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Description
Gene manipulation techniques, such as RNA interference (RNAi), offer a powerful method for elucidating gene function and discovery of novel therapeutic targets in a high-throughput fashion. In addition, RNAi is rapidly being adopted for treatment of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease, etc. However, a major challenge in both of the aforementioned applications is the efficient delivery of siRNA molecules, plasmids or transcription factors to primary cells such as neurons. A majority of the current non-viral techniques, including chemical transfection, bulk electroporation and sonoporation fail to deliver with adequate efficiencies and the required spatial and temporal control. In this study, a novel optically transparent biochip is presented that can (a) transfect populations of primary and secondary cells in 2D culture (b) readily scale to realize high-throughput transfections using microscale electroporation and (c) transfect targeted cells in culture with spatial and temporal control. In this study, delivery of genetic payloads of different sizes and molecular characteristics, such as GFP plasmids and siRNA molecules, to precisely targeted locations in primary hippocampal and HeLa cell cultures is demonstrated. In addition to spatio-temporally controlled transfection, the biochip also allowed simultaneous assessment of a) electrical activity of neurons, b) specific proteins using fluorescent immunohistochemistry, and c) sub-cellular structures. Functional silencing of GAPDH in HeLa cells using siRNA demonstrated a 52% reduction in the GAPDH levels. In situ assessment of actin filaments post electroporation indicated a sustained disruption in actin filaments in electroporated cells for up to two hours. Assessment of neural spike activity pre- and post-electroporation indicated a varying response to electroporation. The microarray based nature of the biochip enables multiple independent experiments on the same culture, thereby decreasing culture-to-culture variability, increasing experimental throughput and allowing cell-cell interaction studies. Further development of this technology will provide a cost-effective platform for performing high-throughput genetic screens.
ContributorsPatel, Chetan (Author) / Muthuswamy, Jitendran (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Jain, Tilak (Committee member) / Caplan, Michael (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2012
Description
The use of electromyography (EMG) signals to characterize muscle fatigue has been widely accepted. Initial work on characterizing muscle fatigue during isometric contractions demonstrated that its frequency decreases while its amplitude increases with the onset of fatigue. More recent work concentrated on developing techniques to characterize dynamic contractions for use in clinical and training applications. Studies demonstrated that as fatigue progresses, the EMG signal undergoes a shift in frequency, and different physiological mechanisms on the possible cause of the shift were considered. Time-frequency processing, using the Wigner distribution or spectrogram, is one of the techniques used to estimate the instantaneous mean frequency and instantaneous median frequency of the EMG signal using a variety of techniques. However, these time-frequency methods suffer either from cross-term interference when processing signals with multiple components or time-frequency resolution due to the use of windowing. This study proposes the use of the matching pursuit decomposition (MPD) with a Gaussian dictionary to process EMG signals produced during both isometric and dynamic contractions. In particular, the MPD obtains unique time-frequency features that represent the EMG signal time-frequency dependence without suffering from cross-terms or loss in time-frequency resolution. As the MPD does not depend on an analysis window like the spectrogram, it is more robust in applying the timefrequency features to identify the spectral time-variation of the EGM signal.
ContributorsAustin, Hiroko (Author) / Papandreou-Suppappola, Antonia (Thesis advisor) / Kovvali, Narayan (Committee member) / Muthuswamy, Jitendran (Committee member) / Arizona State University (Publisher)
Created2012
Description
Statistical process control (SPC) and predictive analytics have been used in industrial manufacturing and design, but up until now have not been applied to threshold data of vital sign monitoring in remote care settings. In this study of 20 elders with COPD and/or CHF, extended months of peak flow monitoring (FEV1) using telemedicine are examined to determine when an earlier or later clinical intervention may have been advised. This study demonstrated that SPC may bring less than a 2.0% increase in clinician workload while providing more robust statistically-derived thresholds than clinician-derived thresholds. Using a random K-fold model, FEV1 output was predictably validated to .80 Generalized R-square, demonstrating the adequate learning of a threshold classifier. Disease severity also impacted the model. Forecasting future FEV1 data points is possible with a complex ARIMA (45, 0, 49), but variation and sources of error require tight control. Validation was above average and encouraging for clinician acceptance. These statistical algorithms provide for the patient's own data to drive reduction in variability and, potentially increase clinician efficiency, improve patient outcome, and cost burden to the health care ecosystem.
ContributorsFralick, Celeste (Author) / Muthuswamy, Jitendran (Thesis advisor) / O'Shea, Terrance (Thesis advisor) / LaBelle, Jeffrey (Committee member) / Pizziconi, Vincent (Committee member) / Shea, Kimberly (Committee member) / Arizona State University (Publisher)
Created2013
Description
Image resolution limits the extent to which zooming enhances clarity, restricts the size digital photographs can be printed at, and, in the context of medical images, can prevent a diagnosis. Interpolation is the supplementing of known data with estimated values based on a function or model involving some or all of the known samples. The selection of the contributing data points and the specifics of how they are used to define the interpolated values influences how effectively the interpolation algorithm is able to estimate the underlying, continuous signal. The main contributions of this dissertation are three fold: 1) Reframing edge-directed interpolation of a single image as an intensity-based registration problem. 2) Providing an analytical framework for intensity-based registration using control grid constraints. 3) Quantitative assessment of the new, single-image enlargement algorithm based on analytical intensity-based registration. In addition to single image resizing, the new methods and analytical approaches were extended to address a wide range of applications including volumetric (multi-slice) image interpolation, video deinterlacing, motion detection, and atmospheric distortion correction. Overall, the new approaches generate results that more accurately reflect the underlying signals than less computationally demanding approaches and with lower processing requirements and fewer restrictions than methods with comparable accuracy.
ContributorsZwart, Christine M. (Author) / Frakes, David H (Thesis advisor) / Karam, Lina (Committee member) / Kodibagkar, Vikram (Committee member) / Spanias, Andreas (Committee member) / Towe, Bruce (Committee member) / Arizona State University (Publisher)
Created2013
Description
Alzheimer's disease (AD) is the leading neurodegenerative disease, affecting roughly 8% of people 65 years of age or older. There exists an imperative need to develop a non-invasive test for the earlier detection of AD. The use of biomarkers is a promising option that examines the toxic mechanisms and metabolic pathways that cause Alzheimer's disease, eventually leading to an early diagnostic method. This thesis presents the use of oligomeric beta-amyloid as a biomarker to detect Alzheimer's disease via a specialized enzyme-linked protein assay. Specifically, this paper details the optimization and development of a novel phage capture enzyme-linked immunosorbent assay (ELISA) that can detect the relative quantity of beta-amyloid oligomers in samples from a mouse model of AD. The objective of this thesis was to optimize a phage capture ELISA using the A4 single-chain variable fragment (scFv) to quantify the amount of beta-amyloid oligomers in various mice samples. A4 selectively recognizes a toxic oligomeric form of beta-amyloid. The level of A4-reactive oligomeric beta-amyloid was measured in triplicate in homogenized mouse brain tissue samples from eight transgenic (TG) and eight nontransgenic (NTG) animals aged five, nine, and thirteen months. There was a significant difference (p < 0.0005) between the five month TG and NTG mice. A decrease in beta-amyloid levels with the aging of the TG mice suggested that the beta-amyloid oligomers may be aggregating to form beta-amyloid fibrils. Conversely, the quantity of beta-amyloid increased with the aging of the NTG mice. This indicated that beta-amyloid oligomers may develop with normal aging.
ContributorsBrownlee, Taylor (Author) / Sierks, Michael (Thesis advisor) / Williams, Stephanie (Committee member) / Xin, Wei (Committee member) / Arizona State University (Publisher)
Created2013
Description
In order to successfully implement a neural prosthetic system, it is necessary to understand the control of limb movements and the representation of body position in the nervous system. As this development process continues, it is becoming increasingly important to understand the way multiple sensory modalities are used in limb representation. In a previous study, Shi et al. (2013) examined the multimodal basis of limb position in the superior parietal lobule (SPL) as monkeys reached to and held their arm at various target locations in a frontal plane. Visual feedback was withheld in half the trials, though non-visual (i.e. somatic) feedback was available in all trials. Previous analysis showed that some of the neurons were tuned to limb position and that some neurons had their response modulated by the presence or absence of visual feedback. This modulation manifested in decreases in firing rate variability in the vision condition as compared to nonvision. The decreases in firing rate variability, as shown through decreases in both the Fano factor of spike counts and the coefficient of variation of the inter-spike intervals, suggested that changes were taking place in both trial-by-trial and intra-trial variability. I sought to further probe the source of the change in intra-trial variability through spectral analysis. It was hypothesized that the presence of temporal structure in the vision condition would account for a regularity in firing that would have decreased intra-trial variability. While no peaks were apparent in the spectra, differences in spectral power between visual conditions were found. These differences are suggestive of unique temporal spiking patterns at the individual neuron level that may be influential at the population level.
ContributorsDyson, Keith (Author) / Buneo, Christopher A (Thesis advisor) / Helms-Tillery, Stephen I (Committee member) / Santello, Marco (Committee member) / Arizona State University (Publisher)
Created2013
Description
This research is focused on two separate but related topics. The first uses an electroencephalographic (EEG) brain-computer interface (BCI) to explore the phenomenon of motor learning transfer. The second takes a closer look at the EEG-BCI itself and tests an alternate way of mapping EEG signals into machine commands. We test whether motor learning transfer is more related to use of shared neural structures between imagery and motor execution or to more generalized cognitive factors. Using an EEG-BCI, we train one group of participants to control the movements of a cursor using embodied motor imagery. A second group is trained to control the cursor using abstract motor imagery. A third control group practices moving the cursor using an arm and finger on a touch screen. We hypothesized that if motor learning transfer is related to the use of shared neural structures then the embodied motor imagery group would show more learning transfer than the abstract imaging group. If, on the other hand, motor learning transfer results from more general cognitive processes, then the abstract motor imagery group should also demonstrate motor learning transfer to the manual performance of the same task. Our findings support that motor learning transfer is due to the use of shared neural structures between imaging and motor execution of a task. The abstract group showed no motor learning transfer despite being better at EEG-BCI control than the embodied group. The fact that more participants were able to learn EEG-BCI control using abstract imagery suggests that abstract imagery may be more suitable for EEG-BCIs for some disabilities, while embodied imagery may be more suitable for others. In Part 2, EEG data collected in the above experiment was used to train an artificial neural network (ANN) to map EEG signals to machine commands. We found that our open-source ANN using spectrograms generated from SFFTs is fundamentally different and in some ways superior to Emotiv's proprietary method. Our use of novel combinations of existing technologies along with abstract and embodied imagery facilitates adaptive customization of EEG-BCI control to meet needs of individual users.
Contributorsda Silva, Flavio J. K (Author) / Mcbeath, Michael K (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Presson, Clark (Committee member) / Sugar, Thomas (Committee member) / Arizona State University (Publisher)
Created2013
Description
Coronary heart disease (CHD) is the most prevalent cause of death worldwide. Atherosclerosis which is the condition of plaque buildup on the inside of the coronary artery wall is the main cause of CHD. Rupture of unstable atherosclerotic coronary plaque is known to be the cause of acute coronary syndrome. The composition of plaque is important for detection of plaque vulnerability. Due to prognostic importance of early stage identification, non-invasive assessment of plaque characterization is necessary. Computed tomography (CT) has emerged as a non-invasive alternative to coronary angiography. Recently, dual energy CT (DECT) coronary angiography has been performed clinically. DECT scanners use two different X-ray energies in order to determine the energy dependency of tissue attenuation values for each voxel. They generate virtual monochromatic energy images, as well as material basis pair images. The characterization of plaque components by DECT is still an active research topic since overlap between the CT attenuations measured in plaque components and contrast material shows that the single mean density might not be an appropriate measure for characterization. This dissertation proposes feature extraction, feature selection and learning strategies for supervised characterization of coronary atherosclerotic plaques. In my first study, I proposed an approach for calcium quantification in contrast-enhanced examinations of the coronary arteries, potentially eliminating the need for an extra non-contrast X-ray acquisition. The ambiguity of separation of calcium from contrast material was solved by using virtual non-contrast images. Additional attenuation data provided by DECT provides valuable information for separation of lipid from fibrous plaque since the change of their attenuation as the energy level changes is different. My second study proposed these as the input to supervised learners for a more precise classification of lipid and fibrous plaques. My last study aimed at automatic segmentation of coronary arteries characterizing plaque components and lumen on contrast enhanced monochromatic X-ray images. This required extraction of features from regions of interests. This study proposed feature extraction strategies and selection of important ones. The results show that supervised learning on the proposed features provides promising results for automatic characterization of coronary atherosclerotic plaques by DECT.
ContributorsYamak, Didem (Author) / Akay, Metin (Thesis advisor) / Muthuswamy, Jit (Committee member) / Akay, Yasemin (Committee member) / Pavlicek, William (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2013
Description
Controlled release formulations for local, in vivo drug delivery are of growing interest to device manufacturers, research scientists, and clinicians; however, most research characterizing controlled release formulations occurs in vitro because the spatial and temporal distribution of drug delivery is difficult to measure in vivo. In this work, in vivo magnetic resonance imaging (MRI) of local drug delivery is performed to visualize and quantify the time resolved distribution of MRI contrast agents. I find it is possible to visualize contrast agent distributions in near real time from local delivery vehicles using MRI. Three dimensional T1 maps are processed to produce in vivo concentration maps of contrast agent for individual animal models. The method for obtaining concentration maps is analyzed to estimate errors introduced at various steps in the process. The method is used to evaluate different controlled release vehicles, vehicle placement, and type of surgical wound in rabbits as a model for antimicrobial delivery to orthopaedic infection sites. I are able to see differences between all these factors; however, all images show that contrast agent remains fairly local to the wound site and do not distribute to tissues far from the implant in therapeutic concentrations. I also produce a mathematical model that investigates important mechanisms in the transport of antimicrobials in a wound environment. It is determined from both the images and the mathematical model that antimicrobial distribution in an orthopaedic wounds is dependent on both diffusive and convective mechanisms. Furthermore, I began development of MRI visible therapeutic agents to examine active drug distributions. I hypothesize that this work can be developed into a non-invasive, patient specific, clinical tool to evaluate the success of interventional procedures using local drug delivery vehicles.
ContributorsGiers, Morgan (Author) / Caplan, Michael R (Thesis advisor) / Massia, Stephen P (Committee member) / Frakes, David (Committee member) / McLaren, Alex C. (Committee member) / Vernon, Brent L (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