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Diverse Roles of RNA-protein Interactions: From Viral Antagonism to Mammalian Development
Get PDFRNA is a widely utilized and integrated component of core cellular function because of its abilities to recognize and hybridize to nucleic acid templates, spatially localize to different compartments within the cell, bind combinatorially to effector molecules, and in some cases directly catalyze chemical reactions. In this thesis, I describe three cases, illustrating the biomolecule’s unique importance in several different aspects of cellular homeostasis. Chapter 1 provides historical context for studying RNA-protein interactions within RNA biology and Virology. Chapter 2 details experiments in which we explored RNA as a central target of host cell takeover by SARS-CoV-2. In the process, we highlight the importance of RNA in many integral complexes within the cell, including components of the spliceosome, the eukaryotic ribosome, and signal recognition particle. Chapter 3 presents data from our consideration of RNA within the context of cis gene regulation. We specifically focus on a model RNA-binding protein, SMRT/HDAC1 Associated Repressor Protein (SHARP), and the paternally imprinted long non-coding RNA, Kcnq1ot1, as case studies. Chapter 4 describes our dissection of a transcriptional circuit involving SHARP and discusses implications of RNA-binding to developmentally sensitive circuits and processes. Finally, Chapter 5 poses new questions raised by these studies. Together these data emphasize the diverse and unique role RNA plays in cellular homeostasis and suggest additional roles in nuclear compartment stabilization and crosstalk.</p
Microstructure-Enabled Plasticity in Nano-to-Microscale Materials
Get PDFMicrostructure-governed damage resistance in materials enables a variety of functional applications, such as durable biomedical implants and robust product packaging. For example, the refined phase compatibility qualifies NiTi for artery stents, while carbon fiber reinforced polymers improve structural strength in aerospace engineering. As the overall size of industrial applications continue to decrease, it has become increasingly apparent that when a material's external structural size and internal microstructural size become comparable, its mechanical behavior starts to deviate from that of bulk, such as the smaller-is-stronger size-effect in metals. This elucidation necessitates the characterization of materials at lengthscales relevant to their internal microstructure to guarantee accuracy in the design of real-world applications.
This thesis aims at deciphering the microstructure-mechanics relationship for materials at lengthscales bridging the gap between 1nm and 1µm, with shape memory ceramics, scorpion shells, and jellyfish biogel as sample systems. We use electron and x-ray diffraction to characterize microstructures such as twinning, defects, and fiber organization, while revealing strength, toughness, and other deformation mechanisms through in-situ nanomechanical experiments. We show improved shape recovery in an otherwise brittle ceramic by tuning its phase compatibility at the nanoscale and reveal unprecedented smaller-is-stronger size-dependence for its twinning-induced plasticity. We then unveil competing fiber orientations in Scorpion shells that follow fiber-mechanics principles and demonstrate a combined poroelasticity/viscoelasticity constitutive relation in jellyfish that explains their self-healing behavior. The correlation between microstructure and mechanical behavior unveils unique damage mitigation and energy dissipation techniques in both brittle ceramics and natural biomaterials at each order of lengthscale, paving the road to designing macroscopic materials with hierarchical mechanical behavior and improved plasticity.</p
Does Richard Feynman Dream of Electric Sheep? Topics on Quantum Field Theory, Quantum Computing, and Computer Science
Get PDFIn this thesis, we mainly discuss three topics in theoretical physics: a proof of the weak gravity conjecture, a basic statement in the string theory landscape using the black hole entropy, solving the critical O(3) model using the conformal bootstrap method involving semidefinite programming, and numerical simulation of the false vacuum decay using tensor network methods. Those topics cover different approaches to deep understanding of quantum field theories using concepts and methods of information theory, and computer science with classical and quantum computations.</p
Molecular Function and Regulation of Aub Arginine Methylation in the piRNA Pathway
Get PDFTransposon elements (TEs, Transposons) are DNA sequences that can change their position within the genome. TEs, so-called 'jump genes', sometimes create mutation which will disrupt genes or damage the genome integrity by causing double-stranded DNA breaks and germ cell death. It is important for living animals to maintain the integrity of genetic information during reproduction. In Metazoa germline, cells use the piwi-interacting RNA (piRNA) pathway, which is an RNA – interference (RNAi) based defense strategy to protects the genome from the attacking of the "selfish" transposons. The core unit of the piRNA pathway is the RNA-induced silencing complex (RISC), a conserved family of Argonaute protein that interacts with small (19–33 nt) RNA guides in eukaryotic species. In Drosophila melanogaster, three PIWI-clade Argonaute proteins are present in the germline – Aubergine (Aub), Argonaute 3 (Ago3) and Piwi. PIWI proteins together with their substrate piRNAs forming the RISC to suppress the TE activity. Arginine (Arg) methylation is an important post-translational modification among Argonaute proteins. Defects of Arginine methylation cause the de-repression of deleterious TE.
The work present in this thesis examines the molecular function and regulation mechanism of Aub Arginine methylation in Drosophila germline cells. Chapter I presents a general introduction to the TEs, key components of the piRNA pathway, potential piRNA processing site, "nuage", and the correlation between arginine methylation and its interaction partner, Tudor domain-containing proteins. Chapter II presents the piRNA biogenesis in Drosophila germline and somatic cells, dividing the piRNA pathway into cytoplasmic and nuclear branches. We describe the mechanism of piRNA 5' end and 3' end formations. Chapter III explores the specific molecular function of Aub arginine methylation in the piRNA ping-pong cycle. Further, we decipher the regulation mechanism of Aub Arginine methylation, addressing its biological meaning for the piRNA biogenesis. In chapter 4, we developed a heterologous two-hybrid system to identify factors that directly interact with Piwi, which can further be applied to elucidate the interaction network of the piRNA pathway. In chapter 5, we discuss the potential role of phase separation in the assembly of ping-pong processing granule and the biological meaning in the piRNA biogenesis. We also propose the future plan and the protocol to examine the hypothesis in the future.</p
Reducing Computational Costs for Many-Body Physics Problems
Get PDFThree different computational physics problems are discussed. The first project is solving the semi-classical Boltzmann transport equation (BTE) to compute the thermal conductivity of 1-D superlattices. We consider various spectral scattering models at each interface. This computation requires the inversion of a matrix whose size scales with the number of points used in the discretization of the Brillouin zone. We use spatial symmetries to reduce the size of data points and make the computation manageable. The other two projects involve quantum systems. Simulating quantum systems can potentially require exponential resources because of the exponential scaling of Hilbert space with system size. However, it has been observed that many physical systems, which typically exhibit locality in space or time, require much fewer resources to accurately simulate within some small error tolerance. The second project in the thesis is a two-step factorization of the electronic structure Hamiltonian that allows for efficient implementation on a quantum computer and also systematic truncation of small contributions. By using truncations that only incur errors below chemical accuracy, one is able to reduce the number of terms in the Hamiltonian from O(N⁴) to O(N³), where N is the number of molecular orbitals in the system. The third project is a tensor network algorithm based on the concept of influence functionals (IFs) to compute long-time dynamics of single-site observables. IFs are high-dimensional objects that describe the influence of the bath on the dynamics of the subsystem of interest over all times, and we are interested in their low-rank approximations. We study two numerical models, the spin-boson model and a model of interacting hard-core bosons in a 1D harmonic trap, and find that the IFs can be efficiently computed and represented using tensor network methods. Consistent with physical intuition, the correlations in the IFs appear to decrease with increased bath sizes, suggesting that the low-rank nature of the IF is due to nontrivial cancellations in the bath.</p
The Progenitors of Fast Radio Bursts
Get PDFFast radio bursts (FRBs) are millisecond duration pulses of radio emission that are bright enough to be seen from other galaxies. The nature of the objects that produce fast radio bursts has captivated the interest of astronomers since their discovery in 2007. The durations and energetics of FRBs imply a compact, highly magnetized progenitor, making magnetars a popular progenitor candidate. However, it is difficult to pin down the progenitors of FRBs because they occur so far away. In this thesis, I will present the Survey for Transient Astronomical Radio Emission 2 (STARE2), an experiment designed to detect FRBs in the Milky Way. I will present a formalism through which to interpret the results of this experiment and demonstrate our experiment's effectiveness with the detection of a solar burst. Using STARE2, we discovered the first FRB that originated within the Milky Way, FRB 200428. This FRB was traced back to the Galactic magnetar SGR J1935+2154. The energetics, spectro-temporal properties, host galaxy, environment, and X-ray counterpart are all consistent with the properties of extragalactic FRBs. In addition, the high volumetric rate of these bright radio bursts from magnetars is consistent with the volumetric rate of FRBs, implying that magnetars are the dominant channel of FRB production. I will then develop a novel statistical technique to compare transient host galaxies in order to evaluate whether the hosts of extragalactic FRBs are consistent with a magnetar origin. I will find that the hosts of FRBs are consistent with the hosts of core-collapse supernovae, supporting the hypothesis that magnetars produce FRBs. Finally, I will present two ideas for future observing campaigns to find FRBs from M82 and more extremely bright pulses from Galactic magnetars.</p
Formation and Function of Ascarosides in the Nematodes C. elegans and C. briggsae
Get PDFAs an easily culturable, hermaphroditic, and short-lived species with a fully annotated genome and neural connectome, the nematode Caenorhabditis elegans is used as a model organism to study many different biological problems. Examining the communication systems among these worms is important not only to understand how they control and affect one another's behavior, but also gives us clues to the communications systems of closely related parasitic worms.
Nematode worms use small-molecule signaling to send messages about their environments in order to influence behavioral decisions of other animals in their vicinity. A main type of pheromone signaling uses a group of stable small molecules, collectively called ascarosides, that are built modularly from common waste products in cells such as sugars, fatty acids, and amino acid derivatives. Ascarosides are synthesized by C. elegans in precise concentrations and combinations to produce finely-tuned messages which control major behaviors such as mating and entry into dauer, an alternative lifestage that allows worms to survive adverse conditions. We are still unraveling exactly how ascarosides are produced and how they affect behaviors in C. elegans and other worms species.
To further understanding of the formation of ascarosides in C. elegans, I studied the O-acyltransferase gene class to see if they helped catalyze the 4' modifications of ascarosides, as predicted based on their chemistry. Surprisingly, oac genes were found to be uninvolved in the biosynthesis of ascarosides; but they do affect ascaroside production and secretion. To understand the underlying mechanisms of formation and function of ascarosides across worm species, I also studied ascarosides in the closely-related species Caenorhabditis briggsae. First, I developed an efficient CRISPR/Cas9 method for use in C. briggsae. From there, I was able to make the C. briggsae mutants Cbr-glo-1 and Cbr-daf-22, genes that we showed were one-to-one orthologs of their C. elegans counterparts. I then showed that ascr#2 was the main component of daumone in C. briggsae. Additionally, I found that there is an anti-dauer signal, hypothesized to be another type of small signaling molecule – a glucoside. These findings further our understanding of the formation and function of ascaroside signaling molecules in nematode worms.</p
Novel Light-Matter Interaction in Quasi-One-Dimensional Graphene Nanomaterials for Photonics
Get PDFNonlinear light-matter interaction in two-dimensional (2D) materials like graphene with unique nanostructured quasi-one-dimensionality (quasi-1D) holds the potential to address major technology opportunities in photonics from on-chip photo detection, modulation of light, and even possibly coherent light sources. In this work, we propose to use graphene, a gapless two-dimensional nanomaterial, for both nano-photonic applications and potentially energy harvesting by nano-structuring the material into nearly quasi-one-dimensional effective optical cavities with defects that act like color centers. These defects are naturally formed during its synthesis or can be engineered in the material by selective plasma radiation, is found to support a broad spectral distribution of color centers that exhibit excitation dependent photoluminescence. Through detailed investigation on the temperature and power dependence of photoluminescence from such defects, excitation dependent photoluminescence emission, we have established that these graphene nanomaterials with metastable energy states can support material excitations (e.g., excitons) that are strongly coupled to the optical modes confined within the nanostructured cavities to produce polaritonic quasiparticles, leading to many interesting nonlinear behaviors. In particular, the manifestation of blue-shifted photoluminescence, polariton lasing-like emission, multimode lasing-like emission, and distinct interference fringes, all points to the presence of novel light-matter interaction in quasi-one-dimensional graphene. Such novel light matter interactions can be exploited, among other applications, within photonic integrated circuits (PIC) by directly synthesizing graphene on silicon from a low temperature, single-step, plasma-enhanced chemical vapor deposition (PECVD) with feedstock gases of methane and hydrogen.</p
Applications and Integration of Optical Frequency Combs
Get PDFOptical frequency combs have a wide range of applications in science and technology, including but not limited to timekeeping, optical frequency synthesis, spectroscopy, searching for exoplanets, ranging, and microwave generation. The integration of microresonator with other photonic components enables the high-volume production of wafer-scale optical frequency combs, soliton microcombs. However, it faces two considerable obstacles: optical isolation, which is challenging to integrate on-chip at acceptable performance levels, and power-hungry electronic control circuits, which are required for the generation and stabilization of soliton microcombs. In this thesis, we describe the design and early commissioning of the laser frequency comb for astronomical calibration using electro-optic modulation. We also focus on the realization of a novel and compact chip-scale optical frequency comb, soliton microcomb, including the progress made towards the visible soliton microcomb generation and the demonstration of low power operation of a soliton microcomb along contours of constant power in the phase space. We introduce a soliton spectrometer using dual-locked counter-propagating soliton microcombs to provide high-resolution frequency measurement. Finally, we look into the integration of lasers and high-Q microresonators. The self-injection locking process has been shown to create a new turnkey soliton operating point that eliminates difficult-to-integrate optical isolation as well as complex startup and feedback loops. Moreover, this technique also simplifies the access to high-efficiency dark soliton states without special dispersion engineering of microresonators
Constraining the Formation and Fate of Hydroperoxides in the Remote Atmosphere
Get PDF Atmospheric hydroperoxides form as second generation products in the atmospheric oxidation of many volatile organic compounds (VOCs) during reactions of these VOCs with OH and HO2 (i.e. HOx), where HOx are among the atmosphere's main oxidants and thus drivers of the majority of atmospheric chemistry. Once formed, the lifetime and ultimate fate of hydroperoxides are set by a variety of potential chemical and physical pathways that have different impacts on the atmosphere's oxidizing capacity, including either recycling HOx or removing HOx. This dissertation explores the role of hydroperoxides with several different structures through field and laboratory studies using CF3O- chemical ionization mass spectrometry (CIMS) to understand the role of these hydroperoxides in the oxidation chemistry of the remote atmosphere.
Hydrogen peroxide (H2O2) and methyl hydroperoxide (MHP, CH3OOH) are two of the most abundant hydroperoxides found in oceanic environments. Both hydroperoxides were measured using time of flight and tandem quadrupole CIMS aboard the NASA DC-8 aircraft during the Atmospheric Tomography Mission, enabling a seasonal investigation into their global distribution with near pole-to-pole coverage across the Pacific and Atlantic Oceans and ranging in altitude from the marine boundary layer to the upper troposphere and lower stratosphere. Hydroxymethyl hydroperoxide (HMHP, HOCH2OOH) and isoprene hydroxy hydroperoxides (ISOPOOH, HOC5H8OOH) are organic hydroperoxides derived from the oxidation of isoprene, one of the dominant biogenic VOCs in forested environments. The loss of HMHP from the atmosphere via reaction with OH is investigated in the laboratory using time of flight CIMS and laser induced fluorescence along with theoretical chemical modeling methods. To better distinguish the varying roles of structurally complex hydroperoxides, a novel field-deployable gas chromatograph integrated with a high resolution time of flight CIMS is developed that sensitively detects hydroperoxides along with a number of other oxidation products. This instrument is deployed at a rural forested site in northern Michigan during the PROPHET field campaign to probe the relative contribution of different ISOPOOH isomers to the oxidation pathways of isoprene.</p