Matching Items (173)
Description
Transient Receptor Potential Vanilloid-1 (TRPV1) is an integral membrane polymodal cation channel involved in various essential biological functions, including thermosensing, thermoregulation, and nociception. Discrete TRPV1 activation modes such as ligand, heat, and proton have been challenging to disentangle. However, dissecting the polymodal nature of TRPV1 is essential for therapeutic development. The human TRPV1 (hTRPV1) voltage-sensing like domain (VSLD; transmembrane helices S1-S4) contains the canonical vanilloid ligand binding site and significantly contributes to thermosensing. Nuclear magnetic resonance (NMR)-detected studies probe the role of the hTRPV1-VSLD in TRPV1 polymodal function. The hTRPV1-VSLD is identified as an allosteric hub for all three primary TRPV1 activation modes and demonstrates plasticity in chemical ligand modulation. The presented results underscore molecular features in the VSLD that dictate TRPV1 function, highlighting important considerations for future therapeutic design.
ContributorsOwens, Aerial M. (Author) / Van Horn, Wade D. (Thesis advisor) / Levitus, Marcia (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023
Description
The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic, declared in March 2020 resulted in an unprecedented scientific effort that led to the deployment in less than a year of several vaccines to prevent severe disease, hospitalizations, and death from coronavirus disease 2019 (COVID-19). Most vaccine models focus on the production of neutralizing antibodies against the spike (S) to prevent infection. As the virus evolves, new variants emerge that evade neutralizing antibodies produced by natural infection and vaccination, while memory T cell responses are long-lasting and resilient to most of the changes found in variants of concern (VOC). Several lines of evidence support the study of T cell-mediated immunity in SARS-CoV-2 infections. First, T cell reactivity against SARS-CoV-2 is found in both (cluster of differentiation) CD4+ and CD8+ T cell compartments in asymptomatic, mild, and severe recovered COVID-19 patients. Second, an early and stronger CD8+ T cell response correlates with less severe COVID-19 disease [1-4]. Third, both CD4+ and CD8+ T cells that are reactive to SARS-CoV-2 viral antigens are found in healthy unexposed individuals suggesting that cross-reactive and conserved epitopes may be protective against infection.
The current study is focused on the T cell-mediated response, with special attention to conserved, non-spike-cross-reactive epitopes that may be protective against SARS-CoV-2. The first chapter reviews the importance of epitope prediction in understanding the T cell-mediated responses to a pathogen. The second chapter centers on the validation of SARS-CoV-2 CD8+ T cell predicted peptides to find conserved, immunodominant, and immunoprevalent epitopes that can be incorporated into the next generation of vaccines against severe COVID-19 disease. The third chapter explores pre-existing immunity to SARS-CoV-2 in a pre-pandemic cohort and finds two highly immunogenic epitopes that are conserved among human common cold coronaviruses (HCoVs). To end, the fourth chapter explores the concept of T cell receptor (TCR) cross-reactivity by isolating SARS-CoV-2-reactive TCRs to elucidate the mechanisms of cross-reactivity to SARS-CoV-2 and other human coronaviruses (HCoVs).
ContributorsCarmona, Jacqueline (Author) / Anderson, Karen S (Thesis advisor) / Lake, Douglas (Thesis advisor) / Maley, Carlo (Committee member) / Mangone, Marco (Committee member) / LaBaer, Joshua (Committee member) / Arizona State University (Publisher)
Created2023
Description
In the last few decades, extensive research efforts have been focused on scaling down silicon-based complementary metal-oxide semiconductor (CMOS) technology to enable the continuation of Moore’s law. State-of-art CMOS includes fully depleted silicon-on-insulator (FDSOI) field-effect-transistors (FETs) with ultra-thin silicon channels (6 nm), as well as other three-dimensional (3D) device architectures like Fin-FETs, nanosheet FETs, etc. Significant research efforts have characterized these technologies towards various applications, and at different conditions including a wide range of temperatures from room temperature (300 K) down to cryogenic temperatures. Theoretical efforts have studied ultrascaled devices using Landauer theory to further understand their transport properties and predict their performance in the quasi-ballistic regime.Further scaling of CMOS devices requires the introduction of new semiconducting channel materials, as now established by the research community. Here, two-dimensional (2D) semiconductors have emerged as a promising candidate to replace silicon for next-generation ultrascaled CMOS devices. These emerging 2D semiconductors also have applications beyond CMOS, for example in novel memory, neuromorphic, and spintronic devices. Graphene is a promising candidate for spintronic devices due to its outstanding spin transport properties as evidenced by numerous studies in non-local lateral spin valve (LSV) geometries. The essential components of graphene-based LSV, such as graphene FETs, metal-graphene contacts, and tunneling barriers, were individually investigated as part of this doctoral dissertation.
In this work, several contributions were made to these CMOS and beyond CMOS technologies. This includes comprehensive characterization and modeling of FDSOI nanoscale FETs from room temperature down to cryogenic temperatures. Using Landauer theory for nanoscale transistors, FDSOI devices were analyzed and modeled under quasi-ballistic operation. This was extended towards a virtual-source modeling approach that accounts for temperature-dependent quasi-ballistic transport and back-gate biasing effects. Additionally, graphene devices with ultrathin high-k gate dielectrics were investigated towards FETs, non-volatile memory, and spintronic devices. New contributions were made relating to charge trapping effects and their impact on graphene device electrostatics (Dirac voltage shifts) and transport properties (impact on mobility and conductivity). This work also studied contact resistance and tunneling effects using transfer length method (TLM) graphene FET structures and magnetic tunneling junction (MTJ) towards graphene-based LSV.
ContributorsZhou, Guantong (Author) / Sanchez Esqueda, Ivan (Thesis advisor) / Vasileska, Dragica (Committee member) / Tongay, Sefaattin (Committee member) / Thornton, Trevor (Committee member) / Arizona State University (Publisher)
Created2023
Description
Mycobacterium tuberculosis (Mtb), the etiological agent of the tuberculosis disease, is estimated to infect one-fourth of the human population and is responsible for 1.5 million deaths annually. The increased emergence of bacterial resistance to clinical interventions highlights the lack in development of novel antimicrobial therapeutics. Prototypical bacterial two-component systems (TCS) allow for sensing of extracellular stimuli and relay thereof to create a transcriptional response. The prrAB TCS is essential for viability in Mtb, presenting itself as an attractive novel drug target. In Mtb, PrrAB is involved in the adaptation to the intra-macrophage environment and recent work implicates PrrAB in the dosR-dependent hypoxia adaptation. This work defines a direct molecular and regulatory connection between Mtb PrrAB and the dosR-dependent hypoxia response. Using electrophoretic mobility shift assays combined with surface plasmon resonance, the Mtb dosR gene is established as a specific target of PrrA, corroborated by fluorescence reporter assays demonstrating a regulatory relationship. Considering the scarce understanding of prrAB essentiality in nontuberculous mycobacteria and the presence of multiple prrAB orthologs in Mycobacterium smegmatis and Mycobacterium abscessus, CRISPR interference was utilized to evaluate the essentiality of PrrAB beyond Mtb. prrAB was found to be inessential for viability in M. smegmatis yet required for in vitro growth. Conversely, M. abscessus prrAB repression led to enhanced in vitro growth. Diarylthiazole-48 (DAT-48) displayed decreased selectivity against M. abscessus but demonstrated enhanced intrinsic activity upon prrAB repression in M. abscessus. Lastly, to aid in the rapid determination of mycobacterial drug susceptibility and the detection of mycobacterial heteroresistance, the large volume scattering imaging (LVSim) platform was adapted for mycobacteria. Using LVSim, Mtb drug susceptibility was detected phenotypically within 6 hours, and clinically relevant mycobacterial heteroresistance was detected phenotypically within 10 generations. The data generated in these studies provide insight into the essential role of PrrAB in Mtb and its involvement in the dosR-dependent hypoxia adaptation, advance the understanding of mycobacterial PrrAB essentiality and PrrAB-associated mycobacterial growth dependency. These studies further establish molecular and mechanistic connection between PrrAB and DAT-48 in Mtb and M. abscessus and develop a rapid phenotypic drug susceptibility testing platform for mycobacteria.
ContributorsHaller, Yannik Alex (Author) / Haydel, Shelley E (Thesis advisor) / Bean, Heather (Committee member) / Nickerson, Cheryl (Committee member) / Plaisier, Christopher (Committee member) / Acharya, Abhinav (Committee member) / Arizona State University (Publisher)
Created2023
Description
The research of alternative materials and new device architectures to exceed the limits of conventional silicon-based devices has been sparked by the persistent pursuit of semiconductor technology scaling. The development of tungsten diselenide (WSe2) and molybdenum disulfide (MoS2), well-known member of the transition metal dichalcogenide (TMD) family, has made great strides towards ultrascaled two-dimensional (2D) field-effect-transistors (FETs). The scaling issues facing silicon-based complementary metal-oxide-semiconductor (CMOS) technologies can be solved by 2D FETs, which show extraordinary potential.This dissertation provides a comprehensive experimental analysis relating to improvements in p-type metal-oxide-semiconductor (PMOS) FETs with few-layer WSe2 and high-κ metal gate (HKMG) stacks. Compared to this works improved methods, standard metallization (more damaging to underlying channel) results in significant Fermi-level pinning, although Schottky barrier heights remain small (< 100 meV) when using high work function metals. Temperature-dependent analysis reveals a dominant contribution to contact resistance from the damaged channel access region. Thus, through less damaging metallization methods combined with strongly scaled HKMG stacks significant improvements were achieved in contact resistance and PMOS FET overall performance. A clean contact/channel interface was achieved through high-vacuum evaporation and temperature-controlled stepped deposition. Theoretical analysis using a Landauer transport adapted to WSe2 Schottky barrier FETs (SB-FETs) elucidates the prospects of nanoscale 2D PMOS FETs indicating high-performance towards the ultimate CMOS scaling limit.
Next, this dissertation discusses how device electrical characteristics are affected by scaling of equivalent oxide thickness (EOT) and by adopting double-gate FET architectures, as well as how this might support CMOS scaling. An improved gate control over the channel is made possible by scaling EOT, improving on-off current ratios, carrier mobility, and subthreshold swing. This study also elucidates the impact of EOT scaling on FET gate hysteresis attributed to charge-trapping effects in high-κ-dielectrics prepared by atomic layer deposition (ALD). These developments in 2D FETs offer a compelling alternative to conventional silicon-based devices and a path for continued transistor scaling. This research contributes to ongoing efforts in 2D materials for future semiconductor technologies. Finally, this work introduces devices based on emerging Janus TMDs and bismuth oxyselenide (Bi2O2Se) layered semiconductors.
ContributorsPatoary, Md Naim Hossain (Author) / Sanchez Esqueda, Ivan (Thesis advisor) / Tongay, Sefaattin (Committee member) / Vasileska, Dragica (Committee member) / Goodnick, Stephen (Committee member) / Arizona State University (Publisher)
Created2023
Description
Doping is the cornerstone of Semiconductor technology, enabling the functionalities of modern digital electronics. Two-dimensional (2D) transition metal dichalcogenides (TMDCs) have tunable direct bandgaps, strong many-body interactions, and promising applications in future quantum information sciences, optoelectronic, spintronic, and valleytronic devices. However, their wafer-scale synthesis and precisely controllable doping are challenging. Moreover, there is no fixed framework to identify the doping concentration, which impedes their process integration for future commercialization. This work utilizes the Neutron Transmutation Doping technique to control the doping uniformly and precisely in TMDCs. Rhenium and Tin dopants are introduced in Tungsten- and Indium-based Chalcogenides, respectively. Fine-tuning over 0.001% doping level is achieved. Precise analytical techniques such as Gamma spectroscopy and Secondary Ion Mass Spectrometry are used to quantify ultra-low doping levels ranging from 0.005-0.01% with minimal error. Dopants in 2D TMDCs often exhibit a broad stokes-shifted emission, with high linewidths, due to extrinsic effects such as substrate disorder and surface adsorbates. A well-defined bound exciton emission induced by Rhenium dopants in monolayer WSe2 and WS2 at liquid nitrogen temperatures is reported along with specific annealing regimes to minimize the defects induced in the Neutron Transmutation process. This work demonstrates a framework for Neutron Doping in 2D materials, which can be a scalable process for controlling doping and doping-induced effects in 2D materials.
ContributorsLakhavade, Sushant Sambhaji (Author) / Tongay, Sefaattin (Thesis advisor) / Alford, Terry (Committee member) / Yang, Sui (Committee member) / Arizona State University (Publisher)
Created2023
Description
Redox homeostasis is described as the net physiologic balance between inter-convertible oxidized and reduced equivalents within subcellular compartments that remain in a dynamic equilibrium. This equilibrium is impacted by reactive oxygen species (ROS), which are natural by-products of normal cellular activity. Studies have shown that cancer cells have high ROS levels and altered redox homeostasis due to increased basal metabolic activity, mitochondrial dysfunction, peroxisome activity, as well as the enhanced activity of NADPH oxidase, cyclooxygenases, and lipoxygenases. Glioblastoma (GBM) is the most prevalent primary brain tumor in adults with a median survival of 15 months. GBM is characterized by its extreme resistance to therapeutic interventions as well as an elevated metabolic rate that results in the exacerbated production of ROS. Therefore, many agents with either antioxidant or pro-oxidant mechanisms of action have been rigorously employed in preclinical as well as clinical settings for treating GBM by inducing oxidative stress within the tumor. Among those agents are well-known antioxidant vitamin C and small molecular weight SOD mimic BMX-001, both of which are presently in clinical trials on GBM patients. Despite the wealth of investigations, limited data is available on the response of normal brain vs glioblastoma tissue to these therapeutic interventions. Currently, a sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method was established for the quantification of a panel of oxidative stress biomarkers: glutathione (GSH), cysteine (Cys), glutathione disulfide (GSSG), and cysteine disulfide in human-derived brain tumor and mouse brain samples; this method will be enriched with additional oxidative stress biomarkers homocysteine (Hcy), methionine (Met), and cystathionine (Cyst). Using this enriched method, we propose to evaluate the thiol homeostasis and the redox state of both normal brain and GBM in mice after exposure with redox-active therapeutics. Our results showed that, compared to normal brain (in intact mice), GBM tissue has significantly lower GSH/GSSG and Cys/CySS ratios indicating much higher oxidative stress levels. Contralateral “normal” brain tissue collected from the mice with intracranial GBM were also under significant oxidative stress compared to normal brains collected from the intact mice. Importantly, normal brain tissue in both studies retained the ability to restore redox homeostasis after treatment with a redox-active therapeutic within 24 hours while glioblastoma tissue does not. Ultimately, elucidating the differential redox response of normal vs tumor tissue will allow for the development of more redox-active agents with therapeutic benefit.
ContributorsShaik, Kamal (Author) / LaBaer, Joshua (Thesis director) / Tovmasyan, Artak (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor) / Historical, Philosophical & Religious Studies, Sch (Contributor) / Dean, W.P. Carey School of Business (Contributor)
Created2022-12
Description
In the past decade, 2D materials especially transition metal dichalcogenides (TMDc), have been studied extensively for their remarkable optical and electrical properties arising from their reduced dimensionality. A new class of materials developed based on 2D TMDc that has gained great interest in recent years is Janus crystals. In contrast to TMDc, Janus monolayer consists of two different chalcogen atomic layers between which the transition metal layer is sandwiched. This structural asymmetry causes strain buildup or a vertically oriented electric field to form within the monolayer. The presence of strain brings questions about the materials' synthesis approach, particularly when strain begins to accumulate and whether it causes defects within monolayers.The initial research demonstrated that Janus materials could be synthesized at high temperatures inside a chemical vapor deposition (CVD) furnace. Recently, a new method (selective epitaxy atomic replacement - SEAR) for plasma-based room temperature Janus crystal synthesis was proposed. In this method etching and replacing top layer chalcogen atoms of the TMDc monolayer happens with reactive hydrogen and sulfur radicals. Based on Raman and photoluminescence studies, the SEAR method produces high-quality Janus materials. Another method used to create Janus materials was the pulsed laser deposition (PLD) technique, which utilizes the interaction of sulfur/selenium plume with monolayer to replace the top chalcogen atomic layer in a single step.
The goal of this analysis is to characterize microscale defects that appear in 2D Janus materials after they are synthesized using SEAR and PLD techniques. Various microscopic techniques were used for this purpose, as well as to understand the
mechanism of defect formation. The main mechanism of defect formation was proposed to be strain release phenomena. Furthermore, different chalcogen atom positions within the monolayer result in different types of defects, such as the appearance of cracks or wrinkles across monolayers. In addition to investigating sample topography, Kelvin probe force microscopy (KPFM) was used to examine its electrical properties to see if the formation of defects impacts work function. Further study directions have been suggested for identifying and characterizing defects and their formation mechanism in the Janus crystals to understand their fundamental properties.
ContributorsSinha, Shantanu (Author) / Tongay, Sefaattin (Thesis advisor) / Alford, Terry (Committee member) / Yang, Sui (Committee member) / Arizona State University (Publisher)
Created2022
Description
DNA methylation (DNAm) is an epigenetic mark with a critical role in regulating gene expression. Altered clinical states, including toxin exposure and viral infections, can cause aberrant DNA methylation in cells, which may persist during cell division. Current methods to study genome-wide methylome profiles of the cells require a long processing time and are expensive. Here, a novel technique called Multiplexed Methylated DNA Immunoprecipitation Sequencing (Mx-MeDIP-Seq), which is amenable to automation. Up to 15 different samples can be combined into the same run of Mx-MeDIP-Seq, using only 25 ng of DNA per sample. Mx-MeDIP-Seq was used to study DNAm profiles of peripheral blood mononuclear cells (PBMCs) in two biologically distinct RNA viral infections with different modes of transmission, symptoms, and interaction with the host immune system: human immunodeficiency virus1 (HIV-1) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Analysis of 90 hospitalized patients with SARS-CoV-2 and 57 healthy controls revealed that SARS-CoV-2 infection led to alterations in 920 methylated regions in PBMCs, resulting in a change in transcription that affects host immune response and cell survival. Analysis of publicly available RNA-Sequencing data in COVID-19 correlated with DNAm in several key pathways. These findings provide a mechanistic view toward further understanding of viral infections. Genome-wide DNAm changes post HIV-1-infection from 37 chronically ill patients compared to 17 controls revealed dysregulation of the actin cytoskeleton, which could contribute to the establishment of latency in HIV-1 infections. Longitudinal DNAm analysis identified several potentially protective and harmful genes that could contribute to disease suppression or progression.
ContributorsRidha, Inam (Author) / LaBaer, Joshua (Thesis advisor) / Murugan, Vel (Thesis advisor) / Plaisier, Christopher (Committee member) / Nikkhah, Mehdi (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2022
Description
Type 1 diabetes (T1D) is the result of an autoimmune attack against the insulin-producing β-cells of the pancreas causing hyperglycemia and requiring the individual to rely on life-long exogenous insulin. With the age of onset typically occurring in childhood, there is increased physical and emotional stress to the child as well as caregivers to maintain appropriate glucose levels. The majority of T1D patients have antibodies to one or more antigens: insulin, IA-2, GAD65, and ZnT8. Although antibodies are detectable years before symptoms occur, the initiating factors and mechanisms of progression towards β-cell destruction are still not known. The search for new autoantibodies to elucidate the autoimmune process in diabetes has been slow, with proteome level screenings on native proteins only finding a few minor antigens. Post-translational modifications (PTM)—chemical changes that occur to the protein after translation is complete—are an unexplored way a self-protein could become immunogenic. This dissertation presents the first large sale screening of autoantibodies in T1D to nitrated proteins. The Contra Capture Protein Array (CCPA) allowed for fresh expression of hundreds of proteins that were captured on a secondary slide by tag-specific ligand and subsequent modification with peroxynitrite. The IgG and IgM humoral response of 48 newly diagnosed T1D subjects and 48 age-matched controls were screened against 1632 proteins highly or specifically expressed in pancreatic cells. Top targets at 95% specificity were confirmed with the same serum samples using rapid antigenic protein in situ display enzyme-linked immunosorbent assay (RAPID ELISA) a modified sandwich ELISA employing the same cell-free expression as the CCPA. For validation, 8 IgG and 5 IgM targets were evaluated with an independent serum sample set of 94 T1D subjects and 94 controls. The two best candidates at 90% specificity were estrogen receptor 1 (ESR1) and phosphatidylinositol 4-kinase type 2 beta (PI4K2B) which had sensitivities of 22% (p=.014) and 25% (p=.045), respectively. Receiver operating characteristic (ROC) analyses found an area under curve (AUC) of 0.6 for ESR1 and 0.58 for PI4K2B. These studies demonstrate the ability and value for high-throughput autoantibody screening to modified antigens and the frequency of Type 1 diabetes.
ContributorsHesterman, Jennifer (Author) / LaBaer, Joshua (Thesis advisor) / Borges, Chad (Committee member) / Sweazea, Karen (Committee member) / Mangone, Marco (Committee member) / Arizona State University (Publisher)
Created2022