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Laboratory Investigation of Shear Ruptures: Supersonic Propagation and Nucleation by Fluid Injection
Get PDFShear rupture nucleation and dynamic propagation is a challenging, non- linear, highly interactive process with important practical implications. Here we focus on two aspects of this problem: propagation speeds and shock front radiation from the dynamic crack tip as well as nucleation of dynamic rupture due to fluid injection.
Spontaneously propagating cracks in solids emit pressure and shear waves and are, in part, driven by energy transfer due to them. When a shear crack propagates faster than the shear wave speed of the material, the coalescence of the shear wavelets emitted by the near-crack-tip region forms a shock front that significantly concentrates particle motion. The equivalent scenario involving a pressure shock front should not be possible, since cracks should not be able to exceed the pressure wave speed, at least in an isotropic linear-elastic solid. Here we present full-field experimental evidence of dynamic shear cracks in viscoelastic polymers that result in the formation of a pressure shock front, in addition to the shear one. In that sense, the crack appears to be supersonic. The apparent violation of classic theories is explained by the strain-rate-dependent material behavior of polymers: the increased wave speeds within the highly- strained region around the crack tip allow for supersonic crack propagation with respect to the (lower) wave speeds at short distances away from the interface, resulting in the formation of the pressure shock front. The crack speed remains below the pressure wave speed prevailing locally, about its tip, in agreement with basic physics and energy considerations of linear-elastic theories.
We find that the shock fronts emitted by the shear cracks in the viscoelastic materials are curved and propose a novel method to quantify the viscoelastic wave speeds of the solids in the dynamic range of strain rates based on the curvature. Only kinematic relationships are used in the method, without the need for the constitutive relationship of the material. Measuring or inferring the material properties at elevated strain rates in viscoelastic solids is a difficult task, because of practical limitations of obtaining accurate measurements in that regime. Under the quasi-elastic solid approximation, in which the strain-rate history is neglected, we use the pressure-wave speed measurements to infer the associated value of the Young’s modulus, estimated by assuming a constant value of the Poisson’s ratio. We complement these results with the characterization of the Young’s modulus at lower strain rates via canonical compressive tests. Our results not only confirm previous findings that the Young’s modulus dependence on the strain rate in PMMA is significant but also demonstrate that its variation is more pronounced in the dynamic strain-rate range, with important consequences for the design of structures employing viscoelastic materials that are required to withstand elevated strain rates.
The second part of the study concentrates on the nucleation of shear dynamic rupture due to fluid injection or, more broadly, on the interaction of frictional faulting with fluids. Fluid overpressure is recognized to play a fundamental role in promoting fault motion. A large number of observations has shed light on the interplay between fluids and faulting, both in natural events and in earth-quakes induced by human activities, such as wastewater disposal associated with oil and gas extraction. Fluids can induce a variety of earthquake source behaviors ranging from unstable, dynamic motions to stable, quasi-static ones, which a number of field studies suggests that can coexist on the same fault areas at different times, depending on the local conditions. In fact, a higher pore pres-sure plays the dual role of reducing the frictional strength of the fault and of increasing the nucleation size, e.g., the critical length for a shear crack to transition from quasi-static to dynamic motions. However, due to the complexity of the frictional problem at the fault interface, the understanding of which of these two effects prevails remains elusive. The assumption of a critical nucleation length represents a powerful, yet simplified concept, which currently does not include the dependence on the rate of the pore pressure increase.
Here, we explore the effect of the rate of the pore pressure increase on the rupture nucleation. We find that elevated injection rates induce triggering of the rupture at lower pressure values and minimal volumes of the injected fluid, if compared to slow injection rates. For the slow injection rates, we experimentally observe a much larger portion of interface wetted by the fluid and a phase of accelerated slip prior to the dynamic event (quasi-dynamic nucleation process). In some cases, we record much smaller foreshock-like events at the injection site. These findings suggest the presence of a prominent quasi-static nucleation process over the interface. In cases of rapid pore pressure increase, the nucleation process is much shorter in time and much more compact in space, being highly concentrated around the injection location. The dynamic events, once initiated, are qualitatively similar across different injection rates, but quantitatively different, with the slow-injection ones experiencing higher stress drops and higher slips, perhaps due to the effect of fluids on the friction properties.
These findings suggest the need to develop nucleation size estimates that include the rate of the pore pressure increase and motivate further investigation of how friction properties depend on the presence of fluids. The details of the obtained experimental findings, once analyzed through numerical modeling, will place important constrains on the forms of the acceptable friction laws, including the effects of pore fluid pressure and its rate of change.</p
Measuring and Modeling the Interplay between Planetary Orbits, Interiors, Surfaces, and Atmospheres
Get PDFTypically, we only have access to observations that directly probe the instantaneous state of a planet. However, these instantaneous properties are often set by the long-term interplay between several aspects of the planet. I thus use quantitative models of the interactions between the orbital, interior, surface, and atmospheric evolution in the case of three planetary bodies (Mars, Pluto, and the extrasolar planet HAT-P-13b) to gain insight into the underlying physical processes that govern the evolution of planets.
In chapter 2, the interplay between the interior structure and orbital evolution of the gas giant exoplanet HAT-P-13b allows measurements of its orbit to reveal its interior structure. I use telescopic observations of HAT-P-13b to measure its orbit and thus determine its core mass.
In chapter 3, cell-shaped landforms on Sputnik Planitia, the surface of a vast deposit of nitrogen ice covering 5% of Pluto’s surface, are the surface expression of convection within the nitrogen ice that is driven by heat flow from Pluto’s interior. The cells have sublimation pits on them, with smaller pits near their centers and larger pits near their edges. Using a simple model, I calculate the sublimation rate of these pits, which allows the determination of a size-age relationship. I then use the spatial size distribution of pits on cells to calculate their convection rate, which constrains the plutonian heat flow and thus the interior properties of Pluto.
In chapter 4, the interplay of condensation and sublimation between the surface and atmosphere of Mars create a baffling array of uniquely martian morphologies carved into the martian residual south polar CO2 cap (RSPC). Using a multi-year baseline of high-resolution observations to track the evolution of these morphologies, I build a self-consistent conceptual framework capable of explaining the basic mechanisms that give rise to the diversity of landforms that make up the RSPC.
In chapter 5, the secular evolution of Mars' orbit drives the evolution of the equilibrium relationship between the martian atmospheric pressure and the large CO2 ice deposit on the martian south polar cap. I construct the first self-consistent conceptual framework capable of predicting the existence and form of the martian residual south polar cap and the buried CO2 deposit. I then use this framework to compute the secular pressure history of Mars.
Together, the results of these investigations provide new perspective into the fundamental processes driving the formation and evolution of planetary bodies.</p
Spin in Conformal Field Theory
Get PDFWe study various questions related to operators with spin in quantum conformal field theory in dimensions higher than two. In particular, we classify conformally-invariant tensor structures which appear in correlation functions of local operators and develop tools for computation of conformal blocks which contribute to these functions. We study the crossing equations for four-point functions using numerical and analytical techniques. Finally, we explore the question of analytic continuation of local operators in spin, which leads us to a simple proof of a generalized Lorentzian inversion formula.</p
Self-Repair and Sleep in Jellyfish
Get PDFStudying the cnidarian jellyfish, we have pursued basic biological questions related to self-repair mechanisms and sleep behavior. Working in Aurelia we have discovered a novel strategy of self-repair; we determined that they can undergo body reorganization after amputations that culminates in the recovery of essential radial symmetry without rebuilding lost parts. Working with Cassiopea, we have, for the first time, identified a behavioral sleep-like state in an animal without a centralized nervous system, supporting the hypothesis that sleep is ancestral in animals.</p
The Effective Field Theory of Fermi Surfaces in the Vicinity of Van Hove Singularities
Get PDFThe use of effective field theories to attack new and seemingly disparate problems has proliferated in the past several decades. In this thesis, we develop effective field theories for systems of fermionic quasiparticles possessing Fermi surfaces, with a particular focus on Fermi surfaces proximal to Van Hove singularities. Such systems are a fruitful source of complex and novel behavior in condensed matter physics. We begin with an overview of the renormalization group procedure at the heart of effective field theory by analyzing a simple example. We emphasize the concept that the RG relates the observables of one theory to those of another theory with precisely the same form but different numerical parameters. We also note the generality and extensibility of these concepts. We then apply this perspective to the study of quasiparticles with a round Fermi surface, employing the technique of binning the quasiparticle fields in momentum space to translate previous treatments into a more modern form. We next develop an effective field theory describing the excitations of modes around a Fermi surface with a Van Hove singularity. We resolve lingering questions about the presence of nonlocal interactions in similar models. We find a rich and complicated theory capable of describing deviations from typical Fermi liquid behavior that nonetheless displays some universal dependence on the interactions involving modes in the vicinity of the Van Hove point. We close with an analysis of the instabilities of this Van Hove effective field theory.</p
Targeted Nanoparticle Delivery of Therapeutics Across the Blood-Brain and Blood-Tumor Barriers to Breast Cancer Brain Metastases
Get PDFBrain metastases of human epidermal growth factor receptor 2 (HER2)-positive breast cancer are presenting an increasing problem in the clinic. While HER2-targeted therapies effectively control systemic disease, their efficacy against brain metastases is hindered by their inability to penetrate the blood-brain and blood-tumor barriers (BBB and BTB). One promising strategy to increase brain penetration of systemic therapeutics is to exploit endogenous transport systems at the BBB to shuttle drugs into the brain. Previous studies showed that gold nanoparticles designed to shed transferrin receptor (TfR)-targeting ligands under acidic conditions encountered during transcytosis of the BBB demonstrated increased accumulation in the brain. The focus of this work was to determine whether therapeutic, TfR-targeted nanoparticles using an improved acid-cleavable chemistry could be used to deliver therapeutically useful amounts of drug to the brain.
To accomplish this goal, a new animal model of HER2-positive breast cancer brain metastasis was developed in an attempt to create a clinically representative, impermeable barrier to standard therapeutics. This new model establishes brain metastases by methods that more closely resemble the human disease, forming whole-body tumors that eventually metastasize to the brain. Brain metastases formed by this new methodology show no response to standard HER2-targeted agents, mimicking the clinical situation.
Next, efficacy and brain uptake of TfR-targeted, single-agent therapeutic nanoparticles were investigated in the newly developed model, as well as two common models from the literature. These nanoparticles show significant tumor growth delay and increased accumulation in both brain metastases and healthy brain tissue in all three models, highlighting their therapeutic potential. Additionally, non-BBB-penetrant small molecule and non-targeted nanoparticle therapeutics elicit a substantial antitumor response as well as brain tumor accumulation in the most commonly used literature model. In contrast, the new model and one gaining popularity in the literature provide for a more clinically relevant, impermeable barrier to non-BBB-penetrant agents, indicating that the method used to establish brain metastases can affect efficacy and brain uptake of therapeutics.</p
Redox Signaling in Eukaryotic DNA Replication and Repair
Get PDFDNA-mediated charge transport chemistry (DNA CT) offers an intriguing regulatory mechanism in biology, as it is long-range, rapid, and sensitive to mismatches and perturbations to base stacking. DNA-processing enzymes in all three domains of life moreover have been shown to contain [4Fe4S] clusters, commonly redox cofactors. Bacterial [4Fe4S] repair proteins have been shown to signal one another using long-range DNA-mediated charge transport (DNA CT), facilitating the redistribution to damaged genomic DNA in cells. The role of metabolically expensive, [4Fe4S] cluster cofactors in eukaryotic systems, however, was less clear than in prokaryotes.
Here we examine the chemical role of the [4Fe4S] cluster in eukaryotic DNA primase and the human base excision repair glycosylase, MUTYH. The primase cluster functions as a redox switch regulating DNA binding and redox signaling activity in humans and yeast. Yeast moreover require the primase redox switch for viability. Human MUTYH, a bifunctional glycosylase which repairs oxidative DNA lesions, performs DNA-mediated redox signaling, similarly to the bacterial homologue MutY. The MUTYH mutation which destabilizes the [4Fe4S] cluster during redox signaling, C306W, promotes degradation and loss of activity, associated with hereditary colorectal cancer.
To assess the redox role of the human primase [4Fe4S] cluster, we perform anaerobic DNA electrochemistry on the [4Fe4S] domain of human primase (p58C), which independently binds DNA. On DNA-modified Au electrodes, we compare the redox activity of electrochemically oxidized and electrochemically reduced p58C. Oxidized [4Fe4S]3+ p58C is electrochemically active, and reduced [4Fe4S]2+ p58C state is redox-inert. This redox-driven switch is electrochemically reversible, and is mediated by a triad of conserved tyrosines between the DNA binding interface and [4Fe4S] cluster. Mutation of residues Y309, Y345, and Y347 to phenylalanine causes attenuation of redox switching on DNA. Single-atom mutations in the redox pathway moreover compromise initiation and truncation of primer synthesis but do not affect RNA polymerase activity. We find that primase truncation is gated by DNA CT in vitro; a single mismatch in the nascent primer abrogates truncation of primase products. As
primase is tethered to DNA polymerase α, a putative [4Fe4S] enzyme to which primase hands off the RNA-primed template, we propose that DNA-mediated signaling between primase and polymerase α chemically regulates this handoff during the first steps of replication.
Eukaryotic primase must bind both DNA and nucleotide triphosphates (NTPs) in order to convert to active form. Using DNA electrochemistry we show that p58C, and full-length DNA primase, display a robust, semi-reversible NTP-dependent signal on DNA, centered near 150mV vs. NHE. This signal is dependent on the tyrosine redox pathway. The presence of reversible redox activity at a physiological potential when primase is bound to DNA and NTPs suggests that reversible redox switching from the [4Fe4S]2+ to the [4Fe4S]3+ state is important for the activity of primase during replication.
The cluster serves as a redox switch governing DNA binding in yeast primase, just as in human primase. Mutation of tyrosines 395 and 397 in yeast primase moreover, alters the same electron transfer chemistry as the mutation of their orthologues, Y345 and Y347, respectively, alters in human primase. Although these tyrosines are arranged differently in the yeast and human proteins, they perform the same reaction to affect the switch. The single-atom Y395F mutation causes some sensitivity to chemically induced oxidative stress in yeast, and single-residue mutation Y397L confers lethality in yeast cells. A constellation of tyrosines for protein-DNA electron transfer mediates the redox switch in eukaryotic primases, regulates the affinity for RNA-primed DNA template, and is required for primase function in vivo.
We finally characterize a novel mutation in the [4Fe4S] human base excision repair protein, MUTYH, which destabilizes the cluster environment and has pathogenic consequences. The MUTYH C306W mutation alters one of the cysteines coordinating the cluster to tryptophan. This mutation moreover is associated with hereditary colorectal cancer and causes defective DNA binding and enzymatic activity. We perform DNA electrochemistry on WT MUTYH, as well as C306W and two cancer-associated mutants, Y197C and G396D, which have an unaltered cluster environment. MUTYH variants participate in redox signaling, but C306W is destabilized upon oxidation from the [4Fe4S]2+ to the [4Fe4S]3+ state during signaling on DNA, leading to degradation to a [3Fe4S]+ cluster and loss of DNA binding and activity. A [4Fe4S] human DNA repair enzyme performs redox signaling on DNA; dysregulation of this signaling activity is linked to tumorigenesis.</p
Why Cervantes' History is His Story
No full text[Introduction] "Historians must and ought to be exact, truthful, and absolutely free of passions, for neither interest, fear, rancor, nor affection should make them deviate from the path of the truth" (Grossman 68
Earthquake Moment-Area Scaling Relations and the Effect of Fault Heterogeneity on Slow to Fast Earthquake Slip
Get PDFEarthquake moment-area scaling relations play a key role in both earthquake physics studies and earthquake hazard assessment. A three-stage moment-area relation, based on advances in earthquake source inversion, is currently in use in Japan. The second stage has a scaling exponent outside the range of commonly accepted models of small and very large earthquakes. We develop theoretical insight on the mechanical origin of this second-stage scaling. We utilize an analytical dislocation model, a numerical crack model and multi-cycle rate-and-state simulations of strike-slip faults with heterogeneous friction properties. We find that the second stage in earthquake moment-area scaling results from a combination of surface rupture effects, comprising an effective rupture elongation along-dip due to a mirror effect and systematic changes of the shape factor relating slip to stress drop. Based on this physical insight, we propose a simplified formula to account for these effects in moment-area scaling relations.
Geological, seismological, geodetic and experimental studies provide evidence of the heterogeneous structure of natural faults. To advance our understanding of the mechanical role of fault heterogeneity on the diversity of earthquake slip behavior, we conduct a theoretical and computational study of heterogeneous fault models. We consider faults with a mixture of frictionally stable and unstable materials and spatial contrasts of fault zone pore fluid pressure, akin to hydraulically sealed brittle asperities embedded in a ductile fault zone matrix. We first study faults with a regular alternation of materials, using linear stability analysis and quasi-dynamic rate-and-state simulations. We find transitions in fault behavior from fast to slow earthquakes to steady slip, and determine how these transitions depend on the composition and strength contrast of the material mixture. Based on these results, we develop rate-and-state models with stochastic distributions of brittle asperities in a ductile matrix to study slow slip and tremor phenomena. We focus on the hierarchical patterns of tremor migration observed in subduction zones, which feature distinct tremor propagation speeds in different directions. Our models are in quantitative agreement with observations of episodic slow slip and tremor events in Cascadia. We discovered that, in contrast to a common view, slow slip might well be a result of tremor activity rather than its cause. The collective interaction of asperities with a broad range of material properties, mediated by creep, is a novel and robust mechanism for the generation of slow slip events. We find that the hierarchical patterns of tremor migration and the nucleation locations of tremor swarms provide constraints on fault rheology. Our study also shows that, despite multiple asperity interactions, there is a close relation between tremor rate and the underlying slip rate which supports an approach to constrain slow slip rate via observed tremor rates.</p
Application, Computation, and Theory for Synthetic Gene Circuits
Get PDFThe field of synthetic gene circuits is concerned with engineering novel gene expression dynamics into organisms. This field, a subset of synthetic biology, was started almost two decades ago with the creation of two synthetic circuits: a bistable toggle switch and an oscillator. From the very outset, modeling has played a role in the development of synthetic circuits. However, modeling has been used to gain qualitative insight into dynamics, and actual quantitative modeling has been lagging behind.
Parameters for quantitative models for biological systems often cannot be adequately estimated from measured data, because far too many sets of parameters can produce the same set of limited measured outputs. Additionally, models for synthetic gene circuits are often not correct the first time, and iterating on cycles of modeling and parameter estimation is difficult. Finally, there is a gap between development of modeling and system identification tools and their application to experiments on actual synthetic gene circuits.
This thesis attempts to work towards addressing these issues with quantitative modeling for synthetic gene circuits. First, we derive theoretical conditions for identifiability of stochastic linear systems from heterogenous types of measurement data. These identifiability conditions can provide insight into what type of model to use and what measurements to collect in order to ensure that the resulting model can be identified.
Second, we develop a software package for fast and flexible modeling and parameter estimation for synthetic gene circuits. The user can input models into our software using a simple text format and perform simulations of all types at optimized speeds. By inputting measured experimental data along with the model, the software can be used to perform Bayesian parameter estimation in an automated manner. To bridge the gap between computation and application, we apply this software to parameter estimation of DNA recombinase dynamics using real experimental data collected in an in vitro cell extract.
Finally, we use modeling to guide the design of an improved single gene synthetic oscillator. While the original synthetic genetic oscillator contained three genes, we show that a simple circuit with a single gene can produce robust and synchronized oscillations across a population.
Our results constitute an additional step towards the incorporation of quantitative modeling and parameter inference as part of the design-build-test cycle for synthetic gene circuits.</p