Matching Items (93)
Description
Alzheimer's Disease (AD) is a progressive neurodegenerative disease accounting for 50-80% of dementia cases in the country. This disease is characterized by the deposition of extracellular plaques occurring in regions of the brain important for cognitive function. A primary component of these plaques is the amyloid-beta protein. While a natively unfolded protein, amyloid-beta can misfold and aggregate generating a variety of different species including numerous different soluble oligomeric species some of which are precursors to the neurofibrillary plaques. Various of the soluble amyloid-beta oligomeric species have been shown to be toxic to cells and their presence may correlate with progression of AD. Current treatment options target the dementia symptoms, but there is no effective cure or alternative to delay the progression of the disease once it occurs. Amyloid-beta aggregates show up many years before symptoms develop, so detection of various amyloid-beta aggregate species has great promise as an early biomarker for AD. Therefore reagents that can selectively identify key early oligomeric amyloid-beta species have value both as potential diagnostics for early detection of AD and as well as therapeutics that selectively target only the toxic amyloid-beta aggregate species. Earlier work in the lab includes development of several different single chain antibody fragments (scFvs) against different oligomeric amyloid-beta species. This includes isolation of C6 scFv against human AD brain derived oligomeric amyloid-beta (Kasturirangan et al., 2013). This thesis furthers research in this direction by improving the yields and investigating the specificity of modified C6 scFv as a diagnostic for AD. It is motivated by experiments reporting low yields of the C6 scFv. We also used the C6T scFv to characterize the variation in concentration of this particular oligomeric amyloid-beta species with age in a triple transgenic AD mouse model. We also show that C6T can be used to differentiate between post-mortem human AD, Parkinson's disease (PD) and healthy human brain samples. These results indicate that C6T has potential value as a diagnostic tool for early detection of AD.
ContributorsVenkataraman, Lalitha (Author) / Sierks, Michael (Thesis advisor) / Rege, Kaushal (Committee member) / Pauken, Christine (Committee member) / Arizona State University (Publisher)
Created2013
Description
Advances in software and applications continue to demand advances in memory. The ideal memory would be non-volatile and have maximal capacity, speed, retention time, endurance, and radiation hardness while also having minimal physical size, energy usage, and cost. The programmable metallization cell (PMC) is an emerging memory technology that is likely to surpass flash memory in all the listed ideal memory characteristics. A comprehensive physics-based model is needed to fully understand PMC operation and aid in design optimization. With the intent of advancing the PMC modeling effort, this thesis presents two simulation models for the PMC. The first model is a finite element model based on Silvaco Atlas finite element analysis software. Limitations of the software are identified that make this model inconsistent with the operating mechanism of the PMC. The second model is a physics-based numerical model developed for the PMC. This model is successful in matching data measured from a chalcogenide glass PMC designed and manufactured at ASU. Matched operating characteristics observable in the current and resistance vs. voltage data include the OFF/ON resistances and write/erase and electrodeposition voltage thresholds. Multilevel programming is also explained and demonstrated with the numerical model. The numerical model has already proven useful by revealing some information presented about the operation and characteristics of the PMC.
ContributorsOleksy, David Ryan (Author) / Barnaby, Hugh J (Thesis advisor) / Kozicki, Michael N (Committee member) / Edwards, Arthur H (Committee member) / Arizona State University (Publisher)
Created2013
Description
Cancer is the second leading cause of death in the United States and novel methods of treating advanced malignancies are of high importance. Of these deaths, prostate cancer and breast cancer are the second most fatal carcinomas in men and women respectively, while pancreatic cancer is the fourth most fatal in both men and women. Developing new drugs for the treatment of cancer is both a slow and expensive process. It is estimated that it takes an average of 15 years and an expense of $800 million to bring a single new drug to the market. However, it is also estimated that nearly 40% of that cost could be avoided by finding alternative uses for drugs that have already been approved by the Food and Drug Administration (FDA). The research presented in this document describes the testing, identification, and mechanistic evaluation of novel methods for treating many human carcinomas using drugs previously approved by the FDA. A tissue culture plate-based screening of FDA approved drugs will identify compounds that can be used in combination with the protein TRAIL to induce apoptosis selectively in cancer cells. Identified leads will next be optimized using high-throughput microfluidic devices to determine the most effective treatment conditions. Finally, a rigorous mechanistic analysis will be conducted to understand how the FDA-approved drug mitoxantrone, sensitizes cancer cells to TRAIL-mediated apoptosis.
ContributorsTaylor, David (Author) / Rege, Kaushal (Thesis advisor) / Jayaraman, Arul (Committee member) / Nielsen, David (Committee member) / Kodibagkar, Vikram (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2013
Description
Liquid-liquid interfaces serve as ideal 2-D templates on which solid particles can self-assemble into various structures. These self-assembly processes are important in fabrication of micron-sized devices and emulsion formulation. At oil/water interfaces, these structures can range from close-packed aggregates to ordered lattices. By incorporating an ionic liquid (IL) at the interface, new self-assembly phenomena emerge. ILs are ionic compounds that are liquid at room temperature (essentially molten salts at ambient conditions) that have remarkable properties such as negligible volatility and high chemical stability and can be optimized for nearly any application. The nature of IL-fluid interfaces has not yet been studied in depth. Consequently, the corresponding self-assembly phenomena have not yet been explored. We demonstrate how the unique molecular nature of ILs allows for new self-assembly phenomena to take place at their interfaces. These phenomena include droplet bridging (the self-assembly of both particles and emulsion droplets), spontaneous particle transport through the liquid-liquid interface, and various gelation behaviors. In droplet bridging, self-assembled monolayers of particles effectively "glue" emulsion droplets to one another, allowing the droplets to self-assembly into large networks. With particle transport, it is experimentally demonstrated the ILs overcome the strong adhesive nature of the liquid-liquid interface and extract solid particles from the bulk phase without the aid of external forces. These phenomena are quantified and corresponding mechanisms are proposed. The experimental investigations are supported by molecular dynamics (MD) simulations, which allow for a molecular view of the self-assembly process. In particular, we show that particle self-assembly depends primarily on the surface chemistry of the particles and the non-IL fluid at the interface. Free energy calculations show that the attractive forces between nanoparticles and the liquid-liquid interface are unusually long-ranged, due to capillary waves. Furthermore, IL cations can exhibit molecular ordering at the IL-oil interface, resulting in a slight residual charge at this interface. We also explore the transient IL-IL interface, revealing molecular interactions responsible for the unusually slow mixing dynamics between two ILs. This dissertation, therefore, contributes to both experimental and theoretical understanding of particle self-assembly at IL based interfaces.
ContributorsFrost, Denzil (Author) / Dai, Lenore L (Thesis advisor) / Torres, César I (Committee member) / Nielsen, David R (Committee member) / Squires, Kyle D (Committee member) / Rege, Kaushal (Committee member) / Arizona State University (Publisher)
Created2013
Description
The dissolution of metal layers such as silver into chalcogenide glass layers such as germanium selenide changes the resistivity of the metal and chalcogenide films by a great extent. It is known that the incorporation of the metal can be achieved by ultra violet light exposure or thermal processes. In this work, the use of metal dissolution by exposure to gamma radiation has been explored for radiation sensor applications. Test structures were designed and a process flow was developed for prototype sensor fabrication. The test structures were designed such that sensitivity to radiation could be studied. The focus is on the effect of gamma rays as well as ultra violet light on silver dissolution in germanium selenide (Ge30Se70) chalcogenide glass. Ultra violet radiation testing was used prior to gamma exposure to assess the basic mechanism. The test structures were electrically characterized prior to and post irradiation to assess resistance change due to metal dissolution. A change in resistance was observed post irradiation and was found to be dependent on the radiation dose. The structures were also characterized using atomic force microscopy and roughness measurements were made prior to and post irradiation. A change in roughness of the silver films on Ge30Se70 was observed following exposure. This indicated the loss of continuity of the film which causes the increase in silver film resistance following irradiation. Recovery of initial resistance in the structures was also observed after the radiation stress was removed. This recovery was explained with photo-stimulated deposition of silver from the chalcogenide at room temperature confirmed with the re-appearance of silver dendrites on the chalcogenide surface. The results demonstrate that it is possible to use the metal dissolution effect in radiation sensing applications.
ContributorsChandran, Ankitha (Author) / Kozicki, Michael N (Thesis advisor) / Holbert, Keith E. (Committee member) / Barnaby, Hugh (Committee member) / Arizona State University (Publisher)
Created2012
Description
The prevalence of antibiotic resistant bacterial pathogens has increased since the introduction of penicillin in the 1940s. Insufficient development of novel antibacterial agents is leaving us with a failing arsenal of therapies to combat these pathogenic organisms. We have identified a clay mineral mixture (designated CB) that exhibits in vitro antibacterial activity against a broad spectrum of bacterial pathogens, yet the antibacterial mechanism of action remains unknown. Antibacterial susceptibility testing of four different clay samples collected from the same source revealed that these natural clays had markedly different antibacterial activity. X-ray diffraction analyses of these minerals revealed minor mineralogical differences across the samples; however, ICP analyses demonstrated that the concentrations of many elements, Fe, Co, Cu, Ni, and Zn in particular, vary greatly across the four clay mixture leachates. Supplementation of a non-antibacterial leachate containing lower concentrations of Fe, Co, Ni, Cu, and Zn to final ion concentrations and a pH equivalent to that of the antibacterial leachate resulted in antibacterial activity against E. coli and MRSA, confirming the role of these ions in the in vitro antibacterial clay mixture leachates. The prevailing hypothesis is that metal ions participate in redox cycling and produce ROS, leading to oxidative damage to macromolecules and resulting in cellular death. However, E. coli cells showed no increase in DNA or protein oxidative lesions and a slight increase in lipid peroxidation following exposure to CB-L. Supplementation of CB-L with ROS scavengers eliminated oxidative damage in E. coli, but did not rescue the cells from killing, indicating that in vitro killing is due to direct metal toxicity and not to indirect oxidative damage. Finally, we ion-exchanged non-antibacterial clays with Fe, Co, Cu, and Zn and established antibacterial activity in these samples. Treatment of MRSA skin infections with both natural and ion-exchanged clays significantly decreased the bacterial load after 7 days of treatment. We conclude that 1) in vitro clay-mediated killing is due to toxicity associated directly with released metal ions and not to indirect oxidative damage and 2) that in vivo killing is due to the physical properties of the clays rather than metal ion toxicity.
ContributorsOtto, Caitin Carol (Author) / Haydel, Shelley (Thesis advisor) / Stout, Valerie (Committee member) / Roberson, Robby (Committee member) / Sandrin, Todd (Committee member) / Rege, Kaushal (Committee member) / Arizona State University (Publisher)
Created2014
Description
Sliding-Mode Control (SMC) has several benefits over traditional Proportional-Integral-Differential (PID) control in terms of fast transient response, robustness to parameter and component variations, and low sensitivity to loop disturbances. An All-Digital Sliding-Mode (ADSM) controlled DC-DC converter, utilizing single-bit oversampled frequency domain digitizers is proposed. In the proposed approach, feedback and reference digitizing Analog-to-Digital Converters (ADC) are based on a single-bit, first order Sigma-Delta frequency to digital converter, running at 32MHz over-sampling rate. The ADSM regulator achieves 1% settling time in less than 5uSec for a load variation of 600mA. The sliding-mode controller utilizes a high-bandwidth hysteretic differentiator and an integrator to perform the sliding control law in digital domain. The proposed approach overcomes the steady state error (or DC offset), and limits the switching frequency range, which are the two common problems associated with sliding-mode controllers. The IC is designed and fabricated on a 0.35um CMOS process occupying an active area of 2.72mm-squared. Measured peak efficiency is 83%.
ContributorsDashtestani, Ahmad (Author) / Bakkaloglu, Bertan (Thesis advisor) / Thornton, Trevor (Committee member) / Song, Hongjiang (Committee member) / Kiaei, Sayfe (Committee member) / Arizona State University (Publisher)
Created2013
Description
Chalcogenide glass (ChG) materials have gained wide attention because of their applications in conductive bridge random access memory (CBRAM), phase change memories (PC-RAM), optical rewritable disks (CD-RW and DVD-RW), microelectromechanical systems (MEMS), microfluidics, and optical communications. One of the significant properties of ChG materials is the change in the resistivity of the material when a metal such as Ag or Cu is added to it by diffusion. This study demonstrates the potential radiation-sensing capabilities of two metal/chalcogenide glass device configurations. Lateral and vertical device configurations sense the radiation-induced migration of Ag+ ions in germanium selenide glasses via changes in electrical resistance between electrodes on the ChG. Before irradiation, these devices exhibit a high-resistance `OFF-state' (in the order of 10E12) but following irradiation, with either 60-Co gamma-rays or UV light, their resistance drops to a low-resistance `ON-state' (around 10E3). Lateral devices have exhibited cyclical recovery with room temperature annealing of the Ag doped ChG, which suggests potential uses in reusable radiation sensor applications. The feasibility of producing inexpensive flexible radiation sensors has been demonstrated by studying the effects of mechanical strain and temperature stress on sensors formed on flexible polymer substrate. The mechanisms of radiation-induced Ag/Ag+ transport and reactions in ChG have been modeled using a finite element device simulator, ATLAS. The essential reactions captured by the simulator are radiation-induced carrier generation, combined with reduction/oxidation for Ag species in the chalcogenide film. Metal-doped ChGs are solid electrolytes that have both ionic and electronic conductivity. The ChG based Programmable Metallization Cell (PMC) is a technology platform that offers electric field dependent resistance switching mechanisms by formation and dissolution of nano sized conductive filaments in a ChG solid electrolyte between oxidizable and inert electrodes. This study identifies silver anode agglomeration in PMC devices following large radiation dose exposure and considers device failure mechanisms via electrical and material characterization. The results demonstrate that by changing device structural parameters, silver agglomeration in PMC devices can be suppressed and reliable resistance switching may be maintained for extremely high doses ranging from 4 Mrad(GeSe) to more than 10 Mrad (ChG).
ContributorsDandamudi, Pradeep (Author) / Kozicki, Michael N (Thesis advisor) / Barnaby, Hugh J (Committee member) / Holbert, Keith E. (Committee member) / Goryll, Michael (Committee member) / Arizona State University (Publisher)
Created2013
Description
Many therapeutics administered for some of the most devastating illnesses can be toxic and result in unwanted side effects. Recent developments have been made in an alternative treatment method, called gene therapy. Gene therapy has potential to rectify the genetic defects that cause a broad range of diseases. Many diseases, such as cancer, cystic fibrosis, and acquired immunodeficiency (AIDS) already have gene therapy protocols that are currently in clinical trials. Finding a non-toxic and efficient gene transfer method has been a challenge. Viral vectors are effective at transgene delivery however potential for insertion mutagenesis and activation of immune responses raises concern. For this reason, non-viral vectors have been investigated as a safer alternative to viral-mediated gene delivery. Non-viral vectors are also easy to prepare and scalable, but are limited by low transgene delivery efficacies and high cytotoxicity at effective therapeutic dosages. Thus, there is a need for a non-toxic non-viral vector with high transgene efficacies. In addition to the hurdles in finding a material for gene delivery, large-scale production of pharmaceutical grade DNA for gene therapy is needed. Current methods can be labor intensive, time consuming, and use toxic chemicals. For this reason, an efficient and safe method to collect DNA is needed. One material that is currently being explored is the hydrogel. Hydrogels are a useful subclass of biomaterials, with a wide variety of applications. This class of biomaterials can carry up to a thousand times their weight in water, and are biocompatible. At smaller dimensions, referred to as micro- and nanogels, they are very useful for many biomedical applications because of their size and ability to swell. Based on a previously synthesized hydrogel, and due to the advantages of smaller dimension in biomedical applications, we have synthesized aminoglycoside antibiotic based nanogels and microgels. Microgels and nanogels were synthesized following a ring opening polymerization of epoxide-containing crosslinkers and polyamine-containing monomers. The nanogels were screened for their cytocompatibilities and transfection efficacies, and were compared to polyethylenimine (PEI), a current standard for polymer-mediated transgene delivery. Nanogels demonstrated minimal to no toxicity to the cell line used in the study even at high concentrations. Due to the emerging need for large-scale production of DNA, microgels were evaluated for their binding capacity to plasmid DNA. Future work with the aminoglycoside antibiotic-based nanogels and microgels developed in this study will involve optimization of nanogels and microgels to facilitate in better transgene delivery and plasmid DNA binding, respectively.
ContributorsMallik, Amrita Amy (Author) / Rege, Kaushal (Thesis advisor) / Dai, Lennore (Committee member) / Nielsen, David (Committee member) / Arizona State University (Publisher)
Created2014
Description
Gold nanoparticles have emerged as promising nanomaterials for biosensing, imaging, photothermal treatment and therapeutic delivery for several diseases, including cancer. We have generated poly(amino ether)-functionalized gold nanorods (PAE-GNRs) using a layer-by-layer deposition approach. Sub-toxic concentrations of PAE-GNRs were employed to deliver plasmid DNA to prostate cancer cells in vitro. PAE-GNRs generated using 1,4C-1,4Bis, a cationic polymer from our laboratory demonstrated significantly higher transgene expression and exhibited lower cytotoxicities when compared to similar assemblies generated using 25 kDa poly(ethylene imine) (PEI25k-GNRs), a current standard for polymer-mediated gene delivery. Additionally, sub-toxic concentrations of 1,4C-1,4Bis-GNR nanoassemblies were employed to deliver expression vectors that express shRNA ('shRNA plasmid') against firefly luciferase gene in order to knock down expression of the protein constitutively expressed in prostate cancer cells. The roles of poly(amino ether) chemistry and zeta-potential in determining transgene expression efficacies of PAE-GNR assemblies were investigated. The theranostic potential of 1,4C-1,4Bis-GNR nanoassemblies was demonstrated using live cell two-photon induced luminescence bioimaging. The PAE class of polymers was also investigated for the one pot synthesis of both gold and silver nanoparticles using a small library poly(amino ethers) derived from linear-like polyamines. Efficient nanoparticle synthesis dependent on concentration of polymers as well as polymer chemical composition is demonstrated. Additionally, the application of poly(amino ether)-gold nanoparticles for transgene delivery is demonstrated in 22Rv1 and MB49 cancer cell lines. Base polymer, 1,4C-1,4Bis and 1,4C-1,4Bis templated and modified gold nanoparticles were compared for transgene delivery efficacies. Differences in morphology and physiochemical properties were investigated as they relate to differences in transgene delivery efficacy. There were found to be minimal differences suggestion that 1,4C-1,4Bis efficacy is not lost following use for nanoparticle modification. These results indicate that poly(amino ether)-gold nanoassemblies are a promising theranostic platform for delivery of therapeutic payloads capable of simultaneous gene silencing and bioimaging.
ContributorsRamos, James (Author) / Rege, Kaushal (Thesis advisor) / Kodibagkar, Vikram (Committee member) / Caplan, Michael (Committee member) / Vernon, Brent (Committee member) / Garcia, Antonio (Committee member) / Arizona State University (Publisher)
Created2014