CD4+ T cells are critical in the fight against parasitic, bacterial, and viral infections, but are also involved in many autoimmune and pathological disorders. Ligation of the T Cell Receptor (TCR) is the primary signal required for T cell activation proliferation, differentiation and cytokine release. Upon TCR activation, several kinases and adaptor proteins are assembled at the TCR/linker for activation of T cells (LAT) signaling complexes, a process indispensable for optimal signal transduction. One important group of proteins recruited to the TCR/LAT complexes is the GRB2 family of adaptors. Due to their role in mediating signaling complexes, the GRB2 family of adaptors are critical for development, proliferation, and survival of diverse cell types. These proteins have been linked to the initiation and progression of numerous pathological conditions including diabetes, asthma/allergy, and solid and hematopoietic malignancies. Therefore, it is essential to characterize and understand the complete functions of these proteins for the generation of safe and efficient targeting treatments for diseases mediated by these proteins. In T cells, GRB2 and its homologs, GADS and GRAP, are crucial for the propagation of signaling pathways through the TCR and adaptor protein LAT. These proteins recruit distinct sets of proline-rich ligands to LAT thereby inducing multiple signaling pathways such as MAP kinase activation, calcium influx and cellular adhesion. However, the role of GRB2 family members in controlling TCR and LAT mediated signaling in mature human T cells is not completely understood. Moreover, the relative role of GRB2 family members in the extent and timing of the recruitment of SH3 domain ligands to the LAT complex is unknown. Our hypothesis is that these proteins recruit distinct sets of ligands to the LAT complex that can drive differential downstream signaling events. As presented in CHAPTER III, we developed microRNA and shRNA targeting viral vectors to effectively inhibit the expression of GRB2 and GADS in human CD4+ T cells to examine the role of these adaptors in mature human T cells. We also established optimized protocols for high efficacy retro or lentiviral transduction of human T cell lines, activated and "hard-to-transduce" non-activated primary human CD4+ T cells. In CHAPTER IV, we demonstrate the requirement for GRB2 in TCR-induced IL-2 and IFN-γ release. The defects in cytokine release in the absence of GRB2 were attributed to diminished formation of LAT signaling microclusters, which resulted in reduced MAP kinase activation, calcium flux and PLC-γ1 recruitment to LAT signaling clusters. Overall, the data presented in this chapter demonstrate that the ability of GRB2 to facilitate protein clustering is as important in regulating TCR-mediated functions as its capacity to recruit effector proteins. This highlights that GRB2 regulates signaling downstream of adaptors and receptors by both recruiting effector proteins and regulating the formation of signaling complexes. In CHAPTER V, we describe the role for GADS in mediating TCR-induced IL-2 and IFN-γ production. GADS was critical for the recruitment of SLP-76 and PLC-γ1 to the LAT complex and subsequent calcium influx. We also show, in contrast to the current paradigm, that recruitment of GADS/SLP-76 complexes to LAT is not required for TCR-mediated adhesion and cytoskeletal arrangement. Overall, our studies reveal novel mechanisms for the role of GRB2 family members in TCR-mediated signaling. They also provide insight into the mechanisms that regulate growth factor, cytokine and insulin receptors. Importantly, studies presented in this thesis will help us understand the mechanisms of T cell activation and highlight potential new therapies for T cell-mediated diseases, including leukemia, lymphomas, autoimmune disorders and cardiovascular disease.

Saved, By Becoming a Slave to the Rhythm!, is a choreographic work that demonstrates how an individual finds purpose through a rite of passage filled with freedom, music, and movement of the House dancing scene. Saved, reveals how DJ Larry Levan gained recognition from the community of the Paradise Garage Club, as one of the best DJs of his time. The work is split into three sections community, individual, and movement. The community section highlights the universal love, freedom, and multiculturalism of Paradise Garage that was generated by the charismatic control of Larry Levan's DJ mastery. Levan's charismatic mastery is what moved the Paradise Garage community to deem him one of the best DJs in House music history. The community section transitions into the individual section. The individual section showcases the demons of Levan's life. A solo, performed to the words of Levan's best friend, Frankie Knuckles, displays how his excessive lifestyle of drugs and sex became the key to his demise. The third section is an homage to Larry Levan, and members of the Paradise Garage community whom have passed on. I title this section the movement section, because it unveils the progression and stability of the House dance community. In addition to this cultural stability, the movement terminology of House dance is solidified. I want the audience to leave Saved, By Becoming a Slave to the Rhythm!, inspired to search for their purpose in life, find it, and live it lovingly, joyfully, and peacefully.

In the history of this country queer-identified individuals have faced discrimination and harassment in their places of school and work for many years. Research has found that exposure to these experiences can have a negative impact on mental health. Prior to this study, no data were available as to whether or not queer-identified Couple and Family Therapists (C/MFTs) also have faced discrimination and harassment within the field of C/MFT. This study explored the lived experiences of queer-identified C/MFTs in an attempt to identify what unique struggles this population faces, and if these struggles include coping with discrimination and harassment. Participants identified concerns over inadequate training and resources, issues related to self-disclosure, the role of being a spokesperson for the queer community, the role that context plays with regard to their experiences, the strengths of being a queer-identified C/MFT, and the relationship that the American Association of Marriage and Family Therapy (AAMFT) has had with queer-identified C/MFTs and the queer community in general. Finally, participants were asked to give words of advice to other therapists based on their own experiences. The results of the study suggest that queer-identified C/MFTs find their sexual orientation as a strength; it not only benefits their clinical work, but can enable a sense of empowerment in advocating for the rights of their community.

Natural aging leads to substantial brain changes. These biological changes can, and often do, precede changes in affect, cognition, and behavior. Even subtle changes, for example in affective experience, can create problematic outcomes in day-to-day emotion regulation and decision-making. For example, poor emotion regulation may lead an individual to fall prey to an emotionally potent scam. Similarly, an overly positive individual may not fully attend to or consider potentially negative future outcomes when faced with a decision. This work characterizes changes in affect across the lifespan, and how affect corresponds to brain function, as indexed by the blood oxygen dependent signal, during tasks taxing emotion regulation and decision-making functions. I predicted that age would correlate with greater positive relative to negative emotions and with a more global (i.e., less specific and less complex) representation of emotions. The former predicted pattern indicates increased "affective optimization" and the latter indicates reduced "affective complexity." I predicted that affective optimization and complexity would correlate with brain function during emotion regulation and decision-making. I used time-based experience sampling, self-reported affect, implicit measures of affect, and performance based measures of affect to determine the associations between age and affective optimization and complexity. Results show that age negatively correlates with affective complexity. Specifically, older age was associated with less negative affect complexity, less positive emotion regulation, less affective awareness. Also, older age corresponded to lower levels of negative affect, as indexed by their experiences and an implicit measure of affect. Next, I examined emotion regulation using a cognitive reappraisal task. I found that older age was associated with less successful reappraisal of negative and positive affect. I also found individual differences in the ventromedial prefrontal cortex among older adults during emotion regulation. Lastly, I examined decision-making patterns using an intertemporal choice task. I found that younger adults’ experienced affect aligned more closely with their decision patterns. Among older adults, affective acceptance correlated with individual differences in the striatum and insula. Taken together, these results support the idea that lower levels of affective competence, rather than higher levels, characterize older age. Also, individual differences in affect parallel individual differences in brain function in the somatic marker circuitry. This suggests possible deficits in interpreting visceral information important to emotion regulation and decision-making. The findings from this work will be important for understanding why some older adults are more susceptible to scams, fraud, and decision-making problems.

The problem of risk-averse decision making under uncertainties is studied from both modeling and computational perspectives. First, we consider a framework for constructing coherent and convex measures of risk which is inspired by infimal convolution operator, and prove that the proposed approach constitutes a new general representation of these classes. We then discuss how this scheme may be effectively employed to obtain a class of certainty equivalent measures of risk that can directly incorporate decision maker's preferences as expressed by utility functions. This approach is consequently utilized to introduce a new family of measures, the log-exponential convex measures of risk. Conducted numerical experiments show that this family can be a useful tool when modeling risk-averse decision preferences under heavy-tailed distributions of uncertainties. Next, numerical methods for solving the rising optimization problems are developed. A special attention is devoted to the class p-order cone programming problems and mixed-integer models. Solution approaches proposed include approximation schemes for $p$-order cone and more general nonlinear programming problems, lifted conic and nonlinear valid inequalities, mixed-integer rounding conic cuts and new linear disjunctive cuts.

Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants that are known to elicit adverse health effects including skin toxicity and cancer to animals and humans. 4-Monochlorobiphenyl (PCB3), a low-chlorinated airborne PCB conger is present in human blood and the environment. 1-(4-Chlorophenyl)-benzo-2,5-quinone (4-ClBQ), a quinone metabolite of PCB3, has been shown to induce oxidative stress and toxicity in human mammary and prostate epithelial cells. These studies were designed to investigate and characterize the cellular responses to 4-ClBQ in HaCaT human skin keratinocytes. We found that 4-ClBQ treatment increased cellular reactive oxygen species (ROS) production, inhibited cell proliferation, and induced toxicity in HaCaT cells. Results from a Human Antioxidant Mechanism PCR array and quantitative RT-PCR assay showed that the mRNA levels of antioxidant gene selenoprotein P (sepp1) and catalase were significantly downregulated by the treatment, which correlated with evident decreases in their protein levels and catalase enzymatic activity. Pharmacological (sodium selenite supplementation) and molecular (sepp1overexpression) manipulation of SEPP1 expression significantly suppressed 4-ClBQ induced oxidative stress and toxicity. Additional results demonstrated that decreased catalase expression was associated with an inhibition in transcriptional coactivator peroxisome proliferator activated receptor Γ coactivator 1α (PGC-1α) expression. Overexpression of pgc-1α restored catalase expression and activity and consequently protected HaCaT cells from 4-ClBQ induced oxidative stress and toxicity. Furthermore, results from metabolic flux analysis using Seahorse XF96 Analyzer showed that 4-ClBQ treatment increased extracellular acidification rate, proton production rate, and oxygen consumption rate, which were associated with increases in glucose uptake and in the expression of glucose metabolism regulatory gene hexokinase 2, pyruvate kinase M2, and glucose-6-phosphate dehydrogenase (G6PD). G6PD is the rate-limiting enzyme of the pentose phosphate pathway. The enhanced expression of G6PD correlated with an increase in cellular glutathione content; and inhibition of G6PD activity sensitized HaCaT cells to 4-ClBQ induced toxicity, suggesting that the protective function of the pentose phosphate pathway is active in 4-ClBQ treated cells. Interestingly, we also found that 4-ClBQ selectively and significantly decreased mitochondrial complex II subunits C (sdhc) and D (sdhd) mRNA expression and subsequently reduced complex II activity leading to metabolic oxidative stress and toxicity, which were significantly suppressed by overexpressing sdhc and sdhd in HaCaT cells. Taken together, findings from this project demonstrate that 4-ClBQ treatment increases ROS production through perturbing cellular metabolism and mitochondrial function and decreases antioxidant capacity by inhibiting SEPP1 and catalase expression in HaCaT cells. This imbalance due to increased mitochondrial prooxidant production and decreased antioxidant capacity leads to oxidative stress and toxicity. Importantly, antioxidant supplementation could abrogate 4-ClBQ induced toxicity, suggesting that antioxidants, especially nutrient-based manipulation of selenoproteins could be promising countermeasures for PCB induced adverse health effects in humans.

Objectives: This retrospective cohort study aimed to assess the survival time and factors associated with survival of anterior composite-resin restoration placed at the University of Iowa, College of Dentistry (UICOD). Methods: Patients at the UICOD who had anterior composite restorations placed between 1995-1997 and could be followed through 2013 were included in this study. Factors included: patient age and gender, tooth type (central or lateral incisor, or canine) and location (maxillary or mandibular), restoration size (1, 2, 3, 4 and more surfaces), provider type (dental student, graduate student, faculty), and clinic (operative, family, or other clinics) where the initial restoration placed. Survival time of a restoration was defined as how long a restoration lasted from the day of placement until the day of subsequent treatment. Subsequent treatment included: restorations, veneer and/or crowns, root canal therapy, and extraction. One restoration per patient was used for the study. Statistical analyses consisted of the Kaplan-Meier analysis and Cox regression (alpha=0.05). Results: Of the 668 subjects (mean±SD age=55±13 years and 60.8% females) who fulfilled the inclusion criteria, the mean±SD survival time of composite resin restoration was 11±7 years and an overall survival rate was 43.3%. Patients' gender, age, tooth location, and clinic type were not significantly associated with the survival time of composite resin restoration. Cox regression model indicated that significant differences in the restoration hazards were found on tooth type (p=0.002), provider type (p=0.003) and restoration sizes (p=0.0072). Central (HR=1.59; CI=1.23-2.07) and lateral (HR=1.36; CI=1.03-1.79) incisors had a significantly higher hazard ratio (HR) than canines, and faculty had significantly lower HR than undergraduate students (HR=0.68, CI=0.55-0.85). Restorations sizes one surface (HR=0.6; CI=0.44-0.81) and two surfaces (HR=0.65; CI=0.48-0.88) had significantly lower HR than four and more surfaces restorations. Conclusion: The mean and median survival time of anterior composite restoration at UICOD was 11 and 13 years, respectively. Tooth type, provider type, and restoration size were significant predictors for the survival time of anterior composite-resin restoration.

A fundamental issue in educational measurement is what frame of reference to use when interpreting students’ performance on an assessment. One frame of reference that is often used to enhance interpretations of test scores is normative, which adds meaning to test score interpretations by indicating the rank of an individual’s score within a distribution of test scores of a well-defined reference group. One of the most commonly used frames of reference on student achievement provided by test publishers of large-scale assessments is national norms, whereby students’ test scores are referenced to a distribution of scores of a nationally representative sample. A national probability sample can fail to fully represent the population because of student and school nonparticipation. In practice, this is remedied by weighting the sample so that it better represents the intended reference population. The focus of this study was on weighting and determining the extent to which weighting grade 4 and grade 8 student records that are not fully representative of the nation can recover distributions of reading and math scores in a national probability sample. Data from a statewide testing program were used to create six grade 4 and grade 8 datasets, each varying in its degree of representativeness of the nation, as well as in the proximity of its reading and math distributions to those of a national sample. The six datasets created for each grade were separately weighted to different population totals in two different weighting conditions using four different bivariate stratification designs. The weighted distributions were then smoothed and compared to smoothed distributions of the national sample in terms of descriptive statistics, maximum absolute differences between the relative cumulative frequency distributions, and chi-square effect sizes. The impact of using percentile ranks developed from the state data was also investigated. By and large, the smoothed distributions of the weighted datasets were able to recover the national distribution in each content area, grade, and weighting condition. Weighting the datasets to the nation was effective in making the state test score distributions more similar to the national distributions. Moreover, the stratification design that defined weighting cells by the joint distribution of median household income and ethnic composition of the school consistently produced desirable results for the six datasets used in each grade. Log-linear smoothing using a polynomial of degree 4 was effective in making the weighted distributions even more similar to those in the national sample. Investigation of the impact of using the percentile ranks derived from the state datasets revealed that the percentile ranks of the distributions that were most similar to the national distributions resulted in a high percentage of agreement when classifying student performance based on raw scores associated with the same percentile rank in each dataset. The utility of having a national frame of reference on student achievement, and the efficacy of estimating such a frame of reference from existing data are also discussed.

Each hydraulic fracturing well uses up to 5,000 tons of silica-containing sand, or proppant, during its operational lifetime. Over one million wells are currently in operation across the continental United States. The resulting increase in demand resulted in the production of 54 million metric tons of sand for use as hydraulic fracturing proppant in 2015. The goal of this study was to determine the relative risk of occupational exposure to respirable crystalline silica to workers performing tasks associated with mining, processing, and transport of proppant. Sand samples were aerosolized in an enclosed chamber. Bulk and respirable samples were submitted to a commercial lab for silica analysis. A risk ratio was calculated by comparing respirable dust concentrations to the current occupational safety regulations. Raw sand produced higher concentrations of respirable dust and a higher risk ratio (3.2), while processed dust contained higher percentages of respirable crystalline silica but a lower risk ratio (0.5). When vibration was introduced prior to aerosolization, concentrations tended to increase as vibration times increased, resulting in an increase of the associated risk ratio (2.3). Results of the study indicate that workers in sand mines and workers exposed to proppant that has undergone low-frequency vibration are at increased risk of exposure to respirable crystalline silica compared to workers who are exposed to proppant that has not undergone vibration.

Intensity-modulated brachytherapy techniques, compensator-based intensity modulated brachytherapy (CBT) and interstitial rotating shield brachytherapy (I-RSBT), are two novel conceptual radiation therapies for treating cervical and prostate cancer, respectively. Compared to conventional brachytherapy techniques for treating cervical cancer, CBT can potentially improve the dose conformity to the high-risk clinical target volume (CTV) of the cervix in a less invasive approach. I-RSBT can reduce the dose delivered to the prostate organ at risks (OARs) with the same radiation dose delivered to the prostate CTV. In this work, concepts and prototypes for CBT and I-RSBT were introduced and developed. Preliminary dosimetric measurements were performed for CBT and I-RSBT, respectively. A CBT prototype system was constructed and experimentally validated. A prototype cylindrical compensator with eight octants, each with different thicknesses, was designed. Direct metal laser sintering (DMLS) was used to construct CoCr and Ti compensator prototypes, and a 4-D milling technique was used to construct a Ti compensator prototype. Gafchromic EBT2 films, held by an acrylic quality assurance (QA) phantom, were irradiated to approximately 125 cGy with an electronic brachytherapy (eBT) source for both shielded and unshielded cases. The dose at each point on the films were calculated using a TG-43 calculation model that was modified to account for the presence of a compensator prototype by ray-tracing. With I-RSBT, a multi-pass dose delivery mechanism with prototypes was developed. Dosimetric measurements for a Gd-153 radioisotope was performed to demonstrate that using multiple partially shielded Gd-153 sources for I-RSBT is feasible. A treatment planning model was developed for applying I-RSBT clinically. A custom-built, stainless steel encapsulated 150 mCi Gd-153 capsule with an outer length of 12.8 mm, outer diameter of 2.10 mm, active length of 9.98 mm, and active diameter of 1.53 mm was used. A partially shielded catheter was constructed with a 500 micron platinum shield and a 500 micron aluminum emission window, both with 180° azimuthal coverage. An acrylic phantom was constructed to measure the dose distributions from the shielded catheter in the transverse plane using Gafchromic EBT3 films. Film calibration curves were generated from 50, 70, and 100 kVp x-ray beams with NIST-traceable air kerma values to account for energy variation. In conclusion, CBT, which is a non-invasive alternative to supplementary interstitial brachytherapy, is expected to improve dose conformity to bulky cervical tumors relative to conventional intracavitary brachytherapy. However, at the current stage, it would be time-consuming to construct a patient-specific compensator using DMLS, and the quality assurance of the compensator would be difficult. I-RSBT is a promising approach to reducing radiation dose delivered to prostate OARs. The next step in making Gd-153 based I-RSBT feasible in clinic is developing a Gd-153 source that is small enough such that the source, shield, and catheter all fit within a 16 guage needle, which has a 1.65 mm diameter.