Matching Items (206)
Description
Cellular redox phenomena are essential for the life of organisms. Described here is a summary of the synthesis of a number of redox-cycling therapeutic agents. The work centers on the synthesis of antitumor antibiotic bleomycin congeners. In addition, the synthesis of pyridinol analogues of alpha-tocopherol is also described. The bleomycins (BLMs) are a group of glycopeptide antibiotics that have been used clinically to treat several types of cancers. The antitumor activity of BLM is thought to be related to its degradation of DNA, and possibly RNA. Previous studies have indicated that the methylvalerate subunit of bleomycin plays an important role in facilitating DNA cleavage by bleomycin and deglycobleomycin. A series of methylvalerate analogues have been synthesized and incorporated into deglycobleomycin congeners by the use of solid-phase synthesis. All of the deglycobleomycin analogues were found to effect the relaxation of plasmid DNA. Those analogues having aromatic C4-substituents exhibited cleavage efficiency comparable to that of deglycoBLM A5. Some, but not all, of the deglycoBLM analogues were also capable of mediating sequence-selective DNA cleavage. The second project focused on the synthesis of bicyclic pyridinol analogues of alpha-tocopherol. Bicyclic pyridinol antioxidants have recently been reported to suppress the autoxidation of methyl linoleate more effectively than alpha-tocopherol. However, the complexity of the synthetic routes has hampered their further development as therapeutic agents. Described herein is a concise synthesis of two bicyclic pridinol antioxidants and a facile approach to their derivatives with simple alkyl chains attached to the antioxidant core. These analogues were shown to retain biological activity and exhibit tocopherol-like behaviour.
ContributorsCai, Xiaoqing (Author) / Hecht, Sidney M. (Thesis advisor) / Gould, Ian R (Committee member) / Hartnett, Hilairy E (Committee member) / Arizona State University (Publisher)
Created2011
Description
In the late 1960s, Granger published a seminal study on causality in time series, using linear interdependencies and information transfer. Recent developments in the field of information theory have introduced new methods to investigate the transfer of information in dynamical systems. Using concepts from Chaos and Markov theory, much of these methods have evolved to capture non-linear relations and information flow between coupled dynamical systems with applications to fields like biomedical signal processing. This thesis deals with the application of information theory to non-linear multivariate time series and develops measures of information flow to identify significant drivers and response (driven) components in networks of coupled sub-systems with variable coupling in strength and direction (uni- or bi-directional) for each connection. Transfer Entropy (TE) is used to quantify pairwise directional information. Four TE-based measures of information flow are proposed, namely TE Outflow (TEO), TE Inflow (TEI), TE Net flow (TEN), and Average TE flow (ATE). First, the reliability of the information flow measures on models, with and without noise, is evaluated. The driver and response sub-systems in these models are identified. Second, these measures are applied to electroencephalographic (EEG) data from two patients with focal epilepsy. The analysis showed dominant directions of information flow between brain sites and identified the epileptogenic focus as the system component typically with the highest value for the proposed measures (for example, ATE). Statistical tests between pre-seizure (preictal) and post-seizure (postictal) information flow also showed a breakage of the driving of the brain by the focus after seizure onset. The above findings shed light on the function of the epileptogenic focus and understanding of ictogenesis. It is expected that they will contribute to the diagnosis of epilepsy, for example by accurate identification of the epileptogenic focus from interictal periods, as well as the development of better seizure detection, prediction and control methods, for example by isolating pathologic areas of excessive information flow through electrical stimulation.
ContributorsPrasanna, Shashank (Author) / Jassemidis, Leonidas (Thesis advisor) / Tsakalis, Konstantinos (Thesis advisor) / Tepedelenlioğlu, Cihan (Committee member) / Arizona State University (Publisher)
Created2011
Description
This study focuses on state estimation of nonlinear discrete time systems with constraints. Physical processes have inherent in them, constraints on inputs, outputs, states and disturbances. These constraints can provide additional information to the estimator in estimating states from the measured output. Recursive filters such as Kalman Filters or Extended Kalman Filters are commonly used in state estimation; however, they do not allow inclusion of constraints in their formulation. On the other hand, computational complexity of full information estimation (using all measurements) grows with iteration and becomes intractable. One way of formulating the recursive state estimation problem with constraints is the Moving Horizon Estimation (MHE) approximation. Estimates of states are calculated from the solution of a constrained optimization problem of fixed size. Detailed formulation of this strategy is studied and properties of this estimation algorithm are discussed in this work. The problem with the MHE formulation is solving an optimization problem in each iteration which is computationally intensive. State estimation with constraints can be formulated as Extended Kalman Filter (EKF) with a projection applied to estimates. The states are estimated from the measurements using standard Extended Kalman Filter (EKF) algorithm and the estimated states are projected on to a constrained set. Detailed formulation of this estimation strategy is studied and the properties associated with this algorithm are discussed. Both these state estimation strategies (MHE and EKF with projection) are tested with examples from the literature. The average estimation time and the sum of square estimation error are used to compare performance of these estimators. Results of the case studies are analyzed and trade-offs are discussed.
ContributorsJoshi, Rakesh (Author) / Tsakalis, Konstantinos (Thesis advisor) / Rodriguez, Armando (Committee member) / Si, Jennie (Committee member) / Arizona State University (Publisher)
Created2013
Description
The bleomycins are a family of glycopeptide-derived antibiotics isolated from various Streptomyces species and have been the subject of much attention from the scientific community as a consequence of their antitumor activity. Bleomycin clinically and is an integral part of a number of combination chemotherapy regimens. It has previously been shown that bleomycin has the ability to selectively target tumor cells over their non-malignant counterparts. Pyrimidoblamic acid, the N-terminal metal ion binding domain of bleomycin is known to be the moiety that is responsible for O2 activation and the subsequent chemistry leading to DNA strand scission and overall antitumor activity. Chapter 1 describes bleomycin and related DNA targeting antitumor agents as well as the specific structural domains of bleomycin. Various structural analogues of pyrimidoblamic acid were synthesized and subsequently incorporated into their corresponding full deglycoBLM A6 derivatives by utilizing a solid support. Their activity was measured using a pSP64 DNA plasmid relaxation assay and is summarized in Chapter 2. The specifics of bleomycin—DNA interaction and kinetics were studied via surface plasmon resonance and are presented in Chapter 3. By utilizing carefully selected 64-nucleotide DNA hairpins with variable 16-mer regions whose sequences showed strong binding in past selection studies, a kinetic profile was obtained for several BLMs for the first time since bleomycin was discovered in 1966. The disaccharide moiety of bleomycin has been previously shown to be a specific tumor cell targeting element comprised of L-gulose-D-mannose, especially between MCF-7 (breast cancer cells) and MCF-10A ("normal" breast cells). This phenomenon was further investigated via fluorescence microscopy using multiple cancerous cell lines with matched "normal" counterparts and is fully described in Chapter 4.
ContributorsBozeman, Trevor C (Author) / Hecht, Sidney M. (Thesis advisor) / Chaput, John (Committee member) / Gould, Ian (Committee member) / Arizona State University (Publisher)
Created2013
Description
This thesis discusses control and obstacle avoidance for non-holonomic differential drive mobile vehicles. The two important behaviors for the vehicle can be defined as go to goal and obstacle avoidance behavior. This thesis discusses both behaviors in detail. Go to goal behavior is the ability of the mobile vehicle to go from one particular co-ordinate to another. Cruise control, cartesian and posture stabilization problems are discussed as the part of this behavior. Control strategies used for the above three problems are explained in the thesis. Matlab simulations are presented to verify these controllers. Obstacle avoidance behavior ensures that the vehicle doesn't hit object in its path while going towards the goal. Three different techniques for obstacle avoidance which are useful for different kind of obstacles are described in the thesis. Matlab simulations are presented to show and discuss the three techniques. The controls discussed for the cartesian and posture stabilization were implemented on a low cost miniature vehicle to verify the results practically. The vehicle is described in the thesis in detail. The practical results are compared with the simulations. Hardware and matlab codes have been provided as a reference for the reader.
ContributorsChopra, Dhruv (Author) / Rodriguez, Armando A (Thesis advisor) / Tsakalis, Konstantinos (Committee member) / Si, Jennie (Committee member) / Arizona State University (Publisher)
Created2013
Description
The F1Fo ATP synthase is required for energy conversion in almost all living organisms. The F1 complex is a molecular motor that uses ATP hydrolysis to drive rotation of the γ–subunit. It has not been previously possible to resolve the speed and position of the γ–subunit of the F1–ATPase as it rotates during a power stroke. The single molecule experiments presented here measured light scattered from 45X91 nm gold nanorods attached to the γ–subunit that provide an unprecedented 5 μs resolution of rotational position as a function of time. The product of velocity and drag, which were both measured directly, resulted in an average torque of 63±8 pN nm for the Escherichia coli F1-ATPase that was determined to be independent of the load. The rotational velocity had an initial (I) acceleration phase 15° from the end of the catalytic dwell, a slow (S) acceleration phase during ATP binding/ADP release (15°–60°), and a fast (F) acceleration phase (60°–90°) containing an interim deceleration (ID) phase (75°–82°). High ADP concentrations decreased the velocity of the S phase proportional to 'ADP-release' dwells, and the F phase proportional to the free energy derived from the [ADP][Pi]/[ATP] chemical equilibrium. The decreased affinity for ITP increased ITP-binding dwells by 10%, but decreased velocity by 40% during the S phase. This is the first direct evidence that nucleotide binding contributes to F1–ATPase torque. Mutations that affect specific phases of rotation were identified, some in regions of F1 previously considered not to contribute to rotation. Mutations βD372V and γK9I increased the F phase velocity, and γK9I increased the depth of the ID phase. The conversion between S and F phases was specifically affected by γQ269L. While βT273D, βD305E, and αR283Q decreased the velocity of all phases, decreases in velocity due to βD302T, γR268L and γT82A were confined to the I and S phases. The correlations between the structural locations of these mutations and the phases of rotation they affect provide new insight into the molecular basis for F1–ATPase γ-subunit rotation.
ContributorsMartin, James (Author) / Frasch, Wayne D (Thesis advisor) / Chandler, Douglas (Committee member) / Gaxiola, Roberto (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2012
Description
The principle of Darwinian evolution has been applied in the laboratory to nucleic acid molecules since 1990, and led to the emergence of in vitro evolution technique. The methodology of in vitro evolution surveys a large number of different molecules simultaneously for a pre-defined chemical property, and enrich for molecules with the particular property. DNA and RNA sequences with versatile functions have been identified by in vitro selection experiments, but many basic questions remain to be answered about how these molecules achieve their functions. This dissertation first focuses on addressing a fundamental question regarding the molecular recognition properties of in vitro selected DNA sequences, namely whether negatively charged DNA sequences can be evolved to bind alkaline proteins with high specificity. We showed that DNA binders could be made, through carefully designed stringent in vitro selection, to discriminate different alkaline proteins. The focus of this dissertation is then shifted to in vitro evolution of an artificial genetic polymer called threose nucleic acid (TNA). TNA has been considered a potential RNA progenitor during early evolution of life on Earth. However, further experimental evidence to support TNA as a primordial genetic material is lacking. In this dissertation we demonstrated the capacity of TNA to form stable tertiary structure with specific ligand binding property, which suggests a possible role of TNA as a pre-RNA genetic polymer. Additionally, we discussed the challenges in in vitro evolution for TNA enzymes and developed the necessary methodology for future TNA enzyme evolution.
ContributorsYu, Hanyang (Author) / Chaput, John C (Thesis advisor) / Chen, Julian (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2013
Description
Solution conformations and dynamics of proteins and protein-DNA complexes are often difficult to predict from their crystal structures. The crystal structure only shows a snapshot of the different conformations these biological molecules can have in solution. Multiple different conformations can exist in solution and potentially have more importance in the biological activity. DNA sliding clamps are a family of proteins with known crystal structures. These clamps encircle the DNA and enable other proteins to interact more efficiently with the DNA. Eukaryotic PCNA and prokaryotic β clamp are two of these clamps, some of the most stable homo-oligomers known. However, their solution stability and conformational equilibrium have not been investigated in depth before. Presented here are the studies involving two sliding clamps: yeast PCNA and bacterial β clamp. These studies show that the β clamp has a very different solution stability than PCNA. These conclusions were reached through various different fluorescence-based experiments, including fluorescence correlation spectroscopy (FCS), Förster resonance energy transfer (FRET), single molecule fluorescence, and various time resolved fluorescence techniques. Interpretations of these, and all other, fluorescence-based experiments are often affected by the properties of the fluorophores employed. Often the fluorescence properties of these fluorophores are influenced by their microenvironments. Fluorophores are known to sometimes interact with biological molecules, and this can have pronounced effects on the rotational mobility and photophysical properties of the dye. Misunderstanding the effect of these photophysical and rotational properties can lead to a misinterpretation of the obtained data. In this thesis, photophysical behaviors of various organic dyes were studied in the presence of deoxymononucleotides to examine more closely how interactions between fluorophores and DNA bases can affect fluorescent properties. Furthermore, the properties of cyanine dyes when bound to DNA and the effect of restricted rotation on FRET are presented in this thesis. This thesis involves studying fluorophore photophysics in various microenvironments and then expanding into the solution stability and dynamics of the DNA sliding clamps.
ContributorsRanjit, Suman (Author) / Levitus, Marcia (Thesis advisor) / Lindsay, Stuart (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2013
Description
The discovery of DNA helical structure opened the door of modern molecular biology. Ned Seeman utilized DNA as building block to construct different nanoscale materials, and introduced a new field, know as DNA nanotechnology. After several decades of development, different DNA structures had been created, with different dimension, different morphology and even with complex curvatures. In addition, after construction of enough amounts DNA structure candidates, DNA structure template, with excellent spatial addressability, had been used to direct the assembly of different nanomaterials, including nanoparticles and proteins, to produce different functional nanomaterials. However there are still many challenges to fabricate functional DNA nanostructures. The first difficulty is that the present finite sized template dimension is still very small, usually smaller than 100nm, which will limit the application for large amount of nanomaterials assembly or large sized nanomaterials assembly. Here we tried to solve this problem through developing a new method, superorigami, to construct finite sized DNA structure with much larger dimension, which can be as large as 500nm. The second problem will be explored the ability of DNA structure to assemble inorganic nanomaterials for novel photonic or electronic properties. Here we tried to utilize DNA Origami method to assemble AuNPs with controlled 3D spacial position for possible chiral photonic complex. We also tried to assemble SWNT with discrete length for possible field effect transistor device. In addition, we tried to mimic in vivo compartment with DNA structure to study internalized enzyme behavior. From our results, constructed DNA cage origami can protect encapsulated enzyme from degradation, and internalized enzyme activity can be boosted for up to 10 folds. In summary, DNA structure can serve as an ideal template for construction of functional nanomaterials with lots of possibilities to be explored.
ContributorsZhao, Zhao (Author) / Yan, Hao (Thesis advisor) / Liu, Yan (Thesis advisor) / Chen, Julian (Committee member) / Seo, Dong-Kyun (Committee member) / Arizona State University (Publisher)
Created2013
Description
Single molecule DNA Sequencing technology has been a hot research topic in the recent decades because it holds the promise to sequence a human genome in a fast and affordable way, which will eventually make personalized medicine possible. Single molecule differentiation and DNA translocation control are the two main challenges in all single molecule DNA sequencing methods. In this thesis, I will first introduce DNA sequencing technology development and its application, and then explain the performance and limitation of prior art in detail. Following that, I will show a single molecule DNA base differentiation result obtained in recognition tunneling experiments. Furthermore, I will explain the assembly of a nanofluidic platform for single strand DNA translocation, which holds the promised to be integrated into a single molecule DNA sequencing instrument for DNA translocation control. Taken together, my dissertation research demonstrated the potential of using recognition tunneling techniques to serve as a general readout system for single molecule DNA sequencing application.
ContributorsLiu, Hao (Author) / Lindsay, Stuart M (Committee member) / Yan, Hao (Committee member) / Levitus, Marcia (Committee member) / Arizona State University (Publisher)
Created2013