Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide and is a risk factor for lung cancer development. COPD encompasses both emphysema and chronic bronchitis, the pathogenesis of which are unclear. In this dissertation, I leveraged genome-wide gene-expression studies of emphysema and lung cancer to investigate pathogenesis and carcinogenesis in COPD. Tobacco smoke is the primary cause of emphysema. The most severe form is also associated with alpha1-antitrypsin deficiency (AATD) resulting from a mutation. In this study, I leveraged multiple lung samples from patients with emphysema, with or without AATD. While genes involved in tissue repair decreased with emphysema severity, the unfolded protein response (UPR) was uniquely changed in AATD lungs. AATD may play multiple roles in emphysema and UPR activation suggests AAT replacement therapy may be insufficient to treat this form of emphysema. Emphysema is a progressive disease, and the mean linear intercept (Lm) can serve as a surrogate of progression. I evaluated whether Lm increases in non-diseased lungs may represent similar processes to those occurring in emphysema, and could offer insight into early stages of disease or homeostasis. Genes involved in tissue repair increased with Lm in controls but decreased in disease. Tissue repair processes may be active in even the non-insulted lung, suggesting their activity is necessary for lung homeostasis and their deficiency may drive emphysema progression. Finally, COPD patients are at increased lung cancer risk, and transcriptomic changes common to both diseases could explain this risk. In both COPD and lung cancer, I discovered that H3K27Me3 regulated genes are repressed, and that the methyltransferase responsible for H3K27me3, EZH2, is induced. H3K27Me3, an oncogenic histone modification, may drive carcinogenesis and pathogenesis in COPD. Though usual and AATD emphysema share transcriptomic signatures associated with tissue repair, which may be active in the normal homeostatic lung, the UPR changes in AATD emphysema only; successful therapeutic strategies in emphysema will need to account for this difference. In COPD, H3K27Me3 may play a role in both pathogenesis and carcinogenesis, making it an attractive target for therapeutic interventions, but one that would need further augmentation in AATD. / 2019-11-01T00:00:00Z

<p> The object of this dissertation is to investigate the properties, associated boundary conditions and generalized resolvents of symmetric ordinary differential operators associated with formally self-adjoint nth order ordinary differential expressions with complex coefficients. </p> <p> While symmetric differential operators with equal deficiency indices have been studied in some detail, expecially the particular case when the underlying differential expression has real coefficients, little research has been done on the properties of symmetric differential operators with unequal deficiency indices which are associated with a differential expression with complex coefficients. </p> <p> By extending the symmetric differential operators with unequal deficiency indices to suitable operators with equal deficiency indices in larger Hilbert spaces and introducing a new type of boundary conditions to these extensions, we obtain important information about the original symmetric differential operators with unequal deficiency indices. We are able to generate some well-known theorems of I. M. Glazman (1950) and E. A. Coddington (1954) dealing with the characterization of self-adjoint extensions of symmetric operators in terms of boundary conditions, the relation between the deficiency indices of operators on the whole real line and on the half-line, and the resolvent of self-adjoint extensions, from the theory of symmetric, in particular real, differential operators with equal deficiency indices. We also generalize the result of W. N. Everitt (1959) concerning the number of integrable-square solutions of differential equations with one particular and one singular end-point to the case in which both end-points are singular. Finally, under certain assumptions, we extend some of the fundamental results of K. Kodaira (1950) based upon the methods of algebraic geometry, concerning Green's functions and the minimal symmetric differential operator associated with an even-order formally self-adjoint ordinary differential expansion with real coefficients to the case of Green's functions and the minimal symmetric differential operator associated with an even-order formally self-adjoint ordinary differential expression with complex coefficients. </p> / Thesis / Doctor of Philosophy (PhD)

Riboflavin transport is mediated, in part, by riboflavin transporter proteins 2 and 3, encoded by SLC52A2 and SLC52A3, respectively. Biallelic mutations in SLC52A2 and SLC52A3 impair riboflavin transporter protein function and riboflavin transport, causing disruptions to mitochondrial metabolism which result in sensory and motor neurodegeneration and give rise to riboflavin transporter deficiency (RTD) in humans. RTD is a rare neurodegenerative disease characterised by respiratory compromise, muscle and limb weakness, and vision and hearing impairments. RTD patients are treated with high-dose riboflavin supplementation which is effective in over 70% of cases but can be ineffective due to rapid excretion of riboflavin when its plasma concentration exceeds 0.5 μM. To address the need for alternative or supplemental RTD treatment, this study generated morpholino-mediated knockdown and CRISPR/Cas9 models of RTD in zebrafish. An RTD-like phenotype is observed in these RTD models including hearing loss, decreased motor axon length, and impaired locomotor activity. The slc52a3 morphant phenotype was found to be specific via coinjection of slc52a3 morpholino/human SLC52A3 mRNA, which achieved effective rescue of the morphant phenotype, as well as slc52a3 morpholino/p53 morpholino coinjection, which maintains the slc52a3 morphant phenotype. In line with clinical findings, riboflavin supplementation resulted in some improvement of the morphant phenotype. Probenecid was selected as a candidate drug due to its inhibitory effect on OAT-3, which mediates riboflavin excretion. However, supplementing riboflavin treatment with probenecid provided no additional benefit to the slc52a3 knockdown model. Further development of CRISPR/Cas9-knockout lines of slc52a2 and slc52a3, as well continued therapeutic screening of riboflavin and probenecid and consideration of alternative therapeutics will provide more opportunities to uncover novel therapeutic strategies to improve RTD treatment.

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Influence of nitrogen (N) deficiency on castor cv. ‘Hale’ growth, physiology, and leaf reflectance properties were investigated. Treatments imposed were complete Hoagland’s nutrient solution (control, 100N), reduced N to 20% of the control (20N) and withheld N from the solution (0N) from 34 to 66 days after sowing (DAS) in 12-L pots grown out doors. N deficiency significantly reduced leaf area, chlorophyll and photosynthesis resulting lower total biomass. Leaf and stem growth rates were more sensitive to leaf N concentration than photosynthesis and leaf addition rates. N deficiency stress increased leaf reflectance at R555 and R715 nm and caused a red-edge shift to shorter wavelengths. Reflectance ratios of R455/R605 and R505/R605 nm was highly correlated with leaf N on weight (r2 = 0.93) and area-based (r2 = 0.90) estimations, respectively. Similarly, reflectance ratio R635/R505 was highly correlated with chlorophylls (r2 = 0.94). The N-specific wavebands and functional relationships between leaf N and growth and developmental processes would be useful for rapid and non-destructive estimation of leaf N and growth rates of castor.

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