate the potential for drug-nutrient transport interactions at the lactating mammary gland. A continuous cefepime infusion to lactating rats reduced L-carnitine transfer into milk at early but not mid lactation. In conjunction with higher milk L-carnitine and cefepime concentrations and higher expression levels of Octn2, the data suggests cefepime competitively inhibited Octn2-mediated L-carnitine transport into milk.<p> The second objective was to assess the influence of lactation stage on milk-to-serum ratios (M/S) for an actively transported drug, cefepime, and its impact on the calculation of neonatal exposure indices. Higher cefepime M/S on day 4 lactation versus day 10 coupled with lower systemic clearance values for cefepime in postnatal day 4 versus day 10 pups resulted in >7-fold higher exposure index values at postnatal day 4. These data confirm the need to determine M/S at different lactation stages for actively transported drugs to avoid over- or underestimation of neonatal exposure risk.<p> The third objective was to examine a drug-nutrient transporter interaction in neonates. Cefepime administered twice daily according to different dosing schedules (postnatal days 1-4, 1-8, 8-11, 8-20 and 1-20) caused significant alterations in the ontogenesis of several mechanisms involved in the L-carnitine homeostasis. These alterations likely represented adaptive responses to cefepime inhibition of L-carnitine transport. Furthermore, these changes seemed to depend on duration and timing of exposure relative to postnatal maturation.<p> The fourth objective was to examine the effects of inflammatory stimuli on energy substrate transporter expression in mammary tissue. Inflammatory stimuli altered expression of glucose, fatty acid and L-carnitine transporters in mammary tissue <i>in vitro</i> and <i>in vivo</i>.<p> Collectively, this research provided experimental evidence for significant disease- or drug-nutrient transport interactions in the nursing mother-neonate dyad. Further research may identify a need for dietary modification during pharmacological management of disease in the nursing mother-neonate dyad.

A key question related to climate change projections is how will aquatic systems respond to changes in variables such as temperature and precipitation? This thesis uses GWLF, a simple catchment scale model to explore potential impacts of climate change on water quantity and quality. River discharge and nutrient loads were modelled for several warmer world scenarios. For one catchment in New York, USA changes in annual dissolved phosphorus loads decreased along with annual streamflow, and particulate phosphorus loads increased for a single future climate scenario. For the Galten catchment of Lake Mälaren, Sweden, the spring melt peak observed historically was reduced for six future scenarios. Peak runoff and dissolved phosphorus and nitrogen load maxima occurred in winter rather than early spring. A synthesis of model results for dissolved inorganic nitrogen (DIN) loadings for five European catchments showed changes in the timing and magnitude of peak DIN load for several future scenarios. In northern Europe, changes were largely due to increased winter streamflow and reduced snow pack and spring melt runoff. In western Europe, DIN loads increased in winter or early spring due to increased precipitation. The biological response for a warmer future scenario was modelled for the Galten basin of Lake Mälaren using GWLF coupled to a lake phytoplankton model and a physical lake model. An increase in cyanobacteria biomass accompanied by a decline in diatom biomass resulted from changes in the timing of nutrient export from the catchment. The projected increase in lake temperature favored an overall increase in total phytoplankton biomass. Lastly, a method based on hourly measurements of colored dissolved organic matter (CDOM) fluorescence provides the appropriate data for dissolved organic carbon (DOC) model parameterization and may also be used for surveillance of organic matter inputs to lakes.

The intrauterine environment plays an important role in fetal development and downstream health. Given the rise in maternal obesity and the incidence of babies being born large-for-gestational-age, research is needed exploring the mechanisms through which maternal obesity and health behaviours affect the delivery of nutrients to the fetus. This thesis includes three manuscripts in the pursuit of two objectives: 1) To determine whether there are changes in placenta nutrient transport-related gene expression in response to obesity, excess gestational weight gain, and variations physical activity and diet, and 2) To examine whether the Pregnancy Physical Activity Questionnaire is a reliable estimate of physical activity during the second trimester of pregnancy. In manuscript 1, we found that maternal obesity was not related to placenta nutrient transport-related gene expression, with the exception of lower placental mTOR expression in obese women who delivered male offspring, however, gestational weight gain was related to the gene expression of key proteins in the placenta. In manuscript 2, it was determined that the Pregnancy Physical Activity Questionnaire significantly overestimates physical activity and is not correlated with direct measures of activity and thus should not be used in future research. In manuscript 3, we found that physical activity and diet modify the expression of the genes involved in placenta nutrient transport. Meeting physical activity guidelines was associated with lower expression of a fatty acid transporter and higher expression of an amino acid transporter, while sugar intake was related to the expression of a glucose transporter. Together, the studies that make up this thesis suggest that there are numerous factors that may be contributing to placenta nutrient transport-related gene expression in humans and that future research on the placenta ought to include direct measures of physical activity and maternal diet, as well as account for gestational weight gain with respect to the guidelines and fetal sex.

No description available.

Winter fallow corn (Zea mays L.) and soybean [Glycine max (L.) Merr.] production systems are susceptible to erosion and agrochemical transport. This research determined the effects of Cover Crop Minimum Tillage (CCMT) on erosion and agrochemical transport from corn-soybean rotations at field scale, while assessing impacts to agroeconomics and irrigation in Mississippi’s Delta Region. CCMT did not affect total suspended solids (p = 0.53), total inorganic phosphorus (TIP) (p = 0.30), or total nitrogen (TN) (p = 0.25) loads, but did reduce TIP (p = 0.018), TN (p = 0.011), and nitrate-nitrite (p = 0.007) concentrations. An economic loss of $281/ha with no effect on yield (p = 0.09), irrigation use efficiency (p = 0.38), or consumptive water use (p = 0.83) was observed. CCMT will not improve profitability of corn-soybean rotations in the Delta and transitioning from fallowing to CCMT will have varying effects on erosion and agrochemical transport.

The runoff of suspended solids and nutrients from land into the nation's lakes and rivers can have severe impacts on the health of these systems and their uses. High-frequency environmental data from sensors can provide insight into fundamental biogeochemical processes that dictate water quality and provide regulators with valuable knowledge on how to manage critical resources. The goal of this research was to utilize sensor technology, telemetry hardware, cyberinfrastructure, and water quality models to create a sensing system that will allow the investigation of the fate and transport of dissolved oxygen, suspended solids, nutrients, and other water quality parameters throughout a watershed dominated by agricultural activity. Deploying these sensors at multiple locations along the stream enabled the investigation of these processes from the fine scale to the larger watershed scale. Results from this research addressed both fundamental science and resource management issues regarding water quality. Using high-frequency data, a dramatic diel cycle in dissolved oxygen was observed with nonlinear dynamics which was successfully modeled mathematically, and excursions in water quality criteria were observed. In addition, a diel pattern in turbidity was discovered with higher levels at night likely caused by bioturbation (i.e. nocturnal activity of bottom feeding fishes) which resulted in higher suspended solids loadings during nighttime. Furthermore, the QUAL2K model was successfully calibrated for water quality using sensor measurements and grab samples from volunteer, IOWATER data. Nutrient loading rates (nitrate-N, orthophosphate, and total dissolved solids) were estimated along the entire creek and were similar to other Iowa streams. Volunteer environmental data were found to be helpful in model calibration for some parameters (e.g. TSS and nitrate). The construction and operation of a sensing system in Clear Creek contributed to water quality science and engineering. Findings from the configuration and field testing of sensing station components such as water quality sensors, power systems and communication hardware will aid the design of future sensing systems and environmental observatories. Integrating the methodology of this research with future observing systems will further our understanding of water quality processes and help maintain the health and value of our nation's water environment.

<p>Tumor hypoxia is an enduring problem for traditional cancer therapies such as radiation and chemotherapy. This obstacle has traditionally been attributed to the widespread presence of chronic, diffusion-limited hypoxia in solid tumors; recent data suggests that tumor hypoxia may also be spatially and temporally variable. In this work we characterize the presence of spatial and temporal fluctuations in hypoxia, as well as use mathematical modeling to predict the impact of fluctuations on the hypoxic cytotoxin, tirapazamine, and examine potential mechanisms of fluctuations in tumor oxygenation. Using phosphorescence lifetime imaging on preclinical tumors, we show that instabilities in tumor oxygenation are a prevalent characteristic of three tumor lines and that previous characterization of tumor hypoxia as being primarily diffusion-limited does not accurately portray the tumor microenvironment. Then, using a one-dimensional theoretical model, we examine the effects of fluctuating hypoxia on metabolized tirapazamine concentration; we find that fluctuating oxygen reduces the concentration of metabolized tirapazamine at distances farther from the source, thereby limiting its ability to reach and kill the most hypoxic cells. Finally, we use a three-dimensional Green's function oxygen transport model to explore the effects of temporal fluctuations in hemoglobin saturation, blood flow, and overall perfusion on tumor tissue oxygenation. Results from the model predict that hemoglobin saturation has a dominant effect on tissue oxygenation. These studies collectively suggest that the pervasive temporal and spatial heterogeneity in tumor oxygenation are highly therapeutically relevant, and future clinical and preclinical studies are needed.</p> / Dissertation

To develop or engineer artificial tissues in tissue engineering, a detailed knowledge of the in vitro culture process including cell and tissue growth inside porous scaffolds, nutrient transport, and the shear stress acting on the cells is of great advantage. It has been shown that obtaining such information by means of experimental techniques is exceedingly difficult and in some ways impossible. Mathematical modelling and computational simulation based on computational fluid dynamics (CFD) has emerged recently to be a promising tool to characterize the culture process. However, due to the complicated structure of porous scaffolds, modelling and simulation of the in vitro cell culture process has been shown to be a challenging task. Furthermore, due to the cell growth during the culture process, the geometry of the scaffold structure is not constant, but changes with time, which makes the task even more challenging. To overcome these challenges, the research presented in this thesis is aimed at developing a CFD-based mathematical model and multi-time scale computational framework for culturing cell-scaffold constructs placed in perfusion bioreactors. To predict the three-dimensional (3D) cell growth in a porous tissue scaffold placed inside a perfusion bioreactor, a model is developed based on the continuity and momentum equations, a convection-diffusion equation and a suitable cell growth equation, which characterize the fluid flow, nutrient transport and cell growth, respectively. To solve these equations in a coupled fashion, an in-house FORTRAN code is developed based on the multiple relaxation time lattice Boltzmann method (MRT LBM), where the D3Q19 MRT LBM and D3Q7 MRT LBM models have been used for the fluid flow and mass transfer simulation, respectively. In the model cell growth equation, the transport of nutrients, i.e. oxygen and glucose, as well as the shear stress induced on the cells are considered for predicting the cell growth rate. In the developed model and computational framework, the influence of the dynamic strand surface on the local flow and nutrient concentration has been addressed by using a two-way coupling between the cell growth and local flow field and nutrient concentration, where a control-volume method within the LBM framework is applied. The simulation results provide quantification of the biomechanical environment, i.e. fluid velocity, shear stress and nutrient concentration inside the bioreactor. The final simulation applied the cell growth model to the culture of a three-zone tissue scaffold where the scaffold strands were initially seeded with cells. The prediction for the 3D cell growth rate indicates that the increase in the cell volume fraction is much higher in the front region of the scaffold due to the higher nutrient supply. The higher cell growth in the front zone reduces the permeability of the porous scaffold and significantly reduces the nutrient supply to the middle and rear regions of the scaffold, which in turn limit the cell growth in those regions. However, implementation of a bi-directional perfusion approach, which reverses the flow direction for second half of the culture period, is shown to significantly improve the nutrient transport inside the scaffold and increase the cell growth in the rear zone of the scaffold. The results in this study also demonstrate that the developed mathematical model and computational framework are capable of realistically simulating the 3D cell growth over extended culture periods. As such, they represent a promising tool for enhancing the growth of tissues in perfusion bioreactors.