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- Genre: Academic theses
Description
Infections caused by the Hepatitis C Virus (HCV) are very common worldwide, affecting up to 3% of the population. Chronic infection of HCV may develop into liver cirrhosis and liver cancer which is among the top five of the most common cancers. Therefore, vaccines against HCV are under intense study in order to prevent HCV from harming people's health. The envelope protein 2 (E2) of HCV is thought to be a promising vaccine candidate because it can directly bind to a human cell receptor and plays a role in viral entry. However, the E2 protein production in cells is inefficient due to its complicated matured structure. Folding of E2 in the endoplasmic reticulum (ER) is often error-prone, resulting in production of aggregates and misfolded proteins. These incorrect forms of E2 are not functional because they are not able to bind to human cells and stimulate antibody response to inhibit this binding. This study is aimed to overcome the difficulties of HCV E2 production in plant system. Protein folding in the ER requires great assistance from molecular chaperones. Thus, in this study, two molecular chaperones in the ER, calreticulin and calnexin, were transiently overexpressed in plant leaves in order to facilitate E2 folding and production. Both of them showed benefits in increasing the yield of E2 and improving the quality of E2. In addition, poorly folded E2 accumulated in the ER may cause stress in the ER and trigger transcriptional activation of ER molecular chaperones. Therefore, a transcription factor involved in this pathway, named bZIP60, was also overexpressed in plant leaves, aiming at up-regulating a major family of molecular chaperones called BiP to assist protein folding. However, our results showed that BiP mRNA levels were not up-regulated by bZIP60, but they increased in response to E2 expression. The Western blot analysis also showed that overexpression of bZIP60 had a small effect on promoting E2 folding. Overall, this study suggested that increasing the level of specific ER molecular chaperones was an effective way to promote HCV E2 protein production and maturation.
ContributorsHong, Fan (Author) / Mason, Hugh (Thesis advisor) / Gaxiola, Roberto (Committee member) / Chang, Yung (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2011
Description
In this thesis, we present the study of several physical properties of relativistic mat- ters under extreme conditions. We start by deriving the rate of the nonleptonic weak processes and the bulk viscosity in several spin-one color superconducting phases of quark matter. We also calculate the bulk viscosity in the nonlinear and anharmonic regime in the normal phase of strange quark matter. We point out several qualitative effects due to the anharmonicity, although quantitatively they appear to be relatively small. In the corresponding study, we take into account the interplay between the non- leptonic and semileptonic weak processes. The results can be important in order to relate accessible observables of compact stars to their internal composition. We also use quantum field theoretical methods to study the transport properties in monolayer graphene in a strong magnetic field. The corresponding quasi-relativistic system re- veals an anomalous quantum Hall effect, whose features are directly connected with the spontaneous flavor symmetry breaking. We study the microscopic origin of Fara- day rotation and magneto-optical transmission in graphene and show that their main features are in agreement with the experimental data.
ContributorsWang, Xinyang, Ph.D (Author) / Shovkovy, Igor (Thesis advisor) / Belitsky, Andrei (Committee member) / Easson, Damien (Committee member) / Peng, Xihong (Committee member) / Vachaspati, Tanmay (Committee member) / Arizona State University (Publisher)
Created2013
Description
Numerical simulations are very helpful in understanding the physics of the formation of structure and galaxies. However, it is sometimes difficult to interpret model data with respect to observations, partly due to the difficulties and background noise inherent to observation. The goal, here, is to attempt to bridge this gap between simulation and observation by rendering the model output in image format which is then processed by tools commonly used in observational astronomy. Images are synthesized in various filters by folding the output of cosmological simulations of gasdynamics with star-formation and dark matter with the Bruzual- Charlot stellar population synthesis models. A variation of the Virgo-Gadget numerical simulation code is used with the hybrid gas and stellar formation models of Springel and Hernquist (2003). Outputs taken at various redshifts are stacked to create a synthetic view of the simulated star clusters. Source Extractor (SExtractor) is used to find groupings of stellar populations which are considered as galaxies or galaxy building blocks and photometry used to estimate the rest frame luminosities and distribution functions. With further refinements, this is expected to provide support for missions such as JWST, as well as to probe what additional physics are needed to model the data. The results show good agreement in many respects with observed properties of the galaxy luminosity function (LF) over a wide range of high redshifts. In particular, the slope (alpha) when fitted to the standard Schechter function shows excellent agreement both in value and evolution with redshift, when compared with observation. Discrepancies of other properties with observation are seen to be a result of limitations of the simulation and additional feedback mechanisms which are needed.
ContributorsMorgan, Robert (Author) / Windhorst, Rogier A (Thesis advisor) / Scannapieco, Evan (Committee member) / Rhoads, James (Committee member) / Gardner, Carl (Committee member) / Belitsky, Andrei (Committee member) / Arizona State University (Publisher)
Created2012
Description
Understanding the temperature structure of protoplanetary disks (PPDs) is paramount to modeling disk evolution and future planet formation. PPDs around T Tauri stars have two primary heating sources, protostellar irradiation, which depends on the flaring of the disk, and accretional heating as viscous coupling between annuli dissipate energy. I have written a "1.5-D" radiative transfer code to calculate disk temperatures assuming hydrostatic and radiative equilibrium. The model solves for the temperature at all locations simultaneously using Rybicki's method, converges rapidly at high optical depth, and retains full frequency dependence. The likely cause of accretional heating in PPDs is the magnetorotational instability (MRI), which acts where gas ionization is sufficiently high for gas to couple to the magnetic field. This will occur in surface layers of the disk, leaving the interior portions of the disk inactive ("dead zone"). I calculate temperatures in PPDs undergoing such "layered accretion." Since the accretional heating is concentrated far from the midplane, temperatures in the disk's interior are lower than in PPDs modeled with vertically uniform accretion. The method is used to study for the first time disks evolving via the magnetorotational instability, which operates primarily in surface layers. I find that temperatures in layered accretion disks do not significantly differ from those of "passive disks," where no accretional heating exists. Emergent spectra are insensitive to active layer thickness, making it difficult to observationally identify disks undergoing layered vs. uniform accretion. I also calculate the ionization chemistry in PPDs, using an ionization network including multiple charge states of dust grains. Combined with a criterion for the onset of the MRI, I calculate where the MRI can be initiated and the extent of dead zones in PPDs. After accounting for feedback between temperature and active layer thickness, I find the surface density of the actively accreting layers falls rapidly with distance from the protostar, leading to a net outward flow of mass from ~0.1 to 3 AU. The clearing out of the innermost zones is possibly consistent with the observed behavior of recently discovered "transition disks."
ContributorsLesniak, Michael V., III (Author) / Desch, Steven J. (Thesis advisor) / Scannapieco, Evan (Committee member) / Timmes, Francis (Committee member) / Starrfield, Sumner (Committee member) / Belitsky, Andrei (Committee member) / Arizona State University (Publisher)
Created2012
Description
This thesis deals with the first measurements done with a cold neutron beam at the Spallation Neutron Source at Oak Ridge National Laboratory. The experimental technique consisted of capturing polarized cold neutrons by nuclei to measure parity-violation in the angular distribution of the gamma rays following neutron capture. The measurements presented here for the nuclei Chlorine ( 35Cl) and Aluminum ( 27Al ) are part of a program with the ultimate goal of measuring the asymmetry in the angular distribution of gamma rays emitted in the capture of neutrons on protons, with a precision better than 10-8, in order to extract the weak hadronic coupling constant due to pion exchange interaction with isospin change equal with one ( hπ 1). Based on theoretical calculations asymmetry in the angular distribution of the gamma rays from neutron capture on protons has an estimated size of 5·10-8. This implies that the Al parity violation asymmetry and its uncertainty have to be known with a precision smaller than 4·10-8. The proton target is liquid Hydrogen (H2) contained in an Aluminum vessel. Results are presented for parity violation and parity-conserving asymmetries in Chlorine and Aluminum. The systematic and statistical uncertainties in the calculation of the parity-violating and parity-conserving asymmetries are discussed.
ContributorsBalascuta, Septimiu (Author) / Alarcon, Ricardo (Thesis advisor) / Belitsky, Andrei (Committee member) / Doak, Bruce (Committee member) / Comfort, Joseph (Committee member) / Schmidt, Kevin (Committee member) / Arizona State University (Publisher)
Created2012
Description
As the world energy demand increases, semiconductor devices with high energy conversion efficiency become more and more desirable. The energy conversion consists of two distinct processes, namely energy generation and usage. In this dissertation, novel multi-junction solar cells and light emitting diodes (LEDs) are proposed and studied for high energy conversion efficiency in both processes, respectively. The first half of this dissertation discusses the practically achievable energy conversion efficiency limit of solar cells. Since the demonstration of the Si solar cell in 1954, the performance of solar cells has been improved tremendously and recently reached 41.6% energy conversion efficiency. However, it seems rather challenging to further increase the solar cell efficiency. The state-of-the-art triple junction solar cells are analyzed to help understand the limiting factors. To address these issues, the monolithically integrated II-VI and III-V material system is proposed for solar cell applications. This material system covers the entire solar spectrum with a continuous selection of energy bandgaps and can be grown lattice matched on a GaSb substrate. Moreover, six four-junction solar cells are designed for AM0 and AM1.5D solar spectra based on this material system, and new design rules are proposed. The achievable conversion efficiencies for these designs are calculated using the commercial software package Silvaco with real material parameters. The second half of this dissertation studies the semiconductor luminescence refrigeration, which corresponds to over 100% energy usage efficiency. Although cooling has been realized in rare-earth doped glass by laser pumping, semiconductor based cooling is yet to be realized. In this work, a device structure that monolithically integrates a GaAs hemisphere with an InGaAs/GaAs quantum-well thin slab LED is proposed to realize cooling in semiconductor. The device electrical and optical performance is calculated. The proposed device then is fabricated using nine times photolithography and eight masks. The critical process steps, such as photoresist reflow and dry etch, are simulated to insure successful processing. Optical testing is done with the devices at various laser injection levels and the internal quantum efficiency, external quantum efficiency and extraction efficiency are measured.
ContributorsWu, Songnan (Author) / Zhang, Yong-Hang (Thesis advisor) / Menéndez, Jose (Committee member) / Ponce, Fernando (Committee member) / Belitsky, Andrei (Committee member) / Schroder, Dieter (Committee member) / Arizona State University (Publisher)
Created2010
Description
Ebola hemorrhagic fever (EHF) is a severe and often fatal disease in human and nonhuman primates, caused by the Ebola virus. Approximately 30 years after the first epidemic, there is no vaccine or therapeutic medication approved to counter the Ebola virus. In this dissertation, a geminiviral replicon system was used to produce Ebola immune complex (EIC) in plant leaves and tested it as an Ebola vaccine. The EIC was produced in Nicotiana benthamiana leaves by fusing Ebola virus glycoprotein (GP1) to the C-terminus of heavy chain of 6D8 monoclonal antibody (mAb), which is specific to the 6D8 epitope of GP1, and co-expressing the fusion with the light chain of 6D8 mAb. EIC was purified by ammonium sulfate precipitation and protein A or protein G affinity chromatography. EIC was shown to be immunogenic in mice, but the level of antibody against Ebola virus was not sufficient to protect the mice from lethal the Ebola challenge. Hence, different adjuvants were tested in order to improve the immunogenicity of the EIC. Among several adjuvants that we used, Poly(I:C), which is a synthetic analog of double-stranded ribonucleic acid that can interact with a Toll-like receptor 3, strongly increased the efficacy of our Ebola vaccine. The mice immunized with EIC co-administered with Poly(I:C) produced high levels of neutralizing anti-Ebola IgG, and 80% of the mice were protected from the lethal Ebola virus challenge. Moreover, the EIC induced a predominant T-helper type 1 (Th1) response, whereas Poly(I:C) co-delivered with the EIC stimulated a mixed Th1/Th2 response. This result suggests that the protection against lethal Ebola challenge requires both Th1 and Th2 responses. In conclusion, this study demonstrated that the plant-produced EIC co-delivered with Poly(I:C) induced strong and protective immune responses to the Ebola virus in mice. These results support plant-produced EIC as a good vaccine candidate against the Ebola virus. It should be pursued further in primate studies, and eventually in clinical trials.
ContributorsPhoolcharoen, Waranyoo (Author) / Mason, Hugh S (Thesis advisor) / Chen, Qiang (Thesis advisor) / Arntzen, Charles J. (Committee member) / Change, Yung (Committee member) / Ma, Julian (Committee member) / Arizona State University (Publisher)
Created2010
Description
Vaccines are one of the most effective ways of combating infectious diseases and developing vaccine platforms that can be used to produce vaccines can greatly assist in combating global public health threats. This dissertation focuses on the development and pre-clinical testing of vaccine platforms that are highly immunogenic, easily modifiable, economically viable to produce, and stable. These criteria are met by the recombinant immune complex (RIC) universal vaccine platform when produced in plants. The RIC platform is modeled after naturally occurring immune complexes that form when an antibody, a component of the immune system that recognizes protein structures or sequences, binds to its specific antigen, a molecule that causes an immune response. In the RIC platform, a well-characterized antibody is linked via its heavy chain, to an antigen tagged with the antibody-specific epitope. The RIC antibody binds to the epitope tags on other RIC molecules and forms highly immunogenic complexes. My research has primarily focused on the optimization of the RIC platform. First, I altered the RIC platform to enable an N-terminal antigenic fusion instead of the previous C-terminal fusion strategy. This allowed the platform to be used with antigens that require an accessible N-terminus. A mouse immunization study with a model antigen showed that the fusion location, either N-terminal or C-terminal, did not impact the immune response. Next, I studied a synergistic response that was seen upon co-delivery of RIC with virus-like particles (VLP) and showed that the synergistic response could be produced with either N-terminal or C-terminal RIC co-delivered with VLP. Since RICs are inherently insoluble due to their ability to form complexes, I also examined ways to increase RIC solubility by characterizing a panel of modified RICs and antibody-fusions. The outcome was the identification of a modified RIC that had increased solubility while retaining high immunogenicity. Finally, I modified the RIC platform to contain multiple antigenic insertion sites and explored the use of bioinformatic tools to guide the design of a broadly protective vaccine.
ContributorsPardhe, Mary (Author) / Mason, Hugh S (Thesis advisor) / Chen, Qiang (Committee member) / Mor, Tsafrir (Committee member) / Wilson, Melissa (Committee member) / Arizona State University (Publisher)
Created2021
Description
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) that emerged from a zoonotic host at the end of 2019 and caused a public health crisis. In this collection of studies, Nicotiana benthamiana plants are used to set the foundation for producing monoclonal antibodies (mAbs) with homogeneous glycosylation to neutralize SARS-CoV-2 and potentially address the immunopathology often observed with severe COVID-19. Specifically, a mAb against the human interleukin (IL)-6 receptor (sarilumab) was generated and evaluated in vitro for its potential to reduce IL-6 signaling that has been shown to be associated with more severe cases of COVID-19. Furthermore, multiple mAbs that bind to the receptor-binding domain (RBD) of SARS-CoV-2 and efficiently neutralize the virus were developed using plant-based expression. Several of these mAbs are from different classes of RBD-binding mAbs that have distinct binding sites from one another. Several mAbs from different classes showed synergy in neutralizing the ancestral strain of SARS-CoV-2 and a smaller subset showed synergy when tested against the highly mutated Omicron (B.1.1.529) variant. Of interest, a novel RBD-binding mAb, termed 11D7, that was raised against the ancestral strain and derived from a hybridoma, appears to have an epitope on the RBD that contributes more synergy to a mAb combination that efficiently neutralizes the B.1.1.529 variant of SARS-CoV-2. This epitope was partially mapped by competitive binding and shows that it overlaps with another known antibody that binds a cryptic, distal epitope, away from the receptor binding site, giving insight into the potential mechanism by which 11D7 neutralizes SARS-CoV-2, as well as potentially allowing it to resist SARS-CoV-2 immune evasion more efficiently. Furthermore, this mAb carries a highly homogeneous glycan pattern when expressed in N. benthamiana, that may contribute to enhanced effector function and provides a tool to elucidate the precise role of crystallizable fragment (Fc)-mediated protection in SARS-CoV-2 infection. Ultimately, these studies provide evidence of the utility of plant-made mAbs to be used as cocktail members, giving clarity to the use of less potent mAbs as valuable cocktail components which will spur further investigations into how mAbs with unique epitopes work together to efficiently neutralize SARS-CoV-2.
ContributorsJugler, Collin (Author) / Chen, Qiang (Thesis advisor) / Lake, Douglas (Committee member) / Steele, Kelly (Committee member) / Mason, Hugh (Committee member) / Arizona State University (Publisher)
Created2022
Description
Scientists are entrusted with developing novel molecular strategies for effective prophylactic and therapeutic interventions. Antivirals are indispensable tools that can be targeted at viral domains directly or at cellular domains indirectly to obstruct viral infections and reduce pathogenicity. Despite their transformative potential in healthcare, to date, antivirals have been clinically approved to treat only 10 out of the greater than 200 known pathogenic human viruses. Additionally, as obligate intracellular parasites, many virus functions are intimately coupled with host cellular processes. As such, the development of a clinically relevant antiviral is challenged by the limited number of clear targets per virus and necessitates an extensive insight into these molecular processes. Compounding this challenge, many viral pathogens have evolved to evade effective antivirals. Therefore, a means to develop virus- or strain-specific antivirals without detailed insight into each idiosyncratic biochemical mechanism may aid in the development of antivirals against a larger swath of pathogens. Such an approach will tremendously benefit from having the specific molecular recognition of viral species as the lowest barrier. Here, I modify a nanobody (anti-green fluorescent protein) that specifically recognizes non-essential epitopes (glycoprotein M-pHluorin chimera) presented on the extra virion surface of a virus (Pseudorabies virus strain 486). The nanobody switches from having no inhibitory properties (tested up to 50 μM) to ∼3 nM IC50 in in vitro infectivity assays using porcine kidney (PK15) cells. The nanobody modifications use highly reliable bioconjugation to a three-dimensional wireframe deoxyribonucleic acid (DNA) origami scaffold. Mechanistic studies suggest that inhibition is mediated by the DNA origami scaffold bound to the virus particle, which obstructs the internalization of the viruses into cells, and that inhibition is enhanced by avidity resulting from multivalent virus and scaffold interactions. The assembled nanostructures demonstrate negligible cytotoxicity (<10 nM) and sufficient stability, further supporting their therapeutic potential. If translatable to other viral species and epitopes, this approach may open a new strategy that leverages existing infrastructures – monoclonal antibody development, phage display, and in vitro evolution - for rapidly developing novel antivirals in vivo.
ContributorsPradhan, Swechchha (Author) / Hariadi, Rizal (Thesis advisor) / Hogue, Ian (Committee member) / Varsani, Arvind (Committee member) / Chen, Qiang (Committee member) / Arizona State University (Publisher)
Created2022