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Molecular Basis for Ribosomal Protein Protection from Cellular Degradation
Get PDFRibosomes are large macromolecular machineries composed of both protein and RNA constituents with a species-dependent molecular mass of at least ~3.3 MDa for the fully assembled eukaryotic 80S ribosome. Their catalytic activity is dependent on ribosomal RNA; therefore, ribosomes are bona fide ribozymes, and as such they mediate the final step of gene expression from DNA to RNA to protein by peptide bond formation between amino acids. Importantly, spatial separation of ribosome function and biogenesis into distinct cellular compartments allows for intricate regulatory mechanisms and rigorous quality control. Ribosome biogenesis occurs predominantly in the nucleolus and nucleus of the cell with final cytoplasmic maturation and quality control steps. Briefly, nucleolar ribosomal RNA together with ~200 trans-acting assembly factors co-transcriptionally forms the 40S and 60S pre-ribosomal subunits into which ~80 ribosomal proteins are incorporated in a hierarchical fashion.
Recent studies, including this thesis, have identified a novel class of dedicated ribosome assembly chaperones, in addition to the ~200 trans-acting ribosome assembly factors, which facilitate ribosomal protein shuttling. Ribosomal proteins are generated in the cytoplasm, and with only few exceptions they all have to enter the nucleus for incorporation into the pre-ribosomal subunits. Assembly chaperones can bind and protect unassembled ribosomal proteins either co-translationally or following nuclear import and shuttle them in a timely fashion to their destination sites at the maturing pre-ribosomal subunits. The first chapter of this thesis describes the identification and characterization of a dedicated assembly chaperone for the large ribosomal subunit protein RpL4, termed Acl4. Interestingly, Acl4 and likely also other dedicated assembly chaperones not only interact with ribosomal proteins to avoid aggregation and to shield them from unfavorable interactions, but also protect their client proteins from cellular degradation by the ubiquitin-proteasome machinery.
Ribosomes are built by assembling equimolar amounts of ribosomal proteins, which generates a challenge for the cell to ensure stoichiometric quantities of ribosomal proteins. Recent studies have demonstrated that stoichiometric levels of ribosomal proteins are established by cellular degradation of excess protein via ubiquitination of unassembled components. The second chapter of this thesis describes a conserved degradation pathway, which is dependent on the E3 ubiquitin ligase Tom1 to mark unprotected and unassembled ribosomal proteins and target them for degradation. Moreover, it is demonstrated in the third chapter for the first time how an assembly chaperone protects its client ribosomal protein from ubiquitination and proteasome-mediated degradation. High resolution structures of the Acl4•RpL4 complex as well as RpL4 in complex with the nuclear transport factor Kap104 visualize the molecular interactions of those proteins and uncover the molecular mechanism of protecting conserved Tom1-target sites within RpL4. Together, the reported results identify and characterize both a novel degradation pathway as well as a protection mechanism for ribosomal proteins and advance the understanding of the intricate regulation of ribosome biogenesis.</p
Electrically-Tunable Light-Matter Interactions in Quantum Materials
Get PDFDynamic control of the flow of light at the nanoscale is critical for next-generation optoelectronic devices that will enable the technologies of the future. Ultra-thin, layered materials are promising building blocks for this functionality, as they are easily fabricated into atom-scale structures, and their optical properties change dramatically under applied electric fields. Many of these material systems, like topological insulators – a subset of layered materials that host spin-polarized surface states, promise more exotic functionality as well. The emerging field of nanophotonics in quantum materials is a route not only to an improved material platform for optoelectronics, but also to new physics, and the potential new device paradigms that follow.
In this work we describe investigations of electrically-tunable light-matter interactions in two different layered materials: few-layer black phosphorus, and bismuth antimony telluride. In few-layer black phosphorus, we demonstrate several in-plane anisotropic optoelectronic phenomena, including Pauli-blocking of intersubband optical transitions under carrier injection, a quantum-confined Stark effect, and a change of quantum well selection rules under applied electric field. We further describe how these optoelectronic phenomena drive anisotropic birefringence and dichroism in few-layer black phosphorus. Lastly, we present theory describing amplitude, phase and polarization control in a black phosphorus integrated microcavity device, with applications that include metasurface beam-steering and more.
We next present experiments demonstrating field-effect control of optical transitions in bismuth antimony telluride. These measurements evidence the merits of topological insulators as optoelectronic materials, and highlight a pathway towards future exploration of spin-plasmon excitations in bismuth antimony telluride.
Lastly, we present a summary of pending work, including initial results of an ongoing study of plasmon excitations in few-layer black phosphorus, and a perspective on next steps for both these projects and nanophotonics in quantum materials at large.</p
Oxygen Transporter and Generator Devices to Treat Diabetic Retinopathy
Get PDFIn recent years, Micro-Electrical Mechanical Systems (MEMS) have opened new areas of the human body to non-pharmacological treatment. Miniaturized implants have started to appear in volume or power constrained areas, such as the eye and the heart. In particular, the eye benefits from miniaturization, as it is very sensitive to pressure and volumetric changes, which can affect eyesight and blood flow.
Diabetic retinopathy is the worldwide leading cause of blindness among working age adults. As the numbers of diabetics increases, so does the number of retinopathies. By 2030, 191 million people are expected to be affected by the disease. As a patient’s retinopathy progresses, the chronic hyperglycemia from diabetes causes permanent changes to the vasculature; vessels become leaky and occluded, tissue becomes hypoxic due to this ischemia and begins to release vascular endothelial growth factor (VEGF) to promote angiogenesis.
Currently, treatments exist only for severe non-proliferative or proliferative DR, and rely on blocking VEGF (vascular endothelial growth factor) or panretinal laser photocoagulation to reduce retinal metabolic demand. VEGF antagonists are expensive; costing up to $164k per quality life adjusted year and must be administered by intravitreal injections monthly. Laser photocoagulation also requires retreatment and is known to reduce peripheral vision—up to 20% of the peripheral retina is ablated. Another treatment approach may be to supply oxygen. Oxygen is a strong vasoconstrictor and suppresses the hypoxic signaling that leads to release of VEGF. These two effects reduce the plasma volume leaked into tissue, which in turn reduces edema, and may help prevent ischemic related cell death. Literature supports this assertion. A study of nasally inspired oxygen in patients with macular edema showed a reduction of edema and improvement of visual acuity following 3 months of treatment. Another study on rabbits with an induced ischemia demonstrated that intravitreal oxygenation maintained the retina to a near healthy condition.
In this thesis, two devices, the oxytransporter and oxygenerator, that treat diabetic retinopathy are designed and tested. The former shuttles oxygen from areas of high concentration to the ischemic retina. The latter generates oxygen by electrolysis.
This thesis is grounded on a computational model of oxygen consumption in the retina. To estimate the oxygen consumption, the model accounts for the anatomical distribution of tissue and vasculature in the retina. Previous models in literature averaged over the effects in the inner retina. The model estimates that the devices must supply 0.25nmol/s of oxygen to the human macula with an oxygen tension dependent on the degree of ischemia.
A nanoporous filler material was developed and integrated into the oxytransporter to allow this device to operate in the high humidity environment of the eye. The material is capable of withstanding an environment with water vapor 1.4 times the bulk saturation pressure. Theory behind the material was tested and compared to simulation. Benchtop testing over a month demonstrated the stability of the device in conditions similar to the eye. This oxytransporter was implanted in rabbits and the diffusor, or output membrane, reached the favorable mark of 100mmHg in the vitreous humor from atmospheric oxygen alone. This is estimated to be sufficient to treat a mild to moderate ischemia in humans.
The oxygenerator is powered from a coil up to 3cm away, and can provide 0.25nmol/s continuously with an oxygen tension of up to 300mmHg for a human sized diffusor. A steady state test demonstrated the capability of maintaining the oxygen tension in the device by modulating the input power. The device is replenished through osmosis from the vitreous humor, and can absorb moisture at a rate comparable to the required oxygen consumption. One week implantation in vivo in rabbits demonstrated that the oxygen tension exceeded 200mmHg at the diffusor, which is estimated to be sufficient to treat severe ischemia.
Future work should involve a study of the long term effects of oxygen in an ischemic animal model.</p
Mechanistic Study of Cu-Mediated, Photoinduced C–S Bond Formation and Demonstration of Electrochemical Ammonia Production by a Surface-Attached Iron Complex
Get PDFThe worldwide reliance on fossil fuels for energy and petrochemicals poses a massive environmental hazard. Furthermore, many chemical processes rely on precious metals that have low abundance on Earth and are threatened. As the world population grows rapidly, these factors pose an increasing threat to our planet and new chemical processes are needed that employ earth-abundant catalysts and alternative chemical currencies such as light and electricity derived from renewable sources.
Chapter 2 discusses an in-depth mechanistic study of the photoinduced, copper-mediated cross-coupling of aryl thiols with aryl halides. This reaction employs light energy and an earth-abundant metal to achieve bond formation through a pathway distinct from that of thermal reactions. In particular, I focus on the stoichiometric photochemistry and subsequent reactivity of a [CuI(SAr)2]– complex (Ar = 2,6-dimethylphenyl). A broad array of experimental techniques furnish data consistent with a pathway in which a photoexcited [CuI(SAr)2]-* complex undergoes SET to generate a CuII species and an aryl radical, which then couple through an in-cage radical recombination.
Chapter 3 discusses the surface attachment of a P3BFe complex to a carbon electrode, and the electrochemical generation of ammonia from N2 by the surface-appended species (P3BFe = tris-phosphinoborane). Ammonia production is achieved industrially by the combination of N2 and H2, the latter of which is derived from methane with concomitant production of CO2. Alternative chemical processes, such as the use of energy derived from electricity, are vital for the decreasing the carbon footprint of ammonia production. Synthetic modification of a previously-reported P3BFe complex by addition of three pyrene substituents onto the catalyst backbone allows non-covalent attachment onto a graphite surface. The resulting functionalized electrode shows good stability towards iron desorption under highly reducing conditions, and produces 1.4 equiv NH3 per iron site. The data presented provide the first demonstration of electrochemical nitrogen fixation by a molecular complex appended to an electrode.</p
Phenotypic Antimicrobial Susceptibility Testing Based on Nucleic Acid Analysis
Get PDFAntimicrobial resistance (AMR) is one of the most widely recognized threats to global health, and one that continues to grow as new mechanisms of resistance evolve and resistant pathogens spread. Antibiotics are a cornerstone of modern medicine, but their misuse and overuse has constantly and consistently reduced their efficacy to the critically low levels we observe today. As a result, the rate of mortality as a direct result of AMR is approaching over a million deaths annually, with 20-year projections in the ten-millions. Rapid, phenotypic antimicrobial susceptibility testing (AST) that could be performed at the point of care (most notably in ≤ 30 min) would decrease the overuse of antimicrobials, allow physicians to make informed choices about which antimicrobials to prescribe, and improve patient outcomes. Today no such method exists. The ultimate goal of the below work is to allow physicians to choose, instead of guess, which antibiotics to use. We envision that development of these tests into distributable diagnostics will drastically improve patient outcomes, curb the spread of resistance, strengthen global antibiotic stewardship, and forestall the post-antibiotic era.</p
Short-Range Entangled Phases of Fermions
Get PDFThis thesis is an attempt to understand the physics of short-range entangled phases of fermions through several related approaches. The first angle is topological quantum field theory. We discuss the classification of interacting fermionic short-range entangled phases by spin cobordism and give an algebraic characterization of unoriented equivariant bosonic topological quantum field theories in one spatial dimension. A second tool is tensor network representation. We develop the formalism of fermionic matrix product states and use it to derive the stacking group law for one dimensional symmetry-enriched fermionic short-range entangled phases. We also study its relationship with state sum constructions of topological quantum field theories and develop a state sum construction for pin-minus theories in one spatial dimension. The third approach is topological band theory. We classify free fermionic phases enriched by a unitary symmetry in any dimension and determine the map into the interacting classification
Impact of Transmission Network Topology on Electrical Power Systems
Get PDFPower system reliability is a crucial component in the development of sustainable infrastructure. Because of the intricate interactions among power system components, it is often difficult to make general inferences on how the transmission network topology impacts performance of the grid in different scenarios. This complexity poses significant challenges for researches in the modeling, control, and management of power systems.
In this work, we develop a theory that aims to address this challenge from both the fast-timescale and steady state aspects of power grids. Our analysis builds upon the transmission network Laplacian matrix, and reveals new properties of this well-studied concept in spectral graph theory that are specifically tailored to the power system context. A common theme of this work is the representation of certain physical quantities in terms of graphical structures, which allows us to establish algebraic results on power grid performance using purely topological information. This view is particularly powerful and often leads to surprisingly simple characterizations of complicated system behaviors. Depending on the timescale of the underlying problem, our results can be roughly categorized into the study of frequency regulation and the study of cascading failures.
Fast-timescale: Frequency Regulation. We first study how the transmission network impacts power system robustness against disturbances in transient phase. Towards this goal, we develop a framework based on the Laplacian spectrum that captures the interplay among network topology, system inertia, and generator/load damping. This framework shows that the impact of network topology in frequency regulation can be quantified through the network Laplacian eigenvalues, and that such eigenvalues fully determine the grid robustness against low frequency perturbations. Moreover, we can explicitly decompose the frequency signal along scaled Laplacian eigenvectors when damping-inertia ratios are uniform across the buses. The insights revealed by this framework explain why load-side participation in frequency regulation not only makes the system respond faster, but also helps lower the system nadir after a disturbance, providing useful guidelines in the controller design. We simulate an improved controller reverse engineered from our results on the IEEE 39-bus New England interconnection system, and illustrate its robustness against high frequency oscillations compared to both the conventional droop control and a recent controller design.
We then switch to a more combinatorial problem that seeks to characterize the controllability and observability of the power system in frequency regulation if only a subset of buses are equipped with controllers/sensors. Our results show that the controllability/observability of the system depends on two orthogonal conditions: (a) intrinsic structure of the system graph, and (b) algebraic coverage of buses with controllers/sensors. Condition (a) encodes information on graph symmetry and is shown to hold for almost all practical systems. Condition (b) captures how buses interact with each other through the network and can be verified using the eigenvectors of the graph Laplacian matrix. Based on this characterization, the optimal placement of controllers and sensors in the network can be formulated as a set cover problem. We demonstrate how our results identify the critical buses in real systems using a simulation in the IEEE 39-bus New England interconnection test system. In particular, for this testbed a single well chosen bus is capable of providing full controllability and observability.
Steady State: Cascading Failures. Cascading failures in power systems exhibit non-monotonic, non-local propagation patterns which make the analysis and mitigation of failures difficult. By studying the transmission network Laplacian matrix, we reveal two useful structures that make the analysis of this complex evolution more tractable: (a) In contrast to the lack of monotonicity in the physical system, there is a rich collection of monotonicity we can explore in the spectrum of the Laplacian matrix. This allows us to systematically design topological measures that are monotonic over the cascading event. (b) Power redistribution patterns are closely related to the distribution of different types of trees in the power network topology. Such graphical interpretation captures the Kirchhoff's Law in a precise way and naturally suggests that we can eliminate long-distance propagation of system disturbances by forming a tree-partition.
We then show that the tree-partition of transmission networks provides a precise analytical characterization of line failure localizability. Specifically, when a non-bridge line is tripped, the impact of this failure only propagates within well-defined components, which we refer to as cells, of the tree-partition defined by the bridges. In contrast, when a bridge line is tripped, the impact of this failure propagates globally across the network, affecting the power flow on all remaining transmission lines. This characterization suggests that it is possible to improve the system robustness by switching off certain transmission lines, so as to create more, smaller components in the tree-partition; thus spatially localizing line failures and making the grid less vulnerable to large-scale outages. We illustrate this approach using the IEEE 118-bus test system and demonstrate that switching off a negligible portion of transmission lines allows the impact of line failures to be significantly more localized without substantial changes in line congestion.
Unified Controller on Tree-partitions. Combining our results from both the fast-timescale and steady state behaviors of power grids, we propose a distributed control strategy that offers strong guarantees in both the mitigation and localization of cascading failures in power systems. This control strategy leverages a new controller design known as Unified Controller (UC) from frequency regulation literature, and revolves around the powerful properties that emerge when the management areas that UC operates over form a tree-partition. After an initial failure, the proposed strategy always prevents successive failures from happening, and regulates the system to the desired steady state where the impact of initial failures are localized as much as possible. For extreme failures that cannot be localized, the proposed framework has a configurable design that progressively involves and coordinates across more control areas for failure mitigation and, as a last resort, imposes minimal load shedding. We compare the proposed control framework with the classical Automatic Generation Control (AGC) on the IEEE 118-bus test system. Simulation results show that our novel control greatly improves the system robustness in terms of the N-1 security standard, and localizes the impact of initial failures in majority of the load profiles that are examined. Moreover, the proposed framework incurs significantly less load loss, if any, compared to AGC, in all of our case studies.</p
A Comparison of p-adic Motivic Cohomology and Rigid Cohomology
Get PDFWe study two conjectures introduced by Flach and Morin in [FM18] for schemes over a perfect field of characteristic p > 0. The first conjecture relates a p-adic extension of the étale motivic cohomology with compact support on general schemes introduced by Geisser in [Gei06] to rigid cohomology with compact support, and is proved here. The second, relates a p-adic Borel-Moore motivic homology with the dual of rigid cohomology with compact support, and is proved in the smooth case. For this, we also prove a generalization of the comparison theorem from rigid cohomology to overconvergent de Rham-Witt cohomology in [DLZ11].</p
The Development of a Synthetic Strategy Toward Oxazine-Containing Natural Products Enabled by Novel Copper Catalysis
Get PDF1,2-oxazine natural products are a small closely related family of highly oxidized compounds. Herein, the development of a synthetic strategy toward gliovirin and the trichodermamides is described which enabled the synthesis of the western fragments of gliovirin and trichodermamide B. To that end, we developed two novel copper-catalyzed transformations:the asymmetric propargylation of an oxime and the diasteroeselective oxidative cyclization of hydroxamic acid with a diene.
The challenge of working with tetrahydro-1,2-oxazines is their sensitivity to a variety of reaction conditions and purification methods. Extensive optimization of each transformation was accomplished, bringing to bear the state-of-the-art in oxidative modifications, including a palladium-catalyzed direct desaturation of an epoxy ketone. As well as this work led to the rare observation of a vinylogous Payne rearrangement.
The successful synthesis of the fully functionalized western and eastern fragments of gliovirin are described toward a late-stage diketopiperazine formation and thiolation. Interrogation of our late-stage strategy with these fragments demonstrates that the coupling of the fully functionalized western and eastern fragments is not an effective strategy toward gliovirin proof-of-concept experiments suggest this chemistry could be used toward the synthesis of the trichodermamides.</p
Chemical Tools for the Control of Biological Systems
Get PDFDescribed within is an exploration of noncanonical amino acids and photochemistry in the context of chemical biology. The thesis first covers attempts to expand the use of chemically acylated tRNA into new systems, before describing explorations into singlet oxygen as a powerful photochemical tool