VictorJuiz/thesis huggingface dataset:
Palladium-catalyzed asymmetric benzylation of prochiral nucleophiles [electronic resource]
Keywords: Chemistry

This dissertation details research in the development of palladium-catalyzed asymmetric benzylation. This methodology expands the scope of palladium-catalyzed substitution chemistry and represents a novel means for synthesizing chiral molecules via addition of a benzyl group. Prochiral nucleophiles, wherein enantiodiscrimination occurs during nucleophilic attack on a cationic pi-benzyl-palladium intermediate, are utilized in the reaction with achiral electrophiles. Initial investigations into use of 1,3-dicarbonyls as nucleophiles revealed that high reactivity could be achieved with methyl carbonate electrophiles under palladium catalysis at high reaction temperature. Asymmetric induction was achieved using a chiral Trost-style bisphosphine ligand, which proved to be superior to other chiral phosphine ligands. Optimization with respect to various reaction parameters was performed, and moderate enantioselectivity with a number of 1,3-diketone nucleophiles was realized. We next describe the use of oxindoles, privileged scaffolds in medicinal chemistry, as nucleophiles for asymmetric benzylation methodology. Initial screening revealed the importance of the substituent on the nitrogen atom, with a free N-H yielding the highest enantioselectivity. Investigation of ligand, solvent, temperature, and additive effects identified a set of conditions to provide high yield and enantioselectivity for the reaction between 3-aryl oxindoles and benzylic methyl carbonate electrophiles. A number of substitution patterns were well-tolerated on the oxindole moiety. The electrophile scope included naphthalene-, indole-, benzofuran-, and furan-substituted electrophiles. This research is the first reported palladium-catalyzed asymmetric benzylation of a prochiral nucleophile. The reaction proceeds under mild conditions and generates a quaternary stereocenter. Benzylic methyl carbonate electrophiles were found to be unreactive. Modest conversion of benzylic phosphates was observed, although with moderate enantioselectivity. Azlactones represent a masked amino acid, and were studied as nucleophiles in asymmetric benzylation to provide precursors to chiral quaternary amino acids. Conditions for highly asymmetric benzylation of azlactone nucleophiles with naphthyl and heterocyclic methyl carbonate electrophiles were developed using a Trost-style ligand for asymmetric induction. Investigation into expansion of scope to include monocyclic benzylic electrophiles was also conducted on these highly reactive nucleophiles. Modest reactivity was observed with carbonate electrophiles; phosphate electrophiles, which contain a more labile leaving group, found greater success in the transformation. A diethyl phosphate leaving group was employed for electron-rich aryl rings, while a diphenyl phosphate was required for high reactivity of electron-neutral substrates. The utility of the methodology was demonstrated in a synthesis of alpha-methyl-D-dopa via a one-step azlactone hydrolysis.
Palladium-catalyzed asymmetric formal [3+2]-cycloadditions with donor-acceptor cyclopropanes [electronic resource]
Keywords: Chemistry

Abstract: The development of new methods for the synthesis of densely-functionalized enantioenriched five-membered hetero- and carbocycles is of importance in organic chemistry. Such functionalized five-membered ring are one of the motifs found in a wide array of biological targets. One atom- and step-economical method for the synthesis of these these five-membered ring systems is via a formal [3+2]-cycloaddition between a 1,3-dipole and a dipolarophile. Vicinally-substituted donor-acceptor cyclopropanes contain an electron-withdrawing group at the 1-position and an electron-donating group at the 2-position. This allows for their heterolytic cleavage to form a 1,3-dipoles under appropriate reaction conditions. Typically, Lewis acid-catalysis has been utilized to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes. However, the use of palladium-catalysis to affect formal [3+2]-cycloadditions with donor-acceptor cyclopropanes has been relatively unexplored, and prior to this work had never been examined in an asymmetric fashion. The asymmetric allylic alkylation ligands developed by Trost and coworkers have been extensively used over the last 15 years in a variety of enantioselective reactions. However, the ability of these ligands to induce enantioselectivity in a bond-forming event two-bonds away from the [pi]-allyl-palladium center had never been demonstrated. The development of an asymmetric formal [3+2]-cycloaddition with donor-acceptor cyclopropanes and Meldrum's acid alkylidenes demonstrated the ability of this class of ligands to direct stereochemistry quite far away from the [pi]-allyl-palladium complex. A range of substituted cyclopentane derivatives were synthesized in this manner. An analysis of the relative stability of the donor-acceptor cyclopropanes in conjunction with the the palladium-ligand complex led to the development of a new class of donor-acceptor cyclopropane, the bis(2,2,2-trifluoroethyl)malonate-substituted vinyl cyclopropane. This new class of donor-acceptor cyclopropane was then utilized successfully in a formal [3+2]-cycloaddition with a variety of dipolarophiles, including the nitroolefins, isocyanates, and N-tosylimines. The azlactone alkylidenes, which represent protected amino acids, were further explored as dipolarophiles for this reaction, and a range of spirocyclic products were synthesized in high yield, enantiomeric excess and diastereomeric excess. Notably, three contiguous stereocenters were set in this reaction. In addition to this project, two approaches towards the synthesis of biyouyanagin A were explored. The initial approach, involving a proposed 11-endo-dig cyclization of an alcohol onto an alkyne ultimately proved to be unsuccessful. A secondary approach involved the use of a palladium-catalyzed dynamic kinetic asymmetric reaction between a hydroxyfuran and isoprene monoepoxide. Use of this strategy successfully synthesized hyperolactone C, which represented a formal synthesis of biyouyanagin A.
The palm oil revolution in Asia [electronic resource]
Keywords: Environment and Resources.

Palm oil has doubled its share of world vegetable oil consumption in the past twenty-five years to become the world's leading source of vegetable oil. Even though the environmental crises associated with oil palm are directly related to its cultivation (tropical forest loss, carbon emissions from drained peat swamps, biodiversity loss), studying supply interventions is insufficient. From a conservation perspective, the demand side of vegetable oils markets matters equally, if not more, since demand patterns affect the incentives facing producers. The dissertation begins by examining demand systems in Indonesia, today the world's largest palm oil producing country and the country with the highest palm oil consumption per capita. In Indonesia, higher palm oil consumption is the result not just of population and income growth but also of government policies that promoted an extraordinary substitution away from an alternative cooking oil. Comparing Indonesia to the other top two palm oil consuming countries in the world, India and China, reveals that Indonesia's experience is not representative of Asia. Different political and economic factors, from livestock production to trade policy, have produced different vegetable oil consumption patterns in each of these three markets. Finally, the dissertation examines the effect that biodiesel has had on vegetable oil demand and describes how a petroleum-price shock might play out in vegetable oils markets. Overall, the dissertation predicts a doubling of palm oil demand over the next twenty-five years and emphasizes how, given the highly substitutable nature of vegetable oils markets, small changes in relative prices can have exaggerated effects on palm oil demand. The elastic, or price sensitive, demand structure that producers face suggests that policies to increase yields are likely to cause more land conversion for oil palm.
Parameter extraction from single cell dynamics using numerical optimization techniques [electronic resource]
Keywords: Chemical and Systems Biology.

Cell signaling networks are complex dynamical systems with mechanisms for adaptation and failure-tolerance such that typical stimulus experiments are often robust to the perturbation of individual components. While such robustness is often advantageous, it also means that the information content of an experiment with respect to internal states and activities is often poor. We treat this problem formally by examining the statistical uncertainty of parameter estimates of corresponding signaling models as a function of experimental protocols that are based on live-cell imaging of fluorescent reporters. The first part of this work uses such model predictions of parameter sensitivity to design numerically optimized live-cell imaging protocols with the goal to maximally constrain the space of possible parameter values. The second part instead uses an experimental approach to define invariant parameters by correlated population estimates in order to reveal changes of regulated parameters in systematic siRNA perturbation experiments. Our results show that the effects of siRNA perturbations on reporter dynamics can be used to infer functional changes of the probed system. We exploit this feature to define not only the key molecules responsible for activity but also direct and indirect regulators.
Parkinson's disease phenotypes and treatments with induced pluripotent stem cells [electronic resource]
Keywords: Bioengineering.

Studies of Parkinson's disease (PD) have been greatly hindered by lack of access to affected human dopaminergic (DA) neurons. Here, we report generation of induced pluripotent stem cells that carry the p.G2019S mutation (LRRK2-G2019S-iPSCs) in the Leucine-Rich Repeat Kinase-2 (LRRK2) gene, the most common PD-related mutation; pluripotent lines that cells that carry a full SNCA gene triplication on one allele; and control pluripotent lines. We demonstrate that these PD autosomal dominant mutant LRRK2-G2019S-iPSCs, SNCA-triplication-iPSCs and Control-iPSCs were able to differentiate into dopaminergic neurons and showed increased expression of key oxidative stress response genes and alpha-synuclein protein. Moreover, LRRK2-G2019S iPSC derived dopaminergic neurons, specifically, were more sensitive to caspase-3 activation caused by exposure to hydrogen peroxide, MG-132, and 6-hydroxydopamine, compared to control dopaminergic neurons. While, SNCA-triplication iPSC derived dopaminergic neurons formed early ubiquitin positive puncta and were more sensitive to peak toxicity hydrogen peroxide induced cell stress. These findings suggest that LRRK2-G2019S and SNCA-triplication iPSC derived dopaminergic neurons exhibit early phenotypes linked to PD. Due to the high penetrance of the LRRK2 mutation, the expression of wild type protein in the SNCA-triplication line, and the clinical resemblance of patients afflicted with these disorders to sporadic PD patients, these neurons may provide a valuable platform for identification of novel pharmacological agents and diagnostics for modeling and alleviation of a subset of disease phenotypes.
Particle accelerator on a chip fabrication and characterization of a three-dimensional photonic crystal accelerator [electronic resource]
Keywords: Applied Physics.

Charged particles are currently accelerated by microwave radiation generated in large klystrons. This is very reminiscent of vacuum tube diodes on which early computers relied. Can particle accelerator technology follow the shift that drove the semiconductor industry from vacuum tubes to solid state devices? Can particle accelerators benefit from the high energy density provided by lasers at optical and infrared wavelengths? Can dielectric materials replace the metallic waveguides allowing us to utilize the high peak powers available in lasers today? In making this jump from microwave to infrared wavelengths, a decrease of 10,000 times in wavelength, entirely new fabrication technologies are needed. And entirely new physics must be applied in transitioning from metals to dielectrics. This thesis focuses on the fabrication and characterization of a three-dimensional photonic crystal designed for accelerating electrons. We present the design for a woodpile structure with a waveguide or defect that supports an accelerating mode. This mode has a speed-of-light phase velocity and longitudinal electric field. It has an estimated accelerating gradient of 351 MV/m. The 17 layer woodpile structure was fabricated at the Stanford Nanofabrication facility using semiconductor processing techniques. The structure was fabricated in a layer-by-layer approach resulting in two half-structures which were then aligned and bonded together. Three versions of structures were fabricated with operating wavelengths of 3.45, 3.95, and 4.94 [micrometers]. Optical characterization of these structures was performed using Fourier transform infrared spectroscopy. Simulations show good agreement with the measurements when the structure parameters are modeled appropriately. Finally, an optical parametric oscillator was built for studying the defect modes in the structure.
Particle populations and high energy emission in pulsar wind nebulae [electronic resource]
Keywords: Physics

Energetic particles streaming out from rapidly spinning neutron stars radiate across the electromagnetic spectrum, creating a pulsar wind nebula (PWN). Many PWNe are spatially resolved in the radio, X-ray, and even gamma-ray wavebands, and thereby provide an excellent laboratory to study not only pulsar winds and dynamics, but also shock processes, magnetic field evolution, and particle transport. Single-zone spectral energy distribution (SED) models have long been used to study the global properties of PWNe, but to fully take advantage of high spatial resolution data one must move beyond these simple models. Supported by multiple X-ray PWN observations, we describe multi-zone time-dependent SED model fitting, with particular emphasis on the spatial variations within nebulae. The SED model constrains the wind velocity profile, magnetic field profile, age and spin-down history of the central pulsar, and the PWN injection spectrum. These constraints are of great value to the study of the gamma-ray pulsar population, and to investigations of particle acceleration and the cosmic ray spectrum. The large size of many PWNe in the very high energy gamma-ray (TeV) regime is indicative of significant particle transport over the pulsar lifetime, and in the case study of HESS J1825-137 we find that rapid diffusion of high energy particles is required to match the multi-wavelength data.
The payoff to skill and earnings inequality in the third industrial revolution [electronic resource]
Keywords: Sociology.

This dissertation develops a new approach to analyzing changes in wage inequality in the United States, based on a comprehensive framework of nonmanual workplace skill, including cognitive, creative, technical and social types of skill, measured at the occupational level. By applying this framework to the individual-level 1983-2010 Current Population Surveys, we are able to adjudicate between competing accounts of the changing market structure, returns to skill, and wage inequality. We find substantial heterogeneity in the payoff to different types of skill. The most important trend under this multidimensional model is a precipitous increase in the payoff to analytical skill that involves synthesis, critical thinking, and abstract reasoning. This multidimensional approach is also helpful in expanding our knowledge on gender and racial gaps in skill and earnings. As we apply this model to different gender and racial groups separately, we find sizeable gender and racial disparities in terms of employment distribution and wage returns across different types of skill. We argue that this multidimensional framework of skill can better gauge the relationship between skill-biased trends and earnings inequality. These trends are driven more by institutional, social, and cultural changes than by narrowly defined technological change.
Peptide-MHC heterodimers reveal differential contribution of weak self-peptides to positive and negative selection [electronic resource]
Keywords: Microbiology and Immunology

T cell central tolerance depends on the T cell receptor's affinity for self peptide/major histocompatibility complex, but how this affinity translates into the decision to mature or apoptose is unclear. In this body of work, we show that the OT-I TCR's affinity for its endogenous positively-selecting ligands, catnb/H-2Kb and cappa1/H-2Kb, is significantly lower than its previously reported affinity for artificial positively-selecting peptide/H-2Kbs. To understand how these extremely weak ligands produce signals in maturing thymocytes, we generated soluble monomeric and dimeric peptide/H-2Kb ligands. Monomeric agonist ovalbumin (ova)/Kb elicited no detectable signaling in OT-I thymocytes, but heterodimers of ova/Kb paired with an endogenous peptide/Kb induced very efficient deletion, for both positively-selecting and nonselecting endogenous peptides but not for an engineered 'null' partner peptide. In contrast, dimer-induced positive selection was much more sensitive to the identity of the partner peptide, because while catnb/Kb-catnb/Kb homodimers induced efficient positive selection, heterodimers of catnb/Kb paired with a nonselecting peptide/Kb could not induce selection, even though both ligands have measurable affinities for the OT-I TCR. Thus, both positive and negative selection can be driven by dimeric but not monomeric ligands, but positive selection has much more stringent requirements for the partner self-pMHC.
The performance of analysis [electronic resource] : habit and conversion in seventeenth-century French thought
Keywords: Comparative Literature

My dissertation examines a cognitive model for conversion, "the performance of analysis", which was prevalent in seventeenth-century French thought. According to the model, an actor seeking conversion should begin by acting as if he or she were already what he or she wants to become, imitating the actions of one already embodying the hypothetical state; habituation then actualizes that which begins as an imaginary hypothesis into a concrete reality. I argue that this model for conversion was correlated to mathematical practice in the period, and I trace its manifestations in Descartes, Pascal, Rotrou, Molière, and La Rochefoucauld.
A phase portrait approach to vehicle stabilization and envelope control [electronic resource]
Keywords: Mechanical Engineering

Loss of control accidents, which lead to thousands of deaths every year in America alone, are often caused by a miscalculated action of the driver or a sudden change in the road surface. Recent years have seen several technologies arise in an attempt to decrease accident rates, one of which is Electronic Stability Control. While ESC is effective at stabilizing the vehicle, it functions without full knowledge of the vehicle states or tire-road coefficient of friction. As more sensors become available and control objectives become more complicated, car designers will need to implement a more holistic control scheme like aircraft envelope control, which integrates multiple sensors and actuators to keep the vehicle within a safe operating regime. This dissertation outlines two initial building blocks for a full vehicle control system. The first, called Vehicle Envelope Control, stabilizes the car by keeping it within a safe region of the yaw rate-sideslip state space. An analysis of the yaw acceleration isoclines in the yaw rate-sideslip phase plane allows for determination of an envelope boundary that is consistent with the natural system dynamics. The chosen boundary is defined by the yaw acceleration nullcline at the maximum steering angle that results in open loop stable dynamics, and the lines of maximum rear slip angle, which prevent rear tire saturation. The envelope boundaries are enforced by an attractive controller defined by the distance of the vehicle states from the safe boundary. An inner boundary proportional controller provides a soft landing at the yaw rate boundaries by limiting the driver's steering angle to the maximum stable steering angle as the vehicle approaches the boundary. To prove the effectiveness of the controller, Stanford's steer-by-wire vehicle, P1, performs several maneuvers during which the controller must activate to stabilize the car. The second building block for the full-vehicle control system involves determining and implementing the mechanical changes necessary to enhance estimation of tire-road coefficient of friction and peak lateral tire force. The ability to estimate friction reliably allows for real-time updates to the envelope boundaries, relaxing them as the friction increases, and constraining them as the friction decreases. Isolating the aligning moment, the portion of steer-axis reaction torque from lateral tire forces, gives information on friction; however, there are typically several other torques felt about the steering axis that must be estimated and subtracted out before the aligning moment can be determined. The suggested suspension design eliminates contributions from these other torques, so that the aligning moment is measured directly.
Photoacoustic imaging using capacitive micromachined ultrasonic transducers [electronic resource]
Keywords: Electrical Engineering

One of the primary goals of a medical imaging procedure is to spatially localize disease in an individual. This dissertation focuses on photoacoustic imaging, which is a relatively new medical imaging modality that shows great promise for disease diagnosis - especially cancer detection. In photoacoustic imaging, short laser pulses absorbed by molecules in tissue induce ultrasonic pressure waves which are then detected to form an image. In this work, using a custom built mechanically scanned single-transducer photoacoustic imaging system, we extend photoacoustic imaging into the molecular imaging domain. In this first such demonstration, we show how an exogenous contrast agent that binds preferentially to an angiogenesis biomarker enables an early cancer diagnosis in living subjects. To accelerate the goal of taking photoacoustic imaging from the lab to the clinic, this thesis introduces capacitive micromachined ultrasonic transducer (CMUT) arrays as an enabling technology platform. CMUT technology allows the fabrication of highly sensitive, wide bandwidth, 2D transducer arrays that can be tightly integrated with electronics. This thesis shows the first results of true 3D volumetric photoacoustic imaging using CMUTs. Deep tissue photoacoustic imaging up to a depth of ~5 cm and preliminary results from real-time photoacoustic imaging are also shown. Finally, in this work, we describe a new CMUT microfabrication process called the Thick-BOX process. The Thick-BOX process promises a simpler fabrication process that produces more reliable and robust CMUTs. Experimental fabrication results of low frequency CMUT devices are presented as a proof-of-concept verification for this fabrication process.