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Description
Random peptide microarrays are a powerful tool for both the treatment and diagnostics of infectious diseases. On the treatment side, selected random peptides on the microarray have either binding or lytic potency against certain pathogens cells, thus they can be synthesized into new antimicrobial agents, denoted as synbodies (synthetic antibodies). On the diagnostic side, serum containing specific infection-related antibodies create unique and distinct "pathogen-immunosignatures" on the random peptide microarray distinct from the healthy control serum, and this different mode of binding can be used as a more precise measurement than traditional ELISA tests. My thesis project is separated into these two parts: the first part falls into the treatment side and the second one focuses on the diagnostic side. My first chapter shows that a substitution amino acid peptide library helps to improve the activity of a recently reported synthetic antimicrobial peptide selected by the random peptide microarray. By substituting one or two amino acids of the original lead peptide, the new substitutes show changed hemolytic effects against mouse red blood cells and changed potency against two pathogens: Staphylococcus aureus and Pseudomonas aeruginosa. Two new substitutes are then combined together to form the synbody, which shows a significantly antimicrobial potency against Staphylococcus aureus (<0.5uM). In the second chapter, I explore the possibility of using the 10K Ver.2 random peptide microarray to monitor the humoral immune response of dengue. Over 2.5 billion people (40% of the world's population) live in dengue transmitting areas. However, currently there is no efficient dengue treatment or vaccine. Here, with limited dengue patient serum samples, we show that the immunosignature has the potential to not only distinguish the dengue infection from non-infected people, but also the primary dengue infection from the secondary dengue infections, dengue infection from West Nile Virus (WNV) infection, and even between different dengue serotypes. By further bioinformatic analysis, we demonstrate that the significant peptides selected to distinguish dengue infected and normal samples may indicate the epitopes responsible for the immune response.
ContributorsWang, Xiao (Author) / Johnston, Stephen Albert (Thesis advisor) / Blattman, Joseph (Committee member) / Arntzen, Charles (Committee member) / Arizona State University (Publisher)
Created2013
Description
The majority of non-small cell lung cancer (NSCLC) patients (70%) are diagnosed with adenocarcinoma versus other histological subtypes. These patients often present with advanced, metastatic disease and frequently relapse after treatment. The tumor suppressor, Liver Kinase B1, is frequently inactivated in adenocarcinomas and loss of function is associated with a highly aggressive, metastatic tumor (1). Identification of the mechanisms deregulated with LKB1 inactivation could yield targeted therapeutic options for adenocarcinoma patients. Re-purposing the immune system to support tumor growth and aid in metastasis has been shown to be a feature in cancer progression (2). Tumor associated macrophages (TAMs) differentiate from monocytes, which are recruited to the tumor microenvironment via secretion of chemotaxic factors by cancer cells. We find that NSCLC cells deficient in LKB1 display increased secretion of C-C motif ligand 2 (CCL2), a chemokine involved in monocyte recruitment. To elucidate the molecular pathway regulating CCL2 up-regulation, we investigated inhibitors of substrates downstream of LKB1 signaling in A549, H23, H2030 and H838 cell lines. Noticeably, BAY-11-7082 (NF-κB inhibitor) reduced CCL2 secretion by an average 92%. We further demonstrate that a CCR2 antagonist and neutralizing CCL2 antibody substantially reduce monocyte migration to NSCLC (H23) cell line conditioned media. Using an in vivo model of NSCLC, we find that LKB1 deleted tumors demonstrate a discernible increase in CCL2 levels compared to normal lung. Moreover, tumors display an increase in the M2:M1 macrophage ratio and increase in tumor associated neutrophil (TAN) infiltrate compared to normal lung. This M2 shift was significantly reduced in mice treated with anti-CCL2 or a CCR2 antagonist and the TAN infiltrate was significantly reduced with the CCR2 antagonist. These data suggest that deregulation of the CCL2/CCR2 signaling axis could play a role in cancer progression in LKB1 deficient tumors.
ContributorsFriel, Jacqueline (Author) / Inge, Landon (Thesis advisor) / Lake, Douglas (Thesis advisor) / Blattman, Joseph (Committee member) / Arizona State University (Publisher)
Created2015
Description
Recent research has shown that reward-related stimuli capture attention in an automatic and involuntary manner, or reward-salience (Le Pelley, Pearson, Griffiths, & Beesley, 2015). Although patterns of oculomotor behavior have been previously examined in recent experiments, questions surrounding a potential neural signal of reward remain. Consequently, this study used pupillometry to investigate how reward-related stimuli affect pupil size and attention. Across three experiments, response time, accuracy, and pupil were measured as participants searched for targets among distractors. Participants were informed that singleton distractors indicated the magnitude of a potential gain/loss available in a trial. Two visual search conditions were included to manipulate ongoing cognitive demands and isolate reward-related pupillary responses. Although the optimal strategy was to perform quickly and accurately, participants were slower and less accurate in high magnitude trials. The data suggest that attention is automatically captured by potential loss, even when it is counterintuitive to current task goals. Regarding a pupillary response, patterns of pupil size were inconsistent with our predictions across the visual search conditions. We hypothesized that if pupil dilation reflected a reward-related reaction, pupil size would vary as a function of both the presence of a reward and its magnitude. More so, we predicted that this pattern would be more apparent in the easier search condition (i.e., cooperation visual search), because the signal of available reward was still present, but the ongoing attentional demands were significantly reduced in comparison to the more difficult search condition (i.e., conflict visual search). In contrast to our predictions, pupil size was more closely related to ongoing cognitive demands, as opposed to affective factors, in cooperation visual search. Surprisingly, pupil size in response to signals of available reward was better explained by affective, motivational and emotional influences than ongoing cognitive demands in conflict visual search. The current research suggests that similar to recent findings involving LC-NE activity (Aston-Jones & Cohen, 2005; Bouret & Richmond, 2009), the measure of pupillometry may be used to assess more specific areas of cognition, such as motivation and perception of reward. However, additional research is needed to better understand this unexpected pattern of pupil size.
ContributorsPhifer, Casey (Author) / Goldinger, Stephen D (Thesis advisor) / Homa, Donald J (Committee member) / McClure, Samuel M. (Committee member) / Papesh, Megan H (Committee member) / Arizona State University (Publisher)
Created2017
Description
Environmental changes are occurring at an unprecedented rate, and these changes will undoubtedly lead to alterations in resource availability for many organisms. To effectively predict the implications of such changes, it is critical to better understand how organisms have adapted to coping with seasonally limited resources. The vast majority of previous work has focused on energy balance as the driver of changes in organismal physiology. While energy is clearly a vital currency, other resources can also be limited and impact physiological functions. Water is essential for life as it is the main constituent of cells, tissues, and organs. Yet, water has received little consideration for its role as a currency that impacts physiological functions. Given the importance of water to most major physiological systems, I investigated how water limitations interact with immune function, metabolism, and reproductive investment, an almost entirely unexplored area. Using multiple species and life stages, I demonstrated that dehydrated animals typically have enhanced innate immunity, regardless of whether the dehydration is a result of seasonal water constraints, water deprivation in the lab, or high physiological demand for water. My work contributed greatly to the understanding of immune function dynamics and lays a foundation for the study of hydration immunology as a component of the burgeoning field of ecoimmunology. While a large portion of my dissertation focused on the interaction between water balance and immune function, there are many other physiological processes that may be impacted by water restrictions. Accordingly, I recently expanded the understanding of how reproductive females can alter metabolic substrates to reallocate internal water during times of water scarcity, an important development in our knowledge of reproductive investments. Overall, by thoroughly evaluating implications and responses to water limitations, my dissertation, when combined previous acquired knowledge on food limitation, will enable scientists to better predict the impacts of future climate change, where, in many regions, rainfall events are forecasted to be less reliable, resulting in more frequent drought.
ContributorsBrusch, George, IV (Author) / DeNardo, Dale F (Thesis advisor) / Blattman, Joseph (Committee member) / French, Susannah (Committee member) / Sabo, John (Committee member) / Taylor, Emily (Committee member) / Arizona State University (Publisher)
Created2019
Description
This paper considers what factors influence student interest, motivation, and continued engagement. Studies show anticipated extrinsic rewards for activity participation have been shown to reduce intrinsic value for that activity. This might suggest that grade point average (GPA) has a similar effect on academic interests. Further, when incentives such as scholarships, internships, and careers are GPA-oriented, students must adopt performance goals in courses to guarantee success. However, performance goals have not been shown to correlated with continued interest in a topic. Current literature proposes that student involvement in extracurricular activities, focused study groups, and mentored research are crucial to student success. Further, students may express either a fixed or growth mindset, which influences their approach to challenges and opportunities for growth. The purpose of this study was to collect individual cases of students' experiences in college. The interview method was chosen to collect complex information that could not be gathered from standard surveys. To accomplish this, questions were developed based on content areas related to education and motivation theory. The content areas included activities and meaning, motivation, vision, and personal development. The developed interview method relied on broad questions that would be followed by specific "probing" questions. We hypothesize that this would result in participant-led discussions and unique narratives from the participant. Initial findings suggest that some of the questions were effective in eliciting detailed responses, though results were dependent on the interviewer. From the interviews we find that students value their group involvements, leadership opportunities, and relationships with mentors, which parallels results found in other studies.
ContributorsAbrams, Sara (Author) / Hartwell, Lee (Thesis director) / Correa, Kevin (Committee member) / Department of Psychology (Contributor) / School of Mathematical and Statistical Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Breast microcalcifications are a potential indicator of cancerous tumors. Current visualization methods are either uncomfortable or impractical. Impedance measurement studies have been performed, but not in a clinical setting due to a low sensitivity and specificity. We are hoping to overcome this challenge with the development of a highly accurate impedance probe on a biopsy needle. With this technique, microcalcifications and the surrounding tissue could be differentiated in an efficient and comfortable manner than current techniques for biopsy procedures. We have developed and tested a functioning prototype for a biopsy needle using bioimpedance sensors to detect microcalcifications in the human body. In the final prototype a waveform generator sends a sin wave at a relatively low frequency(<1KHz) into the pre-amplifier, which both stabilizes and amplifies the signal. A modified howland bridge is then used to achieve a steady AC current through the electrodes. The voltage difference across the electrodes is then used to calculate the impedance being experienced between the electrodes. In our testing, the microcalcifications we are looking for have a noticeably higher impedance than the surrounding breast tissue, this spike in impedance is used to signal the presence of the calcifications, which are then sampled for examination by radiology.
ContributorsWen, Robert Bobby (Co-author) / Grula, Adam (Co-author) / Vergara, Marvin (Co-author) / Ramkumar, Shreya (Co-author) / Kozicki, Michael (Thesis director) / Ranjani, Kumaran (Committee member) / School of Molecular Sciences (Contributor) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Breastfeeding has been shown by a number of studies to have numerous benefits on both the mother and the infant. Major health organizations such as the World Health Organization (WHO), now agree that breastfeeding should be encouraged and supported in all countries. But like many things, the wheels of the law are slow to catch up with scientific evident. Although breastfeeding is supported, working women do not have the option of breastfeeding without consequences. For example, in 2003, Kirstie Marshall, a then member of parliament in Australia was ejected from the lower house chamber on February 23, for breastfeeding her baby [3]. According to standing order 30 at the time, "Unless by order of the House, no Member of this House shall presume to bring any stranger into any part of the House appropriated to the Members of this House while the House, or a Committee of the whole House, is sitting" [3]. The rules did not specify the age of strangers, so the then 11-day-old baby, Charlotte Louise and her mother were shown the exit door of parliament. She had to choose between being present at times of major discussions or leaving the house to breastfeed her child, she chose to leave. More recent statistics show that developed nations like the US and Australia which also have high rates of women employment had low rates of breastfeeding. This might mean that workplace policies do not favor breastfeeding or expressing milk at work. Fortunately, laws have since been introduced in both the United States and Australia that support breastfeeding at the workplace. The next step would be to access how these laws affect breastfeeding statistics and how variation between these two countries like the paid parental leave in Australia (which is not present in all US states) would affect these numbers.
ContributorsSakala, Lydia (Author) / Alison, Alison (Thesis director) / Reddy, Swapna (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Ketone bodies are produced in the liver from the acetyl CoA derived from fatty acids that cannot enter the Krebs cycle. This is a sub-analysis of a larger study which had numerous outcome markers. This analysis focuses on the relationship between ketone blood levels and cognition. The study looked at the relationship between Time Restricted Feeding (TRF), a method of intermittent fasting. TRF is something that can be easily adapted into an individual’s lifestyle and has been shown to have multiple advantages. This 8-week study began with 23 enrolled participants, but due to COVID-19 only 11 participants could be tested for cognition and blood ketone levels after week 4. All participants had similar ranges of weight, height, age, BMI, hip, and waist measurements at baseline. Moreover, these demographic variables were not related to ketone levels or cognition. The data indicate that ketone bodies increased in participants practicing TRF and that the increase in ketone bodies in the blood, specifically β-hydroxybutyrate was strongly correlated to increased cognitive function. This is consistent with theories that elevated ketone levels allowed for early hunter-gather communities and other mammals to survive prolonged periods of nutrient deprivation while keeping high cognitive function.
ContributorsTaha, Basel Mahmoud (Author) / Johnston, Carol (Thesis director) / Karen, Sweazea (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
Many factors are at play within the genome of an organism, contributing to much of the diversity and variation across the tree of life. While the genome is generally encoded by four nucleotides, A, C, T, and G, this code can be expanded. One particular mechanism that we examine in this thesis is modification of bases—more specifically, methylation of Adenine (m6A) within the GATC motif of Escherichia coli. These methylated adenines are especially important in a process called methyl-directed mismatch repair (MMR), a pathway responsible for repairing errors in the DNA sequence produced by replication. In this pathway, methylated adenines identify the parent strand and direct the repair proteins to correct the erroneous base in the daughter strand. While the primary role of methylated adenines at GATC sites is to direct the MMR pathway, this methylation has also been found to affect other processes, such as gene expression, the activity of transposable elements, and the timing of DNA replication. However, in the absence of MMR, the ability of these other processes to maintain adenine methylation and its targets is unknown.
To determine if the disruption of the MMR pathway results in the reduced conservation of methylated adenines as well as an increased tolerance for mutations that result in the loss or gain of new GATC sites, we surveyed individual clones isolated from experimentally evolving wild-type and MMR-deficient (mutL- ;conferring an 150x increase in mutation rate) populations of E. coli with whole-genome sequencing. Initial analysis revealed a lack of mutations affecting methylation sites (GATC tetranucleotides) in wild-type clones. However, the inherent low mutation rates conferred by the wild-type background render this result inconclusive, due to a lack of statistical power, and reveal a need for a more direct measure of changes in methylation status. Thus as a first step to comparative methylomics, we benchmarked four different methylation-calling pipelines on three biological replicates of the wildtype progenitor strain for our evolved populations.
While it is understood that these methylated sites play a role in the MMR pathway, it is not fully understood the full extent of their effect on the genome. Thus the goal of this thesis was to better understand the forces which maintain the genome, specifically concerning m6A within the GATC motif.
To determine if the disruption of the MMR pathway results in the reduced conservation of methylated adenines as well as an increased tolerance for mutations that result in the loss or gain of new GATC sites, we surveyed individual clones isolated from experimentally evolving wild-type and MMR-deficient (mutL- ;conferring an 150x increase in mutation rate) populations of E. coli with whole-genome sequencing. Initial analysis revealed a lack of mutations affecting methylation sites (GATC tetranucleotides) in wild-type clones. However, the inherent low mutation rates conferred by the wild-type background render this result inconclusive, due to a lack of statistical power, and reveal a need for a more direct measure of changes in methylation status. Thus as a first step to comparative methylomics, we benchmarked four different methylation-calling pipelines on three biological replicates of the wildtype progenitor strain for our evolved populations.
While it is understood that these methylated sites play a role in the MMR pathway, it is not fully understood the full extent of their effect on the genome. Thus the goal of this thesis was to better understand the forces which maintain the genome, specifically concerning m6A within the GATC motif.
ContributorsBoyer, Gwyneth (Author) / Lynch, Michael (Thesis director) / Behringer, Megan (Committee member) / Geiler-Samerotte, Kerry (Committee member) / School of Life Sciences (Contributor) / Department of Psychology (Contributor) / Barrett, The Honors College (Contributor)
Created2020-05
Description
The purpose of this thesis experiment was to design and create an Acoustically Active Cannula (AAC), which is furnished by a piezoelectric crystal placed at its tip that produces an acoustic navigation signal. I tested the functionality of the cannula in vitro and demonstrated its navigational abilities in vivo in anesthetized pigs. This experiment was based upon ultrasound science and technology, and thus some practical experience with conventional (B-mode) and Doppler ultrasound was achieved as well. The results of bench and experimental animal studies indicated proper functionality of the AAC for identification and spatial navigation of its tip with color Doppler ultrasound imaging.
ContributorsShamsa, Kayvan (Author) / Tyler, William (Thesis director) / Belohlavek, Marek (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05