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Subunit Selective Degradation of WIZ, a Lenalidomide- and Pomalidomide-Dependent Substrate of E3 Ubiquitin Ligase CRL4CRBN
Get PDFThis dissertation is focused on identifying novel targets of immunomodulatory(IMiD) drugs. IMiDs are a class of drugs that are used to treat multiple myeloma.The first chapter is an introduction to the clinical use of IMiDs, as well as the proteincereblon (CRBN), the primary target of IMiDs. The second chapter describes worktowards the identification of a novel IMiD target, WIZ, that is regulated by CRBNin an IMiD dependent manner. Mass spectrometry was performed to identify novelbinding partners, and IMiD dependent regulation by CRBN was validated usingchemical and genetic methods. Understanding how these drugs work will informthe production of more potent and more selective drugs.</p
Computational Imaging: a Quest for the Perfect Image
Get PDFA physical lens is limited in its ability to capture an image that is both high- resolution and wide-field due to aberrations even with a sophisticated lens design. This thesis explores computational methods that expand on the recently developed Fourier ptychographic microscopy (FPM) to overcome the physical limitations. New algorithms and imaging methods extend the computational aberration correction to more general imaging modalities including fluorescence microscopy and incoherent bright-field imaging so as to allow even a crude lens to perform like an ideal lens. This paradigm shift from the lens design to computational algorithms democratizes high-resolution imaging by making it easier to use and less complicated to build
Hemilabile, Non-Innocent (Poly)arylene Donors for Accessing Novel Reactivity at Transition Metal Centers
Get PDFUnderstanding the effects that ligands have on the coordination environment and reactivity of metal complexes is an endeavor that drives much of the field of inorganic chemistry. The use of ligands capable of flexible binding modes and redox states further enriches the chemistry of these complexes. This dissertation describes studies on metal complexes bearing pendant (poly)arylene donors that demonstrate hemilability and redox non-innocence. Within this context, conditions that result in coordination mode change and the multi-electron bond transformation that is made possible by the hemilability and/or non-innocence of the ligand are discussed.
Chapter 2 investigates the meta-terphenyl diphosphine framework bearing a central phenolate donor as an anionic POP pincer on a variety of first-row transition metals. The circumstances under which coordination mode change from the phenolate donor to the arene face are investigated. Reduction of the cobalt and nickel complexes induced a coordination mode change from phenolate oxygen to metal-arene binding, while Lewis acid additives induced a coordination mode change in some iron POP complexes. Additionally, it was found that iron chloride POP complex initially not amendable to two-electron reduction was cleanly reduced in the presence of Lewis acids, suggesting a role the Lewis acid plays in quenching the negatively charged phenolate and stabilizing the overall transformation.
Chapter 3 discusses reactivity on 1,4-naphthalenediyl diphosphine molybdenum complexes in the context of carbon monoxide (CO) coupling. Similar to the previously studied phenylene system, the reductive coupling of CO can be carried out. However, the naphthalene system showed a distinct and exclusive selectivity for the two-electron reductive CO coupling to a bis(siloxy)acetylene motif, without C–O bond cleavage. This difference in selectivity is proposed to be a result of accessible η4-arene binding modes previously not observed in the phenylene variant. Additionally, the bis(siloxy)acetylene complex also displays η4-binding to the central arene. Further CO catenation can be effected from this species, providing a metallacyclobutenone complex that bears a C3 fragment derived completely from CO.
In Chapter 4, the reactivity of 9,10-anthracenediyl bis(phenoxide) zirconium complexes is presented. The more expanded polyaromatic system with a milder reduction potential allowed the anthracene motif to function as a non-innocent ligand. This enabled facile reductive elimination of ancillary benzyl ligands on the metal center without the use of harsh reductants. This reduced complex was then able to oxidatively couple alkynes, and alkynes with nitriles. Furthermore, further insertion of an additional nitrile followed by reductive elimination, likely facilitated by the non-innocent anthracene motif, allowed for the catalytic synthesis of pyridines and pyrimidines with high yields and selectivities. This reactivity was further leveraged in the final Chapter of this dissertation. Chapter 5 presents the development of a new methodology towards the synthesis of pyridine or pyrimidine-containing polycyclic aromatic hydrocarbons (PAHs) using polyaromatic alkyne and nitrile building blocks. Because conventional methods of oxidative cyclodehydrogenation towards N-doped nanographenes proved ineffective with these PAHs, a new reductive cyclization route was developed offering a complementary method towards the challenging synthesis of these N-doped nanographenes.
Appendix A briefly explores additional reactivity on the 1,4-naphthalenediyl diphosphine complexes with regard to nitrile activation. Appendix B explores the synthesis of iron complexes supported by a benzene tris(thiophenolate) ligand towards potential model compounds for the iron molybdenum cofactor in nitrogenase. Appendix C presents preliminary studies on the 9,10-anthracenediyl bis(phenoxide) zirconium complex towards oxidative coupling of alkynes with CO2.</p
Microresonator Brillouin Laser Gyroscope
Get PDFOptical Gyroscopes are among the most accurate rotation-measuring devices and are widely used for navigation and accurate compasses. With the advent of integrated photonics for complex telecommunication chips, there has been interest in the possibility of chip-scale optical gyroscopes. Besides the potential benefits of miniaturization, such solid-state systems would be robust and resistant to shock. In this thesis, we investigate a chip-based optical gyroscope using counter-propagating Brillouin lasers on a monolithic silicon chip. The near-degenerate lasers mimic a commercial ring laser gyroscope including the existence of a locking band. By using physical properties associated with the Brillouin process, a solid-state unlocking method is demonstrated. We focus on three topics to explore the potential of the counter-propagating Brillouin-laser gyroscope. First, we explore the physics of the counter-propagating Brillouin lasers by deriving the theory to link the passive cavity mode with the lasing gain medium. We explicitly show how the dispersion, Kerr nonlinearity, dissipative coupling, and Sagnac sensing affect the beating frequency of the Brillouin lasers. Second, we experimentally demonstrate the performance of the gyroscope. Most notably, the gyroscope is used to measure the rotation of the Earth, representing an important milestone for chip-scale optical gyroscopes. Third, we investigate the non-Hermitian interaction between the counter-propagating Brillouin lasers. We test the recent prediction of the EP-enhanced Sagnac effect, and observe a Sagnac scale factor boost by over 4X by measurement of rotations applied to the resonator. Our research shows the feasibility of the chip-based Brillouin laser gyroscope. This gyroscope paves the way towards an all-optical inertial guidance system.</p
Light and Heat: Nonlocal Aspects in Conformal Field Theories
Get PDFThis thesis is dedicated to certain nonlocal aspects of conformal quantum field theories (CFTs). Two main directions are the study of CFTs on a particular globally-nontrivial spacetime corresponding to finite temperature, and the study of particular nonlocal CFT observables localized on light-rays. Specifically, we introduce bootstrap techniques for determining finite-temperature data of CFTs, and make novel predictions for the 2+1-dimensional Ising model. We propose the “stringy equivalence principle”, stating that coincident gravitational shocks commute, as a generalization of the strong equivalence principle of Einstein’s General Relativity that must hold in all consistent theories of gravity. We prove it in Anti-de Sitter (AdS) spacetimes by studying light-ray operators in the holographically dual CFT. We also derive an operator product expansion (OPE) for light-ray operators in CFT, by which two light-ray operators on the same light-sheet can be expanded as a sum of single light-ray operators. Light-ray operators model detectors — such as calorimeters. We use the light-ray OPE to compute energy event shape observables suitable for conformal collider physics.
An additional part of this thesis determines the low-energy vacua of two-dimensional maximal super-Yang-Mills theory, which describes the dynamics of stacks of D-strings in Type IIB string theory. By computing an invariant of the renormalization group (RG) flow from high to low energy — a modified thermal partition function named the refined elliptic genus — we prove the existence of multiple vacua, and identify the superconformal field theories capturing their dynamics. The vacua correspond to bound states of (p,q)-strings in Type IIB string theory. Our computation serves as a check of the strong-weak S-duality of the Type IIB string.</p
Tailoring Thermal Radiation from Near Field to Far Field
Get PDFControl of heat flow in both near and far field through thermal radiation is of fundamental interest for applications in thermal management and energy conversion.
One challenge is how we can realize high contrast control of heat flow with high temporal frequencies and without moving parts. We try to resolve this problem and propose two schemes in the near field: one based on electrical tuning of silicon and the other based on optical pumping of doped silicon slabs. Both methods rely on the change of free carriers, leading to tuning of the plasma frequency, resulting in modulation of near-field thermal radiation. Calculations based on fluctuational electrodynamics show that the electric method gives 10% tuning range. On the other hand, heat transfer coefficient between two silicon films can be tuned from near zero to 600 Wm-2K-1 with a gap distance of 100 nm at room temperature with the optical pumping method.
In the far field, we predict and demonstrate two spectrally selective absorbers based on semiconductors, by utilizing their band gap properties and dedicated photonic structure design. The germanium photonic crystals have around 95% absorption from 500 nm to 1000 µm and over 0.9 over the entire visible and near infrared spectrum. The effective absorptivity is as high as 0.91. The black silicon achieves 100% absorption for light with wavelength under 1 µm. The effective absorptivity is as high as 0.96. Field test shows that black silicon is able to maintain at 130 degrees Celcius under unconcentrated condition.
Another interesting topic is to achieve over 100 Wm-2 electricity-free cooling power density with simple fabrication method by passive radiative cooling under direction sunlight. We theoretically predicted three schemes for achieving this goal and experimentally demonstrate that a polymer-coated fused silica mirror, as a near-ideal black-body in the mid-infrared and near-ideal reflector in the solar spectrum, achieves radiative cooling below ambient air temperature under direct sunlight (8.2 °C) and at night (8.4 °C). Its performance exceeds that of a multi-layer thin film stack fabricated using vacuum deposition methods by nearly 3 °C. Furthermore, we estimate the cooler has an average net cooling power of about 127 Wm-2 during daytime at ambient temperature, more than twice that reported previously, even considering the significant influence of external conduction and convection. Our work demonstrates that abundant materials and straight-forward fabrication can be used to achieve daytime radiative cooling, advancing applications such as dry cooling of thermal power plants.</p
Towards a Net-zero Carbon Energy System: High Efficiency Photovoltaics and Electrocatalysts
Get PDFModern society is dependent on energy. Despite increases in energy efficiency, human development and economic goals are expected to increase the global demand for energy by almost 30% in the next 20 years. At the same time, anthropogenic carbon dioxide emissions must approach zero to stabilize global temperatures below the 2°C target set out by international climate agreements. Realizing a net-zero carbon energy system will depend on the development of a highly reliable, sustainable electricity grid to power society and the ability to produce chemicals and fuels in a carbon-free manner. Developing cheap, efficient solar photovoltaics and highly active and selective electrocatalysts is thus pivotal to achieving this goal.
In this work, we address issues limiting photovoltaics and electrocatalysts. Our work on photovoltaics analyzes two effects often neglected in the evaluation of efficiency limits for photovoltaic materials. We show that the shape of the band tail and, in particular, the extent of sub-gap absorption, controls the open-circuit voltage, emission, and ultimately the achievable efficiency of a solar cell. These findings are generalizable to any luminescent material and our analysis suggests that efficiency limits for a material can be determined through simple experimental characterization. In addition, we develop a device physics model which accounts for the presence of excitons, which are the fundamental excitation in a host of emerging photovoltaic materials. A case study in cuprous oxide shows that excitonic effects can play a large role in the device physics of materials with large exciton binding energies and that standard models can drastically underestimate the efficiency limits in these systems. Our work on photovoltaics, culminates in the realization of a novel device architecture for tandem silicon/perovskite solar cells that opens the possibility of achieving efficiencies >30%. Finally, we develop a method to tune the catalytic activity of electrocatalysts for the oxygen-evolution and chlorine-evolution reactions. Our method is based on group electronegativity and is likely generalizable to other reactions and catalysts. The analyses and technologies developed herein are promising steps towards a zero-carbon energy system.</p
Development of Electrocatalysts in Solid Acid Fuel Cells
Get PDFSolid acid fuel cells (SAFCs) can operate at intermediate temperature (near 250 ºC) using a non-toxic, solid proton-conducting electrolyte, CsH2PO4, which allows for fuel flexibility, high efficiency, inexpensive auxiliary components, and easy on-off cycling. Despite these features, large activation overpotentials at the electrodes require high Pt loadings in order to achieve acceptable power output. Few alternatives to Pt have emerged for either the hydrogen oxidation reaction or the oxygen reduction reaction in SAFCs. This thesis explores the use of Pd and Pd-containing alloys for electrocatalysis in SAFCs to reduce overall precious metal loading and therefore reduce cost to commercialization.
First, this work explores the use of Pd at the SAFC anode, assessing both catalytic activity for hydrogen electro-oxidation and reactivity with the CsH2PO4 electrolyte. A thin film geometry, in which nanometric layers of metal were deposited onto a polycrystalline disk of CsH2PO4 was used to simplify the device and facilitate interpretation electrochemical behavior. Using a symmetric geometry, the cells were examined under a uniform hydrogen-rich gas. It was found that Pd reacts with CsH2PO4, forming palladium phosphide (Pd-P) at the metal-electrolyte interface. With the aim studying the behavior of Pd in the absence of this reactivity, Pd overlain on Pt was examined in a bilayer geometry of Pd | Pt | CsH2PO4 | Pt | Pd. The bilayer Pt | Pd films show much higher activity for hydrogen electro-oxidation than films of Pt alone, as measured by AC impedance spectroscopy. Ex-situ low energy ion scattering and scanning transmission electron microscopy revealed that Pd diffused into the Pt layer under operating conditions. The extremely high activity of the interdiffused films suggest that Pd catalyzes reactions at both the metal-gas and metal-electrolyte interfaces, and furthermore facilitates rapid hydrogen diffusion rates through the films.
The high activity of Pt | Pd films, in which Pd eventually contacts the underlying electrolyte due to interdiffusion of the metals, motivates an investigation of Pd-based catalysts (Pd and Pd-P) for hydrogen electro-oxidation in a fuel cell relevant configuration. Working electrodes were formed from a mixture of Pd on carbon and the electrolyte material. The hydrogen oxidation kinetics from Pd, Pd6P, and Pd3P0.8 were observed to be comparable. The result is consistent with the observation that Pd catalyst reacts with CsH2PO4 and converts into Pd-P during cell operation. Both Pd and Pd-P appear to be more effective electrocatalysts for hydrogen oxidation than the equivalent mole percent of Pt supported on carbon. Further enhancement of Pd catalytic activity is achieved by reducing its crystallite size.
Lastly, this work examines the catalytic activity of Pd for oxygen reduction at the SAFC cathode. Evaluation of this system is complicated by the instability of Pd on CsH2PO4 under oxidizing conditions, which causes microstructure collapse and performance degradation. A SnO2 thin film was introduced as a barrier layer to inhibit Pd reactivity with CsH2PO4 and as a structural support for the catalyst. Employing atomic layer deposition, a SnO2 thin film was deposited either between the Pd and CsH2PO4 interface, or over the Pd catalyst. Both Pd-SnO2 bilayers show improved fuel cell performance stability compared to a Pd-only control, forming Pd-Sn alloys under cathode conditions. This suggests that the formation of Pd-Sn alloy stabilizes the metallic phase of Pd, improving catalytic activity. This work presents a new approach for designing the cathode materials for SAFCs.</p
Cell-Selective Chemoproteomics for Biological Discovery
Get PDFCellular protein synthesis changes rapidly in response to internal and external cues in ways that vary from cell to cell. Global proteomic analyses of microbial communities, tissues, and organisms have provided important insights into the behavior of such systems, but can obscure the diversity of responses characteristic of different cellular subpopulations. Recent advances in cell-specific proteomics—fueled in part by the development of bioorthogonal chemistries, more sensitive mass spectrometers and more advanced mining algorithms—have yielded unprecedented glimpses into how proteins are expressed in space and time. Whereas previous cell-specific proteomic analyses were confined to abundant cells in relatively simple systems, recent advances in chemoproteomics allow researchers to map the protein expression patterns of even rare cells in complex tissues and whole organisms.
Chapter 1 highlights recently developed strategies for cell-selective proteomics, including metabolic labeling strategies such as bioorthogonal noncanonical amino acid tagging (BONCAT). Bioorthogonal noncanonical amino acid tagging (BONCAT) is a chemoproteomic technique that enables temporal labeling of proteins. In cell-selective BONCAT, expressing a mutant aminoacyl-tRNA synthetase under the control of cell-specific genetic elements affords cellular resolution; only cells of interest can selectively incorporate a noncanonical amino acid into proteins for subsequent detection and identification. Chapter 2 details protocols to set up a cell-selective BONCAT system.
While BONCAT had previously been applied to studies of microbial pathogenesis in tissue culture-based models of infection, we sought to further develop the method to identify the proteome of methicillin-resistant Staphylococcus aureus (MRSA) within a mouse model of infection, as detailed in Chapter 3. We used this technique to enrich for staphylococcal proteins made within the host and in addition to finding many factors known to be important for infection, we also found many that had not previously been associated with infection. Screening several of these previously unknown factors in vivo led to the discovery of a novel protein important for MRSA infection. This unbiased approach to cell-selectively label pathogenic proteins during infection could be used as a global discovery tool for novel anti-infective strategies.
In Chapter 4, we combine this cell-selective BONCAT strategy with microbial identification after passive clarity technique (MiPACT) to visualize both staphylococcal protein synthesis and ribosomal RNA within whole skin abscesses during infection. In Chapter 5, we continue developing cell-selective BONCAT to study microbial protein synthesis in the context of a living mouse by extending the system to Bacteroides fragilis, a common human gut commensal.
Finally, cell-selective BONCAT is wholly dependent on the bioorthogonal nature of the azide and its detection reagents. Fishing out an azide-tagged molecule from the rest of the cellular milieu requires optimization of enrichment-based strategies. In Chapter 6, we describe the development of a peptide to quantitate the gain of our enrichments.
While innovations in mass spectrometry and computational algorithms have facilitated the identification and quantification of thousands of proteins simultaneously from complex samples, this abundance of data does not necessarily lead to biological insight. Cell-specific proteomic techniques will play a key role in the identification of the mechanisms that govern cell specialization and that allow organisms to respond to changing environments. Overall, this work demonstrates the power of cell-selective chemoproteomics to ascertain biological insights in complex systems.</p
Development of Ferromagnetic Metallic Glasses into Low Loss Power Transformer Cores
Get PDFCurrently, 3% of energy losses in the U.S. electrical grid occur at power transformers. With a transition to Metglas, transformer efficiency could be increased, but is Metglas the best replacement material for power transformers?
With this in mind we develop a Fe-based metallic glass for its glass forming ability and soft magnetic properties. During this development we identify a redox reaction of boron oxide by Si during melt fluxing of the Fe-based glass, which promotes an unexpected exchange of Si and B in the alloy. Taking this reaction into account, a unique optimization strategy is implemented, enabling oxide purification of the melt coupled with a significant but predictable shift in composition. This leads to an optimized Fe-based glass demonstrating a global peak in glass forming ability. Following boron oxide fluxing in the high temperature melt, alloy with composition Fe57.5Co20.2Si10.2B2.05P10.05 transforms to Fe57Co19.2Si6.8B7.4P9.6, and increases its critical rod diameter from 1 mm to 5 mm. The alloy also demonstrates excellent soft ferromagnetic performance characterized by a magnetic saturation of 1.53 T.
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While developing the above alloy, we also analyzed the effect of varying thickness of a Fe68Mo4Ni3Co5Si1P11.5C5B2.5 transformer core as a function of frequency to discover if there was a minimum in the losses. We did not find a single minimum, but found that the optimal thickness exhibits a logarithmic dependency on frequency. This dependence suggests the optimal thickness of a core ranges from 100−400μm, instead of in the < 50μm range currently used. These larger optimal thicknesses are unexpected if anomalous losses are not considered, but the dominance of the anomalous losses at low frequencies, or for thin samples, validates the need for thicker power transformers. While other amorphous metals and casting techniques will yield varying results, the logarithmic dependence on frequency and the 100−400μm optimal thickness range should be broadly applicable.</p