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Many coastal cities around the world are becoming increasingly vulnerable to natural disasters, particularly flooding driven by tropical storm and hurricane storm surge – typically the most destructive feature of these storms, generating significant economic damage and loss of life. This increase in vulnerability is driven by the interactions between a wide number of complex social and climatic factors, including population growth, irresponsible urban development, a decrease in essential service provision, sea level rise, and changing storm regimes. These issues are exacerbated by the short-term strategic planning that dominates political action and economic decision-making, resulting in many vulnerable coastal communities being particularly unprepared for large, infrequent storm surge events. This lack of preparedness manifests in several ways, but one of the most visible is the lack of comprehensive evacuation and rescue operation plans for use after major storm surge flooding occurs. Typical evacuation or rescue plans are built using a model of a region’s intact road network. While useful for pre-disaster purposes, the immediate aftermath of large floods sees enormous swaths of a given region’s road system flooded, rendering most of these plans largely useless. Post-storm evacuation and rescue requires large amounts of atypical travel through a region (i.e., across non-road surfaces). Traditional road network models (such as those that are used to generate evacuation routes) are unable to conceptualize this type of transportation, and so are of limited utility during post-disaster scenarios. To solve these problems, this dissertation introduces an alternative network conceptualization that preserves important on-network information but also accounts for the possibility of off-network travel during a disaster. Providing this in situ context is necessary to adequately model transportation through a post-storm landscape, one in which evacuees and rescuers are regularly departing from roads and one in which many roads are completely interdicted by flooding. This modeling approach is used to automatically generate routes through a flooded coastal urban area, as well as to identify potentially critical road segments in advance of an actual storm. These tools may help both emergency managers better prepare for large storms, and urban planners in their efforts to mitigate flood damage.
Environmental heat is a growing concern in cities as a consequence of rapid urbanization and climate change, threatening human health and urban vitality. The transportation system is naturally embedded in the issue of urban heat and human heat exposure. Research has established how heat poses a threat to urban inhabitants and how urban infrastructure design can lead to increased urban heat. Yet there are gaps in understanding how urban communities accumulate heat exposure, and how significantly the urban transportation system influences or exacerbates the many issues of urban heat. This dissertation focuses on advancing the understanding of how modern urban transportation influences urban heat and human heat exposure through three research objectives: 1) Investigate how human activity results in different outdoor heat exposure; 2) Quantify the growth and extent of urban parking infrastructure; and 3) Model and analyze how pavements and vehicles contribute to urban heat.
In the urban US, traveling outdoors (e.g. biking or walking) is the most frequent activity to cause heat exposure during hot periods. However, outdoor travel durations are often very short, and other longer activities such as outdoor housework and recreation contribute more to cumulative urban heat exposure. In Phoenix, parking and roadway pavement infrastructure contributes significantly to the urban heat balance, especially during summer afternoons, and vehicles only contribute significantly in local areas with high density rush hour vehicle travel. Future development of urban areas (especially those with concerns of extreme heat) should focus on ensuring access and mobility for its inhabitants without sacrificing thermal comfort. This may require urban redesign of transportation systems to be less auto-centric, but without clear pathways to mitigating impacts of urban heat, it may be difficult to promote transitions to travel modes that inherently necessitate heat exposure. Transportation planners and engineers need to be cognizant of the pathways to increased urban heat and human heat exposure when planning and designing urban transportation systems.
MiRNA-based gene regulation occurs in a tissue-specific manner and is implemented by an interplay of poorly understood and complex mechanisms, which control both the presence of the miRNAs and their targets. As a consequence, the precise contributions of miRNAs to gene regulation are not well known. The research presented in this thesis systematically explores the targets and effects of miRNA-based gene regulation in cell lines and tissues.
I hypothesize that miRNAs have distinct tissue-specific roles that contribute to the gene expression differences seen across tissues. To address this hypothesis and expand our understanding of miRNA-based gene regulation, 1) I developed the human 3'UTRome v1, a resource for studying post-transcriptional gene regulation. Using this resource, I explored the targets of two cancer-associated miRNAs miR-221 and let-7c. I identified novel targets of both these miRNAs, which present potential mechanisms by which they contribute to cancer. 2) Identified in vivo, tissue-specific targets in the intestine and body muscle of the model organism Caenorhabditis elegans. The results from this study revealed that miRNAs regulate tissue homeostasis, and that alternative polyadenylation and miRNA expression patterns modulate miRNA targeting at the tissue-specific level. 3) Explored the functional relevance of miRNA targeting to tissue-specific gene expression, where I found that miRNAs contribute to the biogenesis of mRNAs, through alternative splicing, by regulating tissue-specific expression of splicing factors. These results expand our understanding of the mechanisms that guide miRNA targeting and its effects on tissue-specific gene expression.
This study investigated the effect of environmental heat stress on physiological and performance measures during a ~4 mi time trial (TT) mountain hike in the Phoenix metropolitan area. Participants (n = 12; 7M/5F; age 21.6 ± 2.47 [SD]) climbed ‘A’ mountain (~1 mi) four times on a hot day (HOT; wet bulb globe temperature [WBGT] = 31.6°C) and again on a moderate day (MOD; WBGT = 19.0°C). Physiological and performance measures were made before and throughout the course of each hike. Mean pre-hike hydration status (urine specific gravity [USG]) indicated that participants began both HOT and MOD trials in a euhydrated state (1.016 ± 0.010 and 1.010 ± 0.008, respectively) and means did not differ significantly between trials (p = .085). Time trial performance was impaired by -11% (11.1 minutes) in the HOT trial (105 ± 21.7 min), compared to MOD (93.9 ± 13.1 min) (p = .013). Peak core temperatures were significantly higher in HOT (38.5 ± 0.36°C) versus MOD (38.0 ± 0.30°C) with progressively increasing differences between trials over time (p < .001). Peak ratings of perceived exertion were significantly higher in HOT (14.2 ± 2.38) compared to MOD (11.9 ± 2.02) (p = .007). Relative intensity (percent of age-predicted maximal heart rate [HR]), estimated absolute intensity (metabolic equivalents [METs]), and estimated energy expenditure (MET-h) were all increased in HOT, but not significantly so. The HOT condition reduced predicted maximal aerobic capacity (CRFp) by 6% (p = .026). Sweat rates differed significantly between HOT (1.38 ± 0.53 L/h) and MOD (0.84 ± 0.27 L/h) (p = .01). Percent body mass loss (PBML) did not differ significantly between HOT (1.06 ± 0.95%) and MOD (0.98 ± 0.84%) (p = .869). All repeated measures variables showed significant between-subjects effects (p < .05), indicating individual differences in response to test conditions. Heat stress was shown to negatively affect physiological and performance measures in recreational mountain hikers. However, considerable variation exists between individuals, and the degree of physiological and performance impairment is probably due, in part, to differences in aerobic fitness and acclimatization status rather than pre- or during-performance hydration status.
The goal of this research was to identify and characterize biologically active small molecule inhibitors for QSOX1. Chemical inhibition of QSOX1 enzymatic activity was hypothesized to reduce growth and invasion of tumor cells. Recombinant QSOX1 was screened against libraries of small molecules using an enzymatic activity assay to identify potential QSOX1 inhibitors. Two lead QSOX1 inhibitors were confirmed, 2-phenyl-1, 2-benzisoselenazol-3-one (ebselen), and 3-methoxy-n-[4-(1 pyrrolidinyl)phenyl]benzamide. The biological activity of these compounds is consistent with QSOX1 knockdown in tumor cell lines, reducing growth and invasion in vitro. Treatment of tumor cells with these compounds also resulted in specific ECM defects, a phenotype associated with QSOX1 knockdown. Additionally, these compounds were shown to be active in pancreatic and renal cancer xenografts, reducing tumor growth with daily treatment. For ebselen, the molecular mechanism of inhibition was determined using a combination of biochemical and mass spectrometric techniques. The results obtained in these studies provide proof-of-principle that targeting QSOX1 enzymatic activity with chemical compounds represents a novel potential therapeutic avenue worthy of further investigation in cancer. Additionally, the utility of these small molecules as chemical probes will yield future insight into the general biology of QSOX1, including the identification of novel substrates of QSOX1.
I hypothesize that duplication events grant miRNA families with enhanced regulatory capabilities, specifically through distinct targeting preferences by family members. This has relevance for our understanding of vertebrate evolution, as well disease detection and personalized medicine. To test this hypothesis, I apply a conjunction of bioinformatic and experimental approaches, and design a novel high-throughput screening platform to identify human miRNA targets. Combined with conventional approaches, this tool allows systematic testing for functional targets of human miRNAs, and the identification of novel target genes on an unprecedented scale.
In this dissertation, I explore evolutionary signatures of 62 deeply conserved metazoan miRNA families, as well as the targeting preferences for several human miRNAs. I find that constraints on miRNA processing impact sequence evolution, creating evolutionary hotspots within families that guide distinct target preferences. I apply our novel screening platform to two cancer-relevant miRNAs, and identify hundreds of previously undescribed targets. I also analyze critical features of functional miRNA target sites, finding that each miRNA recognizes surprisingly distinct features of targets. To further explore the functional distinction between family members, I analyze miRNA expression patterns in multiple contexts, including mouse embryogenesis, RNA-seq data from human tissues, and cancer cell lines. Together, my results inform a model that describes the evolution of metazoan miRNAs, and suggests that highly similar miRNA family members possess distinct functions. These findings broaden our understanding of miRNA function in vertebrate evolution and development, and how their misexpression contributes to human disease.