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Total Syntheses of the C19 Diterpenoid Alkaloids (–)-Liljestrandisine and (–)-Liljestrandinine
Get PDFA unified synthetic strategy to access diterpenoid alkaloid natural products is presented. The highly bridged hexacyclic natural products are characterized as having a hydrindane bridged piperidyl motif that is common to the C19 aconitine type diterpenoid alkaloids and the C20 napelline and denudatine type diterpenoid alkaloids. A unified strategy to the C19 and C20 diterpenoid alkaloids is developed. An asymmetric synthesis of an epoxy-hydrindane fragment enables the development of the key unified strategy, involving a 1,2-addition followed by a semipinacol rearrangement in a key fragment coupling process. The fragment coupling is demonstrated generally with a variety of substrates, including an aromatic substrate that is advanced to a key bicyclo[2.2.1]heptane intermediate towards the C20 diterpenoid alkaloids.
The developed 1,2-addition/semipinacol-rearrangement strategy is ultimately leveraged in the total synthesis of two different C19 aconitine type diterpenoid alkaloids. An asymmetric synthesis of a bridged bicyclo[3.2.1]octane fragment is presented. The bridged bicyclo[3.2.1]octane fragment is advanced through the developed 1,2-addition/semipinacol rearrangement fragment coupling strategy affording a key tetracyclic intermediate. This work ultimately culminates in the total syntheses of two natural products (–)-liljestrandisine and (–)-liljestrandinine. Key steps for the completion of the total syntheses include advancement of the key tetracyclic intermediate from the fragment coupling through a series of C–N and C–C bond forming reactions, including an intramolecular aziridination reaction and a radical cyclization.</p
Single Particle Motion in Active Matter
Get PDF"Active matter" refers to a broad class of materials in which the constituent particles or organisms are able to self-propel (swim) by some internal physicochemical mechanism. Though the origin of this self-propulsive motion is a rich area of study, we are primarily interested in the collective effects of this motion on the physical properties — and in particular, the rheology — of the active material as a whole. As such we model self-propulsive motion using the minimal active Brownian particle (ABP) model: a particle of size a , swims in a direction q with a speed U0, and the direction of its motion changes randomly over some time scale τR.
On a macroscopic scale, active motion leads to unique hydrodynamic and mechanical stresses exerted by the particles on their embedding medium. These stresses arise from the microscopic force associated with particle locomotion — the swim force F swim. Though the idea of the swim force is widely recognized in the abstract, little attention has been given to the characterization and mechanical consequences of this force. In this work we are particularly interested the role of the swim force in the effective motion of passive constituents in active environments, and how the swim force affects long-ranged hydrodynamic interactions (HI) in active suspensions. We examine these issues through the lens of microrheology: tracking the motion of a colloidal probe particle through an active medium, and using its motions to infer the effective viscoelastic properties of the suspension.
Using generalized Taylor dispersion theory, we find an activity-driven enhancement to the diffusion of the probe in an active medium. This first-principles theory unites many experimental observations of tracer diffusion, and provides simple physical descriptions of the problem that do not rely on the specific self-propulsion mechanism of the swimmer. This same framework is then used to compute the suspension microviscosity (as measured by the drag on the probe particle), and the fluctuation-dissipation relation in an active system. We find that activity reduces the drag on the probe, but the drag is still larger than it would be in a Newtonian fluid; this stands in contrast to experimental measurements of reduced shear viscosities. We show that the microviscosity of a suspension is reduced — and may even become negative! — due to HI, and that this effect is not due to the fluid velocity disturbance associated with the swimmers' self-propulsion.</p
Voyager 1 Observations of Galactic Cosmic Ray Anisotropies in the Local Interstellar Medium
Get PDFSince crossing the heliopause on August 25, 2012, Voyager 1 has observed reductions in galactic cosmic ray counting rates caused by a time-varying depletion of particles with pitch angles near 90-deg, while intensities of particles with other pitch angles remain unchanged. Between late 2012 and mid-2017, three large-scale, durable events occurred, lasting roughly 100 to 630 days. Omnidirectional and directional data from the Cosmic Ray Subsystem's high energy telescopes are used to report observations of the cosmic ray intensity variations. Omnidirectional (>20 MeV) proton-dominated measurements show up to a ~3.8% intensity reduction. Bi-directional (>70 MeV) and unidirectional (~18 to ~70 MeV) proton-dominated measurements are analyzed using data taken from various spacecraft orientations, including during magnetometer roll calibrations and 70-deg-offset maneuvers. The anisotropy is characterized as a "notch" in an otherwise uniform pitch-angle distribution of varying depth and width centered about 90-deg in pitch angle space. The notch averages ~22-deg wide and ~15% deep -- signifying a depletion region that is broad and shallow. However, electron observations reveal that there is only a weak, at most, evidence of pitch angle anisotropy in cosmic-ray electrons with energies of ~3 to ~105 MeV, indicating that the generation of the notch or its evolution differs between electrons and protons, or varies with rigidity. There are indications that the anisotropy is formed by a combination of magnetic trapping and adiabatic cooling in associated shocks or compression regions
An EnKF-Based Flow State Estimator for Aerodynamic Problems
Get PDFRegardless of the plant model, robust flow estimation based on limited measurements remains a major challenge in successful flow control applications. Aiming to combine the robustness of a high-dimensional representation of the dynamics with the cost efficiency of a low-order approximation of the state covariance matrix, a flow state estimator based on the Ensemble Kalman Filter (EnKF) is applied to two-dimensional flow past a cylinder and an airfoil at high angle of attack and low Reynolds number. For development purposes, we use the numerical algorithm as both the estimator and as a surrogate for the measurements. In a perfect-model framework, a reduced number of either pressure sensors on the surface of the body or sparsely placed velocity probes in the wake are sufficient to accurately estimate the instantaneous flow state. Because the dynamics of these flows are restricted to a low-dimensional manifold of the state space, a small ensemble size is sufficient to yield the correct asymptotic behavior. The relative importance of each sensor location is evaluated by analyzing how they influence the estimated flow field, and optimal locations for pressure sensors are determined.
However, model inaccuracies are ubiquitous in practical applications. Covariance inflation is used to enhance the estimator performance in the presence of unmodeled freestream perturbations. A combination of parametric modeling and augmented state methodology is used to successfully estimate the forces on immersed bodies subjected to deterministic and random gusts. The robustness of high-dimensional representation of the dynamics to the choice of parameters such as the Reynolds number is inherited by the estimator, which was shown to successfully estimate the reference Reynolds number on the fly. Spatial and temporal discretization can constitute a second source of errors which can render numerical solutions a biased representation of reality. Left unaccounted for, biased forecast and observation models can lead to poor estimator performance. In this work, we propose a low-rank representation for the bias whose dynamics are represented by a colored-noise process. System state and bias parameters are simultaneously tracked online with the Ensemble Kalman Filter (EnKF) algorithm. The proposed methodology is demonstrated to achieve a 70% error reduction for the problem of estimating the state of the two-dimensional low-Re flow past a flat plate at high angle of attack using an ensemble of coarse-mesh simulations and pressure measurements at the surface of the body, compared to a bias-blind estimator. Strategies to determine the bias statistics and to deal with nonlinear observation functions in the context of ensemble methods are discussed.</p
Controlling the Buckling Behavior of Bilayered Systems
Get PDFA bilayered system is an assembly of two different materials and has the form of flat and thin layers. The two materials are attached to each other at the surface. The attachment method varies depending on the materials properties. Bilayered systems made of materials with different dimensions and stiffness have been widely studied and used for different applications. The characteristic scale of this kind of system can go from hundreds of km in the case of geological layers on the Earth surface to some µm in the case of very small electronic systems or microlenses.
The behavior of a bilayered system, when submitted to a stimulus, is characterized by the conflict between the preferred response of each material and the constraint that one imposes on the other. As a result, the deformation of the bilayered system will be different from that which could be obtained when the materials are taken separately. Of particular interest is the buckling of such systems: when submitted to a particular stress distribution, one material will expand significantly more than the other, but as the two materials are attached at the interface surface, the material displacements must be continuous through this interface. The conflict between the continuity of displacement and the need to expand differently may result in nonlinear patterns at this interface. Those unstable situations can be used to define a limit of constraint for the materials or can be used as actuators for a desired surface pattern. Many studies have focused on characterizing homogeneous buckling within an entire surface due to homogeneous strain distribution within the top surface. This characterization was performed theoretically, numerically, and experimentally. But, some studies have shown different possibilities of evolution of the buckling patterns known today. As a consequence, we can pose two questions: 1) Is there a possibility to modify non-linear patterns regardless of what is imposed by mechanical properties and dimensions? 2) What happens in the case of a non-uniform state of constraints within the bilayered system?
This thesis explores those questions for the case of a thin stiff film attached to a compliant thick substrate. The first part of this thesis serves to describe the initial buckling theory in the case of uniform strain and explains how to define the loading threshold resulting in uniform buckling at the surface characterized by a finite number of spatial frequencies. The second part of the thesis studies the consequences of a non-uniform loading within the surface. A numerical method based on the theory of the first part is implemented to show the emergence of new frequencies due to the discontinuous loading distribution. The third part focuses on the possibility of tuning a uniform buckling by including an electromechanical coupling into the bilayered system. This coupling makes the materials sensitive to electric fields, thus creating a new energy term to interfere with the mechanical energy of deformation, thereby modifying the resulting spatial frequency of the buckling. This study is done theoretically and numerically by finite element modeling.</p
Fundamental Physics Through Gravitational Waves: From No-Hair Theorem to Quantum Structures of Black Holes
Get PDFIn general relativity, black hole is the simplest macroscopic object in the universe: any black hole can be completely described by its mass, charge and angular mo- mentum. However, such a simple picture might be changed if the gravitational field equations are modified or quantum effects are taken into consideration. These additional hairs of black hole, if exist, may provide valuable information to reveal the deepest mystery of the universe: quantum theory of gravity.
In this thesis, we try to relate the hypothetical extra hairs of black hole with the ob- servational evidence as gravitational waves – another prediction of general relativity and are recently detected. In Chapter I, we provide a pedagogical introduction to the black hole hairs introduced by modified gravity and quantum mechanics, and lay out a mathematical framework to describe the gravitational wave emission with the existence of near-horizon quantum hair. In Chapter II we show that in scalar-tensor theory of gravity, the formation process of a black hole from gravitational collapse is accompanied with the emission of scalar hair. This mechanism gives rise to a scalar type memory effect of gravitational wave, which does not exist in general relativity. This phenomenon can further be used to study the parameter space of the scalar-tensor theory. In Chapter III, we find the scalar gravitational memory effect from stellar collapses provide the strongest sources for the stochastic gravita- tional wave background with scalar polarization in Brans-Dicke theory. The energy density spectrum for this background is provided and its model dependencies are studied. In Chapter IV, we provide a Green’s function method to study the echoes, which are the gravitational waves reflected by the quantum hair near the event hori- zon of a black hole. In Chapter V, we build phenomenological models to describe the near-horizon quantum hair and predict its implication to the binary black hole stochastic gravitational wave background. Our study indicates that the existence of the quantum hair will significantly increases such a background and pins down the most relevant model parameter to be the area under the effective potential. Further, we also demonstrate that the result is rather robust against the uncertainties about the nature of the near-horizon quantum hair. In the end, a field theory based treatment to the gravitational waves in general relativity is provided as the appendix.</p
Exploring the Biological Activity of Rhodium Metalloinsertors
Get PDFRhodium metalloinsertors are a unique family of potential anticancer agents that have been show to bind selectively to thermodynamically destabilized DNA base pair mismatches, abasic sites, and insertions/deletions (indels) in vitro. These metalloinsertors are also able to target mismatches in cells: metalloinsertors preferentially kill mismatch repair (MMR)-deficient cancer cells, which have a relative abundance of uncorrected DNA mismatches and indels, over MMR-proficient cells, which can repair these lesions. As such, these complexes have shown great promise as a potential treatment strategy for MMR-deficient cancers, which are often resistant to classic chemotherapies.
Recently, a new class of metalloinsertors that bear a rhodium-oxygen bond was synthesized and shown to have remarkable potency and selectivity towards MMR-deficient cells. We have discovered many key differences between first generation metalloinsertors and these new Rh-O metalloinsertors: (1) the MMR-selectivity of first generation metalloinsertors is heavily influenced by ancillary ligand bulk and lipophilicity, whereas the MMR-selectivity of Rh-O metalloinsertors is strong regardless of ancillary ligand properties, (2) first generation metalloinsertors have toxicities in the micromolar range while Rh-O metalloinsertors have toxicities in the nanomolar range, and (3) first generation metalloinsertors can only bind DNA via the Δ-enantiomer while Rh-O metalloinsertors can bind DNA via both the Δ- and Λ-enantiomers. Excitingly, the improved potency and selectivity of these "Rh-O" metalloinsertors brings them into a realm of clinical relevance.
Here we examine the basis for the improved potency and selectivity of these new Rh-O metalloinsertors. A family of six Rh-O metalloinsertors that vary in the steric bulk and lipophilicity of an ancillary ligand was synthesized and characterized. Regardless of ancillary ligand identity, these Rh-O metalloinsertors exhibit nanomolar or low-micromolar toxicities and all preferentially target MMR-deficient cancer cells over MMR-proficient cells. Notably, the off-target accumulation of these metalloinsertors in mitochondria is very low. This cellular distribution is in stark contrast with first generation metalloinsertors in which increased ligand lipophilicity led to increased mitochondrial uptake and ultimately non-selective mitochondrial-mediated cell death. We believe robust selectivity of these complexes is retained in part due to their low off-target accumulation in the mitochondria, which is further complemented by the low dosing requirements of these potent therapeutic agents.
Our studies also suggest the high potency of these complexes may be due to a difference in DNA-binding abilities, which is supported by observed differences in which enantiomers can bind to DNA mismatches, differences in ligand buckling at physiological pH, and lipophilicity of the therapeutics, with Rh-O metalloinsertors being dramatically more lipophilic than their first generation counterparts. To better understand the structural basis for this increased potency, crystallographic experiments are underway. A first generation metalloinsertor was previously crystallized with mismatched DNA, and the structure was pivotal in identifying the DNA binding mode of metalloinsertion. Using similar methods, we are working to produce a high-resolution crystal structure of an Rh-O metalloinsertor with mismatched DNA in order to gain structural insights into the increased potency of these new complexes. A significant difference in DNA binding could result in different biological activation of proteins and overall higher potency of these Rh-O metalloinsertors.
Finally, as metalloinsertors are moved towards pre-clinical study, understanding their biological activity in diverse cell culture experiments is essential. We examined a metalloinsertor and the FDA approved chemotherapeutic agent cisplatin in 27 diverse colorectal cancer cell lines. The comparison of these drugs revealed the metalloinsertor to be on average five times more potent than cisplatin in this panel. The potency of the metalloinsertor in different cell lines spanned nearly three orders of magnitude and correlated with whole-cell uptake of rhodium. Additionally, a fluorescent metalloinsertor conjugate was used to quantify the number of lesions in DNA that could be targeted by metalloinsertion, a result that correlated well with the potency of a metalloinsertor across several cell lines, consistent with DNA mismatches as the effective biological target of the metalloinsertor.
The experiments described within this thesis have allowed us to gain a better understanding of the biological activity of rhodium metalloinsertors. We have established that Rh-O metalloinsertors are distinct from first generation metalloinsertors, and that these new metalloinsertors can serve as highly tunable, potent, and mismatch-selective anticancer agents. Furthermore, this potency is observed across diverse cell lines and has been shown to correlate with the number of genomic DNA lesions that can be bound by metalloinsertion. The unique biological activity of these complexes makes them ideal candidates for the treatment of MMR-deficient cancers, and the potency and tunability of Rh-O metalloinsertors will allow for the development of previously unattainable diagnostic and therapeutic tools for MMR-deficiencies.</p
Linearity in Cell Signaling Pathways
Get PDFAccurate cellular communication is of paramount importance for the development, growth, and maintenance of multi-cellular organisms. Communication between cells is carried out by a highly conserved set of signaling pathways, whose dysregulation can lead to many diseases. The molecular details of these signaling pathways are now well-characterized, allowing researchers to investigate the emergent properties that arise from the complex signaling networks. These properties often arise from counter-intuitive or paradoxical mechanisms, meaning that systems-level analysis is necessary. Importantly, mathematical models have been constructed for many pathways that capture measured reaction rates and protein levels. These mathematical models successfully recapitulate dynamic responses of each pathway. Here, I investigated the input-output response of the Wnt, MAPK/ERK, and Tgfβ pathways using analytical and numerical treatment of mathematical models. Using this approach, I found that the distinct architectures of the three signaling pathways lead to a convergent behavior, linear input-output response. Specifically, mathematical analysis reveals that a futile cycle in the Wnt pathway, a kinase cascade coupled to feedback in the ERK pathway, and nucleocytoplasmic shuttling in the Tgfβ pathways all yield linear signal transmission. I then verified this finding experimentally in the Wnt and ERK pathways. For the Wnt pathway, direct measurements of the input-output response reveal that β-catenin is linear with respect to Wnt co-receptor LRP5/6 activity up until receptor saturation. For the ERK pathway, direct measurements indicate a linear relationship between phosphorylated ERK1/2 and the concentration of EGF ligand, up until saturation of ERK1/2. Finally, mathematical modeling reveals that linear response in the Wnt pathway, in conjunction with a recently identified cis-regulatory motif, is sufficient to explain gene expression buffering to perturbations. Therefore, this thesis demonstrates how linearity emerges across three dissimilar architectures, and introduces a novel benefit for linear signal transmission in biology.</p
Dynamic Strength of Silica Glasses at High Pressures and Strain Rates
Get PDFUnderstanding the behavior of silica glasses at high pressures and strain rates is of great importance for geological processes and highly relevant to many technological applications including high-powered laser-matter interactions in optical elements and impact/blast damage in defense systems. Materials typically experience large inelastic deformations at high pressures, which are strongly affected by strength-related phenomena such as work hardening, damage and thermal softening. The pressure-shear plate impact experiment (PSPI) provides detailed information on the pressure and strain rate dependent strength properties of materials subjected to uniaxial compression. However, its range of attainable pressures has so far been limited and the assumptions required for its analysis become invalid at pressures beyond the Hugoniot elastic limit of the anvil materials. In this dissertation, a high-pressure PSPI (HP-PSPI) technique is developed that greatly extends the range of attainable experimental conditions by achieving higher terminal projectile velocities in a powder gun setup. A novel fiber-optic heterodyne transverse velocimeter (HTV) is developed to enable the use of robust frequency-based data reduction techniques, which reduce the effect of signal noise and light coupling losses. A forward analysis method, based on finite element simulations, is employed to match the experimentally observed material response during HP-PSPI experiments on soda-lime glass samples while considering the inelastic deformation of the utilized tungsten carbide anvils. Symmetric HP-PSPI experiments on tungsten carbide revealed a loss of strength at normal stresses exceeding 25 GPa, which hint at active damage or softening mechanisms under nominally uniaxial strain compression. A pressure-dependent strain softening model transitions soda-lime glass from an intact strength of 2.8 GPa, below strains of 10-30%, to a failed granular state following extensive inelastic shear deformation, which accurately predicts the measured response over a wide range of stresses (9-21 GPa) and strain rates (3•105-2•107s-1). Extending the range of previously attainable pressures and strain rates in PSPI experiments, combined with more robust diagnostics and analysis tools, will greatly benefit our understanding of material strength in extreme environments and enables the investigation of material behavior in a currently unexplored range of pressures and strain rates.</p
Activity of Py-Im Polyamides in Anti-Androgen Resistant Prostate Cancer Models
Get PDFThe antiproliferative effects of Py-Im polyamides have been evaluated in several cancer models. The work presented here focuses on prostate cancer and the application of Py-Im polyamides targeted to the sequence 5′-WGWWCW-3′, which is found in a subset of androgen response elements. We begin by exploring the effect of a Py-Im polyamide in the VCaP model, which overexpresses wildtype AR and is genomically unstable due to ERG overexpression caused by the TMPRSS2-ERG translocation. In this model, Py-Im polyamide treatment reduces ERG protein level and DNA fragmentation, and reduces VCaP xenograft growth. Transcriptomic analysis of Py-Im polyamide treated VCaP cells provides a novel potential mechanism of blockage of topoisomerase I and II activity by polyamides. We next evaluate the activity of a second generation Py-Im polyamide in two models of anti-androgen resistant prostate cancers, and demonstrate growth inhibition in both cell culture and tumor models. Transcriptomic analysis of the model cell lines revealed suppression of androgen receptor signaling. Further, expression profiles are consistent with transcription inhibition in both cell samples and tumor samples. Finally, we examine the effect of a Py-Im polyamide on the AR cistrome in prostate cancer cells. We find through ChIP-Seq analysis that loci differentially affected by Py-Im polyamide treatment are enriched for potential ARE half-sites consistent with the polyamide target site. In summary, we find that Py-Im polyamides interfere with several DNA dependent processes, similar to other DNA minor groove binders, and we show through AR cistromic analysis that Py-Im polyamides reduce AR occupancy in a pattern that is predicted by Py-Im polyamide pairing rules.</p