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A Unified Synthetic Approach to the Transtaganolide and Basiliolide Natural Products
Get PDFHerein are described the first total syntheses of several members of the transtaganolide and basiliolide natural product family. A general strategy, hinging upon the use of a biomimetic Ireland–Claisen rearrangement/Diels–Alder cycloaddition cascade, was developed. It allowed for the rapid assembly of the most structurally complex, and biologically active members of the family.
A brief introduction that surveys the use of the pyrone Diels–Alder cycloaddition in total synthesis precedes details of our synthetic efforts. The diversity of structural motifs accessible through this reaction manifold is described through literature examples.
The account of our experimental work begins with details of extensive model studies. First, a simple system was prepared which probed the ability to construct basiliolide B via an intramolecular pyrone Diels–Alder reaction. It was demonstrated that the sterically congested core could be constructed in a highly diastereoselective fashion using this technology. Second, a simple prenylated pyrone was constructed, and shown to undergo a facile Ireland–Claisen rearrangement under a variety of conditions. Subsequently, the utilization of these two methods within a cascade allowed for the rapid construction of racemic transtaganolide C, transtaganolide D, basiliolide B, and epi-8-basiliolide B. Furthermore, a novel Pd-catalyzed [5+2] annulation technology is utilized to construct the venerable, carboxy-ketene-acetal containing C-ring present in most of the metabolites.
Integration of asymmetry into our general strategy is also described. Utilization of a chiral silane directing group allowed for the successful and rare application of an enantioselective Ireland–Claisen rearrangement, culminating in the total syntheses of (+)- transtaganolide C, (–)-transtaganolide D, (+)-transtaganolide B, and (–)-transtaganolide A. Furthermore, the impact of this work on existing biosynthetic hypotheses is discussed.</p
Studying Conscious and Unconscious Vision with Functional Magnetic Resonance Imaging : the BOLD Promise
Get PDFWaking up from a dreamless sleep, I open my eyes, recognize my wife’s face and am filled with joy. In this thesis, I used functional Magnetic Resonance Imaging (fMRI) to gain insights into the mechanisms involved in this seemingly simple daily occurrence, which poses at least three great challenges to neuroscience: how does conscious experience arise from the activity of the brain? How does the brain process visual input to the point of recognizing individual faces? How does the brain store semantic knowledge about people that we know? To start tackling the first question, I studied the neural correlates of unconscious processing of invisible faces. I was unable to image significant activations related to the processing of completely invisible faces, despite existing reports in the literature. I thus moved on to the next question and studied how recognition of a familiar person was achieved in the brain; I focused on finding invariant representations of person identity – representations that would be activated any time we think of a familiar person, read their name, see their picture, hear them talk, etc. There again, I could not find significant evidence for such representations with fMRI, even in regions where they had previously been found with single unit recordings in human patients (the Jennifer Aniston neurons). Faced with these null outcomes, the scope of my investigations eventually turned back towards the technique that I had been using, fMRI, and the recently praised analytical tools that I had been trusting, Multivariate Pattern Analysis. After a mostly disappointing attempt at replicating a strong single unit finding of a categorical response to animals in the right human amygdala with fMRI, I put fMRI decoding to an ultimate test with a unique dataset acquired in the macaque monkey. There I showed a dissociation between the ability of fMRI to pick up face viewpoint information and its inability to pick up face identity information, which I mostly traced back to the poor clustering of identity selective units. Though fMRI decoding is a powerful new analytical tool, it does not rid fMRI of its inherent limitations as a hemodynamics-based measure
Signal Transduction with Hybridization Chain Reactions
Get PDFSome of the most exciting developments in the field of nucleic acid engineering include the utilization of synthetic nucleic acid molecular devices as gene regulators, as disease marker detectors, and most recently, as therapeutic agents. The common thread between these technologies is their reliance on the detection of specific nucleic acid input markers to generate some desirable output, such as a change in the copy number of an mRNA (for gene regulation), a change in the emitted light intensity (for some diagnostics), and a change in cell state within an organism (for therapeutics). The research presented in this thesis likewise focuses on engineering molecular tools that detect specific nucleic acid inputs, and respond with useful outputs.
Four contributions to the field of nucleic acid engineering are presented: (1) the construction of a single nucleotide polymorphism (SNP) detector based on the mechanism of hybridization chain reaction (HCR); (2) the utilization of a single-stranded oligonucleotide molecular Scavenger as a means of enhancing HCR selectivity; (3) the implementation of Quenched HCR, a technique that facilitates transduction of a nucleic acid chemical input into an optical (light) output, and (4) the engineering of conditional probes that function as sequence transducers, receiving target signal as input and providing a sequence of choice as output. These programmable molecular systems are conceptually well-suited for performing wash-free, highly selective rapid genotyping and expression profiling in vitro, in situ, and potentially in living cells.</p
Aerosol-Cloud-Precipitation Interactions in Marine Stratocumulus Clouds
Get PDFMarine stratocumulus clouds are generally optically thick and shallow, exerting a net cooling influence on climate. Changes in atmospheric aerosol levels alter cloud microphysics (e.g., droplet size) and cloud macrophysics (e.g., liquid water path, cloud thickness), thereby affecting cloud albedo and Earth’s radiative balance. To understand the aerosol-cloud-precipitation interactions and to explore the dynamical effects, three-dimensional large-eddy simulations (LES) with detailed bin-resolved microphysics are performed to explore the diurnal variation of marine stratocumulus clouds under different aerosol levels and environmental conditions. It is shown that the marine stratocumulus cloud albedo is sensitive to aerosol perturbation under clean background conditions, and to environmental conditions such as large-scale divergence rate and free tropospheric humidity.
Based on the in-situ Eastern Pacific Emitted Aerosol Cloud Experiment (E-PEACE) during Jul. and Aug. 2011, and A-Train satellite observation of 589 individual ship tracks during Jun. 2006-Dec. 2009, an analysis of cloud albedo responses in ship tracks is presented. It is found that the albedo response in ship tracks depends on the mesoscale cloud structure, the free tropospheric humidity, and cloud top height. Under closed cell structure (i.e., cloud cells ringed by a perimeter of clear air), with sufficiently dry air above cloud tops and/or higher cloud top heights, the cloud albedo can become lower in ship tracks. Based on the satellite data, nearly 25% of ship tracks exhibited a decreased albedo. The cloud macrophysical responses are crucial in determining both the strength and the sign of the cloud albedo response to aerosols.
To understand the aerosol indirect effects on global marine warm clouds, multisensory satellite observations, including CloudSat, MODIS, CALIPSO, AMSR-E, ECMWF, CERES, and NCEP, have been applied to study the sensitivity of cloud properties to aerosol levels and to large scale environmental conditions. With an estimate of anthropogenic aerosol fraction, the global aerosol indirect radiative forcing has been assessed.
As the coupling among aerosol, cloud, precipitation, and meteorological conditions in the marine boundary layer is complex, the integration of LES modeling, in-situ aircraft measurements, and global multisensory satellite data analyses improves our understanding of this complex system.</p
Structure of the Turbulent Boundary Layer under Static and Dynamic Impulsive Roughness Perturbation
Get PDFThe zero-pressure gradient turbulent boundary layer at Reynolds numbers (based on momentum thickness) ranging from 2700--4100 was perturbed using an impulsively short patch of two-dimensional, spanwise roughness elements. A spatial perturbation was considered in which the roughness patch was held statically on the flat-plate, and the flow downstream of the perturbation was measured by hotwire and particle-image velocimetry. A dynamic perturbation, in which the roughness patch was actuated periodically in time, was also studied, and additional measurements were taken by phase-locking to the dynamic actuation itself.
The static perturbation distorted the boundary layer through the generation of a `stress bore' which modified the mean streamwise velocity gradient. The effect of this stress bore was observed in a modification of statistical and spectral measures of the turbulence, as well as a redistribution of coherent structures in the boundary layer. The characterization of the statically perturbed boundary layer provided a base flow from which to consider the dynamically perturbed flow. The dynamically perturbed flow manifested both effects analogous to the static perturbation, as well as a coherent, periodic, large-scale velocity fluctuation. The extent to which these two features could be treated as linearly independent was studied by a variety of statistical and spectral means. Moreover, the very large scale motion synthesized by the dynamic perturbation was isolated by phase-locked measurement, and its behavior was predicted with reasonable success by employing a resolvent operator approach to a forced version of the Orr-Sommerfeld equation.
The relationship between large-scale motions and an envelope of small-scale motions in the turbulent boundary layer was studied in both the unperturbed and perturbed flows. A variety of correlation techniques were used to interpret the interaction between the different scale motions in the context of a phase-relationship between large and small scales. This phase relationship was shown to provide a physically-grounded perspective on the relationship between the synthetic very large scale motion produced by the dynamic perturbation and the smaller scales in the flow, and was able to provide a foundation for thinking about new approaches to controlling turbulence through large-scale forcing.</p
Adaptive Methods Exploring Intrinsic Sparse Structures of Stochastic Partial Differential Equations
Get PDFMany physical and engineering problems involving uncertainty enjoy certain low-dimensional structures, e.g., in the sense of Karhunen-Loeve expansions (KLEs), which in turn indicate the existence of reduced-order models and better formulations for efficient numerical simulations. In this thesis, we target a class of time-dependent stochastic partial differential equations whose solutions enjoy such structures at any time and propose a new methodology (DyBO) to derive equivalent systems whose solutions closely follow KL expansions of the original stochastic solutions. KL expansions are known to be the most compact representations of stochastic processes in an L2 sense. Our methods explore such sparsity and offer great computational benefits compared to other popular generic methods, such as traditional Monte Carlo (MC), generalized Polynomial Chaos (gPC) method, and generalized Stochastic Collocation (gSC) method. Such benefits are demonstrated through various numerical examples ranging from spatially one-dimensional examples, such as stochastic Burgers' equations and stochastic transport equations to spatially two-dimensional examples, such as stochastic flows in 2D unit square. Parallelization is also discussed, aiming toward future industrial-scale applications. In addition to numerical examples, theoretical aspects of DyBO are also carefully analyzed, such as preservation of bi-orthogonality, error propagation, and computational complexity. Based on theoretical analysis, strategies are proposed to overcome difficulties in numerical implementations, such as eigenvalue crossing and adaptively adding or removing mode pairs. The effectiveness of the proposed strategies is numerically verified. Generalization to a system of SPDEs is considered as well in the thesis, and its success is demonstrated by applications to stochastic Boussinesq convection problems. Other generalizations, such as generalized stochastic collocation formulation of DyBO method, are also discussed
Structure of the Subduction System in Southern Peru from Seismic Array Data
Get PDFSouthern Peru represents a subduction transition region from normal subduction in the southernmost part of Peru to flat slab subduction in central Peru. In order to learn more about the structure of southern Peru, causes of flat slab subduction, and the nature of the transition from normal to flat slab subduction, we installed three seismic arrays utilizing a total of about 100 broadband stations. The first installed array samples the normal subduction region, while the second samples the transition from normal to flat subduction, and the third samples the flat slab region near where the Nazca Ridge is presently subducting. Data from teleseismic events greater than 30 degrees distance from Peru was analyzed using the receiver function method that makes use of P to S converted phases at interfaces such as the Moho to provide information about the structure directly beneath each station. A strong signal from the Moho was observed for each array and was found to have a maximum depth of around 75 km beneath the Altiplano. The average crustal Vp/Vs ratio was also estimated and was found to have an average value of around 1.75 beneath the Altiplano. The shape of the slab was also clarified for the three arrays. The transition from normal to flat slab subduction appears to be a contortion rather than a break in the slab. In addition to those signals, a positive impedance midcrustal signal at about 40 km depth was widely observed for stations on the eastern side of the arrays. The midcrustal signal is indicative of a velocity increase in the lower crust and is suggested to be an observation of the underthrusting Brazilian shield which would have implications for the timing of uplift in the Andes. Finite difference modeling with velocity models that include a midcrustal structure produces synthetics which are consistent with receiver function observations. Receiver function results and other related methods provide a simple way of making direct observations of key structural interfaces and the current state of the subduction system which has relevance in studies of the tectonic evolution of the region and estimations of causes of flat slab subduction
Diazotrophy in the Deep: An Analysis of the Distribution, Magnitude, Geochemical Controls, and Biological Mediators of Deep-Sea Benthic Nitrogen Fixation
Get PDFBiological nitrogen fixation (the conversion of N2 to NH3) is a critical process in the oceans, counteracting the production of N2 gas by dissimilatory bacterial metabolisms and providing a source of bioavailable nitrogen to many nitrogen-limited ecosystems. One currently poorly studied and potentially underappreciated habitat for diazotrophic organisms is the sediments of the deep-sea. Although nitrogen fixation was once thought to be negligible in non-photosynthetically driven benthic ecosystems, the present study demonstrates the occurrence and expression of a diversity of nifH genes (those necessary for nitrogen fixation), as well as a widespread ability to fix nitrogen at high rates in these locations. The following research explores the distribution, magnitude, geochemical controls, and biological mediators of nitrogen fixation at several deep-sea sediment habitats, including active methane seeps (Mound 12, Costa Rica; Eel River Basin, CA, USA; Hydrate Ridge, OR, USA; and Monterey Canyon, CA, USA), whale-fall sites (Monterey Canyon, CA), and background deep-sea sediment (off-site Mound 12 Costa Rica, off-site Hydrate Ridge, OR, USA; and Monterey Canyon, CA, USA). The first of the five chapters describes the FISH-NanoSIMS method, which we optimized for the analysis of closely associated microbial symbionts in marine sediments. The second describes an investigation of methane seep sediment from the Eel River Basin, where we recovered nifH sequences from extracted DNA, and used FISH-NanoSIMS to identify methanotrophic archaea (ANME-2) as diazotrophs, when associated with functional sulfate-reducing bacterial symbionts. The third and fourth chapters focus on the distribution and diversity of active diazotrophs (respectively) in methane seep sediment from Mound 12, Costa Rica, using a combination of 15N-labeling experiments, FISH-NanoSIMS, and RNA and DNA analysis. The fifth chapter expands the scope of the investigation by targeting diverse samples from methane seep, whale-fall, and background sediment collected along the Eastern Pacific Margin, and comparing the rates of nitrogen fixation observed to geochemical measurements collected in parallel. Together, these analyses represent the most extensive investigation of deep-sea nitrogen fixation to date, and work towards understanding the contribution of benthic nitrogen fixation to global marine nitrogen cycling.</p
Analysis of a Transcriptional Network Involving PU.1, Notch, and Gata3 in the Lymphomyeloid Lineage Decision during Early T-cell Development
Get PDFHematopoiesis is a well-established system used to study developmental choices amongst cells with multiple lineage potentials, as well as the transcription factor network interactions that drive these developmental paths. Multipotent progenitors travel from the bone marrow to the thymus where T-cell development is initiated and these early T-cell precursors retain lineage plasticity even after initiating a T-cell program. The development of these early cells is driven by Notch signaling and the combinatorial expression of many transcription factors, several of which are also involved in the development of other cell lineages. The ETS family transcription factor PU.1 is involved in the development of progenitor, myeloid, and lymphoid cells, and can divert progenitor T-cells from the T-lineage to a myeloid lineage. This diversion of early T-cells by PU.1 can be blocked by Notch signaling. The PU.1 and Notch interaction creates a switch wherein PU.1 in the presence of Notch promotes T-cell identity and PU.1 in the absence of Notch signaling promotes a myeloid identity. Here we characterized an early T-cell cell line, Scid.adh.2c2, as a good model system for studying the myeloid vs. lymphoid developmental choice dependent on PU.1 and Notch signaling. We then used the Scid.adh.2c2 system to identify mechanisms mediating PU.1 and Notch signaling interactions during early T-cell development. We show that the mechanism by which Notch signaling is protecting pro-T cells is neither degradation nor modification of the PU.1 protein. Instead we give evidence that Notch signaling is blocking the PU.1-driven inhibition of a key set of T-regulatory genes including Myb, Tcf7, and Gata3. We show that the protection of Gata3 from PU.1-mediated inhibition, by Notch signaling and Myb, is important for retaining a T-lineage identity. We also discuss a PU.1-driven mechanism involving E-protein inhibition that leads to the inhibition of Notch target genes. This is mechanism may be used as a lockdown mechanism in pro-T-cells that have made the decision to divert to the myeloid pathway
Dirac Spectra, Summation Formulae, and the Spectral Action
Get PDFNoncommutative geometry is a source of particle physics models with matter Lagrangians coupled to gravity. One may associate to any noncommutative space (A, H, D) its spectral action, which is defined in terms of the Dirac spectrum of its Dirac operator D. When viewing a spin manifold as a noncommutative space, D is the usual Dirac operator. In this paper, we give nonperturbative computations of the spectral action for quotients of SU(2), Bieberbach manifolds, and SU(3) equipped with a variety of geometries. Along the way we will compute several Dirac spectra and refer to applications of this computation