<b>Background</b> The term patient-centred care (PCC) is commonly used in the academic literature and UK health policy. However, this concept is ill defined and little is known about its applicability to the management of people with long-term conditions (LTCs). Several methodologies were used to explore the meaning of PCC, identify key experiences that matter to people with LTCs and consider the implications of these findings for the measurement of patient reported experiences of health care. <b>Method</b> Four stages of research were conducted for this thesis. First, a conceptual synthesis of existing PCC and patient experience frameworks to produce an overarching framework of PCC. Second, secondary qualitative analysis of patient interviews to identify key experiences of PCC that matter to people with LTCs. Third, development of a PCC questionnaire for people with LTCs, based on findings from the conceptual synthesis and secondary analysis. Fourth, further exploration of the questionnaire through cognitive debriefing interviews with people with LTCs and health professionals. <b>Results</b> The overarching framework of PCC consisted of 8 domains; access, availability and choice, information, communication and education, relationship with health professionals, involvement in care, respect and dignity, responsiveness to individual needs and preferences, consistency, continuity and co-ordination, and effectiveness of treatment and care. Findings from secondary analysis suggested that many of the domains from the framework were also important in care for people with LTCs, but that some aspects of care held an additional meaning. The themes identified in the secondary analysis were used to generate items for a generic PCC experience questionnaire for people with LTCs. The final questionnaire, ‘Your Experiences of Care in Long-Term Conditions’ consisted of 47 questions across three sections. Feedback from the debriefing interviews suggested that the questionnaire had asked important questions about care for people with LTCs and that it was relevant to people with a range of different LTCs. <b>Conclusion</b> Development of an overarching framework of PCC demonstrated some conceptual problems in understanding and evaluating the notion of PCC. Findings from this thesis suggest that an overarching questionnaire of experiences of PCC is feasible and acceptable to people with a range of different LTCs. Future research needs examine standard features of the newly developed PCC experience questionnaire for people with LTCs and consider the potential use and contribution of data in enhancing care for people with LTCs.

RASSF1A silencing is the most widely reported epigenetic event in sporadic human malignancies and is increasingly observed to be associated with poorer prognosis and outcome in lung, breast and bladder cancers amongst others. By performing a genetic screen in mice using Sleeping Beauty (SB) transposon-mediated insertional mutagenesis, we identified candidate genes associated with tumourigenesis in the absence of Rassf1a. A top hit in our screen was the terminal differentiation transcription factor Runx2. In this study, we describe how together loss of RASSF1A and RUNX2 exacerbate oncogenic YAP1-TEAD complexes and how RUNX2, p73 and TEAD effectively compete for YAP1 association. Interestingly, YAP1-TEAD complexes, as well as RUNX factors have been known to be important regulators of embryonic development by affecting cell fate. We show that RASSF1A is a novel regulator of stem cell pluripotency by introducing a cross link between the Hippo and Wnt signalling pathways, via TEAD and &beta;-catenin. More specifically, we demonstrate that RASSF1A is a barrier to somatic cell reprogramming by activating differentiation circuits, but its loss results in upregulation of the core stem cell marker network (NANOG, OCT4 and SOX2) in embryonic stem cells and the pre-implantation mouse embryo. In addition, we find that deregulation of the Hippo pathway in the absence of RASSF1A also leads to increased prevalence of stem cell characteristics in cancer and higher proportion of 'cancer stem cells'. This effect is mediated through both YAP and its paralog TAZ. Finally, we show that a second isoform of RASSF1, RASSF1C, the expression of which is maintained in cancers, contributes to cancer stem cell generation through a similar mechanism. This work concentrates on establishing the biology of RASSF1A in normal tissue and answering whether the broad prognostic value in tumours from biologically distinct tissues is due to a fundamental control of stem cell pluripotency.

Despite the rapid increase in both adiposity and diabetes in China, substantial uncertainty remains about the relationship between these two conditions in the population. Using data from the China Kadoorie Biobank study of 0.5 million adults recruited during 2004-8 from 10 diverse areas of China, this thesis examines the associations of different adiposity measures (overall adiposity: BMI and percentage body fat; central adiposity: waist circumference, waist-hip ratio, and waist-height ratio) with type 2 diabetes prevalence and incidence. To assess the quality of diagnosis, a separate event-verification study was conducted in ~1,000 reported diabetes cases. Overall at baseline, the mean age of the analysed participants was 52 years, 41% were men, 32% had a BMI≥25 kg/m² (4% ≥30 kg/m²) and 5.2% had self-reported or screen-detected diabetes. Both cross-sectional and prospective analyses of well-characterised diabetic cases (26,622 prevalent and 2,910 incident cases) showed that adiposity is strongly positively associated with diabetes (p<0.0001), throughout all or most of the distribution of each adiposity measure. Per 1 SD higher adiposity measure, measures of central adiposity were associated with ~90% increased risk, compared with ~80-85% increased risk for general adiposity measures. Among measures of central adiposity, waist-hip ratio was the most strongly associated with diabetes prevalence, whereas waist circumference was the most predictive of diabetes incidence. Although measures of central adiposity were the most strongly associated with diabetes risk, there was still a strong positive association with measures of general adiposity after adjusting for central adiposity (p<0.0001), and the combination of both types of measure improved risk prediction. Given waist circumference, hip circumference was inversely associated with both diabetes prevalence and incidence (p<0.0001). For many of the above associations, there was possible effect modification by age and sex. These findings will provide important and reliable evidence to quantify the level of diabetic risk associated with adiposity, hence to inform clinical interventional strategies and future public health programmes.

Traumatic brain injuries are a significant health concern, being responsible for over 52,000 deaths each year. Unfortunately, many traumatic brain injuries often go misdiagnosed or undiagnosed. Primary care providers are the principal and first source of medical contact for individuals, meaning that they are vital in the diagnosis of previous traumatic brain injuries in order to prevent future sequelae. There are currently several well-validated screening tools currently available for use by primary care providers. This study uses a self-reported survey to determine which of these tools are used by primary care nurse practitioners from a northern New England state and to compare the results to the suggestions made in current literature. The tools chosen by different primary care providers vary greatly, as do the indications used for initiation of traumatic brain injury screening. There were a total of 17 participants in the study, all of whom were at least masters level prepared nurse practitioners. The average number of years spent in practice was 11.7, with an average of 10.4 of those years in primary care. The most commonly used screening tool was the Mini Mental Status Exam, followed by the Montreal Cognitive Assessment and the CDC Acute Concussion Evaluation tool. Screening tools developed specifically for TBI assessment, such as the Ohio State University TBI ID Method and the Brief Traumatic Brain Injury Questionnaire were found to be seldom used (17% of total participants). Many primary care providers do not feel confident in their ability to diagnose such injuries, often due to lack of expertise in the area, which was reflected in the self-reported survey. As new screening tools become available, it is imperative that they are tested for validity, and then utilized in practice. Due to the complexity of diagnosing traumatic brain injuries, the most simple and accurate screening tools are often the ones preferred by providers. Moving forward, simple new screening tools need to be evaluated for effectiveness and ease of use. These tools should then be introduced to primary care practitioners, with suggestions as to how to best supplement them with other parts of an exam. Since TBIs are becoming an increasingly more common diagnosis in primary care, future advanced nursing evidence-based practice should focus on the recommended screening tools so as to better identify and guide treatment. Future research is needed to evaluate the extent to which part of an exam yield the most pertinent and accurate findings, as well as to compare the effectiveness of screening models utilized in civilian and military settings.

Background: Athletes continue to strive for an edge over the competition. In recent years, dietary nitrate supplementation, particularly in the form of beetroot juice, has been shown to improve oxygen cost economy in endurance-focused submaximal intensity exercise and extend the time to exhaustion during maximal intensity exercise. However, scarce literature exists on the effects of nitrate supplementation on sports that focus mainly on strength and power. CrossFit is a sport that relies on strength, power, and endurance, and incorporates high-intensity, Olympic-based lifting and interval training exercises. Purpose: To investigate the effects of six days of dietary nitrate supplementation on strength, power and endurance in CrossFit athletes. Methods: Twelve male CrossFit athletes (age, 23 ± 5 years; CrossFit training [greater than]3 days/week for at least 4 months) participated in this randomized, crossover, double-blind, placebo-controlled study. After familiarization, baseline testing for peak aerobic capacity (VO₂peak), anthropometrics, and body composition (BodPod®) was performed. A three-day food log was completed both before and after the completion of the study. The food consumed 24 hours before the first trial was followed for each subsequent trial. Day 1 baseline testing included a blood draw for plasma nitrate and nitrite, as well as strength (Biodex), power (Wingate), and endurance (2K row) tests. Day two consisted of a sport-specific CrossFit circuit known as Grace. After testing, participants consumed either 8 mmol potassium nitrate (N) or 8 mmol of potassium chloride (PL) in pill form for six days. After this period, the participants returned for post-testing, had a 10-day washout period, and then returned for baseline and post-testing consuming the opposite supplement. Repeated measures of analysis of variance and a Student's T-test (SPSS Version 21, Cary, NC) were used to compare results. Results: There were no significant differences in dietary intake except for fiber (PRE: 22 ± 9 vs POST: 27 ± 11 g, P = 0.03). Plasma nitrate did not significantly change in N (PRE: 146.77 ± 69.48 vs POST: 192.05 ± 69.48 nM, P = 0.07) but did significantly increase in PL (PRE: 140.96 ± 59.98 vs POST: 204.82 ± 64.82 nM, P = 0.02). There were no significant differences for isokinetic strength measurements, but for isometric extension 60° there was a main effect of time (P = 0.03) which equated to a 17.23 ± 13.04 Nm (10.19 ± 36.60 %) increase in force in N and a 10.65 ± 6.42 Nm (6.11 ± 17.36 %) increase in PL. The Wingate power test resulted in a main effect of time, but no group x time effect. However, N increased 58.92 ± 7.11 W (6.62 ± 3.96 %), but PL only increased 6.92 ± 26.01 W (0.77 ± 14.19 %; P = 0.08). No significant differences between groups were measured for the 2000-m rowing test. While not statistically significant, the time to complete the Grace circuit improved on average by -32.35 ± 53.24 sec (-8.94 ± 31.14 %) in N compared to a -10.83 ± 12.68 sec (-3.84 ± 8.94 %) in PL. Conclusion: Consuming dietary nitrate in the potassium nitrate salt form did not statistically improve strength, power, or endurance in male CrossFit athletes. However, while not statistically significant, the improvement in the time to complete the sport specific Grace test using N may be meaningful during competition. / A Thesis submitted to the Department of Nutrition, Food and Exercise Sciences in partial fulfillment of the Master of Science. / Fall Semester 2015. / October 26, 2015. / CrossFit, Dietary Nitrate / Includes bibliographical references. / Michael J. Ormsbee, Professor Directing Thesis; Maria T. Spicer, Committee Member; Lynn B. Panton, Committee Member; Michael J. Leeser, Committee Member.

Cardiovascular disease (CVD) remains the leading cause of death in the modern world, markedly in postmenopausal women. Increased arterial stiffness, measured as increased pulse wave velocity (PWV), and endothelial dysfunction are large contributors to the development of CVD during aging. Skeletal muscle mass has an inverse association with arterial stiffness and endothelial dysfunction which may illustrate increased risk for CVD in sedentary normal-weight women. However, age-related loss of strength (dynapenia) greatly exceeds loss of mass (sarcopenia) and while not related to increased PWV, it is associated with increased risk for CVD, disability, and all-cause mortality. High intensity resistance exercise training (RET) is the most effective exercise modality for prevention and treatment of sarcopenia and dynapenia. However, previous research has shown detrimental effects to the vascular system. Low-intensity RET (LIRET) is an effective form of exercise to increase muscle mass and strength, however with no effect in vascular or endothelial function in sedentary populations. Whole-body vibration training (WBVT) uses a vibrating platform to increase muscle activity during exercise and has a proposed thixotropic effect to increase blood flow to the working muscle. Additionally, WBVT reduces blood pressure and arterial stiffness with concurrent increases in muscle mass and strength similar to traditional moderate- and high-intensity RET. However, conventional WBVT uses the body weight as the only workload. Thus, to perform an exercise at a similar intensity as LIRET, an additional external weight may be needed during WBVT. PURPOSE: The aim of this study were; 1) to evaluate the effects of 12 weeks of WBVT and LIRET on hemodynamics and arterial stiffness; 2) to evaluate the effects of WBVT and LIRET on muscle strength as well as physical performance (6-minute walk test); and 3) to evaluate the effect of 12 weeks of WBVT and LIRET on endothelial function and vasodilatory response to exercise. METHODS: Thirty-one postmenopausal women were stratified by age, body mass index (BMI), and maximal voluntary contraction (MVC) (age, 65 ± 4 years; BMI, 23.2 ± 2.6 kg/m2; MVC, 17.3 ± 2.7 kg) and randomized into 2 experimental intervention groups, WBVT and LIRET, or a control group for 12 weeks. WBVT and LIRET consisted of 3 supervised exercise sessions per week (4 leg exercises). The following parameters were measured before and after 12 weeks of the assigned intervention: brachial and aortic systolic blood pressure (SBP), diastolic BP (DBP), mean arterial pressure (MAP), pulse pressure (PP), heart rate, augmented pressure (AP), augmentation index (AIx), AIx adjusted to 75 beats per minute (AIx@75), carotid-femoral PWV (cfPWV), brachial-ankle PWV (baPWV), femoral-ankle PWV (faPWV), fat mass (FM), fat-free mass (FFM), brachial and popliteal diameter, mean blood velocity (MBV), blood flow, vascular conductance, active and reactive hyperemia, 6-minute walk test time (6MWT), and leg strength including leg press (LP), flexion (LFlex), and extension (LExt). RESULTS: There were no significant differences between groups for any variables except for HR and 6MWT distance, which were lower and higher, respectively, in the WBVT compared to the other two groups at baseline. There were no significant changes in peripheral or central pressures over the 12-week intervention period. The WBVT group had significant reductions in AIx (-4.2 ± 1.5%, P = 0.016), AIx@75 (-4.2 ± 1.7 %, P = 0.033), and cfPWV (-.42 ± .18 m/s, P = 0.041) over the 12-week training protocol. There were significant group-by-time interactions for reductions in AP and AIx (with AIx@75 trending P = 0.051) in the WBVT, but not in LIRET or control groups (P < 0.05). Although resting brachial and popliteal characteristics (i.e. diameter and flow) were similar at rest between groups, WBVT and LIRET induced greater vasodilatory responses to flow-mediated dilation compared to control (P < 0.01), illustrating increased endothelial function. Additionally, WBVT elicited a greater vasodilatory response immediately post-exercise in the popliteal artery (4.9 ± 1.4 %, P = 0.007) compared to no change in control. Both, WBVT and LIRET elicited significant increases in LP, LFlex, and LExt over time (P < 0.01). These increases were significantly greater than no change in the control group. Additionally, WBVT induced a greater increase (19.2 ± 3.7%) in LExt strength compared to the increase (8.4 ± 2.6%) observed in the LIRET group (P = 0.007). The increase in LExt strength in the WBVT group was strongly associated with decreased AP (r= -.586, P = 0.045) and AIx (r=-.713, P = 0.009). CONCLUSION: We show that WBVT significantly reduced AIx and increased leg extension strength following 12 weeks of training compared to LIRET and control. The present study demonstrates that WBVT decreases central pressure wave reflection, an effect that was not accomplished by LIRET, despite similar increases in LP and LFlex strength. Interestingly, both WBVT and LIRET increased endothelial function as measured by brachial artery flow-mediated dilation (systemic effect). WBVT increasing exercise-induced vasodilation in the popliteal artery (local effect) following a 6MWT with no changes in LIRET or control. While WBVT and LIRET induced similar changes in leg strength and systemic endothelial function, only WBVT reduced known indices of left ventricle afterload that are associated with cardiovascular morbidity and mortality. Therefore, while LIRET may be a feasible modality to attenuate dynapenia, it is not effective in addressing the cardiovascular risk associated with reduced muscle mass and strength in apparently healthy postmenopausal women. WBVT may be the most efficacious modality to address these concerns. / A Dissertation submitted to the Department of Nutrition, Food, and Exercise Sciences in partial fulfillment of the Doctor of Philosophy. / Summer Semester 2017. / July 7, 2017. / Arterial Stiffness, Endothelial Function, Hemodynamics, Postmenopausal, Strength, Whole-body Vibration / Includes bibliographical references. / Arturo Figueroa, Professor Directing Dissertation; P. Bryant Chase, University Representative; Michael J. Ormsbee, Committee Member; Gloria Salazar, Committee Member.

Breast cancer is one of the most common forms of cancer among women in the United States. Although survival rates have improved following diagnosis, breast cancer survivors (BCS) must contend with the negative effects of the disease and its treatments. Breast cancer treatments can result in accelerated bone and muscle mass loss in conjunction with gains in fat mass. These unfavorable changes lead to reduced strength, physical function, and quality of life (QOL). Resistance training alone as well as a combination of resistance and impact training, such as hopping or jumping movements, have been effective in preventing losses in bone mineral density (BMD) and negative changes in body composition in BCS. More research is needed to determine if there is an alternative exercise mode that can promote improvements in BMD and body composition as well as strength, physical function, and QOL measures. Purpose: The purpose of this study was to examine the effects of 24 weeks of functional impact training (FIT) that combined a circuit of resistance training exercises with high impact exercises compared to a yin yoga program on body composition (lean and fat mass), BMD, blood biomarkers for bone resorption and formation (tartrate-resistant acid phosphatase 5b (TRAP-5b) and bone-specific alkaline phosphatase (BAP)), strength, physical function, fatigue, and QOL in BCS. Methods: Forty-four postmenopausal BCS (60.3 ± 8.3 years) who had completed primary treatment (surgery, chemotherapy, and radiation) were randomly assigned to one of two groups: FIT or yin yoga. Baseline body composition and regional and total BMD were measured via dual energy X-ray absorptiometry (DXA). Blood biomarkers for bone metabolism were analyzed via enzyme-linked immunosorbent assays (ELISA). Upper body strength was assessed using a one-repetition maximum (1RM) chest press, and lower body strength was assessed via isokinetic and isometric knee extension and flexion using the Biodex System 3. The Continuous Scale-Physical Functional Performance (CS-PFP) and a sit-to-stand with the Tendo power analyzer were used to measure physical function. Fatigue and QOL were determined via the Rand 36-Item Health Survey (SF-36), Functional Assessment of Cancer Therapy – Breast Symptom Index (FACT-B), and the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F). Participants completed the 45-minute FIT and yin yoga sessions twice weekly for 24 weeks with 48 hours between the two sessions. Measurements were completed at baseline, after 12 weeks, and at the end of the program. Changes in dependent variables over time were analyzed using repeated measures ANOVA (group by time). An intention-to-treat analysis was used for participants who completed baseline testing, but not the 12- or 24-week assessments. Significance was accepted at p < 0.05. Results: Thirty-two participants completed the study with an adherence rate of 86.6% and 84.4% for the FIT and yin yoga groups, respectively. There were no group by time effects for any measures of BMD. Main time effects were observed for BMD at the left femoral neck (0.883 ± 0.138 g/cm2 to 0.870 ± 0.131 g/cm2) and left forearm measures (total forearm: 0.465 ± 0.078 g/cm2 to 0.457 ± 0.069 g/cm2). There were no other changes in body composition or BMD measures over time. There was a group by time interaction for upper body strength with the FIT group significantly improving in upper body strength (73.2 ± 18.1 kg to 83.2 ± 22.3 kg) compared to the yin yoga group (59.8 ± 14.8 kg to 59.3 ± 15.6 kg). Main time effects were observed for peak isokinetic leg extension and flexion at 60o/sec, 120o/sec and 180o/sec and isometric leg flexion. All participants improved isokinetic leg extension and flexion by an average of 13.2% and 16.2%, respectively. Isometric flexion improved by 7.3%. There were time effects for CS-PFP scores (68.53 ± 12.87 U to 73.66 ± 12.62 U), sit-to-stand peak power (700 ± 202 W to 723 ± 199 W) and peak velocity (0.92 ± 0.22 m/s to 0.95 ± 0.23 m/s), fatigue scores (38.09 ± 11.50 to 42.29 ± 9.88), all domains of the SF-36 except pain, and all domains of the FACT-B and FACIT-F except emotional wellbeing. There were no group by time interactions for any of these measures. Conclusion: Both the FIT and yin yoga interventions improved lower body strength, physical function, fatigue and QOL in BCS. The FIT intervention resulted in improvements in upper body strength compared to yin yoga. Therefore, both programs may be beneficial modes of exercise for BCS looking to improve these outcomes. More research is needed to see if a FIT program of longer duration and higher intensity can elicit improvements in body composition and BMD. / A Dissertation submitted to the Department of Nutrition, Food and Exercise Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Summer Semester 2018. / July 17, 2018. / body composition, bone mineral density, breast cancer, functional impact training, yin yoga / Includes bibliographical references. / Lynn B. Panton, Professor Directing Dissertation; Laurie Grubbs, University Representative; Michael J. Ormsbee, Committee Member; Jeong-Su Kim, Committee Member; Bahram H. Arjmandi, Committee Member; Robert Moffatt, Committee Member.

Obesity is a known pathological condition associated with impaired glucose homeostasis leading to type 2 diabetes and increased susceptibility to loss of skeletal muscle mass and function. Recent investigations have demonstrated potential beneficial effects of vitamin D on insulin sensitivity and skeletal muscle mass and function similarly to the adaptations induced by resistance exercise training (RT). The main objectives of the present study were 1) to investigate physical and metabolic characteristics of a newly introduced mouse model of obesity and insulin resistance, p62 knock-out (KO) mice, in comparison to wildtype control mice (WC) and 2) to evaluate the efficacy of 10 weeks of vitamin D administration with or without RT to reduce adiposity and to alleviate the adverse effects of obesity on neuromuscular function, systemic insulin sensitivity, muscle/myofiber hypertrophy, and myofiber insulin signaling/inflammatory/myogenic regulators in p62 KO mice. In the present study, forty 24-week old p62 KO mice and ten sex-/age-match non-obese WC were utilized. In addition to non-obese, age-/gender-matched WC (n=10), p62 KO mice (n=40) were randomly assigned into one of four experimental groups (10/group) for 10 weeks: p62 KO control group (p62C, no treatment), vitamin D administration group (VD, 75 IU of vitamin D3 (cholecalciferol) 1/3d), resistance exercise training group (RX, ladder climbing 3/wk), or combined treatment group (VRX, VD + RX). Body weight and food intake were monitored in all groups biweekly over the 10-week intervention. In vivo measurements including body composition (dual-energy X-ray absorptiometry, DXA), skeletal muscle function (i.e., grip strength and inclined plane test), and oral glucose tolerance test (OGTT), were performed in all groups at pre- and post-intervention. Upon completion of the intervention, blood samples, the hindlimb muscles, and the spleen were collected from mice in all groups for in vitro analysis including serum vitamin D concentration, tissue wet weights, myofiber cross-sectional area (CSA), and myofiber protein expression levels of regulatory molecules for muscle growth [i.e., mammalian target of rapamycin (mTOR), protein kinase B (AKT), atrogin-1, muscle RING-finger protein-1 (MuRF-1)] and insulin signaling [i.e., insulin receptor ß (IR-ß) and glucose transporter type 4 (GLUT4)], pro-inflammation [i.e., tumor necrosis factor-α (TNF-α)] and bioactivity of vitamin D [i.e., vitamin D receptor (VDR)]. In the present study, p62C exhibited greater daily food intake (+17.1%) as well as increased adiposity compared to WC which involved greater total body mass (TBM) (24 weeks; +18.0%, 34 weeks: 26.2%), fat mass (FM) (24 weeks: +46.7%, 34 weeks: +69.3%), body fat percentage (%FM) (24 weeks: +28.8%, 34 weeks: +31.6%) as well as bone mineral density (BMD) (24 weeks: +8.5%, 34 weeks: +16.5%). In addition, p62C showed significantly increased fasting blood glucose levels (fBG) (+30.0%) and diminished blood glucose clearance leading to greater blood glucose levels during the OGTT [post-15 min blood glucose level (p15BG): +40.5%, post-30 min blood glucose level (p30BG): +28.3%, post-60 min blood glucose level (p60BG): +27.5%] compared to WC. p62C showed significantly lower relative grip strength (-21.7%) and sensorimotor function (-11.4%) despite greater myofiber CSA (+33.3%) compared to WC at the age of 34 weeks. The spleen mass was greater in p62C (+63.7%) than WC. Protein expression levels of total mTOR (+27.1%) and phosphorylated mTOR (+96.6%) in the soleus, total AKT in the soleus (+12.8%) and the gastrocnemius (+53.8%) were greater in p62C compared to WC. Muscle protein expression levels of MuRF-1 (+35.4%) and TNF-α (+200.4%) were higher in p62C compared to WC. Daily food intake, body weight (BW), and BMD were not different between p62C, VD, RX, and VRX. TBM elevation in p62C was attenuated in the intervention groups (VD: +13.5%, RX: +8.3%, VRX: +8.7% vs. p62C: +16.8%), which was associated with preserved FM and %FM in VD, RX, and VRX. VD (+61.1%) and VRX (+37.6%) exhibited greater circulating vitamin D levels compared to p62C. p62C exhibited significant loss of grip strength (absolute: -22.5%, relative: -38.9) and sensorimotor function (-12/8%) over time. In contrast, RX maintained both grip strength and sensorimotor function, and VD and VRX maintained grip strength after the 10-week intervention. Only RX and VRX displayed improved glucose tolerance which suppressed increases in p15BG (p62C: +16.0% vs. RX & VRX: no change), and lowered p30BG (RX: -40.0%, VRX: -36.9%) compared to p62C. No difference was observed between VD and p62C for tissue wet weights of the hindlimb muscles and the spleen, and myofiber CSA. However, RX exhibited lower spleen mass compared to p62C (-26.0%). Muscle protein expression profiles related to myofiber growth, protein degradation, glucose uptake, pro-inflammation, and the bioactivity of vitamin D were not changed by the interventions. In the present study adult p62 KO mice developed obesity, shown as increased adiposity, impaired glucose homeostasis, attenuated physical function, and an enlarged spleen. In addition, the present findings demonstrated that 10 weeks of vitamin D administration with or without RT or RT alone attenuated the progression of obesity and improved neuromuscular function in p62 KO mice. In addition, RT with or without vitamin D was effective in improving insulin sensitivity and systemic inflammation in p62 KO mice. In contrary, vitamin D administration alone was unable to induce favorable changes in insulin sensitivity, wet weights of skeletal muscle and spleen, myofiber CSA, and protein expression profiles of regulatory factors. Moreover, neither synergistic nor additive effects were noted when vitamin D administration was combined with RT. / A Dissertation submitted to the Department of Nutrition, Food and Exercise Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy. / Fall Semester 2018. / November 2, 2018. / Animal Model, Diabetes, Obesity, Resistance Exercise, Vitamin D / Includes bibliographical references. / Jeong-Su Kim, Professor Directing Dissertation; Samuel Grant, University Representative; Bahram Arjmandi, Committee Member; Lynn Panton, Committee Member.

Diagnosing the severity of blunt trauma injuries is difficult and involves the use of diagnostic radiological scanning. The primary diagnostic radiology modality used for assessing these injuries is computed tomography (CT). CT delivers more radiation dose than other diagnostic scanning modalities. Trauma patients are at an increased risk of radiation induced cancer because of the cumulative dose effects from multiple scanning procedures. Current methods for estimating effective dose, the quantity used to describe the whole body health detriment from radiation, involves the use of published conversion coefficients and procedure specific machine parameters such as dose-length-product based on computed tomography dose index and scan length. Other methods include the use of Monte Carlo simulations based upon the specific machine geometry and radiation source. Unless the requisite machine information is known, the only means of estimating the effective dose is through the use of generic estimates that are published by scientific radiation committees and have a wide range of values. This research addressed a knowledge gap in assigning effective doses from computed tomography when machine parameters knowledge is either unknown or incomplete. The research involved the development of a new method of estimating the effective dose from CT through the use of regression models incorporating the use of patient parameters as opposed to machine specific parameters. This new method was experimentally verified using two adult anthropomorphic phantoms and optically stimulated luminescent dosimeters. The new method was then compared against a real patient population undergoing similar computed tomography scanning procedures. Utilizing statistical procedures, the new method was tested for repeatability and bias against the current conversion coefficient method. The analysis of the new method verifies that the estimation ability is similar to recent research indicating that the older conversion coefficient methods can underestimate the effective dose to the patient by up to 40%. The new method can be used as a retrospective tool for effective dose estimation from CT trauma protocols for a patient population with physical characteristics similar to the U.S. Army Soldier population.

Cholesterol is an essential molecule that mediates a myriad of critical cellular processes, such as signal transduction in eukaryotes, membrane fluidity, and steroidogenesis. As such it is not surprising that cholesterol homeostasis is tightly regulated, striking a precise balance between endogenous synthesis and regulated uptake/efflux to and from extracellular acceptors. In mammalian cells, sterol efflux is a key component of the homeostatic equation and is mediated by members of the ATP binding cassette (ABC) transporter superfamily. ATP-binding cassette (ABC) transporters represent a group of evolutionarily highly conserved cellular transmembrane proteins that mediate the ATP-dependent translocation of substrates across membranes. Members of this superfamily, ABCA1 and ABCG1, are key components of the reverse cholesterol transport pathway. ABCG1 acts in concert with ABCA1 to maximize the removal of excess cholesterol from cells by promoting cholesterol efflux onto mature and nascent HDL particles, respectively. To date, mammalian ABC transporters are exclusively associated with efflux of cholesterol. In Saccharomyces cerevisiae, we have demonstrated that the opposite (i.e inward) transport of sterol in yeast is also dependent on two ABC transporters (Aus1p and Pdr11p). This prompts the question what dictates directionality of sterol transport by ABC transporters. The main focus of this study is to define the parameters that result in sterol movement across membranes. The comparison between these contrasting states (outward v. inward transport of the same substrate) will allow us to dissect whether sterol transport across the plasma membrane is defined by the molecule (i.e. the ABC transporter) or by microenvironment (i.e. the status of other proteins and lipids) in which it resides. We have developed the model eukaryote Saccharomyces cerevisiae as a tool to understand the mechanisms that influence ABC-transporter mediated movement of sterols. Specifically, we expressed murine ABCG1 (mABCG1) in yeast and assessed how changes in the intracellular sterol environment affect movement of sterols by this transporter. We found that expression of mABCG1 is able to vary (both increase and decrease) the concentration of exogenous sterols in the cell in response to intracellular sterol changes. We also found that yeast members of the ABCG subfamily, Aus1p and Pdr11p are able to promote either influx of cholesterol or efflux of a cholesterol derivative depending on the sterol context of the cell. This is the first example of an ABC transporter mediating bi-directional transport. These data suggest that direction of transport is not a static property of the transporter but rather can adapt in response to changes in the intracellular microenvironment. In addition to sterols we also found that proteins in the microenvironment may also influence direction of transport. Specifically, we found that the yeast sterol esterifying enzyme Are2p, physically interacts with the ABC transporters Aus1p and Pdr11p. Furthermore, all three proteins were found to co-localize to detergent resistant membrane microdomains. Deletion of either ABC transporter resulted in Are2p re-localization from DRMs to a detergent soluble fraction as well as a significant decrease in the percent of sterol esterified. This phenomenon is evolutionarily conserved in the murine lung where ABCG1 and ACAT1 were observed to co-localize with flotillin-1, a marker of DRMs. We propose that co-localization and complex formation of sterol esterification enzymes and ABC transporters in DRMs reflects a novel mechanism that directs membrane sterols to the esterification reaction. The studies presented in this thesis provide evidence that direction of transport is not a static inherent property of the transporter, but rather that it is mutable and influenced by surrounding sterols and proteins. The data provided here offers further insight as to how ABC transporters move cholesterol from the membrane and therefore may provide a platform for innovative strategies to combat atherosclerosis.