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Methicillin-Resistant Staphylococcus aureus (MRSA) infections are a major challenge to healthcare professionals. Treatment of MRSA is expensive, and otherwise avoidable deaths occur every year in the United States due to MRSA infections. Additionally, such infections lengthen patients’ stays in hospitals, keeping them out of work and adversely affecting the economy. Beta lactam antibiotics used to be highly effective against S. aureus infections, but resistance mechanisms have rendered methicillin, oxacillin, and other beta lactam antibiotics ineffective against these infections. A promising avenue for MRSA treatment lies in the use of synthetic antibodies—molecules that bind with specificity to a given compound. Synbody 14 is an example of such a synbody, and has been designed with MRSA treatment in mind. Mouse model studies have even associated Syn14 treatment with reduced weight loss and morbidity in MRSA-infected mice. In this experiment, in vitro activity of Syn 14 and oxacillin was assessed. Early experiments measured Syn 14 and oxacillin’s effectiveness in inhibiting colony growth in growth media, mouse serum, and mouse blood. Syn14 and oxacillin had limited efficacy against USA300 strain MRSA, though interestingly it was noted that Syn14 outperformed oxacillin in mouse serum and whole mouse blood, indicating the benefits of its binding properties. A second experiment measured the impact that a mix of oxacillin and Syn 14 had on colony growth, as well as the effect of adding them simultaneously or one after the other. While use of either bactericidal alone did not show a major inhibitory effect on USA300 MRSA colony growth, their use in combination showed major decreases in colony growth. Moreover, it was found that unlike other combination therapies, Syn14 and oxacillin did not require simultaneous addition to MRSA cells to achieve inhibition of cell growth. They merely required that Syn14 be added first. This result suggests Syn14’s possible utility in therapeutic settings, as the time insensitivity of synergy removes a major hurdle to clinical use—the difficulty in ensuring that two drugs reach an affected area at the same time. Syn14 remains a promising antimicrobial agent, and further study should focus on its precise mechanism of action and suitability in clinical treatment of MRSA infections.
ContributorsMichael, Alexander (Author) / Diehnelt, Chris (Thesis director) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2015-05
Description
Five immunocompetent C57BL/6-cBrd/cBrd/Cr (albino C57BL/6) mice were injected with GL261-luc2 cells, a cell line sharing characteristics of human glioblastoma multiforme (GBM). The mice were imaged using magnetic resonance (MR) at five separate time points to characterize growth and development of the tumor. After 25 days, the final tumor volumes of the mice varied from 12 mm3 to 62 mm3, even though mice were inoculated from the same tumor cell line under carefully controlled conditions. We generated hypotheses to explore large variances in final tumor size and tested them with our simple reaction-diffusion model in both a 3-dimensional (3D) finite difference method and a 2-dimensional (2D) level set method. The parameters obtained from a best-fit procedure, designed to yield simulated tumors as close as possible to the observed ones, vary by an order of magnitude between the three mice analyzed in detail. These differences may reflect morphological and biological variability in tumor growth, as well as errors in the mathematical model, perhaps from an oversimplification of the tumor dynamics or nonidentifiability of parameters. Our results generate parameters that match other experimental in vitro and in vivo measurements. Additionally, we calculate wave speed, which matches with other rat and human measurements.
ContributorsRutter, Erica (Author) / Stepien, Tracy (Author) / Anderies, Barrett (Author) / Plasencia, Jonathan (Author) / Woolf, Eric C. (Author) / Scheck, Adrienne C. (Author) / Turner, Gregory H. (Author) / Liu, Qingwei (Author) / Frakes, David (Author) / Kodibagkar, Vikram (Author) / Kuang, Yang (Author) / Preul, Mark C. (Author) / Kostelich, Eric (Author) / College of Liberal Arts and Sciences (Contributor)
Created2017-05-31
Description
Peptides offer great promise as targeted affinity ligands, but the space of possible peptide sequences is vast, making experimental identification of lead candidates expensive, difficult, and uncertain. Computational modeling can narrow the search by estimating the affinity and specificity of a given peptide in relation to a predetermined protein target. The predictive performance of computational models of interactions of intermediate-length peptides with proteins can be improved by taking into account the stochastic nature of the encounter and binding dynamics. A theoretical case is made for the hypothesis that, because of the flexibility of the peptide and the structural complexity of the target protein, interactions are best characterized by an ensemble of possible bound configurations rather than a single “lock and key” fit. A model incorporating these factors is proposed and evaluated. A comprehensive dataset of 3,924 peptide-protein interface structures was extracted from the Protein Data Bank (PDB) and descriptors were computed characterizing the geometry and energetics of each interface. The characteristics of these interfaces are shown to be generally consistent with the proposed model, and heuristics for design and selection of peptide ligands are derived. The curated and energy-minimized interface structure dataset and a relational database containing the detailed results of analysis and energy modeling are made publicly available via a web repository. A novel analytical technique based on the proposed theoretical model, Virtual Scanning Probe Mapping (VSPM), is implemented in software to analyze the interaction between a target protein of known structure and a peptide of specified sequence, producing a spatial map indicating the most likely peptide binding regions on the protein target. The resulting predictions are shown to be superior to those of two other published methods, and support the validity of the stochastic binding model.
ContributorsEmery, Jack Scott (Author) / Pizziconi, Vincent B (Thesis advisor) / Woodbury, Neal W (Thesis advisor) / Guilbeau, Eric J (Committee member) / Stafford, Phillip (Committee member) / Taylor, Thomas (Committee member) / Towe, Bruce C (Committee member) / Arizona State University (Publisher)
Created2010
Description
Bacteria with antibiotic resistance are becoming a growing concern as the number of infections they are causing continue to increase. Many potential solutions are being researched in order to combat these pathogens. One such microbe is Pseudomonas aeruginosa, which causes acute and chronic human infections. It frequently colonizes the lungs of cystic fibrosis patients and is deadly. For these reasons, P. aeruginosa has been heavily studied in order to determine a solution to antibiotic resistance. One possible solution is the development of synbodies, which have been developed at the Biodesign Institute at Arizona State University. Synbodies are constructed from peptides that have antibacterial activity and were determined to have specificity for a target bacterium. These synbodies were tested in this study to determine whether or not some of them are able to inhibit P. aeruginosa growth. P. aeruginosa can also form multicellular communities called biofilms and these are known to cause approximately 65% of all human infections. After conducting minimum inhibitory assays, the efficacy of certain peptides and synbodies against biofilm inhibition was assessed. A recent study has shown that low concentrations of a specific peptide can cause biofilm disruption, where the biofilm structure breaks apart and the cells within it disperse into the supernatant. Taking into account this study and peptide data regarding biofilm inhibition from Dr. Aurélie Crabbé’s lab, screened peptides were tested against biofilm to see if dispersion would occur.
ContributorsPatel, Justin Hemant (Author) / Diehnelt, Chris (Thesis director) / Stafford, Phillip (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor) / School of Historical, Philosophical and Religious Studies (Contributor)
Created2015-05
Description
Complex human controls is a topic of much interest in the fields of robotics, manufacturing, space exploration and many others. Even simple tasks that humans perform with ease can be extremely complicated when observed from a controls and complex systems perspective. One such simple task is that of a human carrying and moving a coffee cup. Though this may be a mundane task for humans, when this task is modelled and analyzed, the system may be quite chaotic in nature. Understanding such systems is key to the development robots and autonomous systems that can perform these tasks themselves.
The coffee cup system can be simplified and modeled by a cart-and-pendulum system. Bazzi et al. and Maurice et al. present two different cart-and-pendulum systems to represent the coffee cup system [1],[2]. The purpose of this project was to build upon these systems and to gain a better understanding of the coffee cup system and to determine where chaos existed within the system. The honors thesis team first worked with their senior design group to develop a mathematical model for the cart-and-pendulum system based on the Bazzi and Maurice papers [1],[2]. This system was analyzed and then built upon by the honors thesis team to build a cart-and-two-pendulum model to represent the coffee cup system more accurately.
Analysis of the single pendulum model showed that there exists a low frequency region where the pendulum and the cart remain in phase with each other and a high frequency region where the cart and pendulum have a π phase difference between them. The transition point of the low and high frequency region is determined by the resonant frequency of the pendulum. The analysis of the two-pendulum system also confirmed this result and revealed that differences in length between the pendulum cause the pendulums to transition to the high frequency regions at separate frequency. The pendulums have different resonance frequencies and transition into the high frequency region based on their own resonant frequency. This causes a range of frequencies where the pendulums are out of phase from each other. After both pendulums have transitioned, they remain in phase with each other and out of phase from the cart.
However, if the length of the pendulum is decreased too much, the system starts to exhibit chaotic behavior. The short pendulum starts to act in a chaotic manner and the phase relationship between the pendulums and the carts is no longer maintained. Since the pendulum length represents the distance between the particle of coffee and the top of the cup, this implies that coffee near the top of the cup would cause the system to act chaotically. Further analysis would be needed to determine the reason why the length affects the system in this way.
The coffee cup system can be simplified and modeled by a cart-and-pendulum system. Bazzi et al. and Maurice et al. present two different cart-and-pendulum systems to represent the coffee cup system [1],[2]. The purpose of this project was to build upon these systems and to gain a better understanding of the coffee cup system and to determine where chaos existed within the system. The honors thesis team first worked with their senior design group to develop a mathematical model for the cart-and-pendulum system based on the Bazzi and Maurice papers [1],[2]. This system was analyzed and then built upon by the honors thesis team to build a cart-and-two-pendulum model to represent the coffee cup system more accurately.
Analysis of the single pendulum model showed that there exists a low frequency region where the pendulum and the cart remain in phase with each other and a high frequency region where the cart and pendulum have a π phase difference between them. The transition point of the low and high frequency region is determined by the resonant frequency of the pendulum. The analysis of the two-pendulum system also confirmed this result and revealed that differences in length between the pendulum cause the pendulums to transition to the high frequency regions at separate frequency. The pendulums have different resonance frequencies and transition into the high frequency region based on their own resonant frequency. This causes a range of frequencies where the pendulums are out of phase from each other. After both pendulums have transitioned, they remain in phase with each other and out of phase from the cart.
However, if the length of the pendulum is decreased too much, the system starts to exhibit chaotic behavior. The short pendulum starts to act in a chaotic manner and the phase relationship between the pendulums and the carts is no longer maintained. Since the pendulum length represents the distance between the particle of coffee and the top of the cup, this implies that coffee near the top of the cup would cause the system to act chaotically. Further analysis would be needed to determine the reason why the length affects the system in this way.
ContributorsZindani, Abdul Rahman (Co-author) / Crane, Kari (Co-author) / Lai, Ying-Cheng (Thesis director) / Jiang, Junjie (Committee member) / Electrical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2019-12
Description
Approximately 248 million people in the world are currently living with chronic Hepatitis B virus (HBV) infection. HBV and HCV infections are the primary cause of liver diseases such as cirrhosis and hepatocellular carcinomas in the world with an estimated 1.4 million deaths annually. HBV in the Republic of Peru was used as a case study of an emerging and rapidly spreading disease in a developing nation. Wherein, clinical diagnosis of HBV infections in at-risk communities such the Amazon Region and the Andes Mountains are challenging due to a myriad of reasons. High prices of clinical diagnosis and limited access to treatment are alone the most significant deterrent for individuals living in at-risk communities to get the much need help. Additionally, limited testing facilities, lack of adequate testing policies or national guidelines, poor laboratory capacity, resource-limited settings, geographical isolation, and public mistrust are among the chief reasons for low HBV testing. Although, preventative vaccination programs deployed by the Peruvian health officials have reduced the number of infected individuals by year and region. To significantly reduce or eradicate HBV in hyperendemic areas and countries such as Peru, preventative clinical diagnosis and vaccination programs are an absolute necessity. Consequently, the need for a portable low-priced diagnostic platform for the detection of HBV and other diseases is substantial and urgent not only in Peru but worldwide. Some of these concerns were addressed by designing a low-cost, rapid detection platform. In that, an immunosignature technology (IMST) slide used to test for reactivity against the presence of antibodies in the serum-sample was used to test for picture resolution and clarity. IMST slides were scanned using a smartphone camera placed on top of the designed device housing a circuit of 32 LED lights at 647 nm, an optical magnifier at 15X, and a linear polarizing film sheet. Tow 9V batteries powered the scanning device LED circuit ensuring enough lighting. The resulting pictures from the first prototype showed that by lighting the device at 647 nm and using a smartphone camera, the camera could capture high-resolution images. These results conclusively indicate that with any modern smartphone camera, a small box lighted to 647 nm, and optical magnifier; a powerful and expensive laboratory scanning machine can be replaced by another that is inexpensive, portable and ready to use anywhere.
ContributorsMakimaa, Heyde (Author) / Holechek, Susan (Thesis director) / Stafford, Phillip (Committee member) / Jayasuriya, Suren (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
Monoclonal antibody therapy focuses on engineering immune cells to target specific peptide sequences indicative of disease. An impediment in the continued advancement of this market is the lack of an efficient, inexpensive means of characterization that can be broadly applied to any antibody while still providing high-density data. Many characterization methods address an antibody's affinity for its cognate sequence but overlook other important aspects of binding behavior such as off-target binding interactions. The purpose of this study is to demonstrate how the binding intensity between an antibody and a library of random-sequence peptides, otherwise known as an immunosignature, can be evaluated to determine antibody specificity and polyreactivity. A total of 24 commercially available monoclonal antibodies were assayed on 125K and 330K peptide microarrays and analyzed using a motif clustering program to predict candidate epitopes within each antigen sequence. The results support the further development of immunosignaturing as an antibody characterization tool that is relevant to both therapeutic and non-therapeutic antibodies.
ContributorsDai, Jennifer T. (Author) / Stafford, Phillip (Thesis director) / Diehnelt, Chris (Committee member) / School of Life Sciences (Contributor) / W.P. Carey School of Business (Contributor) / Barrett, The Honors College (Contributor)
Created2018-05
Description
In this project, biochemical characteristics of peptide binding agents, synthetic antibodies or synbodies, were examined with respect to the capture efficiency and specific binding ability to norovirus. Norovirus, although generally not a deadly pathogen, is the most common cause of acute gastroenteritis and outbreaks present a large social and financial burden to the healthcare and food service industries. With Dr. Diehnelt's laboratory group, a platform has been developed that enables us to rapidly construct peptide-based affinity ligands that can be characterized for binding to norovirus. The design needed to display clear results, be simple to operate, and be inexpensive to produce and use. Four synbodies, originally engineered with a specificity to the GII.4 Minerva genotype were tested with different virus strains varying in similarity to the GII.4 Minerva between 43% and 95.4%. Initial assays utilized norovirus-like particles to qualitatively compare the capture efficiency of the different synbodies without utilizing limited resources. To quantify the amount of actual virus captured by the synbodies, western blots with RT-PCR and RT-qPCR were utilized. The results indicated the synbodies were able to enrich the dilute solutions of the different noroviruses utilizing a magnetic bead pull-down assay. The capture efficiencies of the synbodies were comparable to currently utilized binding agents such as aptamers and porcine gastric mucine magnetic beads. This thesis presents data collected over nearly two years of research at the Center for Innovations in Medicine at the Biodesign Institute located at Arizona State University.
ContributorsSlosky, Rachael Marie (Author) / Diehnelt, Chris (Thesis director) / Stafford, Phillip (Committee member) / Chemical Engineering Program (Contributor) / Barrett, The Honors College (Contributor)
Created2016-05
Description
A remarkable phenomenon in contemporary physics is quantum scarring in classically chaoticsystems, where the wave functions tend to concentrate on classical periodic orbits. Quantum
scarring has been studied for more than four decades, but the problem of efficiently detecting
quantum scars has remained to be challenging, relying mostly on human visualization of
wave function patterns. This paper develops a machine learning approach to detecting
quantum scars in an automated and highly efficient manner. In particular, this paper exploits Meta
learning. The first step is to construct a few-shot classification algorithm, under the
requirement that the one-shot classification accuracy be larger than 90%. Then propose a
scheme based on a combination of neural networks to improve the accuracy. This paper shows that
the machine learning scheme can find the correct quantum scars from thousands images of
wave functions, without any human intervention, regardless of the symmetry of the underlying
classical system. This will be the first application of Meta learning to quantum systems. Interacting spin networks are fundamental to quantum computing. Data-based tomography oftime-independent spin networks has been achieved, but an open challenge is to ascertain the
structures of time-dependent spin networks using time series measurements taken locally
from a small subset of the spins. Physically, the dynamical evolution of a spin network under
time-dependent driving or perturbation is described by the Heisenberg equation of motion.
Motivated by this basic fact, this paper articulates a physics-enhanced machine learning framework
whose core is Heisenberg neural networks. This paper demonstrates that, from local measurements, not only the local Hamiltonian can be recovered but the Hamiltonian reflecting the interacting structure of the whole system can
also be faithfully reconstructed. Using Heisenberg neural machine on spin networks of a
variety of structures. In the extreme case where measurements are taken from only one spin,
the achieved tomography fidelity values can reach about 90%. The developed machine
learning framework is applicable to any time-dependent systems whose quantum dynamical
evolution is governed by the Heisenberg equation of motion.
ContributorsHan, Chendi (Author) / Lai, Ying-Cheng (Thesis advisor) / Yu, Hongbin (Committee member) / Dasarathy, Gautam (Committee member) / Seo, Jae-Sun (Committee member) / Arizona State University (Publisher)
Created2022
Description
Few-layer black phosphorous (FLBP) is one of the most important two-dimensional (2D) materials due to its strongly layer-dependent quantized bandstructure, which leads to wavelength-tunable optical and electrical properties. This thesis focuses on the preparation of stable, high-quality FLBP, the characterization of its optical properties, and device applications.Part I presents an approach to preparing high-quality, stable FLBP samples by combining O2 plasma etching, boron nitride (BN) sandwiching, and subsequent rapid thermal annealing (RTA). Such a strategy has successfully produced FLBP samples with a record-long lifetime, with 80% of photoluminescence (PL) intensity remaining after 7 months. The improved material quality of FLBP allows the establishment of a more definitive relationship between the layer number and PL energies.
Part II presents the study of oxygen incorporation in FLBP. The natural oxidation formed in the air environment is dominated by the formation of interstitial oxygen and dangling oxygen. By the real-time PL and Raman spectroscopy, it is found that continuous laser excitation breaks the bonds of interstitial oxygen, and free oxygen atoms can diffuse around or form dangling oxygen under low heat. RTA at 450 °C can turn the interstitial oxygen into dangling oxygen more thoroughly. Such oxygen-containing samples show similar optical properties to the pristine BP samples. The bandgap of such FLBP samples increases with the concentration of the incorporated oxygen.
Part III deals with the investigation of emission natures of the prepared samples. The power- and temperature-dependent measurements demonstrate that PL emissions are dominated by excitons and trions, with a combined percentage larger than 80% at room temperature. Such measurements allow the determination of trion and exciton binding energies of 2-, 3-, and 4-layer BP, with values around 33, 23, 15 meV for trions and 297, 276, 179 meV for excitons at 77K, respectively.
Part IV presents the initial exploration of device applications of such FLBP samples. The coupling between photonic crystal cavity (PCC) modes and FLBP's emission is realized by integrating the prepared sandwich structure onto 2D PCC. Electroluminescence has also been achieved by integrating such materials onto interdigital electrodes driven by alternating electric fields.
ContributorsLi, Dongying (Author) / Ning, Cun-Zheng (Thesis advisor) / Vasileska, Dragica (Committee member) / Lai, Ying-Cheng (Committee member) / Yu, Hongbin (Committee member) / Arizona State University (Publisher)
Created2022