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Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the 10th leading cause of death, worldwide. The prevalence of drug-resistant clinical isolates and the paucity of newly-approved antituberculosis drugs impedes the successful eradication of Mtb. Bacteria commonly use two-component systems (TCS) to sense their environment and genetically modulate adaptive responses.

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the 10th leading cause of death, worldwide. The prevalence of drug-resistant clinical isolates and the paucity of newly-approved antituberculosis drugs impedes the successful eradication of Mtb. Bacteria commonly use two-component systems (TCS) to sense their environment and genetically modulate adaptive responses. The prrAB TCS is essential in Mtb, thus representing an auspicious drug target; however, the inability to generate an Mtb ΔprrAB mutant complicates investigating how this TCS contributes to pathogenesis. Mycobacterium smegmatis, a commonly used M. tuberculosis genetic surrogate was used here. This work shows that prrAB is not essential in M. smegmatis. During ammonium stress, the ΔprrAB mutant excessively accumulates triacylglycerol lipids, a phenotype associated with M. tuberculosis dormancy and chronic infection. Additionally, triacylglycerol biosynthetic genes were induced in the ΔprrAB mutant relative to the wild-type and complementation strains during ammonium stress. Next, RNA-seq was used to define the M. smegmatis PrrAB regulon. PrrAB regulates genes participating in respiration, metabolism, redox balance, and oxidative phosphorylation. The M. smegmatis ΔprrAB mutant is compromised for growth under hypoxia, is hypersensitive to cyanide, and fails to induce high-affinity respiratory genes during hypoxia. Furthermore, PrrAB positively regulates the hypoxia-responsive dosR TCS response regulator, potentially explaining the hypoxia-mediated growth defects in the ΔprrAB mutant. Despite inducing genes encoding the F1F0 ATP synthase, the ΔprrAB mutant accumulates significantly less ATP during aerobic, exponential growth compared to the wild-type and complementation strains. Finally, the M. smegmatis ΔprrAB mutant exhibited growth impairment in media containing gluconeogenic carbon sources. M. tuberculosis mutants unable to utilize these substrates fail to establish chronic infection, suggesting that PrrAB may regulate Mtb central carbon metabolism in response to chronic infection. In conclusion, 1) prrAB is not universally essential in mycobacteria; 2) M. smegmatis PrrAB regulates genetic responsiveness to nutrient and oxygen stress; and 3) PrrAB may provide feed-forward control of the DosRS TCS and dormancy phenotypes. The data generated in these studies provide insight into the mycobacterial PrrAB TCS transcriptional regulon, PrrAB essentiality in Mtb, and how PrrAB may mediate stresses encountered by Mtb during the transition to chronic infection.
ContributorsMaarsingh, Jason (Author) / Haydel, Shelley E (Thesis advisor) / Roland, Kenneth (Committee member) / Sandrin, Todd (Committee member) / Bean, Heather (Committee member) / Arizona State University (Publisher)
Created2019
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Description
Reproduction is energetically costly and seasonal breeding has evolved to capitalize on predictable increases in food availability. The synchronization of breeding with periods of peak food availability is especially important for small birds, most of which do not store an extensive amount of energy. The annual change in photoperiod is

Reproduction is energetically costly and seasonal breeding has evolved to capitalize on predictable increases in food availability. The synchronization of breeding with periods of peak food availability is especially important for small birds, most of which do not store an extensive amount of energy. The annual change in photoperiod is the primary environmental cue regulating reproductive development, but must be integrated with supplementary cues relating to local energetic conditions. Photoperiodic regulation of the reproductive neuroendocrine system is well described in seasonally breeding birds, but the mechanisms that these animals use to integrate supplementary cues remain unclear. I hypothesized that (a) environmental cues that negatively affect energy balance inhibit reproductive development by acting at multiple levels along the reproductive endocrine axis including the hypothalamus (b) that the availability of metabolic fuels conveys alterations in energy balance to the reproductive system. I investigated these hypotheses in male house finches, Haemorhous mexicanus, caught in the wild and brought into captivity. I first experimentally reduced body condition through food restriction and found that gonadal development and function are inhibited and these changes are associated with changes in hypothalamic gonadotropin-releasing hormone (GnRH). I then investigated this neuroendocrine integration and found that finches maintain reproductive flexibility through modifying the release of accumulated GnRH stores in response to energetic conditions. Lastly, I investigated the role of metabolic fuels in coordinating reproductive responses under two different models of negative energy balance, decreased energy intake (food restriction) and increased energy expenditure (high temperatures). Exposure to high temperatures lowered body condition and reduced food intake. Reproductive development was inhibited under both energy challenges, and occurred with decreased gonadal gene expression of enzymes involved in steroid synthesis. Minor changes in fuel utilization occurred under food restriction but not high temperatures. My results support the hypothesis that negative energy balance inhibits reproductive development through multilevel effects on the hypothalamus and gonads. These studies are among the first to demonstrate a negative effect of high temperatures on reproductive development in a wild bird. Overall, the above findings provide important foundations for investigations into adaptive responses of breeding in energetically variable environments.
ContributorsValle, Shelley (Author) / Deviche, Pierre (Thesis advisor) / McGraw, Kevin (Committee member) / Orchinik, Miles (Committee member) / Propper, Catherine (Committee member) / Sweazea, Karen (Committee member) / Arizona State University (Publisher)
Created2018
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Description
Early humans adapted to eating cooked food with increased energy density and absorption of macronutrients. However, in modern times many suffer from diseases like obesity and type 2 diabetes which can result from too much energy being absorbed from food. This study measures glucose responses to a high glycemic meal

Early humans adapted to eating cooked food with increased energy density and absorption of macronutrients. However, in modern times many suffer from diseases like obesity and type 2 diabetes which can result from too much energy being absorbed from food. This study measures glucose responses to a high glycemic meal with a side dish of raw or cooked vegetables. There was a slight trend for raw vegetables to have decreased postprandial blood glucose responses when compared to cooked vegetables.
ContributorsWilkins, Christine Marie (Author) / Johnston, Carol (Thesis director) / Jacobs, Mark (Committee member) / Barrett, The Honors College (Contributor) / School of International Letters and Cultures (Contributor)
Created2014-05
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Description

Depression is a worldwide public health problem that affects millions of people every year. Due to recent reports that depressed individuals have an altered gut microbiome composition, there is speculation that treatments that influence microorganisms in the gut could potentially lead to alleviation of depressive symptoms. Apple cider vinegar has

Depression is a worldwide public health problem that affects millions of people every year. Due to recent reports that depressed individuals have an altered gut microbiome composition, there is speculation that treatments that influence microorganisms in the gut could potentially lead to alleviation of depressive symptoms. Apple cider vinegar has been studied extensively for its health-promoting properties and benefits. Apple cider vinegar’s main ingredient is the short chain fatty acid, acetic acid. Short chain fatty acids have been shown to improve mood state and depressive symptoms, as well as amplify the effect of prebiotics in restoring the gut microbiome. This experimental design study examined the effects of ingesting 2 tbsp. apple cider vinegar (1 g acetic acid) twice daily with a meal on the levels of urinary metabolites in 14 college students compared to a control group of 11 college students that took one vinegar supplement tablet (0.015 g of acetic acid) daily for 28 days. All participants were healthy, normal to underactive (< 300 minutes of moderate exercise a week), and free of chronic or acute illnesses. Urinary metabolite analysis revealed a significant production of enzymes involved in the hexosamine pathway in the liquid vinegar group compared to baseline levels. However, anticipation of an alteration in tryptophan metabolites, a possible consequence of altered metabolism of gut microflora, was not observed. These data suggest that apple cider vinegar might be a potential treatment for depression through the production of hexosamine pathway enzymes.

ContributorsBauer, Shayna Dru (Author) / Johnston, Carol (Thesis director) / Sweazea, Karen (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
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Description
Glucocorticoids are a class of corticosteroids that bind to glucocorticoid receptors
within cells that result in changes in the metabolism of carbohydrates and immune functions.
Ingesting glucocorticoids has also been linked to insulin resistance, a main feature of Type 2
diabetes. Experiments including polymerase chain reaction, western blotting, and glycogen

Glucocorticoids are a class of corticosteroids that bind to glucocorticoid receptors
within cells that result in changes in the metabolism of carbohydrates and immune functions.
Ingesting glucocorticoids has also been linked to insulin resistance, a main feature of Type 2
diabetes. Experiments including polymerase chain reaction, western blotting, and glycogen
synthase analysis were conducted to determine if exposure to higher doses of dexamethasone, a
glucocorticoid, induces insulin resistance in cultured rat skeletal muscle via interaction with
thioredoxin-interacting protein (TXNIP). Treatment with dexamethasone was shown to cause
mild increases in TXNIP while a definitive increase or decrease in insulin signaling was unable
to be determined.
ContributorsCusimano, Jason A (Author) / Sweazea, Karen (Thesis director) / Reaven, Peter (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05