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- Genre: Doctoral Dissertation
- Language: English
- Status: Published
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
Food system and health characteristics were evaluated across the last Waorani hunter-gatherer group in Amazonian Ecuador and a remote neighboring Kichwa indigenous subsistence agriculture community. Hunter-gatherer food systems like the Waorani foragers may not only be nutritionally, but also pharmaceutically beneficial because of high dietary intake of varied plant phytochemical compounds. A modern diet that reduces these dietary plant defense phytochemicals below levels typical in human evolutionary history may leave humans vulnerable to diseases that were controlled through a foraging diet. Few studies consider the health impact of the recent drastic reduction of plant phytochemical content in the modern global food system, which has eliminated essential components of food because they are not considered "nutrients". The antimicrobial and anti-inflammatory nature of the food system may not only regulate infectious pathogens and inflammatory disease, but also support beneficial microbes in human hosts, reducing vulnerability to chronic diseases. Waorani foragers seem immune to certain infections with very low rates of chronic disease. Does returning to certain characteristics of a foraging food system begin to restore the human body microbe balance and inflammatory response to evolutionary norms, and if so, what implication does this have for the treatment of disease? Several years of data on dietary and health differences across the foragers and the farmers was gathered. There were major differences in health outcomes across the board. In the Waorani forager group there were no signs of infection in serious wounds such as 3rd degree burns and spear wounds. The foragers had one-degree lower body temperature than the farmers. The Waorani had an absence of signs of chronic diseases including vision and blood pressure that did not change markedly with age while Kichwa farmers suffered from both chronic diseases and physiological indicators of aging. In the Waorani forager population, there was an absence of many common regional infectious diseases, from helminthes to staphylococcus. Study design helped control for confounders (exercise, environment, genetic factors, non-phytochemical dietary intake). This study provides evidence of the major role total phytochemical dietary intake plays in human health, often not considered by policymakers and nutritional and agricultural scientists.
ContributorsLondon, Douglas (Author) / Tsuda, Takeyuki (Thesis advisor) / Beezhold, Bonnie L (Committee member) / Hruschka, Daniel (Committee member) / Eder, James (Committee member) / Arizona State University (Publisher)
Created2012
Description
This dissertation is intended to tie together a body of work which utilizes a variety of methods to study applied mathematical models involving heterogeneity often omitted with classical modeling techniques. I posit three cogent classifications of heterogeneity: physiological, behavioral, and local (specifically connectivity in this work). I consider physiological heterogeneity using the method of transport equations to study heterogeneous susceptibility to diseases in open populations (those with births and deaths). I then present three separate models of behavioral heterogeneity. An SIS/SAS model of gonorrhea transmission in a population of highly active men-who-have-sex-with-men (MSM) is presented to study the impact of safe behavior (prevention and self-awareness) on the prevalence of this endemic disease. Behavior is modeled in this examples via static parameters describing consistent condom use and frequency of STD testing. In an example of behavioral heterogeneity, in the absence of underlying dynamics, I present a generalization to ``test theory without an answer key" (also known as cultural consensus modeling or CCM). CCM is commonly used to study the distribution of cultural knowledge within a population. The generalized framework presented allows for selecting the best model among various extensions of CCM: multiple subcultures, estimating the degree to which individuals guess yes, and making competence homogenous in the population. This permits model selection based on the principle of information criteria. The third behaviorally heterogeneous model studies adaptive behavioral response based on epidemiological-economic theory within an $SIR$ epidemic setting. Theorems used to analyze the stability of such models with a generalized, non-linear incidence structure are adapted and applied to the case of standard incidence and adaptive incidence. As an example of study in spatial heterogeneity I provide an explicit solution to a generalization of the continuous time approximation of the Albert-Barabasi scale-free network algorithm. The solution is found by recursively solving the differential equations via integrating factors, identifying a pattern for the coefficients and then proving this observed pattern is consistent using induction. An application to disease dynamics on such evolving structures is then studied.
ContributorsMorin, Benjamin (Author) / Castillo-Chavez, Carlos (Thesis advisor) / Hiebeler, David (Thesis advisor) / Hruschka, Daniel (Committee member) / Suslov, Sergei (Committee member) / Arizona State University (Publisher)
Created2012
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
In the last few decades, extensive research efforts have been focused on scaling down silicon-based complementary metal-oxide semiconductor (CMOS) technology to enable the continuation of Moore’s law. State-of-art CMOS includes fully depleted silicon-on-insulator (FDSOI) field-effect-transistors (FETs) with ultra-thin silicon channels (6 nm), as well as other three-dimensional (3D) device architectures like Fin-FETs, nanosheet FETs, etc. Significant research efforts have characterized these technologies towards various applications, and at different conditions including a wide range of temperatures from room temperature (300 K) down to cryogenic temperatures. Theoretical efforts have studied ultrascaled devices using Landauer theory to further understand their transport properties and predict their performance in the quasi-ballistic regime.Further scaling of CMOS devices requires the introduction of new semiconducting channel materials, as now established by the research community. Here, two-dimensional (2D) semiconductors have emerged as a promising candidate to replace silicon for next-generation ultrascaled CMOS devices. These emerging 2D semiconductors also have applications beyond CMOS, for example in novel memory, neuromorphic, and spintronic devices. Graphene is a promising candidate for spintronic devices due to its outstanding spin transport properties as evidenced by numerous studies in non-local lateral spin valve (LSV) geometries. The essential components of graphene-based LSV, such as graphene FETs, metal-graphene contacts, and tunneling barriers, were individually investigated as part of this doctoral dissertation.
In this work, several contributions were made to these CMOS and beyond CMOS technologies. This includes comprehensive characterization and modeling of FDSOI nanoscale FETs from room temperature down to cryogenic temperatures. Using Landauer theory for nanoscale transistors, FDSOI devices were analyzed and modeled under quasi-ballistic operation. This was extended towards a virtual-source modeling approach that accounts for temperature-dependent quasi-ballistic transport and back-gate biasing effects. Additionally, graphene devices with ultrathin high-k gate dielectrics were investigated towards FETs, non-volatile memory, and spintronic devices. New contributions were made relating to charge trapping effects and their impact on graphene device electrostatics (Dirac voltage shifts) and transport properties (impact on mobility and conductivity). This work also studied contact resistance and tunneling effects using transfer length method (TLM) graphene FET structures and magnetic tunneling junction (MTJ) towards graphene-based LSV.
ContributorsZhou, Guantong (Author) / Sanchez Esqueda, Ivan (Thesis advisor) / Vasileska, Dragica (Committee member) / Tongay, Sefaattin (Committee member) / Thornton, Trevor (Committee member) / Arizona State University (Publisher)
Created2023
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
The research of alternative materials and new device architectures to exceed the limits of conventional silicon-based devices has been sparked by the persistent pursuit of semiconductor technology scaling. The development of tungsten diselenide (WSe2) and molybdenum disulfide (MoS2), well-known member of the transition metal dichalcogenide (TMD) family, has made great strides towards ultrascaled two-dimensional (2D) field-effect-transistors (FETs). The scaling issues facing silicon-based complementary metal-oxide-semiconductor (CMOS) technologies can be solved by 2D FETs, which show extraordinary potential.This dissertation provides a comprehensive experimental analysis relating to improvements in p-type metal-oxide-semiconductor (PMOS) FETs with few-layer WSe2 and high-κ metal gate (HKMG) stacks. Compared to this works improved methods, standard metallization (more damaging to underlying channel) results in significant Fermi-level pinning, although Schottky barrier heights remain small (< 100 meV) when using high work function metals. Temperature-dependent analysis reveals a dominant contribution to contact resistance from the damaged channel access region. Thus, through less damaging metallization methods combined with strongly scaled HKMG stacks significant improvements were achieved in contact resistance and PMOS FET overall performance. A clean contact/channel interface was achieved through high-vacuum evaporation and temperature-controlled stepped deposition. Theoretical analysis using a Landauer transport adapted to WSe2 Schottky barrier FETs (SB-FETs) elucidates the prospects of nanoscale 2D PMOS FETs indicating high-performance towards the ultimate CMOS scaling limit.
Next, this dissertation discusses how device electrical characteristics are affected by scaling of equivalent oxide thickness (EOT) and by adopting double-gate FET architectures, as well as how this might support CMOS scaling. An improved gate control over the channel is made possible by scaling EOT, improving on-off current ratios, carrier mobility, and subthreshold swing. This study also elucidates the impact of EOT scaling on FET gate hysteresis attributed to charge-trapping effects in high-κ-dielectrics prepared by atomic layer deposition (ALD). These developments in 2D FETs offer a compelling alternative to conventional silicon-based devices and a path for continued transistor scaling. This research contributes to ongoing efforts in 2D materials for future semiconductor technologies. Finally, this work introduces devices based on emerging Janus TMDs and bismuth oxyselenide (Bi2O2Se) layered semiconductors.
ContributorsPatoary, Md Naim Hossain (Author) / Sanchez Esqueda, Ivan (Thesis advisor) / Tongay, Sefaattin (Committee member) / Vasileska, Dragica (Committee member) / Goodnick, Stephen (Committee member) / Arizona State University (Publisher)
Created2023
Description
Social norms are unwritten behavioral codes. They direct individual behaviors, facilitate interpersonal coordination and cooperation, and lead to variation among human populations. Understanding how norms are maintained and how they change is critical for understanding human evolutionary psychology, social organization, and cultural change. This dissertation uses a mathematical model and a field study to answer two questions: First, what factors determine the content and dynamics of a social norm? Second, how do people make decisions in a normative context? The mathematical model finds that contrary to the popular belief that even arbitrary or deleterious social norms can be maintained once established because deviants suffer coordination failures and social sanctions, norms with continuously varying options cannot be maintained by the pressure to do what others do. Instead, continuous norms evolve to the optimum determined by environmental pressure, individual preferences, or cognitive processes. Therefore, the content of norms across human societies may be less historically constrained than previously assumed. The field study shows that unlike what rational choice theory predicts, people in a small-scale subsistence society do not calculate the ecological and social payoffs of different behaviors in a normative context, even when they have the information to do so. Instead, they rely heavily on social information about what others do. This decision-making algorithm, together with mental categorization that ignores small deviations, and cognitive biases that favor the division prescribed by the norm, maintain an ecologically inefficient and widely disliked cooperative surplus division norm in a Derung village, Dizhengdang, in Yunnan, China.
ContributorsYan, Minhua (Author) / Boyd, Robert (Thesis advisor) / Mathew, Sarah (Thesis advisor) / Hruschka, Daniel (Committee member) / Arizona State University (Publisher)
Created2023
Description
Complex perovskite materials, including Ba(Zn1/3Ta2/3)O3 (BZT), are commonly used to make resonators and filters in communication systems because of their low dielectric loss and high-quality factors (Q). Transition metal additives are introduced (i.e., Ni2+, Co2+, Mn2+) to act as sintering agents and tune their temperature coefficient to zero or near-zero. However, losses in these commercial dielectric materials at cryogenic temperatures increase markedly due to spin-excitation resulting from the presence of paramagnetic defects. Applying a large magnetic field (e.g., 5 Tesla) quenches these losses and has allowed the study of other loss mechanisms present at low temperatures. Work was performed on Fe3+ doped LaAlO3. At high magnetic fields, the residual losses versus temperature plots exhibit Debye peaks at ~40 K, ~75 K, and ~215 K temperature and can be tentatively associated with defect reactions O_i^x+V_O^x→O_i^'+V_O^•, Fe_Al^x+V_Al^"→Fe_Al^'+V_Al^' and Al_i^x+Al_i^(••)→〖2Al〗_i^•, respectively. Peaks in the loss tangent versus temperature graph of Zn-deficient BZT indicate a higher concentration of defects and appear to result from conduction losses.Guided by the knowledge gained from this study, a systematic study to develop high-performance microwave materials for ultra-high performance at cryogenic temperatures was performed. To this end, the production and characterization of perovskite materials that were either undoped or contained non-paramagnetic additives were carried out. Synthesis of BZT ceramic with over 98% theoretical density was obtained using B2O3 or BaZrO3 additives. At 4 K, the highest Q x f product of 283,000 GHz was recorded for 5% BaZrO3 doped BZT.
A portable, inexpensive open-air spectrometer was designed, built, and tested to make the electron paramagnetic resonance (EPR) technique more accessible for high-school and university lab instruction. In this design, the sample is placed near a dielectric resonator and does not need to be enclosed in a cavity, as is used in commercial EPR spectrometers. Permanent magnets used produce fields up to 1500 G, enabling EPR measurements up to 3 GHz.
ContributorsGajare, Siddhesh Girish (Author) / Newman, Nathan (Thesis advisor) / Alford, Terry (Committee member) / Tongay, Sefaattin (Committee member) / Chamberlin, Ralph (Committee member) / Arizona State University (Publisher)
Created2022
Description
Contact tracing was deployed widely during the COVID-19 pandemic to attempt to stop the spread of SARS Co-V-2. This dissertation investigates the research on contact tracing from a scientometric perspective and looks qualitatively at how case investigators and contact tracers conducted public health practice during the pandemic. Through approaching the public health practice of contact tracing from both a broad, top-down angle, and an on the ground experiential approach, this dissertation provides insight into the issues facing contact tracing as a public health tool.
ContributorsWhite, Alexandra C. (Author) / Jehn, Megan (Thesis advisor) / Hruschka, Daniel (Committee member) / Gaughan, Monica (Committee member) / Arizona State University (Publisher)
Created2022