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Beta-blockers and non-steroidal anti-inflammatory drugs (NSAIDs) are often avoided in asthma over risk of bronchospasm which may vary according to drug selectivity and duration of administration. This thesis attempts to quantify the risk of beta-blocker and NSAID exposure in asthma by synthesising clinical trial evidence and conducting observational studies using linked electronic medical records. As part of this thesis, three systematic reviews of clinical trials were conducted evaluating: the prevalence of aspirin-exacerbated respiratory disease (AERD); risk of selective NSAIDs/COX-2 inhibitors in people with AERD; and risk of acute beta-blocker exposure in people with asthma. Electronic primary care data from the Clinical Practice Research Datalink (CPRD) was used to define a cohort of people with active asthma, measure the prevalence of beta-blocker and NSAID prescribing, and perform a series of nested case control studies evaluating asthma death, asthma hospitalisation and primary care asthma exacerbations (PCAE). A self-controlled case-series was performed for PCAE as well. Based upon work in this thesis, the prevalence of AERD in people with asthma was around 9%. Selective NSAIDs triggered respiratory symptoms in 8% of people with AERD whilst no significant changes in lung function or symptoms occurred with COX-2 inhibitors. Acute non-selective beta-blocker exposure caused a significant mean fall in FEV1 of 10%, a significant increase in respiratory symptoms in around 1 in 13 and a non-significant increase in falls in FEV1 of ≥20% in around 1 in 9. Acute selective beta-blocker exposure caused a significant mean fall in FEV1 of 7%, significant falls in FEV1 of ≥20% in around 1 in 8 and a non-significant increase in respiratory symptoms in around 1 in 33. The prevalence of selective beta-blocker prescribing in asthma rose by around 200% over the 12 year period whilst the prevalence of non-selective beta-blocker prescribing rose by around 90%. Changing trends in NSAID prescribing occurred over the 12 year period with COX-2 inhibitors now rarely prescribed. Using the nested case control design, both incident and high-dose non-selective beta-blocker exposure was associated with significantly increased risk of asthma morbidity (hospitalisation and PCAE). In contrast, no significant increased risk of asthma morbidity occurred with any type of selective beta-blocker exposure. Consistent findings were seen for PCAE using the self-controlled case series. No significantly increased risk was seen with different oral NSAIDs apart from weak evidence of an association between asthma death and non-selective NSAID exposure which is unlikely to be causal. Significant numbers of people with asthma are prescribed beta-blockers and NSAIDs. Evidence from clinical trials and observational studies demonstrate that non-selective beta-blockers significantly increase asthma morbidity with risk appearing to vary according to dose and duration of administration. Although selective beta-blockers have the potential to cause significant changes in lung function, no significant increase in asthma morbidity was observed in observational studies. Although around 9% of asthmatics may be susceptible to NSAIDs, no strong evidence was found to suggest that the current practice of NSAID prescribing increases asthma morbidity. At the same time, COX-2 inhibitors are infrequently prescribed despite apparently being well tolerated by people with AERD.

Nebraska’s agricultural landscapes are rapidly changing, affecting natural resources and their successful management. I utilized two surveys and scenario planning (Chapters 1: statewide survey, 2: local survey, and 3: scenario-planning workshop) to investigate attitudes and perceptions of natural resource management and cross-boundary collaboration. My first objective focused on determining what prevents Nebraskans from addressing natural resources challenges, considering demographics amongst generations and the type of areas they live in (rural versus urban). The second objective focused on whether landowners engaged with their community in managing natural resources. The third objective was to develop alternative future scenarios for the Denton Hills landscape of eastern Nebraska and preferred alternative futures. I found that demographics matter and that older generations are more likely to engage in community natural resource management. I discovered that landowners with larger acreages to manage are more likely to view collaboration positively. Scenario planning revealed how local landowners in the Denton Hills view the identity of the Denton Hills landscape and identified both desired and undesired future alternatives. Generally, I found that the public recognizes natural resource challenges and that people are willing to work in cooperative groups to address the challenges. Understanding perceptions of management, factors affecting those perceptions, collaborative management, and a shared future vision will enhance resource management. Advisors: Craig R. Allen and Christopher J. Chizinski

The 5’ cap is an essential modification of mRNAs that is needed for the functionality and lifespan of an mRNA. The cap is added almost immediately after the first nucleotide is transcribed, coordinated by RNGTT and RNMT-RAM bound to the C-terminal tail of RNA Pol II. This process of capping was thought to exclusively occur in the nucleus and loss of the cap was irreversible, leading to the rapid degradation of the mRNA. However, not all mRNAs share this fate. Over the last decade, the Schoenberg lab has characterized cytoplasmic capping, a process where the cap can be restored to previously decapped mRNAs. Cytoplasmic capping is catalyzed by a complex that consists of a cytoplasmic pool of both RNGTT and RNMT-RAM bound to the adapter protein NCK1 along with an unknown 5’ monophosphate kinase. mRNAs that undergo cytoplasmic capping can cycle from being in a decapped state to a recapped state as a way to fine tune gene expression, a process called cap homeostasis. The recapping targets were initially identified using a catalytically inactive and cytoplasmically restricted form of RNGTT termed K294A. Overexpression of K294A resulted in an accumulation of uncapped mRNAs in non-translating mRNPs. A major drawback of this approach was its reliance on detecting uncapped mRNAs, a potentially unstable population that can undergo partial degradation. An alternative tool to study recapping was developed using a catalytically inactive and cytoplasmically restricted form of RNMT termed ΔN-RNMT. ΔN-RNMT expression results in a decrease in the steady state levels of recapped mRNAs. A U2OS stable cell line expressing ΔN-RNMT was developed, and changes in the steady state levels of potential recapping genes were measured by RNA-Seq. 5’ terminal oligopyrimidine (TOP) mRNAs were identified as recapping targets, and I showed direct evidence of recapping occurring at both the canonical site and downstream in the 5’UTR of eIF3D and eIF3K. Expression of ΔN-RNMT also results in a shift in the 3’UTR usage from proximal sites to distal sites. Uncapped mRNAs that accumulated with inhibition of cytoplasmic capping map to downstream CAGE tags (Kiss et al., 2015). If recapping were to occur at these sites, N-terminally truncated proteins could be translated. In collaboration with the Wysocki lab, we examined the relationship of cytoplasmic capping with N-terminally truncated proteins and showed that half of the downstream N-termini identified decrease when cytoplasmic capping is inhibited. These downstream N-terminal peptides correspond to RNA binding proteins, and the mapped downstream N-termini have a translation start site near the vicinity of the peptide. These studies expand the scope of cytoplasmic capping showing both direct evidence of recapping at canonical and downstream sites, and evidence of cytoplasmic capping expanding the proteome through synthesis of truncated proteins.

Currently in the United States, the precast, pre-stressed concrete design method dominates the new construction market in the short to medium span range bridges. One approach to help make steel bridges more competitive with pre-stressed concrete bridges is the continuous for live load method (CLL). The method employs a simply supported interior end restraint configuration for dead loads and a subsequent modification to a continuous span configuration for live loads by way of a concrete diaphragm at interior supports. To determine the feasibility and effectiveness of this method, a cost analysis, an in-situ field load test, and finite element analysis were performed on two CLL bridges in service in New Mexico, USA. The continuous for live load method was found to be more cost and time effective as compared with traditional continuous steel bridge construction. Additionally, it was determined that both case study bridges maintained continuity across the interior supports.