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Applications of Synthesis in Copolymer Upcycling, Reduction of CO₂, Ligand Non-Innocence, and New Weakly-Coordinating Anions
No full textThis dissertation focuses on a very diverse series of studies with synthetic applications to organometallic systems supported by a redox non-innocent ligand architecture, α,ω diene generation, ionomers for tuning performance of electrochemical CO2 reduction, and design of new weakly coordinating anions.
Chapter 2 discusses the reactivity of a 9,10-anthracenediyl bis(phenoxide) titanium complex, where the polyaromatic anthracene motif functions as a non-innocent ligand. This enables access to a reduced Ti complex which is competent for oxidative coupling of alkyne and nitrile substrates, and pyrimidines and substituted benzenes can be accessed catalytically. Additional reactivity with oximes and oxidative coupling of alkynes and CO2 is explored.
Chapter 3 reports a two-step method for generation of a distribution of α,ω-dienes from ethylene and butadiene. Copolymers are prepared with variable butadiene content, where 1,4-butadiene incorporation ensures the double bonds are in the polymer backbone. Subsequent ethenolysis of the copolymers produces α,ω-dienes in the C10-C20 range. The conditions can be modified to control product selectivity.
Chapter 4 presents a series of polystyrene-based ionomers to probe the impact of local [K+] in the Cu electrode microenvironment on CO2R performance (Part A). Partial current density towards C2+ products (|jC2+|) increases with [K+] in ionomer, up to 225 mA cm–2. When K+ is replaced with [Me4N]+, performance lowers to the level of bare Cu, highlighting the crucial role of K+ in improving C2+ product selectivity. Molecular dynamics simulations and partial pressure CO2 experiments support enhanced CO2 mass transport with the ionomers. An expanded series of ionomers is presented (Part B), where the incorporation of different neutral comonomers (vinyl biphenyl) and cross-linking monomers (biphenyl and terphenyl) dramatically boosts performance. Direct tends between K+ content and CO2R performance are not observed with the expanded series, highlighting the non-innocent role of the neutral monomer and polymer structure.
Chapter 5 presents a new, Si-based weakly-coordinating anion. A library of anions bearing a variety of R groups is prepared, enabling facile tuning of sterics and solubility. A range of cations employed in chemical reactivity is supported by these anions, including ether-free alkali cations, Ph3C+, and an ethylene/CO copolymerization catalyst [Pd(dppe)(NCMe)Me]+ (generated by salt metathesis or protonation of a metal-alkyl bond). Electrochemical studies on the [Bu4N]+ variant show an exceptionally wide stability window for the [MeSiF]- anion of 7.5 V in MeCN. The [C6F5SiF]- variant can be readily modified to access additional diverse and/or dianionic variants.
Chapter 6 discusses the electrochemical performance of a new class of magnesium electrolytes for next-generation batteries. [Mg(DME)3][MeSiF]2 demonstrates remarkable performance with good stability, moderate conditioning, high coulombic efficiency ( > 96%), and high current density ( ~100 mA cm-2). However, the sensitivity of the experiments requires careful study of many parameters including impact of MgR2 additives (identity and concentration), cycling protocol, synthetic route, and the Pt working electrode to understand how the electrochemical performance is impacted. While addition of MgMe2 improves electrochemical performance, it is not inherently required for reversible Mg deposition and stripping. Following an extensive investigation of the cyclic voltammetry (CV) performance of [Mg(DME)3][MeSiF]2, preliminary screening of additional [Mg(DME)3][RSiF]2 variants is discussed.
Appendix I discusses the characterization of ethylene/α-olefin copolymers generated from monometallic and bimetallic Zr catalysts. The decreased polar monomer incorporation for the bimetallic vs. monometallic catalysts is attributed to the steric clash of larger comonomers with the distal metal site in bimetallic catalysts.
Appendix II discusses the preparation of bulky anthracene phenoxide ligands for Ti and Ta.
Appendix III discusses the preparation of mixed aryl/hydride borates as electrolytes for next-generation Mg batteries.</p
Implementing and Modeling Gene Drives for Population Modification and Suppression
No full textGene drive as a technology has immense potential for modifying species from the local to the global population level. While the advent of the CRISPR-Cas9 system has paved the way for many previously untenable gene drives, it has also illuminated two substantial pitfalls: homing based gene drives are particularly susceptible to generating drive breaking resistance alleles and many if not most gene drives are too powerful to be regionally contained. Lack of confinability makes such gene drives impractical for real world application where international law would be violated by their usage. We developed a new general form of gene drive known as cleave and rescue (ClvR), then built and simulated the potential of multiple variants of this drive which are capable of modifying or suppressing target populations, including variants with and without introduction thresholds for drive. We also developed scripts in Python capable of generating population dynamics simulations of a user-defined gene drive, either as a deterministic, population proportion model or a stochastic, discrete individual model. This tool provides a very useful first pass answer about a given gene drive’s ability to modify or suppress a population under varying fitness costs, drive activity rates, and release proportions
The Role of Kinetochores in Mammalian Neural Development
No full textThe kinetochore is a protein complex found at the centromere of chromosomes. It plays an essential role in mitosis, but our lab is investigating the role of the kinetochore in a surprising post-mitotic setting. Specifically, we are focusing on the presence of kinetochores in the synapses and axons of mammalian nerve cells, implying that kinetochores play a key role in neural development.
Here we have engineered strains of mouse embryonic hippocampal nerve cells with certain kinetochore-encoding genes knocked out, and then fluorescently imaged their axonal growth cones. To quantify the change in dynamicity of the growth cones after gene knockout, we used image classification and machine learning techniques and found statistically significant results between the knockout and wildtype strains of nerve cells, indicating that kinetochores are essential to functional axon growth.</p
Depositional and Structural History of the Pavian and Kudu Nappes in the Naukluft Mountains, Namibia
Get PDFThe termination of the Marinoan Snowball Earth glacial epoch was one of the most extreme climate events in Earth history. Yet, the transition from global glaciation to an ice-free warmer climate is still poorly constrained. The Naukluft Nappe Complex of south-central Namibia contains several stratigraphic formations that record the environmental and tectonic transitions of the Neoproterozoic, including glaciogenic deposits and basal-Ediacaran cap carbonate of the Marinoan Snowball Earth. This stratigraphic record has the potential to provide a critical record of the climate, sea-level history, ocean chemistry, and time frames across the climate transition of the Marinoan Snowball deglaciation.
We first show a detailed study of the sedimentology and stratigraphy of the upper Blässkranz Formation and Tsabisis Formation cap carbonate to develop an environmental and sequence stratigraphic history spanning and following the deglaciation. In downdip areas Marinoan diamictite transitions upward into dolostone intermixed with sandstone and extrabasinal clasts that is gradually overlain by fine grained laminated dolostone. Updip localities show the diamictite is overlain by intercalated sandstones, gravels, and shales before an abrupt change to laminated dolostone of the cap carbonate. A succession of stromatolites, which become strongly elongate upward, prograde into the laminated dolostone in the updip localities. The stromatolites are overlain by laminated dolostone that grades upward into rhythmite with intercalations of shale. Near the top of the cap, rhythmites may be reworked into tabular intraclast conglomerate, locally intercalated with hummocky cross stratified sandstone, which passes upward into the shale and limestone members of the Tsabisis Formation. The lateral and vertical distribution of facies indicate a retreat of the shoreline and glacially sourced siliciclastics near the base of the cap carbonate, a shallowing succession to fair-weather wave base at the top of the stromatolite facies, and a second shallowing succession to storm wave base near the top of the cap carbonate. Maximum flooding occurred soon after the initiation of carbonate deposition and two sequence boundaries mark higher stratigraphic levels within the cap carbonate. With a sea-level history and chronological framework inferred from the sequence stratigraphy we can consider different mechanisms of sea-level change, which may reflect the timescale and synchronicity of deglaciation.
Next, we consider the structural and stratigraphic relationships between the Neoproterozoic units of the Naukluft Mountains to define and contextualize the extent of the terminal Marinoan geologic record. We show that the Northern Pavian Nappe, which includes the Marinoan-associated Blässkranz and Tsabisis formations, is stratigraphically succeeded by the dolostone dominated Kudu Nappe and is not correlated or genetically related to the nearby Southern Pavian Nappe. Additionally, the modified stratigraphic and structural relationships allow for a simplified nappe emplacement history that reduces the magnitude of shortening associated with convergence along the Damara Orogen.
Finally, we use sea-level modeling of the Naukluft Marinoan record to constrain the duration of global deglaciation. Using a range of reconstructed synchronous and continuous deglaciation models, we evaluate if the observed sea-level patterns of the Naukluft can be fully explained by glacial isostatic mechanisms driven by the deglaciation. Short Snowball deglaciation durations, on the order of ~2 kyr, result in exclusive sea-level rise, or sea-level rise followed by sea-level fall, but cannot drive two distinct phases of sea-level fall. However, for longer duration snowball deglaciations, of ~10-30 kyr, we can drive two distinct intervals of sea-level rise and fall across much of the width of a continental margin, consistent with the stratal patterns observed in Naukluft Mountains cap carbonate succession. Our spatially varying sea-level predictions resulting from longer duration deglaciations may be applicable in interpreting stratal patterns of other cap carbonate successions. Furthermore, this work underlines the need for better constraints on the areal distribution and volume of Marinoan ice sheets, including improved understanding of plausible deglacial durations using updated global climate models.</p
Engineering Heme Proteins for C(sp³)–H Primary Amination
Get PDFPrimary amine is one of the most prevalent moieties in synthetic intermediates and pharmaceutical compounds. The preparation of aliphatic primary amines via C−H functionalization would provide direct access to the nitrogen-containing compounds from hydrocarbon substrates. While the enzymatic oxyfunctionalization of C–H bonds is well established, the analogous strategy for nitrogen incorporation is unknown in Nature. Likewise, a synthetic method for selective primary amination of aliphatic C–H bonds remains elusive. Combining chemical intuition and inspiration from Nature, chemists and protein engineers have created new heme-containing enzymes for the C(sp³)–H primary amination via directed evolution. This thesis describes some of the efforts in the continued pursuit of these new-to-nature reactions. Chapter I discusses directed evolution in the context of biocatalysis, the strategies for introducing new-to-nature chemistry in enzymes, the discovery of nitrene transferases from the cytochrome P450 monooxygenase, and finally, the development of C(sp³)–H primary aminases. Chapter II details the discovery and engineering of serine-ligated cytochrome P411 enzymes that catalyze the first primary amination of C(sp³)–H bonds with excellent selectivity, affording a broad scope of enantioenriched primary amines. Chapter III demonstrates that these new-to-nature nitrene transferases were engineered to aminate and amidate unactivated, unbiased C(sp³)–H bonds with unprecedented selectivity. In Chapter IV, engineered protoglobins are shown to utilize hydroxylamine (NH₂OH) for nitrene transfer reactions, including benzylic C–H primary amination and styrene aminohydroxylation. Overall, these new-to-nature reactions can be considered the nitrogen analogs to the C–H oxidation chemistry performed by monooxygenases and peroxygenases. By offering a direct path from saturated precursors, these enzymes present a new biochemical logic for accessing nitrogen-containing compounds. Finally, this work hints at the possible future discovery of natural enzymes that use hydroxylamine precursors for amination chemistry.</p
Unexpected Partisan Unity Among Congressional Leaders and Legislators Using New Latent Variable Estimation Techniques and Frameworks
Get PDFThis dissertation is intended as a collection of essays which explore innovations in the development and estimation of latent variable models. These methods have many applications, including Natural Language Processing and latent correlation structures, which this dissertation explores. In addition to the statistical challenge of innovating on this class of model, latent variable methods are computationally demanding, requiring research insights related to how to render such methods feasible, both in terms of memory constraints and in terms of achieving rates of convergence in realistic time frames. The overall substantive angle of this dissertation is related to political representation, in particular to U.S. Congress. This substantive focus allows me to study the quality of our democratic institutions and their responsiveness to and interactions with the public. This dissertations harnesses novel, large datasets, which demand the innovative methods developed throughout this dissertation to answer pressing questions related to these issues of political representation. The dissertation focuses on three main data sources: social media data from members of the U.S. House on Twitter, public speech data derived from Congressional Record from 1877-2016 and elections data from the U.S. House from 1956 to 2022. All of these data relate how politicians relate to their constituents: by communicating with them through social media or in public speeches in the first and second cases; and further by trying to earn their votes in the third case. Thus, this dissertation aims to answer questions relating to the use of innovative statistical methods to recover latent features of the data. It explores these questions through the lens of their applications to questions of American legislature. A key finding across domains is the relative unity and stability between legislative leaders and members of their respective parties. In fact, this stability is apparent both in contemporaneous studies of social media, electoral representation in the post-war era, and over historical speeches on the floor of the U.S. House.
Methodologically, this dissertation argues for new frameworks for thinking about large data in political science contexts. It emphasizes the importance of descriptive statistical approaches that consider the full distribution of the data generation process, including higher-order moments beyond the mean. In Chapter 2, it shows how calibrating statistical models for accurate generative descriptions can significant implications for how researchers interpret their statistical results and can accurately uncover important quantities of interest. In Chapter 3, this dissertation proposes new ways to think about external validity when using unsupervised methods for textual analysis. Finally, all three chapters contend with approaches to latent features in the data: topical structure in chapters 1 and 3, and contemporaneous correlations in Chapter 2. All three chapters employ these latent variable methods while proposing solutions to contend with the estimation and computational obstacles imposed by using such methods on large-scale data. In doing so, these papers find unexpected stability and unity among congressional leaders and legislators, with important implications for legislative representation in the United States.</p
The Role of Integral Gain and its Neuromuscular Implementation in the Flight Control System of Drosophila
Get PDFSmall flying insects, such as the fruit fly Drosophila melanogaster, can navigate along a relatively straight path for long distances. During these journeys, they need a long-range navigational strategy to maintain a constant heading over time, as well as stabilizing behaviors to deal with perturbations, such as a sudden gust of wind or a broken wing. In this work, I characterize a behavioral strategy flies use to maintain stable flight using a combination of experimental and control theoretic approaches. I then investigate how this control strategy is implemented in the flight motor system. In Chapter 1, I describe release-and-recapture experiments performed in the Mojave Desert to investigate how flies interact with the wind to travel long distances. These experiments provide key insight into the dispersal behavior of small insects and suggest that these animals employ a single algorithm that is functionally robust in both still air and under windy conditions. In Chapter 2, I present an extensive set of behavioral experiments showing that the optomotor response, a well-described stabilizing flight reflex, can be accurately modelled by a proportional-integral controller. I also show simulations that exemplify the potential functional advantage of this controller model in natural flight conditions. In Chapter 3, I show the results from muscle imaging experiments designed to investigate how the integral gain of a proportional integral controller might be implemented within the flight motor system. Finally, in Chapter 4, I summarize the main findings, and discuss the limitations of this work and future directions.</p
Qital and Jihad: The Faces of Holy War in Islam
No full text[Introduction] When reviewing Muslim sources on the early Crusades, what seems to set apart the Third
Crusade from the earlier ones is a focus on the concept of “holy war” which seems to be absent
from earlier Crusades. It is as if the idea of “holy war” that would come to dominate the Muslim
view of the Crusades developed as a response to the religious fervor of the crusaders. However,
upon further study of the history of the Islamic world, two things become clear: the Islamic
concept of “holy war” is different from that of Christendom, and its history is not so simple. The
majority of the accounts written on the first three Crusades were written by historians during the
time of Nur ad-Din and Saladin, who both used religion to legitimize their conquests and
subsequent rule. Their religious piety gave Muslim historians an avenue to explain their
successes where those before them had failed. However, it is undeniable that most early Muslim
historians, and often those in power, saw all three Crusades as deeply religious conflicts. An
Islamic concept of “holy war” was present throughout all three Crusades, but the piety that Nur
ad-Din and Saladin displayed led to an increase in the use of the concept of a “holy war” by
Muslim historians trying to legitimize the rule and analyze the response of Muslim leaders to the
Crusades
How We Imagine: Insights from Single Neuron Recordings in the Human Brain
No full textAs human beings interact with the world, we sample it, build representations of its underlying structure, and subsequently use that knowledge for future reasoning - also called modeling the world. This model is generative, allowing our knowledge of the world to influence our perception and in extreme cases induce perception in the absence of any external stimulus. This phenomenon called mental imagery is a remarkable cognitive ability that allows us to remember previous experiences, imagine new ones, make plans, and solve problems. In the visual domain, our ability to generate visual percepts without external stimulation is the basis of our memory for experiences, as episodic memories are simply a subset of all possible experiences we could imagine. Animal studies have yielded rich insight into bottom-up visual processing, from the first discovery of neurons that respond to complex objects like faces to determining the precise code for general objects in macaque inferotemporal (IT) cortex. However, the neural mechanisms of internally generated top-down processing have been much more elusive. Here we present findings on the mechanisms of visual imagery at single neuron resolution. We approached deciphering visual imagery by first laying out coding principles for object perception and then directly comparing responses during viewing to subsequent imagery of those images. We recorded 384 visually responsive neurons in inferotemporal (IT) cortex of 12 epilepsy patients as they viewed and subsequently imagined carefully parametrized visual objects. We verified that neurons in IT cortex are ‘axis tuned’, i.e. as in macaques they represent visual objects by encoding specific axes that span a high dimensional object feature space. 218/384 visually responsive neurons (~58%) were axis tuned, and the axis model explained more variance than other models tested. Armed with this code for visual objects we examined neural responses during pure imagery in the same neurons. We demonstrate robust reactivation of individual neurons across the brain (~35% of neurons across the brain and ~50% of neurons in IT cortex) and a recapitulation of viewing stimulus preference during pure visual imagery in IT. By first uncovering the code for visual objects and examining it during imagery, we demonstrate that neurons in IT cortex subserve visual imagery by reinstating visual context. This study marks the first detailed exploration of visual perception and imagery in the human brain
Chemo-Selective Proteomics for Discovery of Polymicrobial Interactions
Get PDFThe future of microbiome research lies in our ability to engineer polymicrobial interactions toward improved host health outcomes, which requires a fundamental molecular understanding of how microbial species sense and respond to ecological competition. Chronic respiratory infection by polymicrobial communities is the leading cause of mortality and morbidity in people living with cystic fibrosis (CF). My thesis work adapts chemo-selective proteomics to dissect molecular mechanisms that drive interspecies dynamics between two notorious opportunistic pathogens dominating chronic CF infection, Pseudomonas aeruginosa and Staphylococcus aureus.
In Chapter 1, I introduce bioorthogonal noncanonical amino acid tagging (BONCAT)-based comparative proteomics, focusing on time-resolved, cell-specific, and cellular state-selective proteomic applications in the dissection of complex microbial systems. In Chapter 2, I discuss a new usage of time-resolved BONCAT
to monitor immediate competition-sensing responses in interbacterial warfare. While coinfection by the Gram-negative Pseudomonas aeruginosa and the Gram-positive Staphylococcus aureus is associated with poor patient outcomes, the interspecies interactions responsible for such decline remain unknown. We
discovered that P. aeruginosa senses S. aureus secreted cytotoxic peptides from a distance and preempts potential competition through activation of type six secretion system (T6SS). P. aeruginosa enhances such competition-sensing-induced antagonism through concomitant attraction toward S. aureus peptides, effectively reducing cellular distances between neighboring species and providing a competitive advantage. In Chapter 3, I discuss a new usage of cell-selective BONCAT to target protein synthesis analysis of the lowabundance organism, S. aureus, in a coculture environment predominated by P. aeruginosa. P. aeruginosa robustly outcompetes S. aureus, and conventional shotgun proteomics, which is biased toward highly abundant proteins on principle, could only identify and quantify less than 5% of total protein synthesis by S. aureus in coculture. We demonstrate that chemical enrichment affords a more than 12-fold increase in total protein abundances synthesized by S. aureus. About 50% of protein “hits” with statistically significant changes in expression were not detected in pre-enrichment lysates, highlighting BONCAT as a powerful strategy that facilitates high-resolution proteomic analysis of low-abundance organisms in polymicrobial communities.</p