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Description
Blood donations today undergo extensive screening for transfusion transmitted infections (TTI) since the discovery of the first infectious agent in the early 1900s. Nucleic Acid Testing (NAT) is a serological test used widely in disease detection. NAT is known to rapidly and effectively detect pathogenic genomic material in blood by reducing the "window period" of infection. However, NAT produces false negative results for disease positive samples posing a risk of disease transmission. Therefore, NAT is used in conjunction with the Enzyme-Linked Immunosorbent Assay (ELISA) to mitigate these risks. However, the ELISA assay also poses the same risk as NAT. This study proposes immunosignaturing as an alternative serological test that may combat this risk and investigates whether it would be more effective than other standardized serological tests in disease detection. Immunosignaturing detects antibodies by utilizing a microarray of randomized peptide sequences. Immunosignaturing provides information about an individual's immune health from the pattern of reactivity of antibody-peptide binding. Unlike ELISA and NAT, immunosignaturing can be programmed to detect any disease and detect multiple diseases simultaneously. Using ELISA, NAT, and immunosignaturing, immune profiles of asymptomatic patients were constructed for 10 different classes of blood borne diseases. A pattern of infection was identified for each disease and the sensitivity and specificity of these assays were assessed relative to each other. Results indicate that immunosignaturing can be a viable diagnostic tool in blood testing. Immunosignatures demonstrated increased sensitivity and specificity compared to ELISA and NAT in discerning disease positive and negative samples within and across different classes of disease.
ContributorsSharma, Megumi (Author) / McFadden, Grant (Thesis director) / Nickerson, Cheryl (Committee member) / Green, Alex (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
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
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
Transorbital surgery has gained recent notoriety due to its incorporation into endoscopic skull base surgery. The body of published literature on the field is cadaveric and observation. The pre-clinical studies are focused on the use of the endoscope only. Furthermore the methodology utilised in the published literature is inconsistent and does not embody the optimal principles of scientific experimentation. This body of work evaluates a minimally invasive novel surgical corridor - the transorbital approach - its validity in neurosurgical practice, as well as both qualitatively and quantitatively assessing available technological advances in a robust experimental fashion. While the endoscope is an established means of visualisation used in clinical transorbital surgery, the microscope has never been assessed with respect to the transorbital approach. This question is investigated here and the anatomical and surgical benefits and limitations of microscopic visualisation demonstrated. The comparative studies provide increased knowledge on specifics pertinent to neurosurgeons and other skull base specialists when planning pre-operatively, such as pathology location, involved anatomical structures, instrument maneuvrability and the advantages and disadvantages of the distinct visualisation technologies. This is all with the intention of selecting the most suitable surgical approach and technology, specific to the patient, pathology and anatomy, so as to perform the best surgical procedure. The research findings illustrated in this body of work are diverse, reproducible and applicable. The transorbital surgical corridor has substantive potential for access to the anterior cranial fossa and specific surgical target structures. The neuroquantitative metrics investigated confirm the utility and benefits specific to the respective visualisation technologies i.e. the endoscope and microscope. The most appropriate setting wherein the approach should be used is also discussed. The transorbital corridor has impressive potential, can utilise all available technological advances, promotes multi-disciplinary co-operation and learning amongst clinicians and ultimately, is a means of improving operative patient care.
ContributorsHoulihan, Lena Mary (Author) / Preul, Mark C. (Thesis advisor) / Vernon, Brent (Thesis advisor) / O' Sullivan, Michael G.J. (Committee member) / Lawton, Michael T. (Committee member) / Santarelli, Griffin (Committee member) / Smith, Brian (Committee member) / Arizona State University (Publisher)
Created2021
Description
A description of numerical and analytical work pertaining to models that describe the growth and progression of glioblastoma multiforme (GBM), an aggressive form of primary brain cancer. Two reaction-diffusion models are used: the Fisher-Kolmogorov-Petrovsky-Piskunov equation and a 2-population model that divides the tumor into actively proliferating and quiescent (or necrotic) cells. The numerical portion of this work (chapter 2) focuses on simulating GBM expansion in patients undergoing treatment for recurrence of tumor following initial surgery. The models are simulated on 3-dimensional brain geometries derived from magnetic resonance imaging (MRI) scans provided by the Barrow Neurological Institute. The study consists of 17 clinical time intervals across 10 patients that have been followed in detail, each of whom shows significant progression of tumor over a period of 1 to 3 months on sequential follow up scans. A Taguchi sampling design is implemented to estimate the variability of the predicted tumors to using 144 different choices of model parameters. In 9 cases, model parameters can be identified such that the simulated tumor contains at least 40 percent of the volume of the observed tumor. In the analytical portion of the paper (chapters 3 and 4), a positively invariant region for our 2-population model is identified. Then, a rigorous derivation of the critical patch size associated with the model is performed. The critical patch (KISS) size is the minimum habitat size needed for a population to survive in a region. Habitats larger than the critical patch size allow a population to persist, while smaller habitats lead to extinction. The critical patch size of the 2-population model is consistent with that of the Fisher-Kolmogorov-Petrovsky-Piskunov equation, one of the first reaction-diffusion models proposed for GBM. The critical patch size may indicate that GBM tumors have a minimum size depending on the location in the brain. A theoretical relationship between the size of a GBM tumor at steady-state and its maximum cell density is also derived, which has potential applications for patient-specific parameter estimation based on magnetic resonance imaging data.
ContributorsHarris, Duane C. (Author) / Kuang, Yang (Thesis advisor) / Kostelich, Eric J. (Thesis advisor) / Preul, Mark C. (Committee member) / Crook, Sharon (Committee member) / Gardner, Carl (Committee member) / Arizona State University (Publisher)
Created2023
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
Description
Trees serve as a natural umbrella to mitigate insolation absorbed by features of the urban environment, especially building structures and pavements. For a desert community, trees are a particularly valuable asset because they contribute to energy conservation efforts, improve home values, allow for cost savings, and promote enhanced health and well-being. The main obstacle in creating a sustainable urban community in a desert city with trees is the scarceness and cost of irrigation water. Thus, strategically located and arranged desert trees with the fewest tree numbers possible potentially translate into significant energy, water and long-term cost savings as well as conservation, economic, and health benefits. The objective of this dissertation is to achieve this research goal with integrated methods from both theoretical and empirical perspectives.
This dissertation includes three main parts. The first part proposes a spatial optimization method to optimize the tree locations with the objective to maximize shade coverage on building facades and open structures and minimize shade coverage on building rooftops in a 3-dimensional environment. Second, an outdoor urban physical scale model with field measurement is presented to understand the cooling and locational benefits of tree shade. The third part implements a microclimate numerical simulation model to analyze how the specific tree locations and arrangements influence outdoor microclimates and improve human thermal comfort. These three parts of the dissertation attempt to fill the research gap of how to strategically locate trees at the building to neighborhood scale, and quantifying the impact of such arrangements.
Results highlight the significance of arranging residential shade trees across different geographical scales. In both the building and neighborhood scales, research results recommend that trees should be arranged in the central part of the building south front yard. More cooling benefits are provided to the building structures and outdoor microclimates with a cluster tree arrangement without canopy overlap; however, if residents are interested in creating a better outdoor thermal environment, open space between trees is needed to enhance the wind environment for better human thermal comfort. Considering the rapid urbanization process, limited water resources supply, and the severe heat stress in the urban areas, judicious design and planning of trees is of increasing importance for improving the life quality and sustaining the urban environment.
ContributorsZhao, Qunshan (Author) / Wentz, Elizabeth (Thesis advisor) / Sailor, David (Committee member) / Wang, Zhi-Hua (Committee member) / Arizona State University (Publisher)
Created2017
Description
Many Fic domain proteins, through catalyzing post translational modifications (PTM) of protein substrates, functionally contribute to bacterial pathogenesis and the regulation of bacterial growth. Furthermore, one form of Fic-mediated regulation is the Fic toxin-antitoxin system, whereby an antitoxin interacts with and inhibits the Fic toxin. This study sought to determine the functional importance of Mycobacterium tuberculosis Fic and its putative antitoxin protein, Rv3642c. Using M. tuberculosis H37Rv genetic deletion mutants, fic and Rv3642c were demonstrated to promote intracellular survival in human THP-1 macrophage-like cells. Unlike other Fic toxins, of Fic toxin-antitoxin systems, Fic did not inhibit bacterial growth in vitro in the absence of Rv3642c. Notably, Fic demonstrated in vitro AMPylation of a THP-1 cell extract protein as shown by immunodetection. Fic also exhibited auto-AMPylation activity. Interestingly, a mutation of the conserved histidine in the Fic domain motif, a residue previously shown to be critical for AMPylation, had no effect on Fic-mediated ATP hydrolysis or AMPylation activity. Rv3642c was demonstrated to form a complex with Fic when co-expressed in Escherichia coli, indicating a toxin-antitoxin interaction. Screening M. tuberculosis protein fractions and culture filtrate with α-Fic and α-Rv3642c rabbit antisera did not detect monomers of Fic or Rv3642c, thus the cellular localization of Fic and the Rv3642c-Fic complex remains unclear. The results of this study provide insight into the function of M. tuberculosis Fic, and suggest that Fic and Rv3642c are important for M. tuberculosis survival in the intracellular macrophage environment. Furthermore, these findings challenge the current dogma that Fic domain catalysis is dependent on the conserved histidine of the Fic motif.
ContributorsLaMarca, Ryan (Author) / Haydel, Shelley (Thesis advisor) / Lake, Douglas (Committee member) / Nickerson, Cheryl (Committee member) / Arizona State University (Publisher)
Created2017
Description
Heart transplantation is the final treatment option for end-stage heart failure. In the United States, 70 pediatric patients die annually on the waitlist while 800 well-functioning organs get discarded. Concern for potential size-mismatch is one source of allograft waste and high waitlist mortality. Clinicians use the donor-recipient body weight (DRBW) ratio, a standalone metric, to evaluate allograft size-match. However, this body weight metric is far removed from cardiac anatomy and neglects an individual’s anatomical variations. This thesis body of work developed a novel virtual heart transplant fit assessment tool and investigated the tool’s clinical utility to help clinicians safely expand patient donor pools.
The tool allowed surgeons to take an allograft reconstruction and fuse it to a patient’s CT or MR medical image for virtual fit assessment. The allograft is either a reconstruction of the donor’s actual heart (from CT or MR images) or an analogue from a health heart library. The analogue allograft geometry is identified from gross donor parameters using a regression model build herein. The need for the regression model is donor images may not exist or they may not become available within the time-window clinicians have to make a provisional acceptance of an offer.
The tool’s assessment suggested > 20% of upper DRBW listings could have been increased at Phoenix Children’s Hospital (PCH). Upper DRBW listings in the UNOS national database was statistically smaller than at PCH (p-values: < 0.001). Delayed sternal closure and surgeon perceived complication variables had an association (p-value: 0.000016) with 9 of the 11 cases that surgeons had perceived fit-related complications had delayed closures (p-value: 0.034809).
A tool to assess allograft size-match has been developed. Findings warrant future preclinical and clinical prospective studies to further assess the tool’s clinical utility.
The tool allowed surgeons to take an allograft reconstruction and fuse it to a patient’s CT or MR medical image for virtual fit assessment. The allograft is either a reconstruction of the donor’s actual heart (from CT or MR images) or an analogue from a health heart library. The analogue allograft geometry is identified from gross donor parameters using a regression model build herein. The need for the regression model is donor images may not exist or they may not become available within the time-window clinicians have to make a provisional acceptance of an offer.
The tool’s assessment suggested > 20% of upper DRBW listings could have been increased at Phoenix Children’s Hospital (PCH). Upper DRBW listings in the UNOS national database was statistically smaller than at PCH (p-values: < 0.001). Delayed sternal closure and surgeon perceived complication variables had an association (p-value: 0.000016) with 9 of the 11 cases that surgeons had perceived fit-related complications had delayed closures (p-value: 0.034809).
A tool to assess allograft size-match has been developed. Findings warrant future preclinical and clinical prospective studies to further assess the tool’s clinical utility.
ContributorsPlasencia, Jonathan (Author) / Frakes, David H (Thesis advisor) / Kodibagkar, Vikram (Thesis advisor) / Sadleir, Rosalind (Committee member) / Kamarianakis, Yiannis (Committee member) / Zangwill, Steven (Committee member) / Pophal, Stephen (Committee member) / Arizona State University (Publisher)
Created2018
Description
Understanding how microorganisms adapt and respond to the microgravity environment of spaceflight is important for the function and integrity of onboard life support systems, astronaut health and mission success. Microbial contamination of spacecraft Environmental Life Support Systems (ECLSS), including the potable water system, are well documented and have caused major disruption to spaceflight missions. The potable water system on the International Space Station (ISS) uses recycled wastewater purified by multiple processes so it is safe for astronaut consumption and personal hygiene. However, despite stringent antimicrobial treatments, multiple bacterial species and biofilms have been recovered from this potable water system. This finding raises concern for crew health risks, vehicle operations and ECLSS system integrity during exploration missions. These concerns are further heightened given that 1) potential pathogens have been isolated from the ISS potable water system, 2) the immune response of astronauts is blunted during spaceflight, 3) spaceflight induces unexpected alterations in microbial responses, including growth and biofilm formation, antimicrobial resistance, stress responses, and virulence, and 4) different microbial phenotypes are often observed between reductionistic pure cultures as compared to more complex multispecies co-cultures, the latter of which are more representative of natural environmental conditions. To advance the understanding of the impact of microgravity on microbial responses that could negatively impact spacecraft ECLSS systems and crew health, this study characterized a range of phenotypic profiles in both pure and co-cultures of bacterial isolates collected from the ISS potable water system between 2009 and 2014. Microbial responses profiled included population dynamics, resistance to silver, biofilm formation, and in vitro colonization of intestinal epithelial cells. Growth characteristics and antibiotic sensitivities for bacterial strains were evaluated to develop selective and/or differential media that allow for isolation of a pure culture from co-cultures, which was critical for the success of this study. Bacterial co-culture experiments were performed using dynamic Rotating Wall Vessel (RWV) bioreactors under spaceflight analogue (Low Shear Modeled Microgravity/LSMMG) and control conditions. These experiments indicated changes in fluid shear have minimal impact on strain recovery. The antimicrobial efficacy of silver on both sessile co-cultures, grown on 316L stainless steel coupons, and planktonic co-cultures showed that silver did not uniformly reduce the recovery of all strains; however, it had a stronger antimicrobial effect on biofilm cultures than planktonic cultures. The impact of silver on the ability of RWV cultured planktonic and biofilm bacterial co-cultures to colonize human intestinal epithelial cells showed that, those strains which were impacted by silver treatment, often increased adherence to the monolayer. Results from these studies provide insight into the dynamics of polymicrobial community interactions, biofilm formation and survival mechanisms of ISS potable water isolates, with potential application for future design of ECLSS systems for sustainable human space exploration.
ContributorsKing, Olivia G (Author) / Nickerson, Cheryl (Thesis advisor) / Barrila, Jennifer (Committee member) / Ott, C (Committee member) / Yang, Jiseon (Committee member) / Arizona State University (Publisher)
Created2019