Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.
These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.
This dissertation proposes two PageRank-based analytical methods, Pathways of Topological Rank Analysis (PoTRA) and miR2Pathway, discussed in Chapter 1 and Chapter 2, respectively. PoTRA focuses on detecting pathways with an altered number of hub genes in corresponding pathways between two phenotypes. The basis for PoTRA is that the loss of connectivity is a common topological trait of cancer networks, as well as the prior knowledge that a normal biological network is a scale-free network whose degree distribution follows a power law where a small number of nodes are hubs and a large number of nodes are non-hubs. However, from normal to cancer, the process of the network losing connectivity might be the process of disrupting the scale-free structure of the network, namely, the number of hub genes might be altered in cancer compared to that in normal samples. Hence, it is hypothesized that if the number of hub genes is different in a pathway between normal and cancer, this pathway might be involved in cancer. MiR2Pathway focuses on quantifying the differential effects of miRNAs on the activity of a biological pathway when miRNA-mRNA connections are altered from normal to disease and rank disease risk of rewired miRNA-mediated biological pathways. This dissertation explores how rewired gene-gene interactions and rewired miRNA-mRNA interactions lead to aberrant activity of biological pathways, and rank pathways for their disease risk. The two methods proposed here can be used to complement existing genomics analysis methods to facilitate the study of biological mechanisms behind disease at the systems-level.
Exertional heat stroke continues to be one of the leading causes of illness and death in sport in the United States, with an athlete’s experienced microclimate varying by venue design and location. A limited number of studies have attempted to determine the relationship between observed wet bulb globe temperature (WBGT) and WBGT derived from regional weather station data. Moreover, only one study has quantified the relationship between regionally modeled and on-site measured WBGT over different athletic surfaces (natural grass, rubber track, and concrete tennis court). The current research expands on previous studies to examine how different athletic surfaces influence the thermal environment in the Phoenix Metropolitan Area using a combination of fieldwork, modeling, and statistical analysis. Meteorological data were collected from 0700–1900hr across 6 days in June and 5 days in August 2019 in Tempe, Arizona at various Sun Devil Athletics facilities. This research also explored the influence of surface temperatures on WBGT and the changes projected under a future warmer climate. Results indicate that based on American College of Sports Medicine guidelines practice would not be cancelled in June (WBGT≥32.3°C); however, in August, ~33% of practice time was lost across multiple surfaces. The second-tier recommendations (WBGT≥30.1°C) to limit intense exercise were reached an average of 7 hours each day for all surfaces in August. Further, WBGT was calculated using data from four Arizona Meteorological Network (AZMET) weather stations to provide regional WBGT values for comparison. The on-site (field/court) WBGT values were consistently higher than regional values and significantly different (p<0.05). Thus, using regionally-modeled WBGT data to guide activity or clothing modification for heat safety may lead to misclassification and unsafe conditions. Surface temperature measurements indicate a maximum temperature (170°F) occurring around solar noon, yet WBGT reached its highest level mid-afternoon and on the artificial turf surface (2–5PM). Climate projections show that WBGT values are expected to rise, further restricting the amount of practice and games than can take place outdoors during the afternoon. The findings from this study can be used to inform athletic trainers and coaches about the thermal environment through WBGT values on-field.
Interdisciplinary research has highlighted how social-ecological dynamics drive the structure and function of the urban landscape across multiple scales. Land management decisions operate across various levels, from individuals in their backyard to local municipalities and broader political-economic forces. These decisions then scale up and down across the landscape to influence ecological functioning, such as the provisioning of biodiversity. Likewise, people are influenced by, and respond to, their environment. However, there is a lack of integrated research, especially research that considers the spatial and temporal complexities of social-ecological dynamics, to fully understand how people influence ecosystems or how the resulting landscape in turn influences human decision making, attitudes, and well-being.
My dissertation connects these interdisciplinary themes to examine three questions linked by their investigation of the interactions between people and biodiversity: (1) How do the social and spatial patterns within an arid city affect people’s attitudes about their regional desert environment? (2) How are novel communities in cities assembled given the social-ecological dynamics that influence the processes that structure ecological communities? (3) How can we reposition bird species traits into a conservation framework that explains the complexity of the interactions between people and urban bird communities? I found that social-ecological dynamics between people, the environment, and biodiversity are tightly interwoven in urban ecosystems. The regional desert environment shapes people’s attitudes along spatial and social configurations, which holds implications for yard management decisions. Multi-scalar management decisions then influence biodiversity throughout cities, which shifts public perceptions of urban nature. Overall, my research acts as a bridge between social and ecological sciences to theoretically and empirically integrate research focused on biodiversity conservation in complex, social-ecological systems. My goal as a scholar is to understand the balance between social and ecological implications of landscape change to support human well-being and promote biodiversity conservation.
This study aimed to investigate the effects of specific macronutrient feedings on competitive golf performance and perceived levels of fatigue and alertness. Participants played three, nine hole rounds of golf, consuming an isocaloric beverage as a control (CON), with the addition of carbohydrate (CHO), or combination of protein and carbohydrate (COM). Physiological and performance measurements were taken before, during, and following each nine hole round. Performance measurements include driving accuracy (DA), driving distance (DD), iron accuracy (IA), chipping accuracy (CA), and putting accuracy (PA). Pre-golf hydration status (urine specific gravity [USG]) and Sweat Rate during golf performance showed no significant differences between trials. All nine hole rounds were performed in ~2 hours. Environmental conditions were similar for all three testing days (mean WBGT=10.946). No significant differences were seen in Driving Distance, Driving Accuracy, and Iron Accuracy for all nine holes between groups receiving different macronutrient feedings. Chipping Accuracy was significantly better in CON trial compared to CHO (p=0.004) and COM (p=0.019). No significant differences were seen in putting make percentages. COM trial significantly lowered Perceived Levels of Fatigue (p=0.019) compared to CON. The CHO trial showed significant improvements in DA compared to CON (13.7 vs. 44.1, p=0.012) and COM (13.7 vs. 33.6, p=0.004) in the first four holes. In the last five holes, the COM trial showed significant improvements in DA compared to CHO (17.5 vs. 29.7, p=0.007). Low Handicap golfers (3 +/- 3) performed significantly better than High Handicap golfers (14 +/- 3.6) in DD (265 vs. 241, p<0.001), DA (15.0 vs. 29.3, p=0.004), IA (15.2 vs. 25.2, p<0.001), CA (52.0 vs. 61.5, p=0.027), and PA 5ft (64% vs. 40%, p=0.003). High Handicap players showed no significant differences between the three trials for any golf performance measurements. Low Handicap players showed significant improvements in DA for COM trial compared to CON trial (13.6 vs. 27.6, p=0.003). The results suggest that carbohydrates at the start and a combination of carbohydrate and protein is beneficial at the second part of 9 holes to improve golf performance and maintain levels of fatigue, however, it needs to be investigated how this knowledge will relate to playing more holes.
Urban heat is a growing problem that impacts public health, water and energy use, and the economy and affects population subgroups differently. Exposure and sensitivity, two key factors in determining vulnerability, have been widely researched. This dissertation focuses on the adaptive capacity component of heat vulnerability at the individual, household, and community scale. Using a mixed methods approach and metropolitan Phoenix as a test site, I explored how vulnerable communities understand and adapt to increasing extreme urban heat to uncover adaptive capacity that is not being operationalized well through current heat vulnerability frameworks. Twenty-three open-ended interviews were conducted where residents were encouraged to tell their stories about past and present extreme heat adaptive capacity behaviors. A community-based participatory research project consisting of three workshops and demonstration projects was piloted in three underserved neighborhoods to address urban heat on a local scale and collaboratively create community heat action plans. Last, a practitioner stakeholder meeting was held to discuss how the heat action plans will be integrated into other community efforts. Using data from the interviews, workshops, and stakeholder meeting, social capital was examined in the context of urban heat. Although social capital has been measured in a multitude of ways to gauge social relationships, trust, and reciprocity within a community, it is situational and reflects a position within the formal and informal aspects of any issue. Three narratives emerged from the interviews illuminating differentiated capacities to cope with urban heat: heat is an inconvenience, heat is a manageable problem, and heat is a catastrophe. For each of these narratives, generic adaptive capacity is impacted differently by specific heat adaptive capacity. The heat action plan workshops generated hyper-local heat solutions that reflected the neighborhoods’ different identities. Community-based organizations were instrumental in the success of this program. Social capital indicators were developed specific to urban heat that rely on heavily on family and personal relationships, attitudes and beliefs, perceived support, network size and community engagement. This research highlights how extreme heat vulnerability may need to be rethought to capture adaptive capacity nuances and the dynamic structure of who is vulnerable under what circumstances.
designing personalized treatments and improving clinical outcomes of cancers. Such
investigations require accurate delineation of the subclonal composition of a tumor, which
to date can only be reliably inferred from deep-sequencing data (>300x depth). The
resulting algorithm from the work presented here, incorporates an adaptive error model
into statistical decomposition of mixed populations, which corrects the mean-variance
dependency of sequencing data at the subclonal level and enables accurate subclonal
discovery in tumors sequenced at standard depths (30-50x). Tested on extensive computer
simulations and real-world data, this new method, named model-based adaptive grouping
of subclones (MAGOS), consistently outperforms existing methods on minimum
sequencing depth, decomposition accuracy and computation efficiency. MAGOS supports
subclone analysis using single nucleotide variants and copy number variants from one or
more samples of an individual tumor. GUST algorithm, on the other hand is a novel method
in detecting the cancer type specific driver genes. Combination of MAGOS and GUST
results can provide insights into cancer progression. Applications of MAGOS and GUST
to whole-exome sequencing data of 33 different cancer types’ samples discovered a
significant association between subclonal diversity and their drivers and patient overall
survival.
The City of Phoenix has committed to public transit improvements in the Transportation 2050 plan and has recently adopted a Complete Streets Policy. Proposed changes include mobility improvements and creating a safe and comfortable environment for non-motorized road participants. To understand what kind of improvements would benefit thermal comfort the most, it is necessary to understand heat exposure at finer spatial scales, explore whether current bus shelter designs are adequate in mitigating heat-health effects, and comprehensively assess the impact of design on physical, psychological and behavioral aspects of thermal comfort. A study conducted at bus stops in one Phoenix neighborhood examined grey and green infrastructure types preferred for cooling and found relationships between perception of pleasantness and thermal sensation votes. Walking interviews conducted in another neighborhood event examined the applicability of a framework for walking behavior under the stress of heat, and how differences between the streets affected perceptions of the walkers. The interviews revealed that many of the structural themes from the framework of walking behavior were applicable, however, participants assessed the majority of the elements in their walk from a heat mitigation perspective. Finally, guiding questions for walkability in hot and arid climates were developed based on the literature review and results from the empirical studies. This dissertation contributes to filling the gap between walkability and outdoor thermal comfort, and presents methodology and findings that can be useful to address walkability and outdoor thermal comfort in the world’s hot cities as well as those in temperate climates that may face similar climate challenges in the future as the planet warms.
Environmental hazards and disaster researchers have demonstrated strong associations between sociodemographic indicators, such as age and socio-economic status (SES), and hazard exposures and health outcomes for individuals and in certain communities. At the same time, behavioral health and risk communications research has examined how individual psychology influences adaptive strategies and behaviors in the face of hazards. However, at present, we do not understand the explanatory mechanisms that explain relationships between larger scale social structure, individual psychology, and specific behaviors that may attenuate or amplify risk. Extreme heat presents growing risks in a rapidly warming and urbanizing world. This dissertation examines the social and behavioral mechanisms that may explain inequitable health outcomes from exposure to concurrent extreme heat and electrical power failure in Phoenix, AZ and extreme heat in Detroit, MI. Exploratory analysis of 163 surveys in Phoenix, AZ showed that age, gender, and respondent’s racialized group identity did not relate to thermal discomfort and self-reported heat illness, which were only predicted by SES (StdB = -0.52, p < 0.01). Of the explanatory mechanisms tested in the study, only relative air conditioning intensity and thermal discomfort explained self-reported heat illness. Thermal discomfort was tested as both a mechanism and outcome measure. Content analysis of 40 semi-structured interviews in Phoenix, AZ revealed that social vulnerability was associated with an increase in perceived hazard severity (StdB = 0.44, p < 0.01), a decrease in perceived adaptation efficacy (StdB = -0.38, p = 0.02), and an indirect increase (through adaptive efficacy) in maladaptive intentions (StdB = 0.18, p = 0.01). Structural equation modeling of 244 surveys in Phoenix, AZ and Detroit, MI revealed that relationships between previous heat illness experience, perceived heat risk, and adaptive intentions were significantly moderated by adaptive capacity: high adaptive capacity households were more likely to undertake adaptive behaviors, and those decisions were more heavily influenced by risk perceptions and previous experiences. However, high adaptive capacity households had lower risk perceptions and fewer heat illness experiences than low adaptive capacity households. A better understanding of the mechanisms that produce social vulnerability can facilitate more salient risk messaging and more targeted public health interventions. For example, public health risk messaging that provides information on the efficacy of specific adaptations may be more likely to motivate self-protective action, and ultimately protect populations.
Domestic dogs have assisted humans for millennia. However, the extent to which these helpful behaviors are prosocially motivated remains unclear. To assess the propensity of pet dogs to spontaneously and actively rescue distressed humans, this study tested whether sixty pet dogs would release their seemingly trapped owners from a large box. To examine the causal mechanisms that shaped this behavior, the readiness of each dog to open the box was tested in three conditions: 1) the owner sat in the box and called for help (“Distress” test), 2) an experimenter placed high-value food rewards in the box (“Food” test), and 3) the owner sat in the box and calmly read aloud (“Reading” test).
Dogs were as likely to release their distressed owner as to retrieve treats from inside the box, indicating that rescuing an owner may be a highly rewarding action for dogs. After accounting for ability, dogs released the owner more often when the owner called for help than when the owner read aloud calmly. In addition, opening latencies decreased with test number in the Distress test but not the Reading test. Thus, rescuing the owner could not be attributed solely to social facilitation, stimulus enhancement, or social contact-seeking behavior.
Dogs displayed more stress behaviors in the Distress test than in the Reading test, and stress scores decreased with test number in the Reading test but not in the Distress test. This evidence of emotional contagion supports the hypothesis that rescuing the distressed owner was an empathetically-motivated prosocial behavior. Success in the Food task and previous (in-home) experience opening objects were both strong predictors of releasing the owner. Thus, prosocial behavior tests for dogs should control for physical ability and previous experience.