Thesis (Ph. D.)--University of Kentucky, 2004. / Title from document title page (viewed Oct. 11, 2004). Document formatted into pages; contains ix, 131 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 109-129).

Thesis (Ph. D.)--University of Kentucky,2004. / Title from document title page (viewed Oct. 12, 2004). Document formatted into pages; contains ix, 111 p. : ill. Includes abstract and vita. Includes bibliographical references (p. 97-110).

Thesis (Ph. D.)--University of Texas at Austin, 2000. / Vita. Includes bibliographical references (leaves 102-109). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph.D.)--Bowling Green State University, 2008. / Document formatted into pages; contains x, 126 p. : ill. Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2005. / Supervisor: Alan M. Lambowitz. Vita. Includes bibliographical references.

Thesis (M.S.)--Ohio University, August, 2003. / Title from PDF t.p. Includes bibliographical references (leaves 114-117)

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Pt(II) chemotherapies, including cisplatin and oxaliplatin, have been used in cancer treatment since the 1970s, however, a full understanding of the mechanism by which these drugs function is still lacking. While the interaction between Pt(II) drugs and DNA has been extensively studied and subsequently indicted in the cellular response to Pt(II) drugs, recent data indicates non-DNA targets play important roles as well. To gain insight into the non-DNA damage-based effects induced by these drugs, MDA-MB-468 cells were treated at therapeutic concentrations of cisplatin between 30 minutes and 24 hours. Not only does this data provide insight into the complex time-dependent nature of the cellular response to cisplatin, but novel responses were also observed. First, I describe how the expression of numerous snoRNAs decreases as early as 30 minutes post-treatment with either cisplatin or oxaliplatin, and differential expression analysis indicates this occurs before activation of the DNA damage response. Since snoRNAs are necessary components in ribosome processing, we sought to determine the role snoRNAs play in the cellular response to Pt(II) drugs. A subgroup of our identified snoRNAs direct modification of helix 69 on the 28S ribosome. Quantification of methylation of helix 69 and other locations suggests cisplatin induced changes in snoRNA expression leads to dysregulation of rRNA modification, likely altering ribosome activity. I also observe varied activation of different types of DNA damage and cell cycle arrest between 3 and 12 hours of cisplatin treatment while early expression changes show downregulation of mitochondrial genes. We also identify a number of lncRNAs previously associated with TNBC that are downregulated after cisplatin treatment. This study establishes a gene expression profile induced by cisplatin treatment of triple-negative breast cancer that demonstrates the complex interplay of multiple means of stress induction. Lastly, we establish a method for analyzing direct DNA binding targets of platinum(II) chemotherapeutics. This pilot study confirms high accumulation of platinum(II) compounds on guanine-rich DNA and suggests DNA binding of significant genes leads to changes in their RNA expression. / 10000-01-01

O objetivo do presente estudo foi avaliar os efeitos da suplementação de levedura hidrolisada (fonte de nucleotídeos) em dietas de porcas em fase de lactação sobre o consumo de ração e peso corporal, composição bromatológicas do leite, concentração de RNA e nucleotídeos, e desempenho da progênie. Os nucleotídeos foram derivados de uma levedura hidrolisada (Hilyses®, ICC Brazil). Foram utilizadas 80 porcas (Agroceres PIC®) distribuídas em um delineamento inteiramente casualizado, com 4 tratamentos (0, 4, 8 e 12 kg/ton de Hilyses) e 20 repetições, sendo cada porca uma unidade experimental. As porcas foram alimentadas com as dietas experimentais 3 dias antes da parição, quando foram transferidas para a maternidade, até o desmame dos leitões aos 21,57 ± 0,88 dias de idade. O número de leitões por matriz (10,48 ± 0,26) e peso dos leitões (1,70 ± 0,04 kg) foram ajustados (equalizados) ao nascimento. Os parâmetros avaliados nas porcas foram peso ao parto (PPP, kg), peso ao desmame (PPD, kg), perda de peso (PPC, %) e consumo de ração (CR, kg). O número de leitões desmamados (NLD), peso do leitão ao desmame (PD, kg), peso da leitegada ao desmame (PLD, kg), ganho de peso da leitegada (GPL, kg), mortalidade (M, %) e produção de leite (PL = 1kg de GPL = 4kg de leite produzido) foram mensurados. Amostras de colostro e leite (aos 11 e 20 dias de lactação) foram coletadas para análises bromatológicas, RNA (mg/ml de leite) e nucleotídeos e nucleosídeos (g/ml leite). Os dados foram analisados pelo GLM (SAS), e as médias comparadas pelo teste de Tukey (P=0,05). A suplementação de nucleotídeos na dieta de porcas em fase de lactação não resultou em diferenças (P>0,05) no PPP, PPD, PPC e CR. Os leitões das porcas alimentadas com dietas suplementadas com levedura hidrolisada tiveram uma melhora (P<0,05) no NLD, PLD, GPL, M e PL quando comparados com as não suplementadas com a levedura hidrolisada. Não houve diferença (P>0,05) entre os tratamentos no PD. Em geral os níveis 8 e 12 kg/ton de inclusão de Hilyses mostraram os melhores resultados de desempenho dos leitões (6% e 4,5% maiores sobre o GPL) e menor M (41,7% e 53,5% comparados ao grupo controle). Os resultados das análises bromatológicas do colostro e leite de porcas tiveram uma composição similar entre os tratamentos, no entanto houve uma tendência de aumento na lactose com o aumento da inclusão de Hilyses. A concentração de RNA no leite (aos 11 e 20 dias de idade) foram maiores (P<0,05) nos tratamentos com suplementação da levedura hidrolisada. O total de nucleotídeos e nucleosídeos no leite foram afetados (P<0,05) pelos tratamentos aos 20 dias de lactação. Este estudo demonstrou que a suplementação para porcas lactantes teve um efeito positivo na qualidade do leite, e consequentemente, aumentou o ganho de peso da leitegada e o número de leitões desmamados (+3,5%). / The objective of this study was to evaluate effects of hydrolyzed yeast (nucleotide source) in farrowing sows diets on feed intake and body weight, milk bromatological composition, RNA and nucleotides, and progeny performance. The nucleotides were derived from a yeast source (Hilyses®, ICC Brazil).The trial was conducted with 80 sows (Agroceres PIC®) distributed in a completely randomized design, with 4 treatments (0, 4, 8, or 12 kg/MT Hilyses®) and20 replications of 1 sow in each per treatment. The sows were fed experimental diets starting 3 days before farrowing, when sows were transferred to the maternity unit, until weaning of piglets at 21 days of age. The number of piglets per sow (10.48±0.26) and piglet weight (1.70±0.04kg) was adjusted (equalized) at birth. The sow parameters were weight after farrowing (WF,kg), weight after weaning (WW,kg), weight loss (WL,%), and feed intake (FI,kg). The number of weaned piglets (NWP), piglet weight at weaning (PWW,kg), litter weight at weaning (LWW,kg), litter weight gain (LWG,kg), mortality (MORT,%), and milk production (MP,kg; 1kg of piglet weight = 4kg of milk) were measured. Samples of colostrum and milk (11, 20 days of lactation) were collected for laboratory bromatological analysis, RNA (mg/ml milk) and nucleotides and nucleosides (&#956;g/ml milk). The data were analyzed using the GLM (SAS), and means were compared by Tukeys test (P=0.05). Nucleotide supplementation in the diet of farrowing sows resulted in no difference (P>0.05) in WF, WW, WL, or FI. The piglets from sows fed diets supplemented with nucleotides had improved (P<0.05) NWP, LWW, LWG, MORT, and MP compared with unsupplemented diets. There were no differences (P>0.05) between treatments in PWW. In general, the 8kg/MT and 12kg/MT levels showed best piglet performance results (6% and 4.5% higher LWG than control group) and lower MORT (41.7% and 53.5% lower than control group). The results of bromatological analysis of colostrum and milk had a similar composition between the treatments, however, there was a numerical increase tendency in lactose with hydrolyzed yeast supplementation. Hilyses® supplementation gave no significant response (P>0.05) in Total RNA in colostrums, but the amount of RNA present in milk at 11 and 20 days of lactation significantly increased (P<0.05). The total of nucleotides and nucleosides in milk at 20 days of lactation period were affected (P<0.05) by treatments. This study demonstrated that supplementation of nucleotides to farrowing sows had a positive carryover effect on milk quality, which, consequently, increased the litter weight gain and the number of, weaned piglets (+3.5%).

RNA molecules play important roles, including catalysis of chemical reactions and control of gene expression, and their functions largely depend on their folded structures. Since determining these structures by biochemical means is expensive, there is increased demand for computational predictions of RNA structures. One computational approach is to find the secondary structure (a set of base pairs) that minimizes a free energy function for a given RNA conformation. The forces driving RNA folding can be approximated by means of a free energy model, which associates a free energy parameter to a distinct considered feature. The main goal of this thesis is to develop state-of-the-art computational approaches that can significantly increase the accuracy (i.e., maximize the number of correctly predicted base pairs) of RNA secondary structure prediction methods, by improving and refining the parameters of the underlying RNA free energy model. We propose two general approaches to estimate RNA free energy parameters. The Constraint Generation (CG) approach is based on iteratively generating constraints that enforce known structures to have energies lower than other structures for the same molecule. The Boltzmann Likelihood (BL) approach infers a set of RNA free energy parameters which maximize the conditional likelihood of a set of known RNA structures. We discuss several variants and extensions of these two approaches, including a linear Gaussian Bayesian network that defines relationships between features. Overall, BL gives slightly better results than CG, but it is over ten times more expensive to run. In addition, CG requires software that is much simpler to implement. We obtain significant improvements in the accuracy of RNA minimum free energy secondary structure prediction with and without pseudoknots (regions of non-nested base pairs), when measured on large sets of RNA molecules with known structures. For the Turner model, which has been the gold-standard model without pseudoknots for more than a decade, the average prediction accuracy of our new parameters increases from 60% to 71%. For two models with pseudoknots, we obtain an increase of 9% and 6%, respectively. To the best of our knowledge, our parameters are currently state-of-the-art for the three considered models. / Science, Faculty of / Computer Science, Department of / Graduate