Matching Items (979)
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
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
Although high performance, light-weight composites are increasingly being used in applications ranging from aircraft, rotorcraft, weapon systems and ground vehicles, the assurance of structural reliability remains a critical issue. In composites, damage is absorbed through various fracture processes, including fiber failure, matrix cracking and delamination. An important element in achieving reliable composite systems is a strong capability of assessing and inspecting physical damage of critical structural components. Installation of a robust Structural Health Monitoring (SHM) system would be very valuable in detecting the onset of composite failure. A number of major issues still require serious attention in connection with the research and development aspects of sensor-integrated reliable SHM systems for composite structures. In particular, the sensitivity of currently available sensor systems does not allow detection of micro level damage; this limits the capability of data driven SHM systems. As a fundamental layer in SHM, modeling can provide in-depth information on material and structural behavior for sensing and detection, as well as data for learning algorithms. This dissertation focusses on the development of a multiscale analysis framework, which is used to detect various forms of damage in complex composite structures. A generalized method of cells based micromechanics analysis, as implemented in NASA's MAC/GMC code, is used for the micro-level analysis. First, a baseline study of MAC/GMC is performed to determine the governing failure theories that best capture the damage progression. The deficiencies associated with various layups and loading conditions are addressed. In most micromechanics analysis, a representative unit cell (RUC) with a common fiber packing arrangement is used. The effect of variation in this arrangement within the RUC has been studied and results indicate this variation influences the macro-scale effective material properties and failure stresses. The developed model has been used to simulate impact damage in a composite beam and an airfoil structure. The model data was verified through active interrogation using piezoelectric sensors. The multiscale model was further extended to develop a coupled damage and wave attenuation model, which was used to study different damage states such as fiber-matrix debonding in composite structures with surface bonded piezoelectric sensors.
ContributorsMoncada, Albert (Author) / Chattopadhyay, Aditi (Thesis advisor) / Dai, Lenore (Committee member) / Papandreou-Suppappola, Antonia (Committee member) / Rajadas, John (Committee member) / Yekani Fard, Masoud (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
This thesis presents approaches to develop micro seismometers and accelerometers based on molecular electronic transducers (MET) technology using MicroElectroMechanical Systems (MEMS) techniques. MET is a technology applied in seismic instrumentation that proves highly beneficial to planetary seismology. It consists of an electrochemical cell that senses the movement of liquid electrolyte between electrodes by converting it to the output current. MET seismometers have advantages of high sensitivity, low noise floor, small size, absence of fragile mechanical moving parts and independence on the direction of sensitivity axis. By using MEMS techniques, a micro MET seismometer is developed with inter-electrode spacing close to 1μm, which improves the sensitivity of fabricated device to above 3000 V/(m/s^2) under operating bias of 600 mV and input acceleration of 400 μG (G=9.81m/s^2) at 0.32 Hz. The lowered hydrodynamic resistance by increasing the number of channels improves the self-noise to -127 dB equivalent to 44 nG/√Hz at 1 Hz. An alternative approach to build the sensing element of MEMS MET seismometer using SOI process is also presented in this thesis. The significantly increased number of channels is expected to improve the noise performance. Inspired by the advantages of combining MET and MEMS technologies on the development of seismometer, a low frequency accelerometer utilizing MET technology with post-CMOS-compatible fabrication processes is developed. In the fabricated accelerometer, the complicated fabrication of mass-spring system in solid-state MEMS accelerometer is replaced with a much simpler post-CMOS-compatible process containing only deposition of a four-electrode MET structure on a planar substrate, and a liquid inertia mass of an electrolyte droplet encapsulated by oil film. The fabrication process does not involve focused ion beam milling which is used in the micro MET seismometer fabrication, thus the cost is lowered. Furthermore, the planar structure and the novel idea of using an oil film as the sealing diaphragm eliminate the complicated three-dimensional packaging of the seismometer. The fabricated device achieves 10.8 V/G sensitivity at 20 Hz with nearly flat response over the frequency range from 1 Hz to 50 Hz, and a low noise floor of 75 μG/√Hz at 20 Hz.
ContributorsHuang, Hai (Author) / Yu, Hongyu (Thesis advisor) / Jiang, Hanqing (Committee member) / Dai, Lenore (Committee member) / Si, Jennie (Committee member) / Arizona State University (Publisher)
Created2014
Description
Alzheimer's disease (AD) is the most common type of dementia, affecting one in nine people age 65 and older. One of the most important neuropathological characteristics of Alzheimer's disease is the aggregation and deposition of the protein beta-amyloid. Beta-amyloid is produced by proteolytic processing of the Amyloid Precursor Protein (APP). Production of beta-amyloid from APP is increased when cells are subject to stress since both APP and beta-secretase are upregulated by stress. An increased beta-amyloid level promotes aggregation of beta-amyloid into toxic species which cause an increase in reactive oxygen species (ROS) and a decrease in cell viability. Therefore reducing beta-amyloid generation is a promising method to control cell damage following stress. The goal of this thesis was to test the effect of inhibiting beta-amyloid production inside stressed AD cell model. Hydrogen peroxide was used as stressing agent. Two treatments were used to inhibit beta-amyloid production, including iBSec1, an scFv designed to block beta-secretase site of APP, and DIA10D, a bispecific tandem scFv engineered to cleave alpha-secretase site of APP and block beta-secretase site of APP. iBSec1 treatment was added extracellularly while DIA10D was stably expressed inside cell using PSECTAG vector. Increase in reactive oxygen species and decrease in cell viability were observed after addition of hydrogen peroxide to AD cell model. The increase in stress induced toxicity caused by addition of hydrogen peroxide was dramatically decreased by simultaneously treating the cells with iBSec1 or DIA10D to block the increase in beta-amyloid levels resulting from the upregulation of APP and beta-secretase.
ContributorsSuryadi, Vicky (Author) / Sierks, Michael (Thesis advisor) / Nielsen, David (Committee member) / Dai, Lenore (Committee member) / Arizona State University (Publisher)
Created2014
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
This research focuses on the benefits of using nanocomposites in aerospace structural components to prevent or delay the onset of unique composite failure modes, such as delamination. Analytical, numerical, and experimental analyses were conducted to provide a comprehensive understanding of how carbon nanotubes (CNTs) can provide additional structural integrity when they are used in specific hot spots within a structure. A multiscale approach was implemented to determine the mechanical and thermal properties of the nanocomposites, which were used in detailed finite element models (FEMs) to analyze interlaminar failures in T and Hat section stringers. The delamination that first occurs between the tow filler and the bondline between the stringer and skin was of particular interest. Both locations are considered to be hot spots in such structural components, and failures tend to initiate from these areas. In this research, nanocomposite use was investigated as an alternative to traditional methods of suppressing delamination. The stringer was analyzed under different loading conditions and assuming different structural defects. Initial damage, defined as the first drop in the load displacement curve was considered to be a useful variable to compare the different behaviors in this study and was detected via the virtual crack closure technique (VCCT) implemented in the FE analysis.
Experiments were conducted to test T section skin/stringer specimens under pull-off loading, replicating those used in composite panels as stiffeners. Two types of designs were considered: one using pure epoxy to fill the tow region and another that used nanocomposite with 5 wt. % CNTs. The response variable in the tests was the initial damage. Detailed analyses were conducted using FEMs to correlate with the experimental data. The correlation between both the experiment and model was satisfactory. Finally, the effects of thermal cure and temperature variation on nanocomposite structure behavior were studied, and both variables were determined to influence the nanocomposite structure performance.
Experiments were conducted to test T section skin/stringer specimens under pull-off loading, replicating those used in composite panels as stiffeners. Two types of designs were considered: one using pure epoxy to fill the tow region and another that used nanocomposite with 5 wt. % CNTs. The response variable in the tests was the initial damage. Detailed analyses were conducted using FEMs to correlate with the experimental data. The correlation between both the experiment and model was satisfactory. Finally, the effects of thermal cure and temperature variation on nanocomposite structure behavior were studied, and both variables were determined to influence the nanocomposite structure performance.
ContributorsHasan, Zeaid (Author) / Chattopadhyay, Aditi (Thesis advisor) / Dai, Lenore (Committee member) / Jiang, Hanqing (Committee member) / Rajadas, John (Committee member) / Liu, Yongming (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