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- Genre: Doctoral Dissertation
- Language: English
Description
The study of bacterial resistance to antimicrobial peptides (AMPs) is a significant area of interest as these peptides have the potential to be developed into alternative drug therapies to combat microbial pathogens. AMPs represent a class of host-mediated factors that function to prevent microbial infection of their host and serve as a first line of defense. To date, over 1,000 AMPs of various natures have been predicted or experimentally characterized. Their potent bactericidal activities and broad-based target repertoire make them a promising next-generation pharmaceutical therapy to combat bacterial pathogens. It is important to understand the molecular mechanisms, both genetic and physiological, that bacteria employ to circumvent the bactericidal activities of AMPs. These understandings will allow researchers to overcome challenges posed with the development of new drug therapies; as well as identify, at a fundamental level, how bacteria are able to adapt and survive within varied host environments. Here, results are presented from the first reported large scale, systematic screen in which the Keio collection of ~4,000 Escherichia coli deletion mutants were challenged against physiologically significant AMPs to identify genes required for resistance. Less than 3% of the total number of genes on the E. coli chromosome was determined to contribute to bacterial resistance to at least one AMP analyzed in the screen. Further, the screen implicated a single cellular component (enterobacterial common antigen, ECA) and a single transporter system (twin-arginine transporter, Tat) as being required for resistance to each AMP class. Using antimicrobial resistance as a tool to identify novel genetic mechanisms, subsequent analyses were able to identify a two-component system, CpxR/CpxA, as a global regulator in bacterial resistance to AMPs. Multiple previously characterized CpxR/A members, as well as members found in this study, were identified in the screen. Notably, CpxR/A was found to transcriptionally regulate the gene cluster responsible for the biosynthesis of the ECA. Thus, a novel genetic mechanism was uncovered that directly correlates with a physiologically significant cellular component that appears to globally contribute to bacterial resistance to AMPs.
ContributorsWeatherspoon-Griffin, Natasha (Author) / Shi, Yixin (Thesis advisor) / Clark-Curtiss, Josephine (Committee member) / Misra, Rajeev (Committee member) / Nickerson, Cheryl (Committee member) / Stout, Valerie (Committee member) / Arizona State University (Publisher)
Created2013
Description
Mycobacterial infections, as represented by leprosy and tuberculosis, have persisted as human pathogens for millennia. Their environmental counterparts, nontuberculous mycobacteria (NTM), are commodious infectious agents endowed with extensive innate and acquired antimicrobial resistance. The current drug development process selects for antibiotics with high specificity for definitive targets within bacterial metabolic and replication pathways. Because these compounds demonstrate limited efficacy against mycobacteria, novel antimycobacterial agents with unconventional mechanisms of action were identified. Two highly resistant NTMs, Mycobacterium abscessus (Mabs) a rapid-growing respiratory, skin, and soft tissue pathogen, and Mycobacterium ulcerans (MU), the causative agent of Buruli ulcer, were selected as targets. Compounds that indicated antimicrobial activity against other highly resistant pathogens were selected for initial screening. Antimicrobial peptides (AMPs) have demonstrated activity against a variety of bacterial pathogens, including mycobacterial species. Designed antimicrobial peptides (dAMPs), rationally-designed and synthetic contingents, combine iterative features of natural AMPs to achieve superior antimicrobial activity in resistant pathogens. Initial screening identified two dAMPs, RP554 and RP557, with bactericidal activity against Mabs. Clay-associated ions have previously demonstrated bactericidal activity against MU. Synthetic and customizable aluminosilicates have also demonstrated adsorption of bacterial cells and toxins. On this basis, two aluminosilicate materials, geopolymers (GP) and ion-exchange nanozeolites (IE-nZeos), were screened for antimicrobial activity against MU and its fast-growing relative, Mycobacterium marinum (Mmar). GPs demonstrated adsorption of MU cells and mycolactone, a secreted, lipophilic toxin, whereas Cu-nZeos and Ag-nZeos demonstrated antibacterial activity against MU and Mmar. Cumulatively, these results indicate that an integrative drug selection process may yield a new generation of antimycobacterial agents.
ContributorsDermody, Roslyn June (Author) / Haydel, Shelley E (Thesis advisor) / Bean, Heather (Committee member) / Nickerson, Cheryl (Committee member) / Stephanopoulos, Nicholas (Committee member) / Arizona State University (Publisher)
Created2022
Description
ABSTRACT Over the past several decades, the dilemma of free-roaming horses in the U.S. has proven to be one of the most divisive issues in management of public lands. According to federal land management agencies, without population regulation, horses can increase at the rate of 15-20% a year on arid rangelands with inadequate numbers of natural, large predators. Horses compete for valuable forage and water resources alongside cattle and native wildlife in delicate riparian areas highly susceptible to the negative ecological effects of soil compaction and overgrazing. Most U.S. management policies, therefore, call for increased removal of free-roaming horses as they are categorized as “un-authorized livestock” or "non-native" species. Wild horse advocates, however, continue to petition for improvement in animal welfare and expansion of the horses’ territory. With heightened social conflict spurred by animal rights and ecological concerns, not to mention the often-stark differences over what really “belongs” on the landscape, the success of appropriate management strategies hinges on managing agencies’ preparedness and ability to respond in a timely and inclusive manner. A critical element of the management context is the public’s views toward the wild horse and the science used to manage them. Synthesizing the vast literature in the history and philosophy of wildlife management in the American West, and utilizing an ethnographic and case study approach, my research examines the range of stakeholder concerns and analyzes the factors that have led to the disconnect between public values of wild horses and public policy for the management of the federally protected free-roaming horses in Arizona’s Apache-Sitgreaves National Forests.
ContributorsMurphree, Julie Joan (Author) / Minteer, Ben A. (Thesis advisor) / Schoon, Michael (Thesis advisor) / Bradshaw, Karen (Committee member) / Chew, Matthew (Committee member) / Arizona State University (Publisher)
Created2022
Description
Mycobacterium tuberculosis (Mtb), the etiological agent of the tuberculosis disease, is estimated to infect one-fourth of the human population and is responsible for 1.5 million deaths annually. The increased emergence of bacterial resistance to clinical interventions highlights the lack in development of novel antimicrobial therapeutics. Prototypical bacterial two-component systems (TCS) allow for sensing of extracellular stimuli and relay thereof to create a transcriptional response. The prrAB TCS is essential for viability in Mtb, presenting itself as an attractive novel drug target. In Mtb, PrrAB is involved in the adaptation to the intra-macrophage environment and recent work implicates PrrAB in the dosR-dependent hypoxia adaptation. This work defines a direct molecular and regulatory connection between Mtb PrrAB and the dosR-dependent hypoxia response. Using electrophoretic mobility shift assays combined with surface plasmon resonance, the Mtb dosR gene is established as a specific target of PrrA, corroborated by fluorescence reporter assays demonstrating a regulatory relationship. Considering the scarce understanding of prrAB essentiality in nontuberculous mycobacteria and the presence of multiple prrAB orthologs in Mycobacterium smegmatis and Mycobacterium abscessus, CRISPR interference was utilized to evaluate the essentiality of PrrAB beyond Mtb. prrAB was found to be inessential for viability in M. smegmatis yet required for in vitro growth. Conversely, M. abscessus prrAB repression led to enhanced in vitro growth. Diarylthiazole-48 (DAT-48) displayed decreased selectivity against M. abscessus but demonstrated enhanced intrinsic activity upon prrAB repression in M. abscessus. Lastly, to aid in the rapid determination of mycobacterial drug susceptibility and the detection of mycobacterial heteroresistance, the large volume scattering imaging (LVSim) platform was adapted for mycobacteria. Using LVSim, Mtb drug susceptibility was detected phenotypically within 6 hours, and clinically relevant mycobacterial heteroresistance was detected phenotypically within 10 generations. The data generated in these studies provide insight into the essential role of PrrAB in Mtb and its involvement in the dosR-dependent hypoxia adaptation, advance the understanding of mycobacterial PrrAB essentiality and PrrAB-associated mycobacterial growth dependency. These studies further establish molecular and mechanistic connection between PrrAB and DAT-48 in Mtb and M. abscessus and develop a rapid phenotypic drug susceptibility testing platform for mycobacteria.
ContributorsHaller, Yannik Alex (Author) / Haydel, Shelley E (Thesis advisor) / Bean, Heather (Committee member) / Nickerson, Cheryl (Committee member) / Plaisier, Christopher (Committee member) / Acharya, Abhinav (Committee member) / Arizona State University (Publisher)
Created2023
Description
Understanding the dynamic interactions between humans and wildlife is essential to establishing sustainable wildlife-based ecotourism (WBE). Animal behavior exists within a complex feedback loop that affects overall ecosystem function, tourist satisfaction, and socioeconomics of local communities. However, the specific value that animal behavior plays in provisioning ecosystem services has not been thoroughly evaluated. People enjoy activities that facilitate intimate contact with animals, and there are many perceived benefits associated with these experiences, such as encouraging pro-environmental attitudes that can lead to greater motivation for conservation. There is extensive research on the effects that unregulated tourism activity can have on wildlife behavior, which include implications for population health and survival. Prior to COVID-19, WBE was developing rapidly on a global scale, and the pause in activity caused by the pandemic gave natural systems the chance to recover from environmental damage from over-tourism and provided insights into how tourism could be less impactful in the future. Until now it has been undetermined how changes in animal behavior can alter the relationships and socioeconomics of this multidimensional system. This dissertation provides a thorough exploration of the behavioral, ecological, and economic parameters required to model biosocial interactions and feedbacks within the whale watching system in Las Perlas Archipelago, Panama. Through observational data collected in the field, this project assessed how unmanaged whale watching activity is affecting the behavior of Humpback whales in the area as well as the socioeconomic and conservation contributions of the industry. Additionally, it is necessary to consider what a sustainable form of wildlife tourism might be, and whether the incorporation of technology will help enhance visitor experience while reducing negative impacts on wildlife. To better ascertain whether this concept of this integration would be favorably viewed, a sample of individuals was surveyed about their experiences about using technology to enhance their interactions with nature. This research highlights the need for more deliberate identification and incorporation of the perceptions of all stakeholders (wildlife included) to develop a less-impactful WBE industry that provides people with opportunities to establish meaningful relationships with nature that motivate them to help meet the conservation challenges of today.
ContributorsSurrey, Katie (Author) / Gerber, Leah (Thesis advisor) / Guzman, Hector (Committee member) / Minteer, Ben (Committee member) / Schoon, Michael (Committee member) / Arizona State University (Publisher)
Created2023
Description
Heavy metals and persistent organic pollutants contribute to human health risks worldwide. Among the most common routes of exposure to pollutants for humans are through the consumption of contaminated water and food, with fish being among the greatest vectors for ingestion of heavy metals in humans, particularly mercury.This dissertation consists of three chapters with a central theme of investigating heavy metal and persistent organic pollutant concentrations in fish and corned beef, which are two commonly consumed food items in American Samoa. A literature review illustrated that historically the primary pollutants of concern in fish muscle tissue from American Samoa have been mercury, arsenic, and polycyclic aromatic hydrocarbon mixtures. To better understand the changes in heavy metals and persistent organic pollutants in fish, this study reports an updated data set, comparing concentrations in pollutants as they have changed over time. To further investigate pollutants in fish tissue, 77 locally caught and commonly consumed fish were analyzed for heavy metals and persistent organic pollutants, and baseline human health risk assessments were calculated for contaminants that had available oral reference doses. While in American Samoa collecting fish for contaminant analyses, it was realized that canned corned beef appeared to be more commonly consumed than fresh fish. An IRB approved consumption survey revealed that 89% of American Samoan adults regularly consume fish, which is the same percentage of people that reported eating canned corned beef, indicating a dramatic increase in this food item to their diet since its introduction in the 20th century.
Results of this study indicate that fish muscle tissue generally has higher heavy metal concentrations than canned corned beef, and that mercury continues to be a main contaminant of concern when consuming fresh and canned fish in American Samoa. While none of the heavy metal concentrations in corned beef exceeded calculated action levels, these foods might contribute to negative health outcomes in other ways. One of the main findings of this study is that either the presence or the ability to detect persistent organic pollutant concentrations are increasing in fish tissue and should be periodically monitored to adequately reflect current conditions.
ContributorsLewis, Tiffany Beth (Author) / Polidoro, Beth (Thesis advisor) / Neuer, Susanne (Thesis advisor) / Halden, Rolf (Committee member) / Schoon, Michael (Committee member) / Arizona State University (Publisher)
Created2023
Description
Effective collaboration and cooperation across difference are at the heart of present and future sustainability challenges and solutions. Collaboration among social groups (intragenerational), across time (intergenerational), and across species (interspecies) is each central to achieving sustainability transitions in the 21st century. In practice, there are three types of differences that limit collaboration and cooperation toward sustainability outcomes: differences among social groups, differences across time, and differences across species. Each of these differences have corresponding cognitive biases that challenge collaboration. Social cognitive biases challenge collaboration among social groups; temporal cognitive biases challenge collaboration across time; and anthropocentric cognitive biases challenge collaboration across species. In this work, I present three correctives to collaboration challenges spanning the social, temporal, and species cognitive biases through intervention-specific methods that build beyond traditional framings of empathy, toward social, futures, and ecological empathy. By re-theorizing empathy across these domains, I seek to construct a multidimensional theory of empathy for sustainability, and suggest methods to build it, to bridge differences among people, time horizons, and species for sustainability practice.
ContributorsLambert, Lauren Marie-Jasmine (Author) / Selin, Cynthia (Thesis advisor) / Schoon, Michael (Thesis advisor) / Tomblin, David (Committee member) / Berbés-Blázquez, Marta (Committee member) / Arizona State University (Publisher)
Created2023
Description
Though controversial in its utility to the scientific study of nonhuman animals, anthropomorphism, or the attribution of human characteristics to a nonhuman being, is omnipresent in our interactions with other animals. Anthropomorphism is undeniably a fixture of modern zoos, but how anthropomorphism relates to zoos’ contributions to conservation is unclear. In this dissertation, I investigate these potentially dueling, potentially overlapping, messages within great ape exhibits in accredited zoos. Given the complexity of both anthropomorphism and conservation, this dissertation reveals some nuances of how both play out in zoological spaces. Human psychology literature on anthropomorphism indicates that there are a variety of uses for this lens that benefit humans; from feeling we can understand a confusing animal action, to feeling social connection. Whereas the comparative psychology literature highlights a contested utility of anthropomorphism in studies of nonhuman animals. The main findings from this study are four-fold. Firstly, surveys conducted with zoo visitors show that many bring anthropomorphic beliefs with them on their trek through the zoo. Visitors are prone to viewing great apes as strikingly like humans in terms of emotions, emotional expression, and understanding of the world. Secondly, surveyed zoo visitors who agreed more with anthropomorphic statements also agreed more with statements about feeling interconnected with nature. Thirdly, there is no uniform understanding within the zoo community about how zoo exhibits do or should contribute to conservation efforts given that exhibits have multiple goals, one being the safety and wellness of their animal residents. Fourthly, interviews of zoo staff show that they mediate a variety of messages for zoo visitors and walk a sometimes-divisive line between when it’s acceptable to use anthropomorphic framing to discuss zoo animals and when it’s inaccurate. By leveraging a better understanding of these attitudes and relationships, zoos can further empower their staff to navigate these complex issues and improve their mission-based goal of promoting conservation outcomes by acknowledging the human practices embedded in our perceptions of and interactions with zoo animals. This work speaks to the importance of carefully considering the ways we understand animals in zoos, in the wild, and all the places in-between.
ContributorsLyon, Cassandra (Author) / Minteer, Ben A. (Thesis advisor) / Wynne, Clive D.L. (Committee member) / Maynard, Lily (Committee member) / Schoon, Michael (Committee member) / Arizona State University (Publisher)
Created2024
Description
With global environmental systems under increasing Anthropogenic influence, conservationists and environmental managers are under immense pressure to protect and recover the world’s imperiled species and ecosystems. This effort is often motivated by a sense of moral responsibility, either to nature itself, or to the end of promoting human wellbeing over the long run. In other words, it is the purview of environmental ethics, a branch of applied philosophy that emerged in the 1970s and that for decades has been devoted to understanding and defending an attitude of respect for nature, usually for its own sake. Yet from the very start, environmental ethics has promoted itself as contributing to the resolution of real-world management and policy problems. By most accounts, however, the field has historically failed to deliver on this original promise, and environmental ethicists continue to miss opportunities to make intellectual inroads with key environmental decisionmakers. Inspired by classical and contemporary American philosophers such as Charles Sanders Peirce, William James, John Dewey, and Richard Rorty, I defend in this dissertation the virtues of a more explicitly pragmatic approach to environmental ethics. Specifically, I argue that environmental pragmatism is not only commensurate with pro-environmental attitudes but that it is more likely to lead to viable and sustainable outcomes, particularly in the context of eco-social resilience-building activities (e.g., local experimentation, adaptation, cooperation). In doing so, I call for a recasting of environmental ethics, a project that entails: 1) a conceptual reorientation involving the application of pragmatism applied to environmental problems; 2) a methodological approach linking a pragmatist environmentalism to the tradition and process of adaptive co-management; and 3) an empirical study of stakeholder values and perspectives in conservation collaboratives in Arizona. I conclude that a more pragmatic environmental ethics has the potential to bring a powerful set of ethical and methodological tools to bear in real-world management contexts and, where appropriate, can ground and justify coordinated conservation efforts. Finally, this research responds to critics who suggest that, because it strays too far from the ideological purity of traditional environmental ethics, the pragmatic decision-making process will, in the long run, weaken rather than bolster our commitment to conservation and environmental protection.
ContributorsRojas, Christopher A (Author) / Minteer, Ben A (Thesis advisor) / Carr Kelman, Candice (Committee member) / Kinzig, Ann (Committee member) / Schoon, Michael (Committee member) / Arizona State University (Publisher)
Created2019
Description
Despite the safe and effective use of attenuated vaccines for over fifty years, measles virus (MV) remains an insidious threat to global health. Problematically, infants less than one year of age, who are the most prone to severe infection and death by measles, cannot be immunized using current MV vaccines. For this dissertation, I generated and performed preclinical evaluation of two novel MV vaccine candidates. Based on data from clinical trials that showed increasing the dosage of current MV vaccines improved antibody responses in six-month-old recipients, I hypothesized that increasing the relevant antigenic stimulus of a standard titer dose would allow safe and effective immunization at a younger age. I generated two modified MVs with increased expression of the hemagglutinin (H) protein, the most important viral antigen for inducing protective neutralizing immunity, in the background of a current vaccine-equivalent. One virus, MVvac2-H2, expressed higher levels of full-length H, resulting in a three-fold increase in H incorporation into virions, while the second, MVvac2-Hsol, expressed and secreted truncated, soluble H protein to its extracellular environment. The alteration to the virion envelope of MVvac2-H2 conferred upon that virus a measurable resistance to in vitro neutralization. In initial screening in adult mouse models of vaccination, both modified MVs proved more immunogenic than their parental strain in outbred mice, while MVvac2-H2 additionally proved more immunogenic in the gold standard MV-susceptible mouse model. Remarkably, MVvac2-H2 better induced protective immunity in the presence of low levels of artificially introduced passive immunity that mimic the passive maternal immunity that currently limits vaccination of young infants, and that strongly inhibited responses to the current vaccine-equivalent. Finally, I developed a more physiological infant-like mouse model for MV vaccine testing, in which MV-susceptible dams vaccinated with the current vaccine-equivalent transfer passive immunity to their pups. This model will allow additional preclinical evaluation of the performance of MVvac2-H2 in pups of immune dams. Altogether, in this dissertation I identify a promising candidate, MVvac2-H2, for a next generation measles vaccine.
ContributorsJulik, Emily (Author) / Reyes del Valle, Jorge (Thesis advisor) / Chang, Yung (Committee member) / Blattman, Joseph (Committee member) / Hogue, Brenda (Committee member) / Nickerson, Cheryl (Committee member) / Arizona State University (Publisher)
Created2016