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Development of Analytical Tools and Animal Models for Studies of Small-Intestine Dysbiosis
Get PDFOur appreciation of the role of human-associated microbial communities in the context of human health and disease has grown dramatically in the past two decades, with modern research tools enabling deeper insights into the mechanisms of host-microbial interactions. The elusive notion of dysbiosis, a state of microbial imbalance related to a disease, has achieved widespread distribution across popular, scientific, and medical literature (on September 16, 2019 PubMed search yielded 6,064 records of scientific and medical publications containing this keyword). The conventional wisdom further narrows down the definition and understanding of dysbiosis towards a compositional "imbalance" of the microbiota (a community of all microorganisms inhabiting human body). There exists an additional and frequently overlooked aspect of microbial imbalance in the context of the human gastrointestinal system, something that we can define as a "spatial imbalance": a state of the microbial community in the host gastrointestinal system where even a "healthy" and "balanced" microbiota may be associated with or causative of a disease by being present in sections of the gastrointestinal tract where it is not "supposed" to be, with the most prominent example being small intestinal bacterial overgrowth (SIBO). This thesis describes the progress in the development of analytical tools (quantitative microbiome profiling described in Chapter I) and refinement of animal mouse models (non-coprophagic mouse model described in Chapter II) for exploring the normal function of small-intestine microbiota in health and for dissecting the mechanisms of emergence and the persistence of the small-intestine dysbiosis (SIBO) in the future.</p
Proton-Coupled Electron Transfer in Nitrogen Fixation
Get PDFThis thesis focuses on the management of protons and electrons in the formation of X−H bonds. In our pursuit of better understanding this process, we have been particularly interested in the nitrogen fixation reaction (N2-to-NH3) because of the high number of protons and electrons involved in this conversion (6) and the significant difficulty of functionalizing N2. The first chapter introduces the important themes of this thesis: (i) multiple bonding, (ii) proton-coupled electron transfer, (iii) overpotential in N2 fixation, and (iv) selectivity in N2 fixation. The second chapter discusses the bonding of an iron complex with a small molecule (NO) and how this bonding is key to activating the small molecule for reactivity. The third chapter looks at how employing a new proton and electron source allows an Fe catalyst to achieve improved selectivity and turnover number for the reduction of N2 to NH3 despite a lowered overpotential relative to previous reactions. It also raises the hypothesis that this is possible due to proton-coupled electron transfer mediated by a metallocene. The fourth chapter studies the effect of acid strength on N2 fixation selectivity and demonstrates circumstantial evidence for the involvement of a decamethylcobaltocene (Cp*2Co) in the formation of N−H bonds via proton-coupled electron transfer. It also highlights how the addition of co-catalytic [Cp*2Co]+ to electrochemical experiments with our Fe catalyst enabled truly electrocatalytic N2 fixation for the first time. The fifth chapter provides both atomistic detail on the protonation reactivity of Cp*2Co and experimentally verifies the prediction that this species would be an extremely strong hydrogen-atom donor. It also develops a conceptual framework to explain the uniquely weak C−H bonds both homolytic and heterolytic that result from metallocene protonation and discusses their potential to play a role in not only the hydrogen evolution reaction (HER), but also the N2 fixation reaction. In the final chapter, we develop a synthetic route to a base appended cobaltocene. We demonstrate that this second-generation cobaltocene can, unlike the first generation, serve as a net hydrogen-atom donor under electrocatalytic conditions. As a demonstration of the utility of this, we use the base-appended cobaltocene for the selective, proton-coupled reduction of ketones to pinacols via a rate-determing concerted proton-electron transfer.</p
Shock Compression of Molybdenum Single Crystals to High Stresses
Get PDFTo investigate the role of crystal anisotropy and the impact stress on the shock induced elastic-plastic deformation of BCC single crystals at high stresses, molybdenum single crystals were shock compressed along [100], [111], and [110] orientations. A series of plate impact experiments were conducted with various impact stresses (23 - 190 GPa) along each orientation. Along the [100] and [111] orientations, two-wave structure - an elastic shock wave trailed by a plastic shock wave - was observed to 110 GPa. Along the [110] orientation, the two-wave structure was observed only up to 90 GPa.
Based on the measured quantities, in-material quantities at the elastic limit and at the peak state were calculated. The elastic wave amplitudes were analyzed to determine the crystal anisotropy effects, the impact stress dependence, and the activated slip systems on the elastic limit. The elastic wave amplitude increased linearly with
increasing impact stress, and that was significantly larger along the [111] orientation compared to the other orientations. The difference between calculated maximum resolved shear stresses at the elastic limit and corresponding Peierls stress suggested the activation of {110}<111> slip systems.
At the peak state, the Hugoniot relations were calculated along each orientation and compared with polycrystalline molybdenum Hugoniot relations. The Hugoniot relations along three orientations were in agreement within experimental uncertainties, even though the elastic limit showed considerable anisotropy. Also, they agreed reasonably well with the polycrystalline molybdenum data. This implied that the in-material quantities at the peak state do not depend on crystal orientation or the presence of grain boundaries.
In addition to the plate impact experiments, finite element simulations of shock compressed molybdenum single crystals were conducted using Abaqus Explicit in order to gain insight into deformation mechanisms activated during the elasticplastic
deformation. Shear strains on slip systems were explicitly considered by the crystal plasticity model implemented using Abaqus VUMAT subroutine. The results of FEM simulations indicated that {110}<111> systems were likely to be operating at the elastic limit. This observation was consistent with the experimental results from the present study.</p
Boundary Integral Equation Methods for Simulation and Design of Photonic Devices
Get PDFThis thesis presents novel boundary integral equation (BIE) and associated optimization methodologies for photonic devices. The simulation and optimization of such structures is a vast and rapidly growing engineering area, which impacts on design of optical devices such as waveguide splitters, tapers, grating couplers, and metamaterial structures, all of which are commonly used as elements in the field of integrated photonics. The design process has been significantly facilitated in recent years on the basis of a variety of methods in computational electromagnetic (EM) simulation and design. Unfortunately, however, the expense required by previous simulation tools has limited the extent and complexity of the structures that can be treated. The methods presented in this thesis represent the results of our efforts towards accomplishing the dual goals of 1) Accurate and efficient EM simulation for general, highly-complex three-dimensional problems, and 2) Development of effective optimization methods leading to an improved state of the art in EM design.
One of the main proposed elements utilizes BIE in conjunction with a modified-search algorithm to obtain the modes of uniform waveguides with arbitrary cross sections. This method avoids spurious solutions by means of a certain normalization procedure for the fields within the waveguides. In order to handle problems including nonuniform waveguide structures, we introduce the windowed Green function (WGF) method, which used in conjunction with auxiliary integral representations for bound mode excitations, has enabled accurate simulation of a wide variety of waveguide problems on the basis of highly accurate and efficient BIE, in two and three spatial dimensions. The "rectangular-polar" method provides the basic high-order singular-integration engine. Based on non-overlapping Chebyshev-discretized patches, the rectangular-polar method underlies the accuracy and efficiency of the proposed general-geometry three-dimensional BIE approach. Finally, we introduce a three-dimensional BIE framework for the efficient computation of sensitivities — i.e. gradients with respect to design parameters — via adjoint techniques. This methodology is then applied to the design of metalenses including up to a thousand parameters, where the overall optimization process takes in the order of three hours using five hundred computing cores. Forthcoming work along the lines of this effort seeks to extend and apply these methodologies to some of the most challenging and exciting design problems in electromagnetics in general, and photonics in particular.</p
Evolving Strategies Toward the Synthesis of Curcusone C
Get PDFCurcusone C is a tricyclic diterpenoid natural product possessing potent anti-cancer activities as well as a structurally unusual 2,3,7,8-tetrahydroazulene-1,4-dione skeleton. Herein, we report our evolving synthetic efforts toward the divergent total syntheses of ent-curcusone C and several structural congeners, which commenced with a Suzuki coupling of the peripheral carbon-based rings. Whereas the boronate partner was constructed from cyclopentenone, the halide partner could be elaborated from (S)-perillaldehyde. The alcohol coupling product was next esterified, then subjected to diazo transfer and cyclopropanation to produce a lactone. The resulting vinyl cyclopropane moiety was exposed to Kauffmann olefination conditions in order to form a divinylcyclopropane, which upon reductive lactone opening smoothly underwent a Cope rearrangement to establish the essential tricyclic core embedded in the curcusones.
Due to ongoing issues of scalability as well as unsatisfactory yields for the key cyclopropanation step, this route was ultimately abandoned, and an alternative strategy was devised which instead relied on a cross-electrophile coupling to join the peripheral rings. We further found that a central ring could be constructed via either Stetter annulation or ring-closing metathesis (RCM), accessing the tricyclic core of the curcusones in only 9 steps. Potential end-game strategies are further described.
We additionally report our experimental research into the acyl-amination of in situ-generated arynes using symmetrical imides. The difunctionalized aryl products could be further derivatized to synthetically useful indoles and quinolones via McMurray coupling and Camps cyclization, respectively.</p
Phonon Thermodynamics and Elastic Behavior of GaN and GaAs at High Temperatures and Pressures
Get PDFThe work herein studies how high temperatures and pressure impact the properties of four materials: two phases of Gallium Nitride (GaN) and two phases of Gallium Arsenide (GaAs). The particular phases we study are the wurtzite and zinc blende phases of each chemical composition. The properties we study concern (1) the phonon thermodynamics and (2) the elastic behavior. In particular, phonons were calculated at simultaneously elevated temperature and pressure, and elastic constants were calculated as functions of pressure at 0 K.
Our studies of phonon thermodynamics included comparing the results of phonon calculations accounting for full temperature effects to the results of a quasiharmonic approximation (QHA) for each material, allowing us to assess the importance of explicitly anharmonic contributions to the phonons with changing temperature and pressure.
In GaN, the QHA gave reasonable results for the temperature dependence of the phonon DOS at zero pressure, but unreliably predicted the combined effects of temperature and pressure.
Pressure was found to change the explicit anharmonicity, altering the thermal shifts of phonons, and more notably qualitatively changing the evolution of phonon lifetimes with increasing temperature. These effects were largest for the optical modes, and phonon frequencies below approximately 5 THz were adequately predicted with the QHA.
In GaAs, the QHA failed to account for temperature-induced phonon frequency shifts at all pressures. As in GaN, the QHA was not able to predict the combined effects of temperature and pressure. In GaAs, the QHA clearly became less reliable with elevated pressure. In particular, the number of three-phonon processes increased with pressure, thereby increasing the temperature-driven broadening of phonon spectral lineshapes.
So, why did pressure change the possible three-phonon processes in both GaN and GaAs, but cause them to net increase in GaAs? In all materials, the frequencies of phonon branches were sensitive to pressure to varying degrees. Showing the greatest contrast, transverse acoustic modes in all four materials softened with increasing pressure, whereas all other modes stiffened, albeit at different rates. If the frequencies of all modes scaled uniformly with pressure, we might expect that phonon decay channels consisting of equivalent input and output total phonon frequencies would persist independent of pressure; non-uniform frequency scaling, however, destroys some phonon decay channels and creates others in order to conserve energy. The dissimilar atomic masses of Ga and N create a phonon bandgap in GaN that increased with pressure. The increasing phonon bandgap frequently pushed some of the high frequency optical modes out of range of previously available down-conversion processes, ultimately causing GaN to become more quasiharmonic with pressure. More similar atomic masses in GaAs, however, prevent GaAs from exhibiting a true phonon bandgap; in this case, pressure was not able to drive the acoustic and optical branches away from each other, and instead created more opportunities for conversion.
Our understanding of the elastic behavior of each material derived from both calculations of the elastic constants and from additional information we could extract from the phonons. We used elastic constants to study elastic anisotropy and to predict the onset of elastic instability using the Born stability criteria. In GaN, elastic anisotropy increased with pressure until reaching elastic instabilities at 65 GPa (wurtzite) and 40 GPa (zinc blende). In GaAs, elastic anisotropy again increased with pressure through the onset of lattice instability, but the Born stability criteria failed to accurately predict this instability. Instead, pressure caused instabilities of shorter-wavelength transverse acoustic modes in both phases of GaAs that preceded the onset of instability predicted by the Born stability criteria, which depend on elastic constants and thereby only long wavelength phonons. In particular, pressure drove the frequencies of shorter-wavelength transverse acoustic phonon instabilities down until they reached 0 THz, inducing instability at 18 GPa (wurtzite) and 20 GPa (zinc blende). Interestingly, temperature caused a significant stabilization of these phonon modes, however, slowing their softening with pressure.</p
Development and Mechanistic Investigation of Potassium Tert-Butoxide Catalyzed C–H Silylation
Get PDFThe synthetic organic community has a long history of concurrent development of new methods, total syntheses, and mechanistic investigations. For example, new methods may allow the synthesis of previously inaccessible synthetic targets or a challenging transformation in a total synthesis may lead to the development of new reaction methods. Understanding the mechanism of a reaction may lead to the development of new methods or application in total synthesis. Historically, the Stoltz group has found great success focusing on the synergistic development of reaction methods, total synthesis, and mechanistic investigation. This thesis focuses on the mechanistic investigation of a novel method developed by our group and a number of new methods inspired by this better understanding of the reaction mechanism.
Initially, an overview of transition-metal-free, catalytic C–H silylation reactions is presented. Next, a detailed mechanistic investigation into the KOt-Bu-catalyzed C–H silylation reaction of aromatic heterocycles is presented. This investigation covers a series of experimental, computational, and analytic techniques to probe possible radical or ionic reaction mechanisms. The development of a number of new methods is presented including the catalytic trimethylsilylation of aromatic heterocycles and catalytic silylation of terminal alkynes.
Finally, the current progress of our efforts toward the total synthesis of the natural product illisimonin A are presented.</p
Decision Making Under Threat: An Ecological Framework
Get PDFHumans, like other animals, have evolved a set of neural circuits whose primary function is survival. In the case of predation, these circuits include "reactive fear" circuits involved in fast escape decisions, and "cognitive fear" circuits that are involved in more complex processing associated with slow strategic escape. In the context of flight initiation distance (FID), using neuroimaging combined with computational modeling, we support this differentiation of fear circuits by showing that fast escape decisions are elicited by the periaqueductal gray and midcingulate cortex, regions involved in reactive flight. Conversely, slower escape decisions rely on the hippocampus, posterior cingulate cortex, and prefrontal cortex, a circuit implicated in behavioral flexibility. We further tested whether individual differences in trait anxiety would impact escape behavior and neural responses to slow and fast attacking predators. Behaviorally, we found that trait anxiety was not related to escape decisions for fast threats, but individuals with higher trait anxiety escaped earlier during slow threats. Functional MRI showed that when subjects faced slow threats, trait anxiety positively correlated with activity in the vHPC, mPFC, amygdala and insula. Further, the strength of the functional coupling between the vHPC and mPFC was correlated with the degree of trait anxiety. A similar pattern of separation in survival circuits is also found in a follow up study utilizing the concept of margin of safety (MOS) with multivariate pattern analysis of fMRI data. In addition, we also discussed how decision making under threat was influenced by social factors such as reputation. Overall, these results provide new insights into decision making under threat and a separation of fear into reactive and cognitive circuits.</p
Extremal Results in and out of Additive Combinatorics
Get PDFIn this thesis, we study several related topics in extremal combinatorics, all tied together by various themes from additive combinatorics and combinatorial geometry.
First, we discuss some extremal problems where local properties are used to derive global properties. That is, we consider a given configuration where every small piece of the configuration satisfies some restriction, and use this local property to derive global properties of the entire configuration. We study one such Ramsey problem of Erdős and Shelah, where the configurations are complete graphs with colored edges and every
small induced subgraph contains many distinct colors. Our bounds for this Ramsey
problem show that the known probabilistic construction is tight in various cases. We
study one discrete geometry variant, also by Erdős, where we have a set of points in the
plane such that every small subset spans many distinct distances. Finally, we consider
an arithmetic variant, suggested by Dvir, where we are given sets of real numbers such that
every small subset has a large difference set. In Chapter 2, we derive new bounds for all of the above problems. Along the way, we also essentially answer a question of Erdős and Gyárfás.
Second, we study the behavior of expanding polynomials on sets with additive or multiplicative structure. Given an arbitrary set of real numbers A and a two-variate polynomial f with real coefficients, a remarkable theorem of Elekes and Rónyai from 2000 states that the size |f(A,A)| of the image of f on the cartesian product A × A grows asymptotically faster than |A|, unless f exhibits additive or multiplicative structure. Finding the best quantitative bounds for this intriguing phenomenon (and for variants of it) has generated a lot of interest over the years due to its intimate connection with the sum-product problem in additive combinatorics. In Chapter 3, we discuss new bounds for |f(A,A)| when the set A has few sums or few products.
Another central problem in additive combinatorics is the problem of finding good quantitative bounds for maximal progression-free sets in the integers (or various other groups). In 2017, a major breakthrough of Croot, Lev and Pach took the community by surprise with impressive new bounds for the problem in ℤ4n and in higher order 2-abelian groups. Their new polynomial method was quickly adapted by Ellenberg and Gijswijt to show a similar strong result for the size of the largest three-term progression free subset of 𝔽qn where q is an odd prime power, the so-called cap set problem. This new set of ideas has subsequently led to very exciting developments in a vast range of topics. The rest of the thesis will be dedicated to discussing my joint results around these new developents. In Chapter 4, we develop a new multi-layered polynomial method approach to derive improved bounds for the largest three-term progression free set in ℤ8n (which also improve on the Croot-Lev-Pach bounds for a large family of higher order 2-abelian groups). In Chapter 5, we generalize the Ellenberg-Gijswijt bound for the cap set problem to random progression-free subsets of 𝔽qn, improving on a theorem of Tao and Vu. A result of this type enables one to find four term progressions-free sets which contain three-term progressions in all of their large subsets (with good quantitative bounds), but which do not contain too many three-term progressions overall. Motivated by this application, in Chapter 6 we continue this investigation and study further the question of determining the maximum total number of 3APs in a given 4AP-free set. We show in general, for all fixed integers k > s ≥ 3, that if fs,k(n) denotes the maximum possible number of s-term arithmetic progressions in a set of n integers which contains no k-term arithmetic progression, then fs,k(n) = n2-o(1). This answers an old question of Erdős. In Chapter 7, we study some limitations of the Croot-Lev-Pach approach and discuss some problems at the intersection of extremal set theory and combinatorial geometry where one can use additional linear algebraic ideas to go slightly beyond the Croot-Lev-Pach method.</p
Hypervelocity Shock Tunnel Studies of Blunt Body Aerothermodynamics in Carbon Dioxide for Mars Entry
Get PDFA low mass and reliable thermal protection system for Martian atmospheric entry requires an accurate prediction of the aerothermal environment encountered by the spacecraft. In order to move forward with predictive models for larger vehicles needed for manned and sample return missions, anomalous data needs to be resolved.
This work aims to address two critical problems relevant for Mars missions.
I) We investigate significant discrepancies between experimental and simulated blunt body bow shock standoff distance in ground test facilities. Experiments using high-speed and high-resolution schlieren imaging are conducted in the T5 reflected shock tunnel and the Hypervelocity Expansion Tube (HET) to examine facility
independence of the measurements. A recently-developed model for sphere and sphere-cone behavior is in good agreement with experiments, and with predictions from Navier-Stokes simulations with thermal and chemical nonequilibrium. The need to account for the divergence of the streamlines in conical nozzles is highlighted.
The contributions of vibrational and chemical nonequilibrium to the stagnation-line density profile are quantified using the simulation results in order to compare different reaction rate models.
II) We measure and characterize carbon dioxide mid-wave infrared radiation in hypervelocity flow. Initially assumed negligible in the design of the Mars Science Laboratory (MSL) mission heat shield, this mechanism of heating must be considered for accurate predictions of the heating environment. Specifically, carbon dioxide radiation can be a dominant source of heating in the afterbody, particularly later in the trajectory at lower velocities. Presented are spectral measurements of the 4.3 μm fundamental band of carbon dioxide radiation measured using fiber optics embedded on the surface of an MSL scaled heat shield model. When comparing experiments and simulations, good agreement is found when running the HET in shock tube mode where the shock layer is optically thick, while discrepancies are observed in expansion tube mode where the shock layer is optically thin. A thorough analysis of flow features in the line-of-sight including freestream uncertainties is performed to explore possible reasons for this discrepancy. After developing the spectroscopic calibration technique and obtaining forebody measurements in the expansion tube, an experimental campaign is completed in the T5 Reflected Shock Tunnel to measure spectral radiation in the forebody and afterbody. The accompanying T5 simulations needed for radiation predictions are being carried out by NASA Ames.</p