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- Language: English
- Creators: Ira A. Fulton Schools of Engineering
Description
Fluoroquinolone antibiotics have been known to cause severe, multisystem adverse side effects, termed fluoroquinolone toxicity (FQT). This toxicity syndrome can present with adverse effects that vary from individual to individual, including effects on the musculoskeletal and nervous systems, among others. The mechanism behind FQT in mammals is not known, although various possibilities have been investigated. Among the hypothesized FQT mechanisms, those that could potentially explain multisystem toxicity include off-target mammalian topoisomerase interactions, increased production of reactive oxygen species, oxidative stress, and oxidative damage, as well as metal chelating properties of FQs. This review presents relevant information on fluoroquinolone antibiotics and FQT and explores the mechanisms that have been proposed. A fluoroquinolone-induced increase in reactive oxygen species and subsequent oxidative stress and damage presents the strongest evidence to explain this multisystem toxicity syndrome. Understanding the mechanism of FQT in mammals is important to aid in the prevention and treatment of this condition.
ContributorsHall, Brooke Ashlyn (Author) / Redding, Kevin (Thesis director) / Wideman, Jeremy (Committee member) / Borges, Chad (Committee member) / School of Molecular Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2021-05
Description
Nucleosomes are the basic repetitive unit of eukaryotic chromatin and are responsible for packing DNA inside the nucleus of the cell. They consist of a complex of eight histone proteins (two copies of four proteins H2A, H2B, H3 and H4) around which 147 base pairs of DNA are wrapped in ~1.67 superhelical turns. Although the nucleosomes are stable protein-DNA complexes, they undergo spontaneous conformational changes that occur in an asynchronous fashion. This conformational dynamics, defined by the "site-exposure" model, involves the DNA unwrapping from the protein core and exposing itself transiently before wrapping back. Physiologically, this allows regulatory proteins to bind to their target DNA sites during cellular processes like replication, DNA repair and transcription. Traditional biochemical assays have stablished the equilibrium constants for the accessibility to various sites along the length of the nucleosomal DNA, from its end to the middle of the dyad axis. Using fluorescence correlation spectroscopy (FCS), we have established the position dependent rewrapping rates for nucleosomes. We have also used Monte Carlo simulation methods to analyze the applicability of FRET fluctuation spectroscopy towards conformational dynamics, specifically motivated by nucleosome dynamics. Another important conformational change that is involved in cellular processes is the disassembly of nucleosome into its constituent particles. The exact pathway adopted by nucleosomes is still not clear. We used dual color fluorescence correlation spectroscopy to study the intermediates during nucleosome disassembly induced by changing ionic strength. Studying the nature of nucleosome conformational change and the kinetics is very important in understanding gene expression. The results from this thesis give a quantitative description to the basic unit of the chromatin.
ContributorsGurunathan, Kaushik (Author) / Levitus, Marcia (Thesis advisor) / Lindsay, Stuart (Committee member) / Woodbury, Neal (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2011
Description
As robots are increasingly migrating out of factories and research laboratories and into our everyday lives, they should move and act in environments designed for humans. For this reason, the need of anthropomorphic movements is of utmost importance. The objective of this thesis is to solve the inverse kinematics problem of redundant robot arms that results to anthropomorphic configurations. The swivel angle of the elbow was used as a human arm motion parameter for the robot arm to mimic. The swivel angle is defined as the rotation angle of the plane defined by the upper and lower arm around a virtual axis that connects the shoulder and wrist joints. Using kinematic data recorded from human subjects during every-day life tasks, the linear sensorimotor transformation model was validated and used to estimate the swivel angle, given the desired end-effector position. Defining the desired swivel angle simplifies the kinematic redundancy of the robot arm. The proposed method was tested with an anthropomorphic redundant robot arm and the computed motion profiles were compared to the ones of the human subjects. This thesis shows that the method computes anthropomorphic configurations for the robot arm, even if the robot arm has different link lengths than the human arm and starts its motion at random configurations.
ContributorsWang, Yuting (Author) / Artemiadis, Panagiotis (Thesis advisor) / Mignolet, Marc (Committee member) / Santos, Veronica J (Committee member) / Arizona State University (Publisher)
Created2013
Description
Electromyogram (EMG)-based control interfaces are increasingly used in robot teleoperation, prosthetic devices control and also in controlling robotic exoskeletons. Over the last two decades researchers have come up with a plethora of decoding functions to map myoelectric signals to robot motions. However, this requires a lot of training and validation data sets, while the parameters of the decoding function are specific for each subject. In this thesis we propose a new methodology that doesn't require training and is not user-specific. The main idea is to supplement the decoding functional error with the human ability to learn inverse model of an arbitrary mapping function. We have shown that the subjects gradually learned the control strategy and their learning rates improved. We also worked on identifying an optimized control scheme that would be even more effective and easy to learn for the subjects. Optimization was done by taking into account that muscles act in synergies while performing a motion task. The low-dimensional representation of the neural activity was used to control a two-dimensional task. Results showed that in the case of reduced dimensionality mapping, the subjects were able to learn to control the device in a slower pace, however they were able to reach and retain the same level of controllability. To summarize, we were able to build an EMG-based controller for robot devices that would work for any subject, without any training or decoding function, suggesting human-embedded controllers for robotic devices.
ContributorsAntuvan, Chris Wilson (Author) / Artemiadis, Panagiotis (Thesis advisor) / Muthuswamy, Jitendran (Committee member) / Santos, Veronica J (Committee member) / Arizona State University (Publisher)
Created2013
Description
Humans have an inherent capability of performing highly dexterous and skillful tasks with their arms, involving maintaining posture, movement and interacting with the environment. The latter requires for them to control the dynamic characteristics of the upper limb musculoskeletal system. Inertia, damping and stiffness, a measure of mechanical impedance, gives a strong representation of these characteristics. Many previous studies have shown that the arm posture is a dominant factor for determining the end point impedance in a horizontal plane (transverse plane). The objective of this thesis is to characterize end point impedance of the human arm in the three dimensional (3D) space. Moreover, it investigates and models the control of the arm impedance due to increasing levels of muscle co-contraction. The characterization is done through experimental trials where human subjects maintained arm posture, while perturbed by a robot arm. Moreover, the subjects were asked to control the level of their arm muscles' co-contraction, using visual feedback of their muscles' activation, in order to investigate the effect of the muscle co-contraction on the arm impedance. The results of this study showed a very interesting, anisotropic increase of the arm stiffness due to muscle co-contraction. This can lead to very useful conclusions about the arm biomechanics as well as many implications for human motor control and more specifically the control of arm impedance through muscle co-contraction. The study finds implications for the EMG-based control of robots that physically interact with humans.
ContributorsPatel, Harshil Naresh (Author) / Artemiadis, Panagiotis (Thesis advisor) / Berman, Spring (Committee member) / Helms Tillery, Stephen (Committee member) / Arizona State University (Publisher)
Created2013
Description
Humans' ability to perform fine object and tool manipulation is a defining feature of their sensorimotor repertoire. How the central nervous system builds and maintains internal representations of such skilled hand-object interactions has attracted significant attention over the past three decades. Nevertheless, two major gaps exist: a) how digit positions and forces are coordinated during natural manipulation tasks, and b) what mechanisms underlie the formation and retention of internal representations of dexterous manipulation. This dissertation addresses these two questions through five experiments that are based on novel grip devices and experimental protocols. It was found that high-level representation of manipulation tasks can be learned in an effector-independent fashion. Specifically, when challenged by trial-to-trial variability in finger positions or using digits that were not previously engaged in learning the task, subjects could adjust finger forces to compensate for this variability, thus leading to consistent task performance. The results from a follow-up experiment conducted in a virtual reality environment indicate that haptic feedback is sufficient to implement the above coordination between digit position and forces. However, it was also found that the generalizability of a learned manipulation is limited across tasks. Specifically, when subjects learned to manipulate the same object across different contexts that require different motor output, interference was found at the time of switching contexts. Data from additional studies provide evidence for parallel learning processes, which are characterized by different rates of decay and learning. These experiments have provided important insight into the neural mechanisms underlying learning and control of object manipulation. The present findings have potential biomedical applications including brain-machine interfaces, rehabilitation of hand function, and prosthetics.
ContributorsFu, Qiushi (Author) / Santello, Marco (Thesis advisor) / Helms Tillery, Stephen (Committee member) / Buneo, Christopher (Committee member) / Santos, Veronica (Committee member) / Artemiadis, Panagiotis (Committee member) / Arizona State University (Publisher)
Created2013
Description
Healthy mitochondria are essential for cell survival. Described herein is the synthesis of a family of novel aminoquinone antioxidants designed to alleviate oxidative stress and prevent the impairment of cellular function. In addition, a library of bleomycin disaccharide analogues has also been synthesized to better probe the tumor targeting properties of bleomycin. The first study involves the synthesis of a benzoquinone natural product and analogues that closely resemble the redox core of the natural product geldanamycin. The synthesized 5-amino-3-tridecyl-1,4-benzoquinone antioxidants were tested for their ability to protect Friedreich's ataxia (FRDA) lymphocytes from induced oxidative stress. Some of the analogues synthesized conferred cytoprotection in a dose-dependent manner in FRDA lymphocytes at micromolar concentrations. The biological assays suggest that the modification of the 2-hydroxyl and N-(3-carboxypropyl) groups in the natural product can improve its antioxidant activity and significantly enhance its ability to protect mitochondrial function under conditions of oxidative stress. The second project focused on the synthesis of a library of bleomycin disaccharide-dye conjugates and monitored their cellular uptake by fluorescence microscopy. The studies reveal that the position of the carbamoyl group plays an important role in modulating the cellular uptake of the disaccharide. It also led to the discovery of novel disaccharides with improved tumor selectivity.
ContributorsMathilakathu Madathil, Manikandadas (Author) / Hecht, Sidney M. (Thesis advisor) / Rose, Seth (Committee member) / Woodbury, Neal (Committee member) / Arizona State University (Publisher)
Created2013
Description
Energy efficient design and management of data centers has seen considerable interest in the recent years owing to its potential to reduce the overall energy consumption and thereby the costs associated with it. Therefore, it is of utmost importance that new methods for improved physical design of data centers, resource management schemes for efficient workload distribution and sustainable operation for improving the energy efficiency, be developed and tested before implementation on an actual data center. The BlueTool project, provides such a state-of-the-art platform, both software and hardware, to design and analyze energy efficiency of data centers. The software platform, namely GDCSim uses cyber-physical approach to study the physical behavior of the data center in response to the management decisions by taking into account the heat recirculation patterns in the data center room. Such an approach yields best possible energy savings owing to the characterization of cyber-physical interactions and the ability of the resource management to take decisions based on physical behavior of data centers. The GDCSim mainly uses two Computational Fluid Dynamics (CFD) based cyber-physical models namely, Heat Recirculation Matrix (HRM) and Transient Heat Distribution Model (THDM) for thermal predictions based on different management schemes. They are generated using a model generator namely BlueSim. To ensure the accuracy of the thermal predictions using the GDCSim, the models, HRM and THDM and the model generator, BlueSim need to be validated experimentally. For this purpose, the hardware platform of the BlueTool project, namely the BlueCenter, a mini data center, can be used. As a part of this thesis, the HRM and THDM were generated using the BlueSim and experimentally validated using the BlueCenter. An average error of 4.08% was observed for BlueSim, 5.84% for HRM and 4.24% for THDM. Further, a high initial error was observed for transient thermal prediction, which is due to the inability of BlueSim to account for the heat retained by server components.
ContributorsGilbert, Rose Robin (Author) / Gupta, Sandeep K.S (Thesis advisor) / Artemiadis, Panagiotis (Committee member) / Phelan, Patrick (Committee member) / Arizona State University (Publisher)
Created2012
Description
Cancer claims hundreds of thousands of lives every year in US alone. Finding ways for early detection of cancer onset is crucial for better management and treatment of cancer. Thus, biomarkers especially protein biomarkers, being the functional units which reflect dynamic physiological changes, need to be discovered. Though important, there are only a few approved protein cancer biomarkers till date. To accelerate this process, fast, comprehensive and affordable assays are required which can be applied to large population studies. For this, these assays should be able to comprehensively characterize and explore the molecular diversity of nominally "single" proteins across populations. This information is usually unavailable with commonly used immunoassays such as ELISA (enzyme linked immunosorbent assay) which either ignore protein microheterogeneity, or are confounded by it. To this end, mass spectrometric immuno assays (MSIA) for three different human plasma proteins have been developed. These proteins viz. IGF-1, hemopexin and tetranectin have been found in reported literature to show correlations with many diseases along with several carcinomas. Developed assays were used to extract entire proteins from plasma samples and subsequently analyzed on mass spectrometric platforms. Matrix assisted laser desorption ionization (MALDI) and electrospray ionization (ESI) mass spectrometric techniques where used due to their availability and suitability for the analysis. This resulted in visibility of different structural forms of these proteins showing their structural micro-heterogeneity which is invisible to commonly used immunoassays. These assays are fast, comprehensive and can be applied in large sample studies to analyze proteins for biomarker discovery.
ContributorsRai, Samita (Author) / Nelson, Randall (Thesis advisor) / Hayes, Mark (Thesis advisor) / Borges, Chad (Committee member) / Ros, Alexandra (Committee member) / Arizona State University (Publisher)
Created2012
Description
It has been well established that mitochondria play a critical role in the pathology of Friedreich's Ataxia. This disease is believed to be caused by a deficiency of frataxin, which research suggests is responsible for iron sulfur cluster assembly. This incomplete assembly of iron sulfur clusters is believed to be linked with dysfunctional complexes in the mitochondrial respiratory chain, increased oxidative stress, and potential cell death. Increased understanding of the pathophysiology of this disease has enabled the development of various therapeutic strategies aimed at restoring mitochondrial respiration. This thesis contains an analysis of the biological activity of several classes of antioxidants against oxidative stress induced by diethyl maleate in Friedreich's Ataxia lymphocytes and CEM leukemia cells. Analogues of vitamin E α-tocopherol have been shown to protect cells under oxidative stress. However, these same analogues show various levels of inhibition towards the electron transport chain complex I. Bicyclic pyridinols containing a ten carbon substituent provided favorable cytoprotection. N-hydroxy-4-pyridone compounds were observed to provide little protection. Similarly, analogues of CoQ10 in the form of pyridinol and pyrimidinol compounds also preserved cell viability at low concentrations.
ContributorsJaruvangsanti, Jennifer (Author) / Hecht, Sidney (Thesis advisor) / Woodbury, Neal (Committee member) / Skibo, Edward (Committee member) / Arizona State University (Publisher)
Created2012