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DNA-mediated Charge Transport in a Biological Context: Cooperation among Metalloproteins to Find Lesions in the Genome
Get PDFDamaged bases in DNA are known to lead to errors in replication and transcription, compromising the integrity of the genome. A molecular wire, DNA conducts charge with shallow distance dependence, yet mismatches and lesions attenuate this process. We have proposed a model where repair proteins, containing redox-active [4Fe4S] clusters, utilize DNA charge transport (CT) to scan the genome for lesions. Based on this model, proteins are predicted to redistribute onto strands where DNA CT is inhibited. Using single-molecule atomic force microscopy (AFM) we have probed the redistribution of EndoIII, a base excision repair protein that contains a [4Fe4S] cluster. Consistent with the model, we find a redistribution of EndoIII onto DNA strands (3.8 kbp) containing C:A mismatch, which is not a specific substrate of EndoIII but inhibits CT. Proteins with mutations making them deficient in DNA-mediated CT do not similarly redistribute onto mismatched strands.
Various DNA-binding proteins, such as those involved in repair and pathways that maintain the integrity of DNA, have been found to contain FeS domains and other redox cofactors. We are discovering proteins from alternate repair pathways that may also utilize DNA CT to find damage. XPD, a 5′-3′ helicase involved in nucleotide excision repair, contains a conserved [4Fe4S] cluster and exhibits a DNA-bound redox potential that indicates it is able to carry out DNA CT. In AFM studies, we observe also the redistribution of XPD onto strands containing a mismatch. We further demonstrate that an XPD mutant, L325V, defective in carrying out DNA CT, does not redistribute onto mismatched strands.
DNA CT between distinct repair proteins bound to DNA was also probed by AFM. When XPD and EndoIII are mixed together, they coordinate in relocalizing onto mismatched strands. However, when a CT-deficient mutant of either repair protein is combined with the CT-proficient repair partner, no relocalization occurs. These data not only indicate a general link between the ability of a repair protein to carry out DNA CT and its ability to redistribute onto DNA strands near lesions but also provide evidence for coordinated DNA CT between repair proteins in their search for damage in the genome.</p
Theory and Experiment of Slow-Light Coupled-Resonator Structures
Get PDFSlow light has been an inter-disciplinary topic and a rapidly growing area, especially over the last decade with the improvement of fabrication technology. The ability to slow down and control the group velocity of light may find applications such as optical buffers, optical delay lines, and enhanced light-matter interaction in optical modulator, amplifier, detectors, lasers, and nonlinear optics. The spirit of slow light is to replace a bulky device with a much shorter, compact structure.
This thesis explores the design and experiment of coupled-resonator optical waveguides (CROWs), which consist of arrays of optical resonators in which light propagates through the coupling between resonators. The group velocity of light is dictated by the inter-resonator coupling strength. Light can be significantly slowed down if the inter-resonator coupling is weak. CROWs can be realized with various types of resonators. This thesis focuses on grating resonators in silicon waveguides, including grating-defect resonators and bandgap-modulated resonators. With the strong gratings, the grating resonators are only a few microns long. We control the inter-resonator coupling via the number of holes between adjacent resonators.
The major limitations in the realization of CROWs have been various kinds of transmission losses, including the resonator losses, the discontinuity between CROWs and the coupling waveguides, and the fabrication disorder. These transmission losses limit the achievable group velocity and the maximum number of resonators. We address these transmission losses throughout this thesis. The resonator losses are overcome with the design and optimized fabrication of tapered grating-defect resonators and bandgap-modulated resonators. The discontinuity between CROWs and waveguides is reduced by tailoring the coupling along the CROW for adiabatic conversion. The optimization of the CROW response leads to the study of filter design based on CROW. Filter design formalism based on coupled-mode theory is presented. The effect of fabrication disorder on CROWs is analyzed, and the Butterworth filters are shown to be more robust against fabrication disorder. The fabrication and measurement of grating CROWs are presented, featuring high-Q (Q=105) grating resonators, coupling of up to 50 resonators, control of group velocity between c/13 and c/49, and Butterworth filters.
Finally, an optical analog of electromagnetically induced transparency is presented. The structure consists of two co-spatial gratings imposed on a three-mode waveguide. One of the supermodes, the Dark mode, possesses a group velocity which depends on the ratio of the grating strengths. The group velocity can be nearly zero if the two grating strengths are nearly identical.</p
Electron Neutrino Appearance in the MINOS Experiment
Get PDFThis thesis describes a search for νe appearance in the two-detector long-baseline MINOS neutrino experiment at Fermilab, based on a data set representing an exposure of 8.2 x 1020 protons on the NuMI target. The analysis detailed herein represents an increase in sensitivity to the θ13 mixing angle of approximately 25% over previous analyses, due to improvements in the event discriminant and fitting technique. Based on our observation, we constrain the value of θ13 further, finding 2sin2θ23 sin22θ13 < 0.12 (0.20) at the 90% confidence level for δCP = 0 and the normal (inverted) neutrino mass hierarchy. The best-fit value is 2sin2θ23 sin22θ13 = 0.041+0.047-0.031(0.079+0.071-0.053) under the same assumptions. We exclude the θ13 = 0 hypothesis at the 89% confidence level
Laser Cooling of an Optomechanical Crystal Resonator to Its Quantum Ground State of Motion
Get PDFQuantum mechanics continues to intrigue us with bizarre predictions that seemingly run counter to our everyday classical intuition. Superposition, zero-point motion, entanglement, and inescapable bounds on measurement precision are just a few purely quantum mechanical effects that come to mind. The promise of observing such effects in mesoscale mechanical resonators some orders of magnitude larger than the systems these effects had once been confined to, has resulted in surging interest in the field of cavity electro- and optomechanics. In these systems, the strong interaction of light and matter allows radiation pressure forces to provide significant damping to the mechanical motion, and serves as a means to mitigate the quantum-destroying, decohering effects of the pervasive thermal bath. However, for this backaction cooling to reduce the phonon occupation of a mechanical mode below unity, the confluence of the device and experimental setup must conform to a very strict set of conditions characterized by high optical and mechanical cavity quality factors, low optical absorption, low drive noise, and sufficiently sensitive detection.
In this work, we describe the first optomechanical device and all-optical experimental setup to simultaneously satisfy these conditions, realizing the quantum ground state cooling of a 3.7 GHz mechanical mode (with a final phonon occupation of 0.85 +/- 0.08) in a picogram and micron-scale patterned nanobeam structure from a bath temperature of approximately 20 K. In context, subunity occupation of a mechanical mode in a similar-sized object had previously only been achieved by electromechanical devices operating in millikelvin dilution refrigerator environments. We also discuss the numerical simulation efforts involved in designing and optimizing these novel, coupled optical and mechanical resonators, and the fabrication procedure to realize them in silicon microchips. We recognize that this cooling result represents only an initial step toward the complete optical control of mesoscale mechanical oscillators in the quantum regime. To this end, we summarize an experiment we performed to detect the quantum zero-point motion of a nanobeam via scattering sideband asymmetry. We further show work in improving the optomechanical coupling and quality factors of these devices, as well as devising more efficient coupling schemes to improve measurement sensitivity.</p
Understanding and Applying Extracellular Recordings in Awake, Behaving Animals
Get PDFSection I of this thesis presents specific projects applying extracellular recordings in macaques. The results demonstrate a novel relative position code employed by individual neurons in the dorsal premotor cortex during reaches and saccades, which may be important for hand-eye coordination. Another project suggests low-frequency coherence between dorsal premotor and posterior parietal cortices participates in making internally guided decisions of where to reach. Section II investigates analysis of data collected with this technique. One project compares methodologies for computing trial-by-trial coherence among neuron ensembles, and another documents how the innate nonstationarity of animal behavior can affect conclusions of certain analyses. Section III investigates the acquisition of extracellular electrophysiological data to understand how these recorded voltages relate to underlying neural activity. One project verifies a physical model of the microelectrode recording circuit using electrodes suspended in saline. Some lower-input impedance head stages used in the field are shown to result in electrode impedance and frequency-dependent amplitude attenuations and phase shifts of recorded signals. Other projects present a theoretical argument that local field potentials (LFPs) recorded from in-depth microelectrodes should be independent of electrode impedance within the range of impedances typically used. A simple physical model shows that if and only if gradients of LFP coherence exist at a scale finer than an electrode's recording site size, lower-impedance electrodes report higher coherence. However this is not expected to occur between different microelectrodes, but could explain differences between microelectrode and EEG recordings. The final project uses simultaneous extracellular and intracellular recordings in corticostriatal rat brain slices to show that frequency-dependent phase shifts and amplitude attenuations occur in neural tissue itself and characterize the transfer function between the intracellular and extracellular voltages. Inhomogenous microscale obstructions inherent in neural tissue are shown to differentially distort current flow depending on the severity of the obstructions. This challenges existing beliefs about the nature of current flow in the brain, and should be considered when interpreting electrophysiological data
I. Quantal Effects in Biochemical Cooperativity and a Proposed Mechanism for the Differentiation of Calcium Signaling in Synaptic Plasticity. II. Evolutionary Algorithms for the Optimization of Methods in Computational Chemistry
Get PDFIn Part 1 of this thesis, we propose that biochemical cooperativity is a fundamentally non-ideal process. We show quantal effects underlying biochemical cooperativity and highlight apparent ergodic breaking at small volumes. The apparent ergodic breaking manifests itself in a divergence of deterministic and stochastic models. We further predict that this divergence of deterministic and stochastic results is a failure of the deterministic methods rather than an issue of stochastic simulations.
Ergodic breaking at small volumes may allow these molecular complexes to function as switches to a greater degree than has previously been shown. We propose that this ergodic breaking is a phenomenon that the synapse might exploit to differentiate Ca2+ signaling that would lead to either the strengthening or weakening of a synapse. Techniques such as lattice-based statistics and rule-based modeling are tools that allow us to directly confront this non-ideality. A natural next step to understanding the chemical physics that underlies these processes is to consider in silico specifically atomistic simulation methods that might augment our modeling efforts.
In the second part of this thesis, we use evolutionary algorithms to optimize in silico methods that might be used to describe biochemical processes at the subcellular and molecular levels. While we have applied evolutionary algorithms to several methods, this thesis will focus on the optimization of charge equilibration methods. Accurate charges are essential to understanding the electrostatic interactions that are involved in ligand binding, as frequently discussed in the first part of this thesis.</p
Nonisochronous Oscillations in Piezoelectric Nanomechanical Resonators
Get PDFNanoelectromechanical systems (NEMS) have proven an excellent test bed for exploring nonlinear dynamics due to short decay times, weak nonlinearities, and large quality factors. In contrast to previous research in nonlinear dynamics involving driven or phase fixed NEMS, where time is referenced by an external source, we describe phenomena classified by phase free phenomena. Here we describe NEMS embedded into feedback oscillators with weak nonlinearities.
We make measurements of this mechanical nonlinearity by developing a transduction scheme, the piezoelectric/piezoresistive (PZE/PZR) transduction, which emphasizes the detector dynamic range over absolute sensitivity. Using these measurements, projections on quantum nondemolition schemes involving the mechanical nonlinearity as a detector are made. These measurements also are important for understanding the detection limits of NEMS sensor technology, which uses a mechanical resonator as a frequency reference in a phase locked loop (PLL).
This work identifies ways to reduce noise within ‘nonlinear’ feedback oscillators, and these results have implications for sensing systems using nonlinear mechanical resonators embedded in PLLs. Since the mechanical nonlinearity of PZE/PZR resonators can be accurately calibrated, we make predictions for the behavior of these dynamical systems based on the given mechanical and electrical parameters. We show, theoretically, that local isochronicity above critical nonlinear amplitudes can create special operating points in feedback oscillators at which parametric fluctuations may cause less phase noise in the oscillator than in feedback oscillators driven below critical amplitudes. For these predictions, we present data that show quantitative agreement for the amplitude and frequency, and qualitative agreement for the phase noise.
Finally, we show synchronization, assisted by nonisochronicity, between two feedback NEMS oscillators. We develop a general theoretical framework for two saturated feedback oscillators which use resonators with nonlinear stiffness. In the limit of small coupling, we show that the system obeys the Adler equation with analytical predictions for the oscillators’ individual amplitudes and net frequency difference. We develop an experiment in which the three important parameters of the system (detuning, nonisochronicity, and coupling) can be tuned, and show data that agrees with the predictions for a large range of coupling. We include data on phase slipping between two oscillators in which the aperiodic frequency difference is clearly observed. Finally, we present data on phase noise in synchronized oscillators.</p
Reshaping Elastomers with Light: First Principles Model of Diffusion-Induced Deformation
Get PDFElastomeric photopolymers are a new class of materials originally developed at Caltech for use as intraocular lenses. These materials consist of a host network swollen with short-chain, photoreactive "macromers." Using a light source for selective photopolymerization, gradients in free macromer molecules are created, driving diffusion-induced shape change. Although models exist for external flow of solvent into a swelling gel or for gel deswelling caused by externally imposed forces, no known model exists to account for reaction-induced diffusion-deformation for a force-free material in which solvent can neither enter nor leave. To predict this unique reaction-diffusion-induced shape change, we propose a simple "two-component" model which treats macromer as converting directly into network strands. This model is first shown to be in good agreement with experimental data on the equilibrium swelling of elastomeric photopolymers. We then use mixture theory to develop constitutive laws for the system stress and the flux of macromer by ensuring that the second law of thermodynamics holds. Finally, we implement the theory to a variety of problems - including a finite-element model of the light-adjustable lens - in each case systematically detailing the relative importance of the material parameters on the magnitude and rate of shape change. We determined that the shape change depends upon the rate of consumption of macromer (specified by the initial extent of reaction profile and the initial volume fraction of macromer) and is independent of the network modulus or the macromer molar mass. In addition, we found that the macromer molar mass serves only to determine the rate at which the deformation proceeds, whereas the network modulus serves to determine the magnitude of the internal forces experienced in the photopolymer
Searching for Primordial Gravitational Waves at Degree Scales from the South Pole
Get PDFWe report on the preliminary performance of the Bicep2 mm-wave polarimeter, deployed in 2009 to the South Pole and will observe through 2012. Bicep2 is currently imaging the polarization of the cosmic microwave background at 150 GHz using an array of 512 antenna-coupled superconducting bolometers. It has been designed for high sensitivity and low systematics in order to pursue the primordial B-mode polarization signal. The instrument and its characterization are presented in this thesis, with particular attention to the detectors and readout system. The instrument sensitivity, mapping speed are discussed along with the expected constraint on the scalar-to-tensor ratio that should be made from one year of data
Synthesis and Functionalization of Second Harmonic Generation Nanocrystals and Their Application in Biological Imaging
Get PDFThe discovery and use of fluorescent proteins has been of extreme importance in biological imaging of cells, tissues, and organs. In order to address some of the limitations of fluorescent tags, second harmonic generation can be used. Second harmonic generating nanoprobes allow nontoxic, long-term imaging that, with proper functionalization, can be utilized for biological imaging applications. As a proof of principle, commercial tetragonal barium titanate nanoparticles were functionalized to expose surface amine groups, which could be further modified for a plethora of biological applications. Barium titanate nanoparticles were functionalized for selective targeting of tissue sections, biorthogonal linkages and for nonspecific long-term imaging using biocompatible polymers enabling the study of cells as they differentiate during zebrafish development. Since the commercial barium titanate nanoparticles do not have a narrow size distribution, which limits the application of such nanoprobes, synthesis of monodisperse nanocrystals was attempted.
Zinc oxide nanocrystals were synthesized by solvothermal methods involving the base hydrolysis of zinc salts in the presence of capping ligands. Different synthesis procedures were investigated based on the properties of the prepared nanoparticles. To prevent nanoparticle aggregation and to achieve good dispersion, a capping agent was chosen that provides a tightly bound shell around the nanoparticles. It was observed that the polymerization of PEG molecules with the organic ligands bound to the surface of zinc oxide provided the most adequate coating for the desired size control and dispersion of the nanocrystals. Exploration of the experimental conditions enabled production of variable size hexagonal zinc oxide nanocrystals, which can be used both as SHG probes and as quantum dots.</p