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The Dorrance Center for Rare Childhood Disorders is a unique research division at TGen (The Translational Genomics Research Institute) that provides personalized care to children and young adults facing rare, undiagnosed diseases. TGen scientists believe that the answers to these enigmatic disorders can often be found in a person's genetic code. They aim to solve these genetic mysteries using whole exome sequencing, a method that prioritizes the protein-coding portion of the genome in the search for disease-causing variants. Unfortunately, a communication gap sometimes exists between the TGen scientists and the patients they serve. I have seen, first hand, the kind of confusion that this study elicits in the families of its participants. Therefore, for my thesis, I decided to create a booklet that is meant to provide some clarity as to what exactly The Dorrance Center for Rare Childhood Disorders does to help diagnose children with rare disorders. The purpose of the booklet is to dispel any confusion regarding the study by providing a general review of genetics and an application of these lessons to the relevant sequencing technology as well as a discussion of the causes and effects of genetic mutations that often times are linked to rare childhood disorders.
ContributorsCambron, Julia Claire (Author) / LaBelle, Jeffrey (Thesis director) / Huentelman, Matt (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2015-05
Description
Physical activity as a health or nutrition related intervention might stimulate appetite and increase hunger due to increased energy expenditure. This study analyzed the effect of a postprandial 15-minute walk on the hunger and energy intake of 10 obese, pre-diabetic adults. Subjects participated in three 4-hour trials: a walk treatment (consume highly glycemic meal, walk for 15 minutes at a moderate pace, and rest for 4 hours), a fiber treatment (consume highly glycemic meal enriched with soluble fiber and rest for 4 hours), and a control treatment (consume highly glycemic meal without fiber and rest for 4 hours). The effects of each treatment on hunger and energy intake were measured using a Likert scale analysis (ranging from "completely satisfied" to "extremely hungry") at 4 hours post-treatment and pre/ post 24-hour dietary logs. The results showed no significant increase or decrease on hunger or energy intake for both the walk and the fiber treatment compared to the control treatment. This denies the idea that physical activity might increase short-term hunger, and supports the use of physical activity as a viable nutrition related intervention tool.
ContributorsTerrell, Alayna Franci (Author) / Johnston, Carol (Thesis director) / Vega Lopez, Sonia (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
Description
Despite the 40-year war on cancer, very limited progress has been made in developing a cure for the disease. This failure has prompted the reevaluation of the causes and development of cancer. One resulting model, coined the atavistic model of cancer, posits that cancer is a default phenotype of the cells of multicellular organisms which arises when the cell is subjected to an unusual amount of stress. Since this default phenotype is similar across cell types and even organisms, it seems it must be an evolutionarily ancestral phenotype. We take a phylostratigraphical approach, but systematically add species divergence time data to estimate gene ages numerically and use these ages to investigate the ages of genes involved in cancer. We find that ancient disease-recessive cancer genes are significantly enriched for DNA repair and SOS activity, which seems to imply that a core component of cancer development is not the regulation of growth, but the regulation of mutation. Verification of this finding could drastically improve cancer treatment and prevention.
ContributorsOrr, Adam James (Author) / Davies, Paul (Thesis director) / Bussey, Kimberly (Committee member) / Barrett, The Honors College (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2015-05
Description
There has been an alarming rise in the prevalence of obesity which has been attributed to the paralleled rise in consumption of high-fat foods. It’s commonly accepted that high-fat diets can lead to increased weight gain, however not all fats have the same physiological action. This study primarily focuses on the effect of canola oil, a monounsaturated fat, on energy homeostasis and body composition when it’s given as a supplement to a high-fat diet composed of saturated fatty acid. Rodent models were divided into three dietary groups: 1) low-fat diet (LFD), 2) high-fat diet (HFD) and 3) canola oils supplemented HFD (HF+CAN). After 4 weeks of dietary intervention, samples of epididymal fat, perinephric fat, and liver were analyzed across the three groups to see if the changes in energy homeostasis could be explained by the cellular behavior and composition of these tissues. Interestingly, the supplement of canola oil appeared to reverse the deleterious effects of a saturated fat diet, reverting energy intake, body weight gain and adipose tissue sizes to that (if not lower than that) of the LFD group. The only exception to this effect was the liver: the livers remained larger and fattier than those of the HFD. This occurrence is possibly due to a decrease in free fatty acid uptake in the adipose tissues—resulting in smaller adipose tissue sizes—and increased fatty acid uptake in the liver. The mechanism by which this occurs has yet to be elucidated and will be the primary focus of upcoming studies on the effect of monounsaturated fat on other diets.
ContributorsZuo, Connie Wanda (Author) / Washo-Krupps, Delon (Thesis director) / Deviche, Pierre (Committee member) / Herman, Richard (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2015-05
Description
Patients who are infected with the human immunodeficiency virus (HIV) and who remain adherent to their highly active antiretroviral treatment (HAART) regimen are likely to achieve good virologic control over significant periods of time. Children who start with a low CD4 percentage (below 15%) are associated with adverse clinical outcomes and the risk of never increasing their CD4 counts to normal functioning levels. While adherent adult HIV patients have been studied frequently, this was a retrospective chart study that aimed to describe the immune reconstitution pattern for up to 16 years in virologically controlled pediatric patients who had been or who are currently being treated at the Bill Holt Clinic at Phoenix Children's Hospital. In the preliminary study, 35 patients met criteria for inclusion and three years later for this extension study 7 more were added while 17 of the initial patients were followed further because they have remained in care and virologically controlled. All 28 patients who achieved 5 years of viral suppression were >25% CD4. All 8 patients who achieved 12 years of viral suppression were >31% CD4. All patients who achieved 16 years of viral suppression were >41% CD4. After 12 years, the 8 patients who maintained viral suppression all had absolute CD4 counts of over 600 cells and additionally each had CD4/CD8 ratios greater than 1. Overall, the data shows immune system normalization for up to 16 years, although CD4/CD8 ratios improved but never completely normalized. Some limitations include a small sample size and missing data points due to laboratory testing errors or the lack of technology in different countries to test for CD8 cells. These findings suggest that children who remain adherent to HAART can experience ongoing immune healing for up to 16 years. This may provide additional incentive to providers and caretakers to encourage adherence and maximize long-term immune competence in HIV positive children.
ContributorsRichards, Anne Elizabeth (Author) / Wachter, Rebekka (Thesis director) / Blattman, Joseph (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Human Evolution and Social Change (Contributor)
Created2015-05
Description
An important question that needs to be discussed is whether drug detection dogs can be used the same way as machines in assisting drug detection and how these drug detection dogs should be used under the Fourth Amendment. In answering these questions, the history, training, certifications, and case law relating to drug detection dogs should be reviewed. The dogs are powerful tools in the detection of narcotics, but it is critical to remember that they are only animals and far from flawless. They can make mistakes because of lapses in training, due to irregular training and certification standards, or cues, intentional or not, from their handlers. Under current precedent, walking around something, like a car, is not a search and does not require reasonable suspicion. A dog alert during this non-intrusive, superficial contact can give rise to probable cause to search. If the dog alert is not reliable, it can lead to many unnecessary searches that violate people's privacy. In order to protect Fourth Amendment rights from the, drug detection dogs need to be used carefully and with limitations. A dog's ability to smell is impressive and humans' ability to train them is vast, but a dog is just a dog. The limited accuracy of a dog sniff is not an issue when they are used to search for people in landslides or avalanches, because even 10% accuracy is helpful when trying to save someone's life. However, when a drug detection dog is used to establish probable cause for a search, accuracy becomes an issue. United States v. Place was based on faulty scientific evidence on the accuracy of dogs, and it set the standard for future drug detection dog cases. The courts need to revisit this issue in light of more recent information. Except in certain locations where Fourth Amendment rights are limited, drug detection dogs should only be used when reasonable suspicion of criminal conduct exists. This limitation, as well as enhanced training and certification standards, strikes the appropriate balance between living in a civilized society and living in a secure society.
ContributorsGodinez, Katherine Mary (Author) / Stanford, Michael (Thesis director) / Kirchler, Rebecca (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / Sandra Day O'Connor College of Law (Contributor)
Created2014-05
Description
Quercetin 2,3-dioxygenase from Bacillus subtilis has been identified and characterized as the first known prokaryotic quercetinase. This enzyme catalyzes the cleavage of the O-heteroaromatic ring of the flavonol quercetin to the corresponding depside and carbon monoxide. The first quercetinase was characterized from a species of Aspergillus genus, and was found to contain one Cu2+ per subunit. For many years, it was thought that the B. subtilis quercetinase contained two Fe2+ ions per subunit; however, it has since been discovered that Mn2+ is a much more likely cofactor. Studies of overexpressed bacterial enzyme in E. coli indicated that this enzyme may be active with other metal ions (e.g. Co2+); however, the production of enzyme with full metal incorporation has only been possible with Mn2+. This study explores the notion that metal manipulation after translation, by partially unfolding the enzyme, chelating the metal ions, and then refolding the protein in the presence of an excess of divalent metal ions, could generate enzyme with full metal occupancy. The protocols presented here included testing for activity after incubating purified quercetinase with EDTA, DDTC, imidazole and GndHCl. It was found that the metal chelators had little to no effect on quercetinase activity. Imidazole did appear to inhibit the enzyme at concentrations in the millimolar range. In addition, the quercetinase was denatured in GndHCl at concentrations above 1 M. Recovering an active enzyme after partial or complete unfolding proved difficult, if not impossible.
ContributorsKrojanker, Elan Daniel (Author) / Francisco, Wilson (Thesis director) / Allen, James P. (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2014-05
Description
In the United States, a dispute has arisen over the safety and need for vaccination, particularly in regard to compulsory vaccination laws. New outlets and social media sites publish countless reports about the dangers of vaccines or of known adverse reactions as well as imagined or unproven worries. Individuals' rights to choose to get vaccinated or allow their children to be vaccinated comes to direct conflict with measures needed to protect communities from preventable viral diseases. The controversy surrounding vaccines is not new, nor necessarily are the fundamental reasons for skepticism. Looking back through the history of vaccines as a medical tool, the evolution of the controversy can be observed taking place with each new historical context, scientific development, and social conditions. Despite scientific research and assurances of vaccine safety, opposition and unease about vaccination appear to take Looking individually at the development and distribution of the smallpox (variola virus), polio (poliovirus) and human papilloma virus(HPV) vaccines, concerns regarding the violation of personal rights, safety of vaccines themselves, and social stigmas and connotations surrounding vaccines can be seen to evolve and change. Due to the way doubt can manifest in different ways over time, it may be impossible to fully end the vaccine debate. However, nderstanding the sociological factors behind anti-vaccine sentiment may allow healthcare professionals to work with concerned people with a particular care to address these visceral and sometimes irrational fears surrounding vaccination.
ContributorsStevens, Luke Christian (Author) / Jacobs, Bertram (Thesis director) / Washo-Krupps, Delon (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
In Mexico, the female adolescent population is made up from two groups, single women and married or cohabitating women. Throughout the past decade there has been an increase in the fertility rate amongst the adolescent population in the state of Sonora. Several factors were analyzed to determine their impact on adolescent fertility rate and unplanned pregnancies but ultimately it was found that sexual education was the most influential factor. Comprehensive sexual education has been found to decrease the number of adolescent pregnancies in schools or cities where that curriculum is taught. Many experts believe that this occurs because adolescents are better educated in the proper usage of contraception. Increased contraceptive use directly causes a decrease in unplanned pregnancy rate. With respect to Mexico, it was found that comprehensive sexual education is taught in Sonora but there is no standardized program. Few institutions provide comprehensive sexual education and the programs range between a level 0 and level 3 with respect to the strictness of the abstinence only curricula. Four interviews were conducted between December of 2013 and March of 2014. The purpose of the interviews was to gain a better understanding about how sexual education is perceived in Hermosillo, Sonora, Mexico and what sort of programs are available to adolescents. The questions that comprised the interview consisted of three general parts: background, demographics and sexual education. The interviewees were selected based on their level of expertise reproductive health among adolescents. Two programs were selected for research: Programa Gente Joven (PGJ) and Vive Prevenido. Based on research and data analysis several conclusions were reached. The average age a Mexican woman first has sex, gets married and has her first child within less than 5 years starting in their adolescence. Many years pass between the age of a woman's first childbirth and when she first uses contraception. This is caused by an unmet or unsatisfied need for contraception where the national level is higher than that of Sonora. With respect to sexual education the Guttmacher Institute data suggests that comprehensive sexual education is more effective than abstinence only education. And finally, the experts interviewed all agreed that comprehensive sexual education is what should be taught on a state wide level. The views and opinions of these four interviewees do not reflect those of all who work with adolescents. To gain a more generalized idea on the situation surrounding unplanned pregnancies in adolescents more interviews would need to be conducted. This project was purely exploratory and does not aim to analyze or evaluate either program.
ContributorsGalaz, Mayra Alejandra (Author) / Garcia Perez, Maria (Thesis director) / Lara-Valencia, Francisco (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2014-05
Description
microRNAs (miRNAs) are short ~22nt non-coding RNAs that regulate gene output at the post-transcriptional level. Via targeting of degenerate elements primarily in 3'untranslated regions (3'UTR) of mRNAs, miRNAs can target thousands of varying genes and suppress their protein translation. The precise mechanistic function and bio- logical role of miRNAs is not fully understood and yet it is a major contributor to a pleth- ora of diseases, including neurological disorders, muscular disorders, and cancer. Cer- tain model organisms are valuable in understanding the function of miRNA and there- fore fully understanding the biological significance of miRNA targeting. Here I report a mechanistic analysis of miRNA targeting in C. elegans, and a bioinformatic approach to aid in further investigation of miRNA targeted sequences. A few of the biologically significant mechanisms discussed in this thesis include alternative polyadenylation, RNA binding proteins, components of the miRNA recognition machinery, miRNA secondary structures, and their polymorphisms. This thesis also discusses a novel bioinformatic approach to studying miRNA biology, including computational miRNA target prediction software, and sequence complementarity. This thesis allows a better understanding of miRNA biology and presents an ideal strategy for approaching future research in miRNA targeting.
ContributorsWeigele, Dustin Keith (Author) / Mangone, Marco (Thesis director) / Katchman, Benjamin (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Life Sciences (Contributor)
Created2014-12