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Mechanisms of Transcriptional Silencing by the Nuclear Piwi Protein in Drosophila Germ Cells
Get PDFAn important characteristic for life is the ability to persist – to reproduce and defend oneself against different stresses. The ability of a species to persist from one generation to the next heavily depends on the integrity of the genetic material being passed down, and thus organisms have developed strategies to ensure the integrity of their genomes remain in tact. In Metazoan germlines, piwi proteins and their associated piwi-interacting RNAs (piRNAs) provide a RNA-interference (RNAi) based defense system against the expression of transposable elements (TEs). TE expression is detrimental to an organism’s genome – resulting in disruption of genes, double-stranded DNA breaks, and germ cell death – ultimately leading to the sterility of the organism. In Drosophila melanogaster, the piRNA pathway is composed of two cytoplasmic piwi clade Argonuate proteins, Aubergine (Aub) and Argonaute3 (Ago3), and a single nuclear piwi clade Argonuate protein, Piwi. The piwi clade Argonaute proteins bind piRNAs to form effector complexes that repress TE sequences.
The work presented in this thesis examines the role of the nuclear piwi clade Argonaute – Piwi – and the mechanisms by which Piwi accomplishes its functions. Chapter Two presents how Piwi/piRNA complexes identify genomic loci expressing TEs and direct the establishment of a repressive chromatin state to transcriptionally silence the loci. In Chapter Three, we explore the piRNA-induced transcriptional silencing (piRITS) pathway using a heterologous reporter based tethering system in vivo. We discuss how the recruitment of Piwi alone to a locus is not sufficient to induce repression, and establish a model for the connection bridging the Piwi/piRNA complex and effector silencing complex in the piRITS pathway. In Chapter Four, we employ our heterologous reporter based tethering system to explore the mechanism of piRNA precursor selection in the two cell types that make up Drosophila ovaries. We uncover a common mechanism of piRNA biogenesis in the two cell types and establish a unifying model of piRNA substrate selection. Finally, in Chapter Five, as essential step to understanding how Piwi achieves its nuclear function, we developed a heterologous two-hybrid system to identify factors that directly interact with Piwi. Overall, the work presented in this thesis provides a piece of the groundwork in understanding the mechanisms of transcriptional silencing of TEs in germ cells by Piwi. The work proposes that Piwi has dual functions in the nucleus. First, upon target recognition, Piwi recruits the piRITS complex to target loci to accomplish Piwi- mediated transcriptional silencing by deposition of H3K9me3. Then, Piwi recruits the RDC complex to specifically bind H3K9me3 at target loci to allow piRNA-production from the locus.</p
Copper Carbazolides in Photoinduced C–N Couplings
Get PDFPhotoinduced, copper-catalyzed reactions of organohalides have emerged in recent years as a powerful tool to construct a wide array of C–N bonds, which are prevalent in organic materials and polymers, pharmaceuticals, natural products, and ligands in transition metal catalysts. Described herein is the study and applications of copper complexes ligated by carbazole and its derivatives in photoinduced, copper-catalyzed C–N bond-constructing transformations. Various areas of synthetic inorganic and organic chemistry are explored, including in-depth mechanistic elucidation, ligand and catalyst design, reaction development, as well as spectroscopic and structural characterization of reactive copper complexes.
Chapter 2 describes the mechanistic investigation on photoinduced, copper-catalyzed couplings of carbazoles with unactivated alkyl halides. A wide array of mechanistic tools suggests the viability of an out-of-cage C(sp³)–N coupling pathway. Spectroscopic and structural characterization data of the key intermediates are detailed.
Chapter 3 outlines the design and preparation of a new copper-based photoredox catalyst supported by a tridentate bis(phosphino)carbazole ligands. The ground- and excited-state properties of the new photocatalyst are examined.
Chapter 4 details the development of photoinduced, copper-catalyzed C(sp³)–N couplings of carbamates with unactivated alkyl bromides using the new copper photoredox system. The scope with respect to the nucleophile and the electrophile and mechanistic investigations are communicated.
Chapter 5 illustrates the chemistry of copper complexes supported by bidentate (phosphino)carbazole ligands. A diverse array of copper complexes in both the S = 0 and S = 1/2 states are reported, including a rare, paramagnetic copper–phosphine complex that may serve as a structural model for key copper intermediates of the enantioselective C(sp³)–N couplings of carbazoles
Essays on Investor Beliefs and Asset Pricing
Get PDFThis dissertation is composed of three chapters addressing the connections between investor beliefs and asset pricing. Specifically, I focus on one prevailing pattern of investor beliefs in the finance literature, return extrapolation. The idea is that investor expectations about future market returns are a positive function of the recent past returns. In this dissertation, I use this concept to understand a number of facts in the asset pricing literature.
Return extrapolation attracts growing attention in the literature, not only because it well explains real-world investors' expectations in the survey, but also because it significantly drives investor demand towards stocks. Therefore, we should anticipate a connection between return extrapolation measurement and the stock market dynamics. However, contrary to the intuition, previous empirical studies fail to document a significant connection. In Chapter 1, "Time-varying Impact of Investor Sentiment", I recover this connection. Specifically, I formally define investors who extrapolate past returns as extrapolators and incorporate their wealth level into analysis. My main finding is that return extrapolation interacts strongly with extrapolators' wealth level in predicting future market returns. Therefore, conditional on extrapolators' wealth level, return extrapolation significantly explains stock market returns.
The return extrapolation concept also raises challenges to the asset pricing models under the rational expectation frameworks. Specifically, rational expectation theories lead to a positive correlation between expectations and future realized returns, whereas return extrapolation indicates a negative correlation. Given this discrepancy, there is a clear demand for a behavioral asset pricing model that can simultaneously explain survey evidence on investor expectations and the classical asset pricing puzzles. In Chapter 2, "Asset Pricing with Return Extrapolation", coauthored with Lawrence Jin, we present a new model of asset prices based on return extrapolation. The model is a Lucas-type general equilibrium framework, in which the agent has Epstein-Zin preferences and extrapolative beliefs. Unlike earlier return extrapolation models, our model allows for a quantitative comparison with the data on asset prices. When the agent's beliefs are calibrated to match survey expectations of investors, the model generates excess volatility and predictability of stock returns, a high equity premium, a low and stable risk-free rate, and a low correlation between stock returns and consumption growth.
In Chapter 3, "Dark Matter" of Finance in the Survey, I investigate another attribute of investor beliefs—tail risk perceptions. Although tail risks play significant roles in explaining asset pricing puzzles, researchers have very limited knowledge about them because tail events are difficult to observe. I use Shiller tail risk survey to empirically investigate tail risk perceptions. In this survey, investors are asked to report their estimated probability for a crash event in the U.S. stock market. However, when using survey data to understand investors’ perception of tail risks, there are two fundamental challenges. First, is tail risks survey reliable? Second, to avoid cherry-picking, is there a unified framework to explain different attributes of investor beliefs? My analysis provides positive answers to both questions. First, I show that Shiller tail risk survey is reliable. More importantly, I show that return extrapolation can serve as a unified belief formation framework to explain not only variations in investor expectations but also in tail risk perceptions.</p
A Synthetic Nitrogenase: Insights into the Mechanism of Nitrogen Fixation by a Single-Site Fe Catalyst
Get PDFNitrogen fixation, specifically the conversion of molecular nitrogen into ammonia, is a fundamental reaction necessary to support life. Our group has recently discovered the first family of well-defined iron complexes that catalyze the conversion of dinitrogen to ammonia. This thesis details mechanistic study of the nitrogen fixation chemistry these complexes. Chapter 1 presents an abbreviated overview of catalytic nitrogen fixation, which places our work in a larger context. Chapter 2 details the synthesis and nitrogen fixation activity of a series of cobalt complexes that are homologous to the known iron-based catalysts. The central goal of this work was to provide a structure-function study of the isostructural cobalt and iron complexes, in which the nature of the transition metal ion was changed in a fashion that predictably modulated the electronics of the system. Chapter 3 details in situ mechanistic studies of nitrogen fixation catalyzed by the iron complexes under the originally-reported reaction conditions. In this study, we were able to achieve a nearly order-of-magnitude improvement of catalyst turnover. Study of the reaction dynamics evidence a single-site mechanism for dinitrogen reduction, which is corroborated by in situ monitoring of catalytic reaction mixtures using freeze-quench Mössbauer spectroscopy. In Chapter 4, we study the key N-N bond cleavage step in the catalytic cycle for nitrogen fixation. In this chapter, we demonstrate that sequential reduction and low-temperature protonation of an iron catalyst results in the formation of ammonia and a terminal Fe(IV) nitrido complex. This result provides a compelling proposal for the mechanism of the catalytic nitrogen fixation reaction. Finally, in Chapter 5 we present spectroscopic and computational studies detailing the electronic structures of a redox series of Fe(NNR2) complexes that model key catalytic intermediates occurring prior to the N-N bond cleavage step. We evidence one-electron redox non-innocence of the “NNR2” ligand, which resembles that of the classically non-innocent ligand, NO, and may have mechanistic implications for the divergent nitrogen fixation activity of the some of the iron complexes studied by our group.</p
Improving Seismic Collapse Risk Assessments of Steel Moment Frame Buildings
Get PDFIt is important to be able to accurately assess seismic risk so that vulnerabilities can be prioritized for retrofit, emergency response procedures can be properly informed, and insurance rates can be sustainably priced to manage risk. To assess the risk of a building (or class of buildings) collapsing in a seismic event, procedures exist for creating one or more mathematical models of the structure of interest and performing nonlinear time history analysis with a large suite of input ground motions to calculate the building's seismic fragility and collapse risk. In this dissertation, three aspects of these procedures for assessing seismic collapse risk are investigated for the purpose of improving their accuracy.
It is common to use spectral acceleration with a damping ratio of 5% as a ground motion intensity measure (IM) for assessing collapse fragility. In this dissertation, the use of 70%-damped spectral acceleration as an IM is investigated, with a focus on evaluating its sufficiency and efficiency. Incremental dynamic analysis (IDA) is performed for 22 steel moment frame (SMF) models with 50 biaxial ground motion records to formally evaluate the performance of 70%-damped spectral acceleration as an IM for highly nonlinear response and collapse. It is found that 70%-damped spectral acceleration is much more efficient than 5%-damped spectral acceleration and much more sufficient with respect to epsilon for all considered levels of highly nonlinear response. Its efficiency and sufficiency compares also compares well with more advanced IMs such as average spectral acceleration.
When selecting input ground motions for nonlinear time history analysis, most engineers select ground motion records from the NGA-West2 database, which are processed with high-pass filters to remove long-period noise. In this dissertation, the extent to which these filters remove actual ground motion that is relevant to nonlinear time history analysis is evaluated. 52 near-source ground motion records from large-magnitude events are considered. Some records are processed by applying high-pass filters and others are processed by record-specific tilt corrections. Raw and NGA-West2 records are also considered. IDA is performed for 9-, 20-, and 55-story steel moment frame models with these processed records to assess the effects of ground motion processing on the calculated collapse capacity. It is found that if the cutoff period (Tc) is at least 40 seconds, then applying a high-pass filter does not have more than a negligible effect on collapse capacity for any of the considered records or building models. For shorter Tc (e.g. 10 or 15 seconds), it is found that the filters sometimes have a large effect on calculated collapse capacity, in some cases by over 50%, even if Tc is much larger than the building’s fundamental period. Of the considered ground motions, simply using the raw, uncorrected records usually yields more accurate results than using ground motions that have been processed with Tc less than or equal to 20 seconds.
For an existing building with unknown design plans, one might perform a collapse risk assessment using an archetype model for which the specific member sizes are assumed based on the relevant design code and building site. In this dissertation, the sensitivity of seismic collapse risk estimates to design criteria and procedures are evaluated for six 9-story and four 20-story post-Northridge SMFs. These SMFs are designed for downtown Los Angeles using different design procedures according to ASCE 7-05 and ASCE 7-10. Seismic risk analysis is performed using the results of IDA with 44 ground motion records and the results are compared to those of pre-Northridge models. It is found that the collapse risk of 9-story SMFs designed according to performance-based design vary by 3x, owing to differences in GMPEs used to generate site-specific response spectra. There is generally less variation in the collapse risk estimates of 20-story post-Northridge SMFs when compared to 9-story post-Northridge SMFs because wind drift limits control the design of many members of the 20-story SMFs. Differences in collapse risk between pre- and post-Northridge SMFs are found to be at least 4x and 8x for the 9- and 20-story models, respectively. Furthermore, in response to four strong ground motion records from large-magnitude events, some of the 9-story and all of the 20-story pre-Northridge SMFs experience collapse and most of the post-Northridge SMFs experience significant damage (MIDR > 0.03).</p
Simulation, Experiments, and Modeling of Cloud Cavitation with Application to Burst Wave Lithotripsy
Get PDFModeling, numerical simulations, and experiments are used to investigate the dynamics of cavitation bubble clouds induced by strong ultrasound waves.
A major application of this work is burst wave lithotripsy (BWL), recently proposed method of lithotripsy that uses pulses (typically 10 wavelengths each) of highintensity, focused ultrasound at a frequency of O(100) kHz and an amplitude of O(1) MPa to break kidney stones. BWL is an alternative to standard shockwave lithotripsy (SWL), which uses much higher amplitude shock waves delivered at a typically much lower rate. In both SWL and BWL, the tensile component of the pressure can nucleate cavitation bubbles in the human body. For SWL, cavitation is a significant mechanism in stone communition, but also causes tissue injury. By contrast, little is yet known about cavitation in BWL.
To investigate cloud cavitation in BWL, two numerical tools are developed: a model of ultrasound generation from a medical transducer, and a method of simulating clouds of cavitation bubbles in the focal region of the ultrasound. The numerical tools enable simulation of the cavitation growth and collapse of individual bubbles, their mutual interactions, and the resulting bubble-scattered acoustics. The numerics are implemented in a massively parallel framework to enable large-scale, three-dimensional simulations. Next, the numerical tools are applied to bubble clouds associated with BWL. Additionally, laboratory experiments are conducted in vitro in order to calibrate and validate the simulations. A major feature of the resulting bubble clouds is that the cloud size is similar to the ultrasound wavelength. This results in an anisotropic structure where the bubbles closest to the wave source grow to larger size and oscillate more rapidly. A new scaling parameter is introduced to characterize the nonlinear bubble cloud dynamics that generalizes the cloud interaction parameter of d'Agostino and Brennen (1989) defined for weak (linearized), bubble cloud dynamics excited uniformly by long-wavelength pressure waves. The mechanisms leading to the observed bubble dynamics are identified. The results further show that bubble clouds can scatter a large portion of incident ultrasound and consequently shield distal regions, including kidney stones, from irradiation. This energy shielding is quantified, and the simulations show that even a thin layer of bubbles can scatter up to 90% of the incident wave energy. A strong correlation is identified between the magnitude of energy shielding and the amplitude of the bubble-scattered acoustics. The correlation may be of use to control cavitation in the human body in real time by ultrasound monitoring for better outcomes of BWL.</p
Design, Analysis, And Computational Methods For Engineering Synthetic Biological Networks
Get PDFThis thesis advances our understanding of three important aspects of biological systems engineering: analysis, design, and computational methods. First, biological circuit design is necessary to engineer biological systems that behave consistently and follow our design specifications. We contribute by formulating and solving novel problems in stochastic biological circuit design. Second, computational methods for solving biological systems are often limited by the nonlinearity and high dimensionality of the system’s dynamics. This problem is particularly extreme for the parameter identification of stochastic, nonlinear systems. Thus, we develop a method for parameter identification that relies on data-driven stochastic model reduction. Finally, biological system analysis encompasses understanding the stability, performance, and robustness of these systems, which is critical for their implementation. We analyze a sequestration feedback motif for implementing biological control.
First, we discuss biological circuit design for the stationary and the transient distributional responses of stochastic biochemical systems. Noise is often indispensable to key cellular activities, such as gene expression, necessitating the use of stochastic models to capture their dynamics. The chemical master equation is a commonly used stochastic model that describes how the probability distribution of a chemically reacting system varies with time. Here we design the distributional response of these stochastic models by formulating and solving it as a constrained optimization problem.
Second, we analyze the stability and the performance of a biological controller implemented by a sequestration feedback network motif. Sequestration feedback networks have been implemented in synthetic biology using an array of biological parts. However, their properties of stability and performance are poorly understood. We provide insight into the stability and performance of sequestration feedback networks. Additionally, we provide guidelines for the implementation of sequestration feedback networks.
Third, we develop computational methods for the parameter identification of stochastic models of biochemical reaction networks. It is often not possible to find analytic solutions to problems where the dynamics of the underlying biological circuit are stochastic, nonlinear or both. Stochastic models are often challenging due to their high dimensionality and their nonlinearity, which further limits the availability of analytical tools. To address these challenges, we develop a computational method for data-driven stochastic model reduction and we use it to perform parameter identification. Last, we provide concluding remarks and future research directions.</p
A Planetary Perspective of Life
Get PDFJoin me on my journey to Jupiter, Titan, Pluto, Earth, and Mars as I seek a deeper understanding of life through the lessons that I learn from each world. How should we define life? What does life do? Why does life exist, and how did it begin? And what do the answers to these questions mean for the prospect of life beyond Earth? No, you’re not going to get any spoilers here. Yes, you actually have to read the manuscript. I spent a lot of time weaving this story together, adding supplementary material to each chapter, connecting the dots between the five planetary bodies that I’ve chosen to tell this tale. There’s a lot in here besides just my published work, including two essays on the origin of life (presented in the Interlude) and two scientific works in progress (presented in the Prologue and the Epilogue). I encourage you to follow the wending tale of my graduate school career from start to finish as I build a planetary perspective of life that I now proudly present to you.</p
Laboratory and Astronomical Rotational Spectroscopy
Get PDFRotational spectroscopy is a capable technique with a rich history in a variety of chemical physics applications that is undergoing a renaissance thanks to new approaches and powerful new experimental capabilities. This thesis demonstrates that flexibility by examining multiple uses of rotational spectroscopy from instrument development, analytical chemistry, fundamental chemical physics, and astrochemistry.
In chapter 2 we discuss the development of two novel coherent microwave spectrometers. These low cost instruments have only recently become feasible thanks to the burgeoning development of highly flexible digital electronics. The first instrument is designed for undergraduate teaching labs and can be used to demonstrate many new concepts of coherent spectroscopy that are used in modern spectroscopy. It is a rotational spectrometer and can, therefore, also be used for a variety of basic spectroscopy experiments. The second instrument uses the stability and consistency of waveguides and broadband microwave instruments to measure the rotational spectrum and abundance of isotopologues to high accuracy.
Chapter 3 describes the measurement of the rotational spectrum of the cyclopentanol--water dimer. Using microwave spectroscopy, the spectrum is measured and assigned, and the structure of the dimer is determined. The cyclopentanol--water dimer shows a structure dominated by both strong hydrogen bonding and multiple weaker hydrogen bonds from the hydrocarbon ring. The monomer spectrum is measured, though unassigned due to the strong perturbation from the motion of the ring. Dimerization with water is shown to suppress this motion. This system is shown to be an excellent example of the effect of weak hydrogen bonding on the secondary structure and dynamics of molecular systems.
Chapter 4 moves to astronomical observations of rotational transitions with the detection of a new species: propylene oxide. Measuring the inventory, abundance, and distribution of molecular species provides tests of our understanding of interstellar chemistry. Propylene oxide is an important addition to this inventory because it is the first chiral species detected beyond our solar system. Chiral species play an enormously important role in biology on Earth, and it is believed that interstellar chemistry may contribute to the early inventory of prebiotic species on newly formed planets. The detection of propylene oxide is discussed in the context of the origin and distribution of chiral molecules in the universe.
Chapter 5 discusses recent data from the Atacama Large Millimeter/Submillimeter Array. The data maps the distribution of CH3CN isotopologues at incredibly high spatial resolution toward the Orion KL region. The measurement of isotopic ratios in CH3CN is used to inform our understanding the formation mechanisms of cyanides in star forming regions. More broadly, the maps are used to show the extreme spatial heterogeneity of the region, with numerous dense clumps roughly the size of a solar system, each with their own unique chemical and physical structure that reflects their distinct evolutionary histories.
Finally, chapter 6 discusses the non-detection of trans ethylmethyl ether. Ethylmethyl ether is one of the largest molecules claimed to be detected in the interstellar medium. Due to its size, it is believed to be produced on grain surfaces as a secondary or tertiary product from dissociation of ice constituents. Given its complexity, its abundance may be an important metric of the accuracy of chemical models of ice chemistry. The study claiming its detection reported an unusually high abundance of the species toward W51 e1/e2. Follow up observations and analysis showed that the original detection was mistaken, likely caused by interference from other features.</p
Cathode Design for High Energy Molten Salt Lithium-Oxygen Batteries
Get PDFState of the art commercial lithium ion batteries use cathodes such as lithium cobalt oxide which rely on insertion and removal of lithium ions from a host material. However, insertion cathode materials are limited in their capacity, and replacing them with a cathode that employs growth and dissolution of new phases could significantly increase a battery’s energy density. For example, oxygen and sulfur cathodes have been widely researched to this end, with both cases involving the growth of a lithium-rich compound on a current collector/catalyst support.
We begin by describing the effect of using a molten salt electrolyte in a lithium-oxygen battery. In particular, we focus on how the electrochemical performance and discharge product, lithium peroxide, differ from that of a traditional organic electrolyte. In addition, we discuss the enhanced peroxide solubility in a molten salt and its implications for lithium peroxide growth and coulombic efficiency. Finally, we address the cell death of a galvanostatically cycled battery.
We then introduce a similar phase-forming conversion chemistry, whereby a molten nitrate salt serves as both an active material and the electrolyte. Molten nitrate salts were previously studied as an active material in a primary lithium battery where lithium oxide irreversibly forms as nitrate reduces to nitrite. We will describe how the use of a nanoparticle heterogeneous catalyst allows the reversible growth and dissolution of micron-scale lithium oxide crystals in this system.
After introducing these molten salt lithium batteries, we address the effect of cathode geometry on electrochemical performance. In particular, we note that the growth of such large, solid phase species on the surface of the catalyst support imposes new design restrictions when optimizing a cathode for energy density. As a proof of concept, we design and implement an architected electrode with large pore volume and relatively small surface area, comparing it with the more typical geometries of thin films and nanoparticles.</p