Barrett's esophagus (BE) is a premalignant disease associated with esophageal adenocarcinoma (EAC). This condition is highly associated with gastroesophageal reflux disease (GERD) which is characterized as chronic exposure of the esophagus to acid and bile acids. An understanding of the cytotoxic and tumorigenic capacity of bile acids and acid during a reflux episode will lead to the identification of markers for therapeutic intervention. The major goal of the following studies was to determine the mechanisms responsible for bile acid-induced alteration in intracellular pH (pHi) the effect on DNA damage, apoptosis and the adaptive resistance to reflux episodes in cells derived from normal esophagus (HET1A) or BE (CP-A) and EAC (JH-EsoAd1). In addition, I explored the therapeutic potential of UDCA oral therapy in BE cells.Here we show a novel mechanism of bile acid-induced, nitric oxide-mediated inhibition of the sodium-hydrogen exchanger (NHE) is a pathway bile acids utilize to induce acid-mediated DNA damage. This same mechanism can elicit apoptosis-resistance which we demonstrate by the complete inhibition of NHE with pharmacological inhibitor of NHE, EIPA. In addition, chronic exposure of bile acids and acid, in-vitro, confers resistance to cytotoxicity and makes cells derived from the squamous epithelium of the esophagus resemble BE and EAC. Finally, modifying the bile acid composition with glycol-Ursodeoxycholic acid (GUDCA) prevents many of the malignant effects of bile acids and acid and suggests a possible therapeutic strategy for those that suffer from GERD. The conclusion from this study suggest that bile acid reflux should be controlled in patients who suffer from GERD

Guanine-rich DNA and RNA sequences can fold, in the presence of alkali metal ions such as Na+ and K+, into G-quadruplex structures. These alkali metal ions are necessary for the stabilization of G-quadruplex structures. However, little is known about the ion dynamics in G-quadruplex structures. In this thesis, we used molecular dynamics (MD) simulations to study the energetics of ion transport in G-quadruplex DNA channels. In particular, we applied, for the first time, adaptive biasing force (ABF) and umbrella sampling (US) methods to obtain potential of mean force (PMF) profiles for Na+, K+, and NH4+ ion movement along [d(TG4T)]4 and [d(G3T4G4)]2 channels. We found that the ABF and US methods produce very similar PMF profiles, in qualitative agreement with the very limited experimental data in the literature. We found that, within a G-quadruplex channel, K+ and NH4+ ions experience significant energy barriers (13-17 kcal/mol) to cross a G-quartet, whereas the Na+ movement encounters minimal resistance (5-7 kcal/mol). All ions are nearly fully dehydrated inside the channel but quickly become hydrated after exiting the channel. Our simulations suggested that the free energy landscapes for ion movement between the channel exit points and bulk solution are quite flat (ca. 2-4 kcal/mol) regardless of the loop topology in the region. We discovered that the directional symmetry of the ion movement within any G-quadruplex channel depends critically on both the DNA sequence and the folding of the G-quadrupelx structure. While the ion movement inside the [d(TG4T)]4 channel shows the same free energy barrier in either direction, the [d(G3T4G4)]2 channel exhibits a free energy difference of 3-4 kcal/mol for NH4+ ions exiting from the two ends. We hypothesized that the mode of base-stacking is the determining factor for the G-quartet stiffness and this stiffness then contributes to the free energy barrier for any ion to across it. This hypothesis appears to be consistent with all currently available experimental observations. When a G-quadruplex channel contains multiple ions, we found that the ion-ion repulsion is an important factor that must be considered in order to have a complete understanding of the ion movement within G-quadruplex DNA channels. / Thesis (Ph.D, Chemistry) -- Queen's University, 2013-01-25 17:38:07.489

An investigation of the sympathetic cooling method for the studies of large ultra-cold molecular ions in a quadrupole ion trap has been conducted.Molecular dynamics simulations are performed to study the rf heating mechanisms in the ion trap. The dependence of rf heating rates on the ion temperature, trapping parameters, and the number of ions is obtained. New rf heating mechanism affecting ultra-cold ion clouds exposed to laser radiation is described.The saturation spectroscopy setup of the hyperfine spectra of the molecular iodine has been built to provide an accurate frequency reference for the laser wavelength. This reference is used to obtain the fluorescence lineshapes of the laser cooled Mg$^+$ ions under different trapping conditions.The ion temperatures are deduced from the measurements, and the influence of the rf heating rates on the fluorescence lineshapes is also discussed. Cooling of the heavy ($m=720$a.u.) fullerene ions to under 10K by the means of the sympathetic cooling by the Mg$^+$ ions($m=24$a.u.) is demonstrated. The single-photon imaging system has been developed and used to obtain the images of the Mg$^+$ ion crystal structures at mK temperatures.

No description available.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第18951号 / 工博第3993号 / 新制||工||1615(附属図書館) / 31902 / 京都大学大学院工学研究科合成・生物化学専攻 / (主査)教授 北川 進, 教授 松田 建児, 教授 安部 武志 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

This thesis presents results of investigations that have been carried out to understand dynamics in nonlinear Paul trap mass spectrometers. Of the three problems that have been taken up for study in this thesis, the first concerns understanding early/delayed ejection of ions in mass selective boundary ejection experiments. The second looks at the differential resolution observed in forward and reverse scan resonance ejection experiments. The third study explores a coupled nonlinear resonance within the nominally stable region of trap operation. The method of multiple scales has been to elucidate dynamics associated with early and delayed ejection of ions in mass selective ejection experiments in Paul traps. We develop a slow flow equation to approximate the solution of a weakly nonlinear Mathieu equation to describe ion dynamics in the neighborhood of the stability boundary of ideal traps (where the Mathieu parameter qz = qz* = 0.908046). For positive even multipoles in the ion trapping field, in the stable region of trap operation, the phase portrait obtained from the slow flow consists of three fixed points, two of which are saddles and the third is a center. As the qz value of an ion approaches qz*, the saddles approach each other, and a point is reached where all nonzero solutions are unbounded, leading to an observation of early ejection. The phase portraits for negative even multipoles and odd multipoles of either sign are qualitatively similar to each other and display bounded solutions even for qz > qz*, resulting in the observation of delayed ejection associated with a more gentle increase in ion motion amplitudes, a mechanism different from the case of the positive even multipoles. The second study investigates constraints on pre-ejection dynamical states which cause differential resolution in resonance ejection experiments using Paul traps with stretched geometry. Both analytical and numerical computations are carried out to elucidate the role of damping and scan rate in influencing coherence in ion motion associated with the forward and reverse scan. It has been shown that in the forward scan experiments, for a given damping, low scan rates result in coherent motion of ions oof a given mass at the jump point. At this point, the amplitude and phase of ions of a given mass, starting at different initial conditions, become effectively identical. As the scan rate is increased, coherence is destroyed. For a given scan rate, increasing damping introduces coherence in ion motion, while decreasing damping destroys this coherence. In reverse scan experiments, for a given damping, very low scan rates will cause coherent ion motion. Increasing the scan rate destroys this coherence. The effect of damping in reverse scan experiments is qualitatively similar to that in the forward scan experiments, but settling times in the forward scan are shorter, leading to improved coherence and resolution. For mass spectrometrically relevant scan rates and damping values, significantly greater coherence is obtained in the forward scan. In the third study we investigate the weakly coupled and nonlinear Mathieu equations governing ion motion in axial and radial directions in a Paul trap in the neighborhood of a nonlinear resonance point at az* = -0.2313850427 and qz* = 0.9193009931$. Using harmonic balance based approximate averaging up to second order; we obtain a slow flow that, we numerically demonstrate, approximates the actual ion dynamics. We find that the slow flow is Hamiltonian. We study the slow flow numerically with the objective of exploring and displaying some of the possible types of interesting ion motions. In particular, we choose specific but arbitrary parameter values; study the stability of the individual radial and axial motion invariant manifolds; examine the rather large times associated with escape of ions; notice regions in the averaged phase space wherein trajectories do not, in fact, escape; observe apparently chaotic dynamics preceding escape for ions that do escape; and note that trajectories that do not escape appear to be confined to 4-tori. We conclude with some comments on the implications for practical operation of the Paul trap near this resonant point.

<p>This thesis evaluates several solid-state NMR spectroscopy approaches to studying lithium ion dynamics in solid-state electrolytes. With the goal of reducing the risks associated with current liquid electrolytes, solid-state electrolytes provide non-flammable materials that are also stable against attack by cathode and anode materials. Solid-state NMR spectroscopy offers a versatile method to determine structural details and can also provide information about ion mobility in solid-state electrolytes. Challenges involved in the study of solid-state electrolytes include the difficulty in distinguishing between ^6,7Li resonances due to the small chemical shift range of diamagnetic lithium species. The NMR methods selected in this thesis aim to circumvent some of these issues in order to determine structural and dynamic properties in solid-state electrolytes. Several different electrolytes have been examined including LaLi_0.5Fe_0.2O_2.09 and related materials, which exhibit intricate structural properties. ¹³⁹La NMR spectroscopy, in combination with ⁷Li MAS NMR spectroscopy, was used to determine the nature of this disorder. In addition, studies of the quadrupolar framework ⁸⁷Rb nucleus, which take advantage of its large electric field gradient, have been used to indirectly probe the activation energy for Ag⁺ ion hopping in the solid-state silver ion electrolyte RbAg₄I₅. Alternatively, dipolar coupling between ⁶Li and ⁷Li has been used to compare lithium ion hopping rates in Li₆BaLa₂M₂O₁₂ (M = Ta, Nb) using ⁶Li{⁷Li}-REDOR NMR studies. Finally, T₂ relaxation studies have been used to probe ion dynamics in Li₃V₂(PO₄)₃ and LiVO₃ in order to determine if this is a viable method to study dynamics in these materials.</p> / Doctor of Philosophy (PhD)

This thesis considers four nonlinear systems with parametric forcing. The first problem involves an inverted pendulum with asymmetric elastic restraints subjected to harmonic vertical base excitation. On linearizing trigonometric terms the pendulum is governed by an asymmetric Mathieu equation. Solutions to this equation are scaleable. The stability regions in the parameter plane are studied numerically. Periodic solutions at the boundaries of stable regions in the parameter plane are found numerically and then their existence is proved theoretically. The second problem involves use of the method of multiple scales to elucidate the dynamics associated with early and delayed ejection of ions from Paul traps. A slow flow equation is developed to approximate the solution of a weakly nonlinear Mathieu equation to describe ion dynamics in the neighborhood of the nominal stability boundary of ideal traps. Since the solution to the unperturbed equation involves linearly growing terms, some care in identification and elimination of secular terms is needed. Due to analytical difficulties, harmonic balance approximations are used within the formal implementation of the method. The third problem involves the attenuation, caused by weak damping, of harmonic waves through a discrete, periodic structure with wave frequency nominally within the Propagation Zone. Adapting the transfer matrix method and using the harmonic balance for nonlinear terms, a four-dimensional map governing the dynamics is obtained. This map is analyzed by applying the method of multiple scales upto first order. The resulting slow evolution equations give the amplitude decay rate in the structure. The fourth problem involves the dynamic response of a strongly nonlinear single-degree-of-freedom oscillator under a constant amplitude, parametric, periodic, impulsive forcing, e.g., a pendulum with strongly nonlinear torsional spring that is periodically struck in the axial direction. Single-term harmonic balance gives an approximate, but explicit, 2-dimensional map governing the dynamics. The map exhibits many fixed points (both stable and unstable), higher period orbits, transverse intersections of stable and unstable manifolds of unstable fixed points, and chaos.

No description available.

Axially symmetric rf ion traps consists of a mass analyser having three electrodes, one of which is a central ring electrode and the other two are endcap electrodes. In the ideal Paul trap mass spectrometer, the electrodes have hyperboloidal shape (March and Hughes, 1989) and in mass analyser with simplified geometry, such as the cylindrical ion trap (Wu et al.,2005) the central electrode is a cylinder and the two endcap electrode and flat plates. rf-only or rf/dc potential is applied across the ring electrode and the grounded endcap electrodes for conducting the basic experiments of the mass spectrometer. In recent times, the miniaturisation of ion trap is one of the research interests in the field of mass spectrometry. The miniaturisation has the advantages of compactness, low power consumption and portability. However, this is achieved at the cost of the overall performance of the mass spectrometer with its deleterious effect on resolution. Research groups study the field distribution in the trap for better understanding of ion dynamics in the direction of achieving improved performance with the miniaturised traps. One aspect which has not received any attention in research associated with quadrupole ion traps is the possible role of the magnetic field in improving performance of these traps. Since in the quadrupole ion trap mass analyser ion is confined by an oscillating (rf) field, magnetic fields have been considered superfluous. The motivation of the thesis is to understand the dynamics of ions in axially symmetric rf ion traps, in the presence of the magnetic field. The axially symmetric rf ion trap geometries considered in this thesis are the Paul trap and the cylindrical ion trap (CIT). The changes incurred to the ion motion and Mathieu stability diagram in the presence of magnetic field is observed in this work. Also, the relation between the magnetic field and the Mathieu parameter is shown. The thesis contains 4 chapters: Chapter 1 provides the basic back ground of mass spectrometry and the operating principles. The equations of ion motion in the Paul trap is derived and also the solution to Mathieu equation is provided. The solution to the Mathieu equation are the Mathieu parameters and , when plotted with on the x-axis and on the y-axis, results in the Mathieu stability plot, the explanation of which is also given in the chapter. A brief description of the secular frequency associated with the ion dynamics is given in this chapter. The popular experiments conducted (i.e. the mass selective boundary ejection and resonance ejection) with a mass spectrometer is described here. Finally at the end of the chapter is the scope of the thesis. Chapter 2 facilitates with the preliminary study required fort he accomplishment of the task. The Paul trap and the CIT are the rf ion traps considered in this work. The geometries of these two traps are described in this chapter. The computational methods used for the analysis of various aspects of mass spectrometer is introduced. The computational methods used involve the methods used for calculating the charge distribution on the electrodes, potentials, multipole co-efficients and trajectory calculations. The boundary element method(BEM), calculation for Potentials and the Runge-Kutta method used for the trajectory calculations are introduced in this chapter. The expressions for calculating the multipole co-efficients are also specified. Chapter 3 presents the results obtained. The equations of ion motion in a quadrupole ion trap in the presence of magnetic field is derived here. Verification of numerical results with and without the magnetic field are presented at the end of this chapter. The chapter also presents various graphs showing the impact of magnetic field on the ion dynamics in the Paul trap and the CIT. The impact of the presence of magnetic field on the micro motion in -, -and -directions of the rf ion traps are shown in this chapter. Also the figures showing the variation in the Mathieu stability plots, with varying magnetic field intensity are presented in the chapter. At the end of this chapter the relation between the magnetic field and the Mathieu parameter is derived and plotted. Chapter 4 explains the various observations made from the results obtained. This chapter also highlights the future scope of the work for making this a more applicable one. References in the text have been given by quoting the author’s name and year of publication. Full references have been provide, in an alphabetic order, at the end of the thesis.