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Quantitative Characterization of Composition and Regulation of Cullin-RING Ubiquitin Ligases
Get PDFInduced proteolysis of pathogenic proteins via degrader molecules, such as Proteolysis Targeting Chimeras (PROTACs), is emerging as a promising therapeutic strategy. In particular, induced proximity of Cullin-RING ubiquitin Ligases (CRLs) with various neo-substrates has proven successful in mediating proteasomal degradation of previously undruggable proteins. Hijacking enzymes to carry out biochemical reactions on neo-substrates stands in stark contrast to conventional pharmacological approaches and exposes degrader molecules to unusually complex pharmacodynamics. While the first PROTACs entered the clinic in 2019, much about the organization and regulation of the frequently co-opted CRLs remains elusive. In particular, the COP9 Signalosome (CSN) is essential to regulate CRL activity and assembly through cleaving Nedd8 from cullin scaffolds, yet it remains unknown how CSN becomes activated. We combine structural and kinetic analyses to identify mechanisms that contribute to CSN activation and Nedd8 deconjugation, detailing the kinetic picture of the deneddylation-disassembly cycle that promotes rapid remodeling of the cellular CRL network. Furthermore, we establish Protein Interaction Kinetics and Estimation of Stoichiometries (PIKES) analysis, a systematic proteomic profiling platform that integrates cellular engineering, affinity purification, chemical stabilization and quantitative mass spectrometry to investigate the dynamics of interchangeable multiprotein complexes. Using PIKES, we show that ligase assemblies of Cullin4 with individual substrate receptors differ in abundance by up to 200-fold and that Cand1 acts as an exchange factor to remodel the CRL4 ligase pool. Integrating quantitative data and model simulations of CRL-mediated substrate turnover, we show that high substrate receptor levels can enhance the potency of degraders
Mechanics of River Avulsions on Lowland River Deltas
Get PDFLowland deltas are home to over 0.5 billion people and some of the most biodiverse ecosystems on Earth. Deltas are highly dynamic landscapes, and at the largest scale grow through repeated construction of depositional lobes punctuated by river avulsions – abrupt shifts in river course to the shoreline. River avulsions have been responsible for dangerous floods and civil unrest over human history, but also counter land loss due to sea-level rise and coastal subsidence by nourishing wetlands with sediment. Despite the central role avulsions play on lowland deltas, the processes controlling their location and frequency remain poorly understood compared to steeper environments such as alluvial fans. This thesis is focused on the mechanics of river avulsions on lowland deltas, and the factors controlling their location and frequency. Chapter 1 addresses the origin of a preferential avulsion site on river deltas, using a novel modeling framework that unites previous work to incorporate backwater hydrodynamics, river-mouth progradation, relative sea-level rise, variable flood regimes, and cycles of lobe construction, abandonment, and reoccupation. Chapter 2 focuses on changes to avulsion frequency caused by relative sea-level rise, incorporating a combination of theory, field data, and numerical modeling. Chapter 3 explores general model predictions for avulsion location and timing during climate change, including rising and falling sea level, imbalances in upstream water and sediment supply, and the magnitude and frequency of storm events. Finally, Chapter 4 presents a scaled laboratory experiment where models and theory for lowland delta avulsion mechanics were put to the test. The work presented in this thesis offers new tools to predict river avulsions on densely populated lowland deltas, and allows for comparison with existing models of coastal restoration that fail to account for river avulsion mechanics and the hydrodynamics of lowland rivers.</p
Information Scrambling in Quantum Many-Body Systems
Get PDFA closed quantum system never forgets its initial state, but the encoded information can get scrambled and become inaccessible without measuring a large fraction of all the system degrees of freedom. This scrambling can be diagnosed by studying the spatial spreading of initially local operators under the Heisenberg time evolution, and the decay of the out-of-time-ordered correlators (OTOC). What insights can OTOCs provide to understand the dynamics of quantum many-body systems? What are the characteristic behaviors of OTOCs during the time evolution? How is information scrambling affected by the dissipation in open quantum many-body systems?
We first study slow scrambling in many-body localized systems via calculating various correlators, two-point retarded correlators and OTOCs. Comparing with retarded correlators, OTOCs provide more information about the dynamics. We find that disorder slows and partially halts the onset of information scrambling. Instead of ballistic spreading, propagation of information forms a logarithmic light cone.
Next, we study the finite-size scaling of OTOCs at late times in generic thermalizing quantum many-body systems. When energy is conserved, the late-time saturation value of the OTOC of generic traceless local operators scales as an inverse polynomial in the system size. This is in contrast to the inverse exponential scaling expected for chaotic dynamics without energy conservation.
We also study information scrambling in open quantum many-body systems. We define a dissipative version of OTOC and study its behaviors in a prototypical chaotic quantum chain with dissipation. We find that dissipation leads to not only the overall decay of the scrambled information due to leaking, but also structural changes so that the information light cone can only reach a finite distance even when the effect of overall decay is removed.
Finally, we construct a family of local Hamiltonians for understanding the asymmetric information scrambling. Our models live on a one-dimensional lattice and exhibit asymmetric butterfly light cone between the left and right spatial directions.</p
Physics and Applications of Graphene-Based Nanostructures and Nano-Meta Materials
Get PDFGraphene, a single layer of carbon atoms forming a honeycomb lattice structure, has been considered a wonder material for both scientific research and technological applications. Structural distortions in nano-materials can induce dramatic changes in their electronic properties. In particular, strained graphene can result in both charging effects and pseudo-magnetic fields, so that controlled strain on a perfect graphene lattice can be tailored to yield desirable electronic properties.
In the first part of this thesis (Chapter 2 to 5), we explore a new approach to manipulating the topological states in monolayer graphene via nanoscale strain engineering. By placing strain-free monolayer graphene on architected nanostructures to induce global inversion symmetry breaking, we demonstrate the development of giant pseudo-magnetic fields, global valley polarization, and periodic one-dimensional topological channels for protected propagation of chiral modes in strained graphene. We have also observed pseudo-magnetic field-induced quantum oscillations and valley Hall signals, including quantum valley Hall effect, by transport measurements at 1.8K.
The second part of this thesis focuses on the development and applications of other graphene-based nanostructures. We report PECVD techniques for the synthesis of various graphene and graphene-based nanostructures, including horizontal growth of graphene sheets, vertical growth of graphene nanostructures such as graphene nanostripes with large aspect ratios, and direct and selective deposition of multi-layer graphene on nanostructured substrates. By properly controlling the gas environment of the plasma, it is found that no active heating is necessary for the PECVD growth processes and that high-yield growth can take place in a single step on a variety of surfaces, including metallic, semiconducting, and insulating materials.</p
Thermal Conduction in Amorphous Materials and the Role of Collective Excitations
Get PDFThe atomic vibrations and thermal properties of amorphous dielectric solids are of fundamental and practical interest. For applications, amorphous solids are widely used as thermal insulators in thermopile and other detectors where low thermal conductivity directly sets the sensitivity of the detector. Amorphous solids are of fundamental interest themselves because the lack of atomic periodicity complicates theoretical development. As a result, the lower limits of thermal conductivity in solids as well as the nature of the vibrational excitations that carry heat remain active topics of research.
In this thesis, we use numerical and experimental methods to investigate the thermal conduction in amorphous dielectrics. We begin by using molecular dynamics to investigate the thermal conductivity of amorphous nanocomposites. We find that mismatching the vibrational density of states of constituent materials in the composite is an effective route to achieve exceptionally low thermal conductivity in fully dense solids.
We then transition to examining the properties of the atomic vibrations transporting heat in amorphous solids. For decades, normal mode methods have been used extensively to study thermal transport in amorphous solids. These methods naturally assume that normal modes are the fundamental vibrational excitations transporting heat. We examine the predictions from normal mode analysis that are now able to be tested against experiments, and we find that the predictions from these methods do not agree with experimental observations. For instance, normal mode methods predict that the low frequency normal modes are scattered by anharmonic interactions as in single crystalline solids. However, temperature dependent thermal conductivity measurements demonstrate a typical glassy temperature dependence inconsistent with normal modes scattering through anharmonic interactions. These discrepancies suggest that normal modes are not the fundamental heat carriers in amorphous dielectrics.
To identify the actual heat carriers, we draw on fundamental concepts from many- body physics and inelastic scattering theory that dictate that the excitation energies of a many-body interacting system are given by the poles of the single-particle Green's function. The imaginary part of this function is proportional to the dynamic structure factor that is directly measured in inelastic scattering experiments. Collective excitations of a given energy and wavevector can thus be identified from peaks in the dynamic structure factor; their damping is given by the broadening of the peak. Using these concepts from many-body physics, the physical picture that emerges is that heat is carried in large part by a gas of weakly interacting collective excitations with a cutoff frequency that depends on the atomic structure and composition of the glass.
We test this picture using numerical and experimental inelastic scattering measurements on amorphous silicon, a commonly studied amorphous solid. We observe collective excitations up to 10 THz, well into the thermal spectrum, and far higher than previous inelastic scattering measurements on other glasses. Our numerical and experimental evidence also confirms that the collective excitations are damped by structural disorder rather than anharmonic interactions and that they dominate the thermal conduction in amorphous silicon. Subsequent analysis shows that these high frequency acoustic excitations are supported in amorphous silicon due to a large sound velocity and monatomic composition, suggesting that other monatomic amorphous solids with large sound velocities may also support these thermal excitations.
Overall, our results provide strong evidence that the heat carriers in amorphous dielectrics are collective excitations rather than normal modes. This change in physical picture advances our understanding of atomic dynamics in glasses and also provides a foundation for realizing dielectric solids with ultralow thermal conductivity.</p
Linking Micro-Structure to Macro-Behavior of Granular Matter: From Flowing Heterogeneously to Morphing Adaptively
Get PDFFrom concrete gravels unloaded from trucks to wheat seeds discharged through funnels, from polymeric beads filled in shoe cushions to metallic pellets packed in robotic grippers, granular matter is becoming increasingly relevant in coping with our evolvingly sophisticated societal needs in many respects (e.g. expanding urbanization, growing population and advancing manufacturing). This increasing relevance urges developing micro-structural understandings of granular matter regarding its two basic macro-scale behaviors: flowing heterogeneously and morphing adaptively. However, findings in this regard so far suffered from a disconnection in length-scale - some adopting a top-down perspective lacking predictability due to few insights taken from underpinning micro-scale details (e.g. particle shape), while others adopting a bottom-up perspective lacking practicality due to few specificities incorporated from overlaying macro-scale conditions (e.g. heterogeneities).
In this dissertation, via Discrete Element Method (DEM) simulations, we bridge the divide between length-scales in this regard by revealing the fundamental role of microstructures. To begin with, we evaluate and verify the robustness of DEM in capturing granular microstructures, by systematically comparing simulation results with experimental measurements on quasi-statically sheared granular assemblies. Then, we first numerically study spatial phase transitions in heterogeneous granular flows from a top-down perspective. We start by calibrating and validating a DEM model using experiments we perform on fluidizing spherical particle pile formed in a rotating drum. We next take the validated model to produce flows with different microstructures by systematically varying boundary condition and loading rate, and lastly we study their correlations with phase transitions ranging from gas-like layers near the free surface, to underneath liquid-like layers, and to solid-like layers deep in the bulk. We propose a micro-scale parameter quantifying the level of structural anisotropy, that can for the first time elucidate the spatial phase transitions between these layers independent of imposed boundary conditions and loading rates. Further, we find that, in solid-like layers, this micro-structural quantity correlates to bulk effective friction, an integral macro-scale quantity in constitutive modeling. Next, we numerically study bending modulus adaptations in shape-morphing granular sheets from a bottom-up perspective. We start by calibrating and validating a DEM model using experiments we perform on bending 3D printed granular sheets enclosed in a flexible membrane. We next take the validated model to construct granular sheets with different microstructures by varying constituent particle shape, initial configuration and confining pressure. Lastly we study the correlation between microstructure variations and modulus adaptations. We discover a universal power-law correlation between bending modulus (a macro-scale quantity) and coordination number (a micro-scale quantity) in reminiscence of the canonical power-law scaling for packings of frictionless sphere near jamming. We also find larger coordination number favors interlocked particles over non-interlocked ones, leading to significantly better shape-morphing performance of chain-like sheets over discrete assemblies.</p
Strongly Amenable Groups, Choquet-Deny Groups, and the Infinite Conjugacy Class Property
Get PDFThis thesis consists of two main parts. In the first part, we study a space of symbolic dynamical systems for countable discrete ICC groups and show that minimal proximal actions in that space are generic. This study leads to a characterization of countable discrete strongly amenable groups; a countable discrete group is strongly amenable if and only if it has no ICC quotients.
In the second part, we show that a countable discrete group is Choquet-Deny if and only if it has no ICC quotients, where a group is called Choquet-Deny if the Poisson boundary of every non-degenerate measure on the group is trivial. Combining the aforementioned results, we get that a countable discrete group is Choquet-Deny if and only if it is strongly amenable.
In the case of finitely generated groups, by an old result due to McLain (1956) and Duguid and McLain (1956) and our classifications, we see that strongly amenable groups and Choquet-Deny groups are the same as virtually nilpotent groups.</p
An Experimental and Economic Analysis of Electrochemical Technologies to Reduce Greenhouse Gas Emissions
Get PDFGlobal warming and the related problem of water scarcity are predicted to cause widespread environmental, humanitarian, and economic challenges. New technologies may be able to reduce greenhouse gas emissions enough to prevent many of the worst consequences of climate change However, in order to be competitive in the market, new, low emissions technologies much be affordable. In this thesis I present work on building a technology to lower the cost of decentralized, electrochemical wastewater treatment technologies by improving maintenance. I also show that atomic layer deposition of TiO2 can be used to tune the catalytic activity and stability of multiple electrocatalysts for both the chlorine and oxygen evolution reactions (two of the most widely used electrochemical reactions used to make chlorine gas and in electroplating metals respectively). With more development, this phenomenon has the potential to be used to reduce the cost of many electrochemical systems. I modeled the techno-economics of a low-cost industrial hydrogen production technology and found the first process, to my knowledge, which is able to make industrially relevant quantities of hydrogen at a large scale. I conclude by urging researchers who are trying to solve environmental problems to consider both the potential for the cost of the entire technology to be competitive with existing technologies and to determine what the most effective way to reduce costs are. Finally, I propose that cogeneration of hydrogen and other chemicals may be a viable strategy to producing large quantities of inexpensive, clean hydrogen.</p
Electronic Structures of Perfunctionalized Dodecaborate Clusters
Get PDFDodecahydro-closo-dodecaborate is only stable as a dianionic closed-shell species, however, some alkyloxy- and aryloxy-perfunctionalized dodecaborate clusters ([B12(OR)12], R = alkyl or aryl) can be isolated in hypoelectronic hypocloso-dodecaborate(1-) and hypercloso-dodecaborate(0) states. These hypoelectronic clusters display strong visible absorption bands and highly reversible redox behavior, which have inspired applications in photochemistry, charge-storage and as dopants in conducting polymers. Chapter 1 provides a historic overview of dodecaborate research with particular focus on the development and applications of hypoelectronic clusters. Chapter 2 summarizes our spectroscopic investigtion of the photochemistry and photophysical properties of aryloxy-perfunctionalized hypercloso-dodecaborate(0) clusters. Obtaining reliable photophysical data proved exceedingly difficult due to formation of reduced hypocloso-dodecaborate(1-) species through solvent photooxidation, disproportionation and solvent-cluster interactions. A detailed discussion on these issues is presented, along with the final luminescence data collected for hypercloso-dodecaborate(0) and hypocloso-dodecaborate(1-) clusters. In Chapter 3, we present evidence indicating that certain alkyloxy-perfunctionalized dodecaborate clusters can be further oxidized to a cationic state. Electrochemical and spectroelectrochemical characterization indicate reversible conversion between the dodecaborate(0) and dodecaborate(1+) state. The results are further corroborated by EPR studies on dodecaborate(1+) clusters in-situ generated using the strong oxidant tris(2,4-dibromophenyl)ammoniumyl hexachloroantimonate. In chapter 4, we present Q-band pulsed EPR results that give a quantitative measure of the spin distribution of both hypercloso-dodecaborate(1-) and super-oxidized dodecaborate(1+) clusters. This is to our knowledge the first time pulsed EPR techniques have been applied to hypoelectronic dodecaborate clusters. The EPR data indicate that the frontier orbitals of hypoelectronic dodecaborate clusters are confined to the cluster core and delocalized evenly across the B12 pseudo-icosahedron. Furthermore, we provide UV–vis–NIR evidence indicating that the visible and NIR electronic transitions of these clusters occur between orbitals that are largely confined to the cluster core. Chapter 5 summarizes our results and discusses future directions
Searching for the Astrophysical Gravitational-Wave Background and Prompt Radio Emission from Compact Binaries
Get PDFGravitational-wave astronomy is now a reality. During my time at Caltech, the Advanced LIGO and Virgo observatories have detected gravitational waves from dozens of compact binary coalescences. All of these gravitational-wave events occurred in the relatively local Universe. In the first part of this thesis, I will instead look towards the remote Universe, investigating what LIGO and Virgo may be able to learn about cosmologically-distant compact binaries via observation of the stochastic gravitational-wave background. The stochastic gravitational-wave background is composed of the incoherent superposition of all distant, individually-unresolvable gravitational-wave sources. I explore what we learn from study of the gravitational-wave background, both about the astrophysics of compact binaries and the fundamental nature of gravitational waves. Of course, before we can study the gravitational-wave background we must first detect it. I therefore present searches for the gravitational-wave background using data from Advanced LIGO's first two observing runs, obtaining the most stringent upper limits to date on strength of the stochastic background. Finally, I consider how one might validate an apparent detection of the gravitational-wave background, confidently distinguishing a true astrophysical signal from spurious terrestrial artifacts.
The second part of this thesis concerns the search for electromagnetic counterparts to gravitational-wave events. The binary neutron star merger GW170817 was accompanied by a rich set of electromagnetic counterparts spanning nearly the entire electromagnetic spectrum. Beyond these counterparts, compact binaries may additionally generate powerful radio transients at or near their time of merger. First, I consider whether there is a plausible connection between this so-called "prompt radio emission" and fast radio bursts — enigmatic radio transients of unknown origin. Next, I present the first direct search for prompt radio emission from a compact binary merger using the Owens Valley Radio Observatory Long Wavelength Array (OVRO-LWA). While no plausible candidates are identified, this effort successfully demonstrates the prompt radio follow-up of a gravitational-wave source, providing a blueprint for LIGO and Virgo follow-up in their O3 observing run and beyond.</p