ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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- All Subjects: Biology
- Creators: Wang, Xiao
- Creators: Robert, Jason
Description
Random peptide microarrays are a powerful tool for both the treatment and diagnostics of infectious diseases. On the treatment side, selected random peptides on the microarray have either binding or lytic potency against certain pathogens cells, thus they can be synthesized into new antimicrobial agents, denoted as synbodies (synthetic antibodies). On the diagnostic side, serum containing specific infection-related antibodies create unique and distinct "pathogen-immunosignatures" on the random peptide microarray distinct from the healthy control serum, and this different mode of binding can be used as a more precise measurement than traditional ELISA tests. My thesis project is separated into these two parts: the first part falls into the treatment side and the second one focuses on the diagnostic side. My first chapter shows that a substitution amino acid peptide library helps to improve the activity of a recently reported synthetic antimicrobial peptide selected by the random peptide microarray. By substituting one or two amino acids of the original lead peptide, the new substitutes show changed hemolytic effects against mouse red blood cells and changed potency against two pathogens: Staphylococcus aureus and Pseudomonas aeruginosa. Two new substitutes are then combined together to form the synbody, which shows a significantly antimicrobial potency against Staphylococcus aureus (<0.5uM). In the second chapter, I explore the possibility of using the 10K Ver.2 random peptide microarray to monitor the humoral immune response of dengue. Over 2.5 billion people (40% of the world's population) live in dengue transmitting areas. However, currently there is no efficient dengue treatment or vaccine. Here, with limited dengue patient serum samples, we show that the immunosignature has the potential to not only distinguish the dengue infection from non-infected people, but also the primary dengue infection from the secondary dengue infections, dengue infection from West Nile Virus (WNV) infection, and even between different dengue serotypes. By further bioinformatic analysis, we demonstrate that the significant peptides selected to distinguish dengue infected and normal samples may indicate the epitopes responsible for the immune response.
ContributorsWang, Xiao (Author) / Johnston, Stephen Albert (Thesis advisor) / Blattman, Joseph (Committee member) / Arntzen, Charles (Committee member) / Arizona State University (Publisher)
Created2013
Description
This study aims to unearth monological and monocultural discourses buried under the power of the dominant biomedical model governing the HIV/AIDS debate. The study responds to an apparent consensus, rooted in Western biomedicine and its "standardizations of knowledge," in the production of the current HIV/AIDS discourse, especially in Sub-Saharan Africa. As a result, biomedicine has become the dominant actor (in) writing and rewriting discourse for the masses while marginalizing other forms of medical knowledge. Specifically, in its development, the Western biomedical model has arguably isolated the disease from its human host and the social experiences that facilitate the disease's transmission, placing it in the realm of laboratories and scientific experts and giving full ownership to Western medical discourse. Coupled with Western assumptions about African culture that reproduce a one-sided discourse informing the social construction of HIV/AIDS in Africa, this Western monopoly thus constrained the extent and efficacy of international prevention efforts. In this context, the goal for this study is not to demonize the West and biomedicine in general. Rather, this study seeks an alternative and less monolithic understanding currently absent in scientific discourses of HIV/AIDS that frequently elevates Western biomedicine over indigenous medicine; the Western expert over the local. The study takes into account the local voices of Sub-Saharan Africa and how the system has affected them, this study utilizes a Foucauldian approach to analyze discourse as a way to explore how certain ways of knowledge are formed in relation to power. This study also examines how certain knowlege is maintaned and reinforced within specific discourses.
ContributorsAbdalla, Mohamed (Author) / Jacobs, Bertram (Thesis advisor) / Robert, Jason (Committee member) / Klimek, Barbara (Committee member) / Arizona State University (Publisher)
Created2014
Description
Synthetic gene networks have evolved from simple proof-of-concept circuits to
complex therapy-oriented networks over the past fifteen years. This advancement has
greatly facilitated expansion of the emerging field of synthetic biology. Multistability is a
mechanism that cells use to achieve a discrete number of mutually exclusive states in
response to environmental inputs. However, complex contextual connections of gene
regulatory networks in natural settings often impede the experimental establishment of
the function and dynamics of each specific gene network.
In this work, diverse synthetic gene networks are rationally designed and
constructed using well-characterized biological components to approach the cell fate
determination and state transition dynamics in multistable systems. Results show that
unimodality and bimodality and trimodality can be achieved through manipulation of the
signal and promoter crosstalk in quorum-sensing systems, which enables bacterial cells to
communicate with each other.
Moreover, a synthetic quadrastable circuit is also built and experimentally
demonstrated to have four stable steady states. Experiments, guided by mathematical
modeling predictions, reveal that sequential inductions generate distinct cell fates by
changing the landscape in sequence and hence navigating cells to different final states.
Circuit function depends on the specific protein expression levels in the circuit.
We then establish a protein expression predictor taking into account adjacent
transcriptional regions’ features through construction of ~120 synthetic gene circuits
(operons) in Escherichia coli. The predictor’s utility is further demonstrated in evaluating genes’ relative expression levels in construction of logic gates and tuning gene expressions and nonlinear dynamics of bistable gene networks.
These combined results illustrate applications of synthetic gene networks to
understand the cell fate determination and state transition dynamics in multistable
systems. A protein-expression predictor is also developed to evaluate and tune circuit
dynamics.
complex therapy-oriented networks over the past fifteen years. This advancement has
greatly facilitated expansion of the emerging field of synthetic biology. Multistability is a
mechanism that cells use to achieve a discrete number of mutually exclusive states in
response to environmental inputs. However, complex contextual connections of gene
regulatory networks in natural settings often impede the experimental establishment of
the function and dynamics of each specific gene network.
In this work, diverse synthetic gene networks are rationally designed and
constructed using well-characterized biological components to approach the cell fate
determination and state transition dynamics in multistable systems. Results show that
unimodality and bimodality and trimodality can be achieved through manipulation of the
signal and promoter crosstalk in quorum-sensing systems, which enables bacterial cells to
communicate with each other.
Moreover, a synthetic quadrastable circuit is also built and experimentally
demonstrated to have four stable steady states. Experiments, guided by mathematical
modeling predictions, reveal that sequential inductions generate distinct cell fates by
changing the landscape in sequence and hence navigating cells to different final states.
Circuit function depends on the specific protein expression levels in the circuit.
We then establish a protein expression predictor taking into account adjacent
transcriptional regions’ features through construction of ~120 synthetic gene circuits
(operons) in Escherichia coli. The predictor’s utility is further demonstrated in evaluating genes’ relative expression levels in construction of logic gates and tuning gene expressions and nonlinear dynamics of bistable gene networks.
These combined results illustrate applications of synthetic gene networks to
understand the cell fate determination and state transition dynamics in multistable
systems. A protein-expression predictor is also developed to evaluate and tune circuit
dynamics.
ContributorsWu, Fuqing (Author) / Wang, Xiao (Thesis advisor) / Haynes, Karmella (Committee member) / Marshall, Pamela (Committee member) / Nielsen, David (Committee member) / Brafman, David (Committee member) / Arizona State University (Publisher)
Created2017
Description
Fusion proteins that specifically interact with biochemical marks on chromosomes represent a new class of synthetic transcriptional regulators that decode cell state information rather than deoxyribose nucleic acid (DNA) sequences. In multicellular organisms, information relevant to cell state, tissue identity, and oncogenesis is often encoded as biochemical modifications of histones, which are bound to DNA in eukaryotic nuclei and regulate gene expression states. In 2011, Haynes et al. showed that a synthetic regulator called the Polycomb chromatin Transcription Factor (PcTF), a fusion protein that binds methylated histones, reactivated an artificially-silenced luciferase reporter gene. These synthetic transcription activators are derived from the polycomb repressive complex (PRC) and associate with the epigenetic silencing mark H3K27me3 to reactivate the expression of silenced genes. It is demonstrated here that the duration of epigenetic silencing does not perturb reactivation via PcTF fusion proteins. After 96 hours PcTF shows the strongest reactivation activity. A variant called Pc2TF, which has roughly double the affinity for H3K27me3 in vitro, reactivated the silenced luciferase gene by at least 2-fold in living cells.
ContributorsVargas, Daniel A. (Author) / Haynes, Karmella (Thesis advisor) / Wang, Xiao (Committee member) / Mills, Jeremy (Committee member) / Arizona State University (Publisher)
Created2019
Description
Prior to the first successful allogeneic organ transplantation in 1954, virtually every attempt at transplanting organs in humans had resulted in death, and understanding the role of the immune mechanisms that induced graft rejection served as one of the biggest obstacles impeding its success. While the eventual achievement of organ transplantation is touted as one of the most important success stories in modern medicine, there still remains a physiological need for immunosuppression in order to make organ transplantation work. One such solution in the field of experimental regenerative medicine is interspecies blastocyst complementation, a means of growing patient-specific human organs within animals. To address the progression of immune-related constraints on organ transplantation, the first part of this thesis contains a historical analysis tracing early transplant motivations and the events that led to the discoveries broadly related to tolerance, rejection, and compatibility. Despite the advancement of those concepts over time, this early history shows that immunosuppression was one of the earliest limiting barriers to successful organ transplantation, and remains one of the most significant technical challenges. Then, the second part of this thesis determines the extent at which interspecies blastocyst complementation could satisfy modern technical limitations of organ transplantation. Demonstrated in 2010, this process involves using human progenitor cells derived from induced pluripotent stem cells (iPSCs) to manipulate an animal blastocyst genetically modified to lack one or more functional genes responsible for the development of the intended organ. Instead of directly modulating the immune response, the use of iPSCs with interspecies blastocyst complementation could theoretically eliminate the need for immunosuppression entirely based on the establishment of tolerance and elimination of rejection, while also satisfying the logistical demands imposed by the national organ shortage. Although the technology will require some further refinement, it remains a promising solution to eliminate the requirement of immunosuppression after an organ transplant.
ContributorsDarby, Alexis Renee (Author) / Maienschein, Jane (Thesis advisor) / Robert, Jason (Thesis advisor) / Ellison, Karin (Committee member) / Arizona State University (Publisher)
Created2020
Description
This thesis reviews the initial cases of fetal surgery to correct myelomeningocele, a severe form of spina bifida, and discusses the human and social dimensions of the procedure. Myelomeningocele is a fetal anomaly that forms from improper closure of the spinal cord and the tissues that surround it. Physicians perform fetal surgery on a developing fetus, while it is in the womb, to mitigate its impacts. Fetal surgery to correct this condition was first performed experimentally in the mid-1990and as of 2020, it is commonly performed. The initial cases illuminated important human and social dimensions of the technique, including physical risks, psychological dimensions, physician bias, and religious convictions, which affect decision-making concerning this fetal surgery. Enduring questions remain in 2020. The driving question for this thesis is: given those human and social dimensions that surround fetal surgery to correct myelomeningocele, whether and when is the surgery justified? This thesis shows that more research is needed to answer or clarify this question.
ContributorsEllis, Brianna (Author) / Maienschein, Jane (Thesis advisor) / Ellison, Karin (Thesis advisor) / Robert, Jason (Committee member) / Arizona State University (Publisher)
Created2020
Description
A notable challenge when assembling synthetic gene circuits is that modularity often fails to function as intended. A crucial underlying reason for this modularity failure is the existence of competition for shared and limited gene expression resources. By designing a synthetic cascading bistable switches (Syn-CBS) circuit in a single strain with two coupled self-activation modules to achieve successive cell fate transitions, nonlinear resource competition within synthetic gene circuits is unveiled. However, in vivo it can be seen that the transition path was redirected with the activation of one switch always prevailing over that of the other, contradictory to coactivation theoretically expected. This behavior is a result of resource competition between genes and follows a ‘winner-takes-all’ rule, where the winner is determined by the relative connection strength between the two modules. Despite investigation demonstrating that resource competition between gene modules can significantly alter circuit deterministic behaviors, how resource competition contributes to gene expression noise and how this noise can be controlled is still an open issue of fundamental importance in systems biology and biological physics. By utilizing a two-gene circuit, the effects of resource competition on protein expression noise levels can be closely studied. A surprising double-edged role is discovered: the competition for these resources decreases noise while the constraint on resource availability adds its own term of noise into the system, denoted “resource competitive” noise. Noise reduction effects are then studied using orthogonal resources. Results indicate that orthogonal resources are a good strategy for eliminating the contribution of resource competition to gene expression noise.
Noise propagation through a cascading circuit has been considered without resource competition. It has been noted that the noise from upstream genes can be transmitted downstream. However, resource competition’s effects on this cascading noise have yet to be studied. When studied, it is found that resource competition can induce stochastic state
switching and perturb noise propagation. Orthogonal resources can remove some of the resource competitive behavior and allow for a system with less noise.
ContributorsGoetz, Hanah Elizabeth (Author) / Tian, Xiaojun (Thesis advisor) / Wang, Xiao (Committee member) / Lai, Ying-Cheng (Committee member) / Arizona State University (Publisher)
Created2022