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Directing Cellular Traffic Using Geometric and Biomolecular Signal Alterations
Get PDFDirected cell migration plays a principal role in various aspects of important cellular phenomena such as wound healing, development and cancer metastasis. Although the mechanism of gradient stimulus leading to directed cell migration is well understood and exploited, the geometrical and topographical cues that cause directed migration has been largely unexplored. With the advent of accessible microfabrication techniques to precisely control the topography of the extracellular matrix (ECM) on substrates, researchers are just starting to study the complex mechanical signals that can alter directed cell motility. A key challenge now is to parse out the precise factors that affect directional movement of cells on certain micropatterns, use that understanding to design strategies to enhance the motility and bias of directed cell migration, and further apply these concepts to multiple cell types and higher-order cell systems.
Here, we investigate the tunability of directional bias through various geometrical manipulations using quantitative analysis of cell movement on micropatterns. We observe that MCF-10A epithelial cells in general jump with an unnaturally high bias between teardrop-based islands with specific gap distance, asymmetry and positional placement. Throughout the studies, we observe that lamellipodial protrusions and unilamellar morphology play a crucial role in dictating not only the directional bias of epithelial cells, but also their speed and persistence, and find that moderate alteration of Rac1 signal leads to an unexpected flip of bias. We further extend the concept of directional bias to design patterns to successfully control cell flux and effectively partition cell population, as well as induce unilamellar morphology in different cell types to promote directed cell motility. We also investigate the combinatorial effect of hybrid micropatterns in enhancing motility and unravel the unique properties and possible mechanisms behind directed cell motility on teardrop-based micropatterns.
Our results demonstrate a new type of directed cell motility using a micropattern that involves the use of physical constraints to stabilize the unilamellar morphology and guidance of the unilamella in the correct direction through purely geometrical cues. These studies offer multiple design strategies to modulate the cell motility and directional bias on micropatterns for various applications, such as tissue engineering.</p
A Ku-Band Polarimeter for the Owens Valley Radio Observatory 40-Meter Telescope
No full textBlazars are active galactic nuclei - small, extremely luminous objects at the center of galaxies powered by material accreting around a supermassive black hole - which emit relativistic jets of
highly energetic plasma along our line of sight. There is no accepted model for jet composition, acceleration, and confinement; observations at different wavelengths will help us understand these
emission mechanisms. Since 2007, the 40-Meter Telescope at the Owens Valley Radio Observatory has been monitoring over 1100 blazars every two days. The variability in radio light curves is
likely to be correlated with gamma-rays, which we are observing with the Fermi Gamma-Ray Space Telescope.
A new Ku-band receiver for the 40-Meter Telescope is in development. It will offer increased sensitivity, MHz spectral resolution from 12-18 GHz, and calculation of Stokes I, Q, and U parameters.
In this thesis, I present the design, assembly, and testing of various components in the receiver chain. I evaluate the suitability of a commercial radio frequency over optical link for use in the receiver,
describe the fabrication and verification of bandpass filters and sideband separating modules, and present the design and testing of a digital back end spectrometer which uses field-programmable
gate array devices.
When complete in late 2011 , the new receiver will allow the continuation of the blazar monitoring program with the addition of spectral and polarization information, which will be invaluable in
understanding blazar jet emission.</p
Topics in Gravitation – Numerical Simulations of Event Horizons and Parameter Estimation for LISA
Get PDFIn Part I, we consider numerical simulations of event horizons. Event horizons are the defining physical features of black hole spacetimes, and are of considerable interest in studying black hole dynamics. Here, we reconsider three techniques to find event horizons in numerical spacetimes, and find that straightforward integration of geodesics backward in time is most robust. We apply this method to various systems, from a highly spinning Kerr hole through to an asymmetric binary black hole inspiral. We find that the exponential rate at which outgoing null geodesics diverge from the event horizon of a Kerr black hole is the surface gravity of the hole. In head-on mergers we are able to track quasi-normal ringing of the merged black hole through seven oscillations, covering a dynamic range of about 105. In the head-on "kick" merger, we find that computing the Landau-Lifshitz velocity of the event horizon is very useful for an improved understanding of the kick behaviour. Finally, in the inspiral simulations, we find that the topological structure of the black holes does not produce an intermediate toroidal phase, though the structure is consistent with a potential re-slicing of the spacetime in order to introduce such a phase. We further discuss the topological structure of non-axisymmetric collisions.
In Part II, we consider parameter estimation of cosmic string burst gravitational waves in Mock LISA data. A network of observable, macroscopic cosmic (super-)strings may well have formed in the early Universe. If so, the cusps that generically develop on cosmic-string loops emit bursts of gravitational radiation that could be detectable by gravitational-wave interferometers, such as the ground-based LIGO/Virgo detectors and the planned, space-based LISA detector. We develop two versions of a LISA-oriented string-burst search pipeline within the context of the Mock LISA Data Challenges, which rely on the publicly available MultiNest and PyMC software packages, respectively. We use the F-statistic to analytically maximize over the signal’s amplitude and polarization, A and ψ, and use the FFT to search quickly over burst arrival times tC. We also demonstrate an approximate, Bayesian version of the F-statistic that incorporates realistic priors on A and ψ. We calculate how accurately LISA can expect to measure the physical parameters of string-burst sources, and compare to results based on the Fisher-matrix approximation. To understand LISA’s angular resolution for string-burst sources, we draw maps of the waveform fitting factor [maximized over (A, ψ, tC)] as a function of sky position; these maps dramatically illustrate why (for LISA) inferring
the correct sky location of the emitting string loop will often be practically impossible. In addition, we identify and elucidate several symmetries that are embedded in this search problem, and we derive the distribution of cut-off frequencies fmax for observable bursts.</p
Energy and Force Stepping Integrators in Lagrangian Mechanics
Get PDFThe overarching goal of this thesis is to develop new numerical time integration schemes for Lagrangian mechanics that better cope with the challenges of understanding the dynamic behavior of materials. We specifically address the formulation of convergent time integration schemes that exhibit good long-term behavior---such as conferred by symplecticity and exact conservation properties---and that have the ability to automatically and asynchronously modulate the time step in different regions of the domain. We achieve these properties in a progression of three developments: (i) energy-stepping, (ii) force-stepping, and (iii) asynchronous energy-stepping integrators. These developments are based on a new method of approximation for Lagrangian mechanics, proposed in this thesis, that consists of replacing the Lagrangian of the system by a sequence of approximate Lagrangians that can be solved exactly. Then, energy-stepping integrators result from replacing the potential energy by a piecewise constant approximation, force-stepping integrators result from replacing the potential energy by a piecewise affine approximation, and asynchronous energy-stepping integrators result from replacing localized potential energies by piecewise constant approximations. Throughout the dissertation, the properties of these time integrators are theoretically predicted and born out by a number of selected examples of application. Furthermore, we address the challenges of understanding the propagation of solitary waves in granular crystals at low impact velocity conditions by investigating the role of energy-trapping effects with the numerical time integration schemes developed in this work
Analysis of Drosophila Fibroblast Growth Factor Functional Domains
Get PDFThe exciting Fibroblast Growth Factor (FGF) field lies at the crossroads of cell signaling, development, evolution, trafficking, physiology and human disease. A current challenge is to understand the mechanisms used by this signaling pathway to accomplish its myriad tasks in patterning the embryo, forming organs, and maintaining systems in the adult animal. My thesis work has focused on tackling this challenge in the model system of Drosophila melanogastor, the vinegar fly. By examining functional domains of Thisbe and Pyramus, FGF ligands in the fly, we have begun to understand the properties of Drosophila FGFs and the way in which they may contribute to regulation of FGF signaling.
FGF ligands in vertebrates are small molecules that bind to a corresponding receptor through two immunoglobulin domains. The FGF ligands in Drosophila are predicted to be much larger molecules than their vertebrate homologs. Whether Drosophila FGFs bind to the receptor as full-length proteins or are first cleaved to smaller molecules was previously unknown. My thesis work addressed this question through experiments in Drosophila embryos and Drosophila cell culture. I found evidence that the N-terminal FGF-domain alone is capable of signaling by itself in the embryo. In addition, experiments in cell culture showed that Thisbe and Pyramus are secreted as small forms, presumably as a result of intracellular proteolytic cleavage. Cleaved forms for Thisbe and Pyramus were detected in embryonic extracts as well. The Ths ligand is also present outside the cell as a full-length form and this form may act to regulate the diffusion or activity of the ligand. Addition of the Thisbe C-terminus to the Pyramus N-terminus to make a Pyramus-Thisbe chimeric protein creates a protein that has reduced activity compared to Thisbe alone. The opposite Thisbe-Pyramus chimera creates a protein that has increased activity compared to Ths alone.
Over the course of animal evolution the FGF superfamily has diversified in many ways. Understanding the mechanism of FGF signaling in Drosophila and comparing this to other Drosophilids, insects, and more distantly related animals will reveal the likely makeup of the ancestral FGF signaling system.</p
Investigation of the Role of Hydrides in Zirconocene Catalyzed Olefin Polymerization
Get PDFThe structure and reactivity of zirconocene hydrides in the presence of aluminum alkyls is investigated for both neutral species and cationic species. Unbridged zirconocene dichlorides react with HAliBu2 to yield trihydride dialuminum clusters of the general formula (RnC5H5-n)2Zr(μ-H)3(AliBu2)3(μ-Cl)2. Bridged zirconocenes instead predominantly yield a dihydride monoaluminum cluster of the general form Me2E(RnC5H4-n)2Zr(Cl)(μ-H)2AliBu2 where E = Si or C. For tert-butyl substituted zirconocenes the terminal Cl is replaced by a H. It is shown that steric factors dictate which hydride is formed.
A single type of cationic trihydride dialuminum cluster of general formula [(RnC5H4-n)2Zr(μ-H)3(AliBu2)+] is formed for all zirconocene hydrides upon addition of [Ph3C][B(C6F5)4] regardless of which class of neutral hydride was formed. For {(SBI)Zr} and {(Me2Si)2(C5H3)2Zr} the resulting cations were crystallographically characterized where SBI stands for Me2Si(indenyl)2. [(SBI)Zr(μ-H)3(AliBu2)]+ reacts with propene to make isotactic polypropene while the Me-substituted analogue [(SBI)Zr(μ-H)3(AliMe2)]+ is a catalyst for hydroalumination. These trihydride cations are shown to be dormant species in polymerization reactions. [(SBI)Zr(μ-H)3(AliBu2)]+ is identified as the hydride observed by Babushkin and Brintzinger (Babushkin, D. E.; Brintzinger, H. H. Chem. Eur. J. 2007, 13, 5294) upon addition of AliBu3 or HAliBu2 to a mixture of (SBI)ZrCl2 and methylaluminoxane.</p
Repression of DNA-Binding-Dependent Glucocorticoid Receptor-Mediated Gene Expression
Get PDFGene expression is controlled by transcription factors that regulate the rates at which genes are expressed either by recruiting or inhibiting protein complexes that bind to the promoters or enhancers of target genes. Molecules that can specifically modulate these protein-DNA interfaces show promise as tools for understanding gene regulation pathways and may have application in human medicine. Hairpin pyrrole-imidazole polyamides are programmable oligomers that bind the DNA minor groove in a sequence-specific manner with affinities comparable to those of natural DNA-binding proteins. These cell-permeable small molecules have been shown to enter the nuclei of live cells, disrupt protein-DNA interactions, and downregulate endogenous gene expression. This thesis describes the use of polyamides to modulate gene expression in order to probe gene regulation mechanisms of several different biologically relevant systems. A polyamide is designed to target the glucocorticoid receptor transcription factor DNA binding site located in the promoter of the glucocorticoid-induced leucine zipper gene. This polyamide is shown to bind with high affinity to the promoter sequence, modulate the expression of this gene, and disrupt the binding of the protein to the gene’s promoter. Examination of the global effects of this polyamide on mRNA transcription is used to elucidate a list of genes that are regulated by a glucocorticoid receptor protein-DNA dependent mechanism. Also in this thesis, the specificities of a Cy3-labeled polyamide known to downregulate expression of the Vascular Endothelial Growth Factor is examined using DNA microarrays composed of hairpins harboring all 524,800 unique 10 base pair DNA sequences. We experimentally verify the correlation of Cy3 fluorescence intensity with quantitative DNase I footprint-derived binding affinities. Additionally, progress is made towards the polyamide-mediated inhibition of Myc/Max transcription factor gene regulation
Hydrogen Evolution Catalyzed by Cobaloximes
Get PDFCobaloximes are among a promising class of small molecules which catalytically evolve hydrogen at modest overpotentials. Motivated by the imminent need to develop efficient solar energy conversion processes, a number of research groups have recently revisited the catalytic activity of cobaloximes, which was initially reported by Espenson almost three decades ago. Both Espenson’s seminal work and the studies reported during this recent resurgence are chronicled in the introductory Chapter 1. The next three chapters introduce photochemical methods for detecting catalytic intermediates and determining kinetics associated with the elementary steps of hydrogen evolution. Four catalytic pathways are considered; each beginning with the reduction of a CoII-diglyoxime to generate CoI, which reacts with a proton donor to produce a CoIII-hydride. In a homolytic pathway, two CoIII-hydrides react in a bimolecular step to eliminate H₂. Alternatively, in a heterolytic pathway, protonation of CoIII-hydride produces H₂ and CoIII. The CoIII-hydride may also be reduced further to a CoII-hydride, which can react via analogous heterolytic or homolytic pathways. In Chapter 2, kinetics of electron transfer reactions of a Co-diglyoxime complex are presented. These experimental results, along with a detailed thermodynamic analysis of proposed hydrogen evolution pathways, shed new light on the barriers and driving forces of the elementary reaction steps involved in proton reduction. A strong thermodynamic preference for a CoIII-hydride homolytic pathway over a CoIII-hydride heterolytic route is identified as the key finding from this work. In Chapter 3, phototriggered hydride generation utilized in conjunction with time-resolved spectroscopy is introduced as a novel method for mechanistic investigations. Here, excited-state proton transfer from an organic photoacid to a CoI-diglyoxime triggers the formation of the reactive CoIII-hydride. This and the subsequent reactivity of CoIII-hydride are monitored spectroscopically. The reaction kinetics are consistent with a heterolytic route for hydrogen evolution that proceeds via a CoII-hydride intermediate. Chapter 4 extends these mechanistic investigations to aqueous media by employing photoionization and pulse radiolysis methods to trigger CoII-diglyoxime reduction. Chapters 5 and 6 focus on the design and construction of second generation cobaloximes. In Chapter 5, the thermodynamic preference for bimolecular reactivity of two CoIII-hydrides is probed with a binuclear cobaloxime. A covalent alkyl tether is used to decrease the volume required for diffusional collisions. Electrocatalytic activity is consistent with a rate-limiting step associated with the formation of the hydride, as seen in mononuclear catalysts, and thus no enhancement of catalytic activity is observed. However, as an efficient water splitting device may require the tethering of catalysts to an electrode surface, this ligand should allow binuclear association of immobilized catalysts. A strategy for covalently grafting cobaloxime derivatives to silicon electrodes is introduced in Chapter 6. A terminal olefin is incorporated into a glyoxime backbone, a functionality amenable to surface-based coupling reactions. The bifunctional cobaloxime is an active catalyst, and initial efforts to prepare the chemically modified electrode are discussed. Three appendices are provided, including work on the photochemical generation of powerful OsII reductant, electron transfer reactions of N,N’,3,3’-tetramethyl-4,4’-bipyridinium, and annotated MATLAB scripts utilized for kinetics analysis.</p
Supersingular Distribution, Congruence Class Bias, and A Refinement of Strong Multiplicity One
Get PDFThis thesis consists of four chapters, including an introduction.
In Chapter 2, we take an averaging approach to the question of the distribution of supersingular primes of degree one, for elliptic curves over a number field. We begin by modifying the Lang-Trotter heuristic to address the case of an abelian extension, then we show that it holds on average (up to a constant) for a family of elliptic curves by using ideas of David-Pappalardi.
In Chapter 3, we prove constructively that there exists an infinite number of (arbitrarily) thin families of rational elliptic curves for which the Lang-Trotter conjecture holds on average, in part by using techniques of Fouvry-Murty.
In Chapter 4, we obtain a result related to the strong multiplicity one theorem for non-dihedral cuspidal automorphic representations for GL(2), with trivial central character and non-twist-equivalent symmetric squares. Given a real algebraic number, we also find a lower bound for the lower density of the set of finite places for which the associated Hecke eigenvalue is not equal to that algebraic number.</p
Iridium Corroles: Synthesis, Properties, and Electronic Structure
Get PDFThe synthesis, properties, and electronic structures of a family of iridium corrole complexes are discussed in detail. These compounds represent the first well-characterized examples of third-row metals being inserted successfully into the small corrole binding pocket; they possess a planar macrocycle, which neither saddles nor ruffles upon bromination, and are bound at the axial positions by either two amine ligands or one phosphine. Unlike their well-studied cobalt and rhodium analogues, whose redox activity is restricted primarily to the corrole ring, iridium corroles can be oxidized to produce an electron paramagnetic resonance spectrum that has extremely anisotropic g tensor components, implying mixing of the 5d orbitals into the oxidized ground state and opening the door to possible higher-valent iridium complexes. Detailed experimental and computational studies are presented showing that this oxidized ground state is actually mostly corrole-based, as has been found in the past for numerous other supposedly high-valent corrole compounds, but the percentage of iridium character varies from 10 to 18% and tracks with the electron-donating ability of the ligand. Additionally, the unique (among corrole complexes) near-IR phosphorescence of Ir(III) corroles is presented and discussed. Iridium(III) corroles phosphoresce with lifetimes ranging from hundreds of nanoseconds to a few microseconds at room temperature, with slightly longer lifetimes at low temperature. Unfortunately, the quantum yields of phosphorescence are low, 1% or less, and this appears to be due to an exceptionally slow set of radiative rates for the corroles. An examination of the reactivity of ammine-ligated Ir(III) corroles is also described. These compounds can be oxidized in the presence of an ammonia source to form novel six-coordinate iridium(III) azaporphyrins in an unprecedented chemical transformation. The characterization and properties of these iridium azaporphyrin complexes are detailed as well, with a focus on nuclear magnetic resonance characterization techniques and a discussion of the red phosphorescence of the azaporphyrins