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The effects of turbine aerodynamics and response characteristics of the atmospheric boundary layer on the overall wind farm efficiency are investigated in this research. Various wind farm modelling strategies, which include a theoretical and several CFD models, are presented. This study consists of three main parts: (i) improve and validate an existing theoretical wind farm model, (ii) infinitely large wind farm modelling with actuator-disc and fully-resolved turbine models, and (iii) finite-size wind farm modelling with a numerical weather prediction model. In the first part, an extended theoretical model based on a two-scale coupled momentum balance method is proposed to estimate aerodynamic effects of wind turbine towers on the performance of large wind farms. The modified theoretical model predicts that the optimal turbine spacing should increase with the value of normalised support-structure drag, as well as additional parameters describing the response characteristics of the atmospheric boundary layer to the total farm drag. The Detached-Eddy simulations of a periodic array of fully staggered actuator discs (AD) show a reasonably good agreement (within 10% in the prediction of power) with the modified theoretical model. In the second part, a fully resolved (FR) NREL 5MW turbine model is employed in two URANS simulations (with and without the turbine tower) of a fully developed wind farm boundary layer. The FR-URANS results show stronger tower effects than both AD-RANS and theoretical model predictions, which is a strong indication of the necessity of considering turbine support structure within large wind farm models. The possibility of performing DDES is also investigated with the same FR turbine model and periodic domain setup. The results show complex turbulent flow characteristics within a large wind farm, where typical hairpin and hub vortices have been clearly captured. In addition, the computational cost of DDES has been found to be similar to URANS (for a given number of rotations), which is a positive sign for conducting DDES in future studies. In the third part, a numerical weather prediction model is used as a realistic farm-scale flow model to investigate how the streamwise pressure gradient, Coriolis force and acceleration/deceleration terms in the farm-scale momentum balance equation tend to change in time. The results suggest that the streamwise pressure gradient may be enhanced substantially by the resistance caused by the wind farm, whereas its influence on the other two terms appears to be relatively minor. These results suggest the importance of modelling the farm-induced pressure gradient accurately for various weather conditions in future studies of large wind farms.

ObjectiveThe purpose of this study was to investigate potential differences in chronological and physiological aging in adults, via examination of alveolar bone levels.Materials and MethodsFrom a possible 11,965 charts that met inclusion criteria (within age groups (20-29, 40-49, and 60-69 years old), bitewing images in chart, at least two tooth-bound first molars which opposed a natural tooth), utilizing a random number generator, 60 charts were collected for analysis. No exclusions were made for race, sex, medications, or medical comorbidities. The distance from cemento-enamel junction (CEJ) to alveolar crest (AC) was measured on both the mesial and distal sides of permanent first molars in bitewing images utilizing digital software. ResultsAfter 19 rounds of selection, 60 charts were collected for analysis (20 in each age group). Average distance from CEJ to AC was 1.14 mm in 20-29 year old age group, 1.54 mm in 40-49 year old age group, and 2.03 mm in the 60-69 year old age group. These differences were statistically significant between groups (P < 0.05). When considering bone levels/ amount of bone loss per year of function (achieved by dividing amount of bone loss by age minus 6 (average eruption of first molars is at 6 years old)), an opposing trend emerged; there was 0.065mm bone loss per year of function in the 20-29 year old age group, 0.041 mm bone loss per year of function in the 40-49 year old age group, and 0.036 mm bone loss per year of function in the 60-69 year old age group. These differences were statistically significant between the 20-29 year old age group and the 40-49 year old age group, as well as between the 20-29 year old age group and the 60-69 year old age group (P < 0.05). There was also a trend noted toward more bone loss on the mesial surfaces of the first molars than on the distal surfaces.ConclusionsVia examination of alveolar bone height on the mesial and distal surfaces of first molars, there appears to be a correlation between chronological and physiological age in a random sample of adults in the United States, with increasing amounts of alveolar bone loss noted in older age groups. However, an opposing trend appears when examining proportional amount of bone loss per year of function, which may indicate differences between chronological and physiological age. Additional studies are suggested to examine this trend further.

Cellular protein levels are governed by their rates of synthesis and degradation, and both processes are intricately regulated. One way to study the role of a protein in the cell is to artificially deplete it and observe the effects. The most common methodology for depleting proteins inhibits expression of the target through RNA interference. However, this technique acts at the protein synthesis level and cannot be used to study long-lived proteins or post-translational modifications. Thus, a complementary approach that acts on the proteins themselves would be useful. One method is to target a protein to the cell’s degradation machinery, the Ubiquitin Proteasome System (UPS). Proteins are targeted to the proteasome by the covalent attachment of ubiquitin molecules, which are recognized by the proteasome. The substrate is then translocated into the proteasome’s proteolytic core and degraded into short peptides, while the ubiquitin molecules are cleaved off and recycled. Recently, methods have been developed to deplete proteins by inducing their ubiquitination, which accelerates their degradation by the proteasome. Ubiquitin is a signaling molecule for numerous cellular pathways other than proteolysis, however, and inducing ubiquitination does not always lead to degradation. Therefore, I have developed a system to degrade specific proteins in cells using chimeric adaptors that shuttle proteins directly to the proteasome without the need for ubiquitination. I have shown that this system can be successfully applied to several proteins in vitro and that the adaptors can induce degradation of model and endogenous proteins in cells.

Phosphorylation of tyrosines by protein kinases is a fundamental mode of signal transduction in all eukaryotic cells, leading to a wide variety of cellular outcomes, including proliferation, differentiation, transcriptional activation, and programmed cell death. Perturbations to tyrosine kinase signaling networks by activation, overexpression, or mutation is the driving factor in many diseases, most notably cancers. The development of tyrosine kinase inhibitors, 37 of which are currently FDA-approved, has led to a revolution in cancer treatment. Imatinib, the first FDA-approved kinase inhibitor, has drastically improved prognosis for patients with Bcr-abl-positive leukemias. Despite this unprecedented success, however, up to one-third of patients lose response to imatinib due to mutations within the tyrosine kinase domain of Bcr-abl. Subsequent generations of Bcr-abl inhibitors, including dasatinib and ponatinib, have been developed to overcome these resistance mutations, but in each case, novel resistance mutations have arisen. We present a high-throughput yeast-based assay for the prediction of dasatinib- and ponatinib-resistant mutations in the ABL1 kinase domain. Our results not only recapitulate all known dasatinib-resistant mutations, but confirm recent patient data emphasizing the importance of compound mutations in ponatinib resistance. Furthermore, with hundreds of kinase inhibitors in development for the treatment of a wide range of diseases, understanding the cellular pathway of each kinase is critically important to the selection of ideal drug targets and avoiding potentially toxic side effects. Discovery of novel tyrosine kinase substrates is hindered by the presence of 90 human tyrosine kinases, which are often active in the same pathways. Phosphoproteomics, chemical genetics, and in vitro assays have been used to great success, yet only 30% of phosphorylated tyrosines in the human proteome have been assigned to a specific kinase. Recent advances in predicting tyrosine kinase substrates have been made by combining large data sets on kinase domain specificity, cellular localization, and protein-protein interactions in probabilistic algorithms. However, the high-quality data sets required for accurate predictions are often lacking. In chapter 2, we present a high-throughput yeastbased assay for screening millions of putative kinase substrates, which we then use to build a probabilistic model to accurately predict the in vitro phosphorylation of candidate substrates

Radiation therapy is used to treat many diseases such as cancer. However, off-targeted side-effects called bystander effects are observed in patients post radiotherapy. Bystander effects are when non-irradiated cells exhibit similar effects as directly irradiated cells. Understanding how these bystander effects are mediated can help improve cancer treatment. Previous work from our lab has shown that extracellular vesicles derived from conditioned media of irradiated mouse embryonic fibroblasts mediate radiation-induced bystander effects by inhibiting clonogenic survival, increase γH2AX, and increase ROS. However, when the protein Abl is mutated so that it no longer can enter the nucleus, the EVs from the conditioned media of these irradiated cells do not cause bystander effects. When nuclear Abl is reconstituted into these mutant cells, the EVs from the conditioned media of these irradiated cells cause bystander effects such as increase γH2AX and increase ROS. This suggests that nuclear Abl is required for extracellular vesicle mediated radiation-induced bystander effects. Abl inhibitors are FDA approved and might be viable treatments to reduce bystander effects in patients undergoing radiation therapy. Additionally, in a paper previously published by our lab, nuclear Abl is required for miR-34c processing. Since EVs can contain miRNAs as cargo, miR-34c could be involved in the nuclear Abl dependent extracellular vesicle mediated radiation-induced bystander effects. This offers another possible treatment target to counter radiation-induced bystander effects.

ABL is an ubiquitously expressed non-receptor tyrosine kinase involved in multiple cellular functions including programmed cell death. Upon DNA damage, ABL has been shown to upregulate PUMA, p53 upregulated modulator of apoptosis, and causes downstream mitochondrial intrinsic apoptotic events. However, the mechanism by which ABL regulates PUMA expression remains unknown. We have shown that ABL does not change PUMA protein subcellular localization through immunofluorescence. Through protein and RNA quantification, we showed that overproduction of PUMA RNA leads to an increase in PUMA protein expression. ABL requires a functional kinase domain to stimulate PUMA protein expression. Inhibition of ABL kinase activity using Imatinib diminishes the ability of ABL to induce PUMA protein expression.

Activation of cell surface receptors by ligands leads to the recruitment of a number of signaling molecules that mediate cellular responses. RAS-GTPases are signaling proteins that bring about major changes in cell growth, differentiation, gene expression and cytoskeletal organization upon receptor stimulation. The RAS effector RIN1 is involved in receptor trafficking and signaling. RIN1 is recruited to the receptor following ligand stimulation, but the function of its individual effector domains in this process remained uncharacterized. RIN1 acts as a guanine nucleotide exchange factor (GEF) for the small GTPase RAB5, which is involved in the formation of early endosomes. RIN1 can also directly bind and activate ABL tyrosine kinases, which have been implicated in cellular actin remodeling and receptor trafficking. RIN1 also forms a complex with STAM, an ESCRT complex protein, which favors maturation of receptor-containing endosomes. As all of RIN1's known effectors are involved in modulating receptor trafficking, we resorted to examine the role of individual domains in receptor internalization and fate. Chapters two and three debrief the mechanisms by which RIN1 effectors function in an integrated manner to regulate receptor trafficking and corresponding cellular responses.Using domain-specific mutants of RIN1, we show that the RAB5 and ABL signaling pathways mediate opposing functions, maintaining a balance in the route and rate of receptor internalization. RAB5 promotes actin remodeling, EGF induced macropinocytosis and migration, facilitating receptor degradation. ABL kinases, on the other hand, prevent receptor degradation and migration towards EGF. Our study also shows that regulation of RIN1 localization by the 14-3-3 proteins is a major factor in determining signaling intensity. We characterized a novel binding partner of RIN1, namely, BIN1, a BAR domain protein involved in membrane bending. Intracellular pathogens invade host cells by exploiting host cell surface receptors and signaling pathways. Listeria monocytogenes in a food-borne pathogen that binds host MET to invade epithelial cells and modulates RAB5 GTPases at several stages of the infection. The effect of host RAB5 regulators on pathogenesis remained uncharacterized. We analyzed the role of RIN1, a major RAB5-GEF in epithelial cells, in the process of bacterial invasion and spread (chapter four). This study leads the way to determining the mechanism of pathogenesis of several pathogens that depend on host RAB5-GTPases for effective infection progress. Finally, chapter five discusses the significance of our studies from a therapeutic viewpoint in the context of cancers and infectious diseases.

The design and characterization of organic photovoltaics for improved device performance is described. The work is divided into three targets: 1) creation of a consistent high efficiency organic photovoltaic device to act as a standard, 2) optimization of PEDOT:PSS anode buffer layer for device performance using combined thermal annealing and UV-ozone treatments, and 3) characterization and utilization of novel materials, derivatives of existing organic electronic materials, in organic photovoltaic devices. Through this work a standard was established producing a 1.4% power conversion efficiency using an architecture of ITO/PEDOT:PSS/CuPc:C60/C60/Bphen/Ag. The combined PEDOT:PSS treatments produced devices with the same architecture as the standard but with an power conversion efficiency device of 2.6%. Novel materials acting as a cathode buffer layer produced devices that showed device efficiency of 1.27%.

Adventure-based Learning (ABL) is the purposeful use of activities in sequence to improve personal and social development of participants (Cosgriff, 2000). ABL goes beyond instant activities (i.e. ice-breakers, cooperative games) to create an environment in which students enjoy the challenge while developing emotional and social competencies (Panicucci, Faulkingham Hunt, Kohut, Rheingold, & Stratton, 2002). The ABL curriculum model serves as a good fit in schools for the personal and social development of children and as an alternative to the multi-activity curriculum model (Sutherland, Ressler, Stuhr, 2009). The responsibility of successful, meaningful, adventure based programming lies in how the content is facilitated (Panicucci et al., 2002), and a reason for the limited number of P-12 physical education professionals using ABL as a content area is due to a lack of experience and formal training in this curriculum (Sutherland et al., 2009). The purpose of this study is to review the experiences of two novice ABL facilitators (i.e. two in-service physical education teachers) during training in, and facilitation of a completed 10-day ABL instructional unit in their respective classes. Transformative Learning Theory (TLT) (Mezirow, 1997) guided this qualitative case study. TLT is a reconstructive theory that focuses on adult learning and adult educator, grounded on the nature of human communication, and seeking agreement on our own interpretations and beliefs is central to human communication and the learning process (Mezirow, 1991; 1997). Three themes emerged for each participant. Findings suggest: (a) further training and support of in-service teachers prior to facilitating ABL, (b) development of more in-depth content knowledge in ABL, and (c) an identification of effective and ineffective ABL pedagogies through critical self-reflection.