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Connecting the Speed-Accuracy Trade-Offs in Sensorimotor Control and Neurophysiology Reveals Diversity Sweet Spots in Layered Control Architectures
Get PDFNervous systems sense, communicate, compute, and actuate movement using distributed components with trade-offs in speed, accuracy, sparsity, noise, and saturation. Nevertheless, the resulting control can achieve remarkably fast, accurate, and robust performance due to a highly effective layered control architecture. However, this architecture has received little attention from the existing research. This is in part because of the lack of theory that connects speed-accuracy trade-offs (SATs) in the components neurophysiology with system-level sensorimotor control and characterizes the overall system performance when different layers (planning vs. reflex layer) act work jointly. In thesis, we present a theoretical framework that provides a synthetic perspective of both levels and layers. We then use this framework to clarify the properties of effective layered architectures and explain why there exists extreme diversity across layers (planning vs. reflex layers) and within levels (sensorimotor versus neural/muscle hardware levels). The framework characterizes how the sensorimotor SATs are constrained by the component SATs of neurons communicating with spikes and their sensory and muscle endpoints, in both stochastic and deterministic models. The theoretical predictions are also verified using driving experiments. Our results lead to a novel concept, termed ``diversity sweet spots (DSSs)'': the appropriate diversity in the properties of neurons and muscles across layers and within levels help create systems that are both fast and accurate despite being built from components that are individually slow or inaccurate. At the component level, this concept explains why there are extreme heterogeneities in the neural or muscle composition. At the system level, DSSs explain the benefits of layering to allow extreme heterogeneities in speed and accuracy in different sensorimotor loops. Similar issues and properties also extend down to the cellular level in biology and outward to our most advanced network technologies from smart grid to the Internet of Things. We present our initial step in expanding our framework to that area and widely-open area of research for future direction
Γ(p)-Level Structure on p-Divisible Groups
Get PDFThe main result of the thesis is the introduction of a notion of Γ(p)-level structure for p-divisible groups. This generalizes the Drinfeld-Katz-Mazur notion of full level structure for 1-dimensional p-divisible groups. The associated moduli problem has a natural forgetful map to the Γ0(p)-level moduli problem. Exploiting this map and known results about Γ0(p)-level, we show that our notion yields a flat moduli problem. We show that in the case of 1-dimensional p-divisible groups, it coincides with the existing Drinfeld-Katz-Mazur notion.
In the second half of the thesis, we introduce a notion of epipelagic level structure. As part of the task of writing down a local model for the associated moduli problem, one needs to understand commutative finite flat group schemes G of order p2 killed by p, equipped with an extension structures 0→ H1→ G→ H2→ 0, where H1,H2 are finite flat of order p. We investigate a particular class of extensions, namely extensions of Z/pZ by μp over Zp-algebras. These can be classified using Kummer theory. We present a different approach, which leads to a more explicit classification.</p
Functional Evaluation and Development of Novel Agonists and Modulators of Neuronal Ion Channels
Get PDFThis dissertation describes studies of activation of neuronal ion channels and evaluating new ligands to modulate this process. In chapter two, we expanded the binding model of cytisine to the α4β2 nicotinic acetylcholine receptor. We also determined how C(10)-modification of cytisine impacts the key binding interactions between cytisine and its binding site. To achieve this, we used non-canonical amino acid mutagenesis to probe the electrostatic binding interactions of a novel series of C(10)-cytisine derivatives. In order to perform similar studies in the α3β4 nAChR subtype, we describe the heterologous expression of mouse and human α3β4 nAChRs in Xenopus Laevis oocytes in appendix one. Chapter three describes the development and functional evaluation of a novel series of pyrrolidinoindolines for agonism and modulation of the GABAA receptor. Additionally, we performed mutagenesis studies to identify the binding site of these novel ligands. Appendix two describes a different screen for activation or modulation of GABAA receptors using a set of phenolic compounds implicated in Autism Spectrum Disorder. Chapter four shifts focus to voltage-gated ion channels: in this chapter, the ultimate goal was to photochemically control the activation of VGSCs and make progress towards developing a RubpyC17-based photoswitch that could be used in an artificial retina. To this end, we determined the functional effects of several ruthenium bipyridine analogs on voltage-gated sodium and potassium channels.</p
Dynamics of Southern Ocean Mixed Layers
Get PDFWhile it is often conceptualized in a spatially and/or temporally averaged sense, the mixed layer depth of the global ocean exhibits significant variability in both space and time. The mixed layer plays a key role in controlling the exchange of heat and gases between the atmosphere and the ocean interior; an inaccurate portrayal of mixed layer depths can be a major source of error in global climate models. In particular, the Southern Ocean, or the waters around Antarctica, take up a significant portion of anthropogenically released carbon dioxide and subduct it into the deep ocean, affecting global climate on both relatively short and glacial timescales. Variability in the mixed layer also affects the formation and subduction of mode waters, the partitioning of waters between the upper and lower overturning cells, and biological productivity. The stratification of the mixed layer is significantly modified by submesoscale dynamics, which are not resolved in current state-of-the-art climate models. The parameterization of these dynamics represents a large source of uncertainty, and better observations and a better understanding of the submesoscale can be used to improve climate predictions.
In this work, the variability of Southern Ocean mixed layers is examined using both numerical and observational methods. General circulation model output is combined with a simple advection scheme to examine upwelling pathways, mixed layer residence times, and air-sea equilibrium in the Southern Ocean. Virtual Lagrangian drifters are released around the basin and tracked as they outcrop into the mixed layer, where they can exchange properties with the atmosphere. These studies are combined with high-resolution observations of mesoscale and submesoscale dynamics in the Southern Ocean, which play a leading order role in setting the stratification of the mixed layer. Seaglider data are used to construct potential vorticity fields, which are used to identify possible instances of different submesoscale instabilities in Drake Passage. Seasonal and zonal mixed layer variability are also examined using these observations. A second set of Seaglider observations are used to diagnose changes in ventilation and eddy stirring on sub-seasonal timescales at the Polar Front, one of the major fronts of the Southern Ocean. This thesis aims to expand current knowledge of mixed layer dynamics, especially at the submesoscale, and examine their implications for global circulation and climate.</p
The Ethology of Stress in Nematodes
Get PDFAnimals can respond to stress in two ways: one is through innate, reflexive behaviors and physiological responses. For example, bees sting invaders when they feel threatened, and heat shock proteins in our body ensure the proper folding of proteins under stressful conditions. The other strategy is through the more active and dynamic phenotypic plasticity responses, for example the transformation of spadefoot tadpoles into cannibals in crowded environments.
When Caenorhabditis elegans roundworms face harsh environmental conditions they can develop into the dauer larvae stage instead of reproductive adult. Dauers are long-lived, stress-resistant, and specialized for dispersal. Dauer biology has much to reveal about stress resistance, neural state, and tissue coordination.
Using RNA-seq we compared dauers vs non-dauers and found 8,042 genes that are differentially expressed. By bioinformatically clustering these genes, we discovered the significant up-regulation of neuropeptide genes during dauer development. In particular, the FMRFamide neuropeptides are coordinatelly up-regulated as a family. Peptidergic signaling downstream of sbt-1 promotes dauer entry decision and nication coordination, and it is necessary for CO2 chemoattraction. We further identified that flp-10 and flp-17 together have the same effect as sbt-1 on nictation and CO2 attraction. Finally, we showed that the upregulation of flp might be a shared strategy in the host-seeking parasitic infective juvenile (IJ) stage.
From the RNA-seq data we also identified four good marker genes for labeling the dauer entry decision and driving gene expression, specifically during dauer commitment. By overexpressing daf-9 in the hypodermis during dauer-commitment, we can manipulate the decision and promote reproductive development. Combining the markers with partial dauer mutants allowed me to confirm their subtle phenotypes in tissue-coordination breakdown. Furthermore, this approach allowed me to uncover the novel neuronal partial dauer phenotype for daf-18 mutants.
In work done outside of the lab, I investigated the innate stress response of extremophiles to Mono Lake. I isolated nine new nematode species that were diversely related in phylogeny, morphology, and feeding lifestyles. We were able to culture one of the species, Auanema tufa, in the laboratory, and demonstrated a high level of arsenic stress-resistance in the species. These data suggest that Mono Lake—particularly its more buffered tide zone—has been invaded independently and multiple times by nematodes. We also speculate that pre-adaptation to arsenic in the tide zones on Mono Lake could lead to the genomic evolution necessary to adapt to the high pH and salinity of inner Mono Lake.
Altogether, I have investigated innate and plastic stress responses in and outside of the lab through my work on dauer development and arsenic resistance in Mono Lake. This has allowed me to survey the strategies nematodes use to maximize the use of their simple body plans. In particular, dauers up-regulate 64 neuropeptide genes that encode for 215 peptides to massively rewire their neural state. This likely allows them to overcome the physical limitations of their un-compartmentalized nervous system, and I speculate that such a strategy would be useful in other organisms lacking compartmentalized brains, as well as in local regions of a brain that are low complexity.</p
Core-Collapse Supernova Physics in the Multi-Messenger Era
Get PDFEighty-five years following the historic proposal that core-collapse supernovae accompanied the transition of evolved massive stars to neutron stars [1], the mechanism through which these collapsing stars explode remains uncertain. While supernovae are observed on a daily basis across the electromagnetic spectrum, neutrinos and gravitational waves, emitted from the very heart of the core-collapse supernova central engine, provide a direct glimpse of the dynamics driving the explosion. The joint gravitational wave and electromagnetic observations of a colliding neutron star binary system on 17th August 2017 heralded a new era for multi-messenger astronomy [2]. The next galactic core-collapse supernova presents an unparalleled opportunity to directly probe core-collapse supernova physics and the explosion mechanism.
This thesis explores a number of topics in multi-messenger astronomy and core-collapse supernova physics. First, it tackles the observation problem; detailing an astrophysically motivated search protocol for gravitational waves from core-collapse supernovae triggered by observations of neutrino and/or electromagnetic counterparts. Applying these methods to a number of hypothetical observational scenarios, it presents sensitivity estimates for the second generation of gravitational wave interferometric detectors to both realistic and speculative emission mechanisms associated with core-collapse supernovae. Next, it addresses the prospects for post-detection inference; developing a Bayesian toolkit to interpret gravitational wave observations from core-collapse supernovae and augment current understanding of the explosion mechanism. A proof-of-principle study is also presented, using tailor-made simulations to demonstrate the viability of extracting the angular momentum distribution of nascent millisecond proto-neutron stars from their gravitational wave echoes. Thereafter, it considers the ramifications of failure to accurately capture proto-neutron star hydrodynamics in core-collapse supernova simulations; exploring the influence on the explosion mechanism of gravito-acoustic waves generated by convection in the proto-neutron star mantle. Finally, it ponders the impact of advances in multi-messenger astronomy and source modelling over the next twenty years on the understanding of core-collapse supernova physics.</p
Online Platforms in Networked Markets: Transparency, Anticipation and Demand Management
Get PDFThe global economy has been transformed by the introduction of online platforms in the past two decades. These companies, such as Uber and Amazon, have benefited and undergone massive growth, and are a critical part of the world economy today. Understanding these online platforms, their designs and how participation change with anticipation and uncertainty can help us identify the necessary ingredients for successful implementation of online platforms in the future, especially for those with underlying network constraints, e.g., the electricity grid.
This thesis makes three main contributions. First, we identify and compare common access and allocation control designs for online platforms, and highlight their trade-offs between transparency and control. We make these comparisons under a networked Cournot competition model and consider three popular designs: (i) open access, (ii) discriminatory access, and (iii) controlled allocation. Our findings reveal that designs that control over access are more efficient than designs that control over allocations, but open access designs are susceptible to substantial search costs. Next, we study the impact of demand management in a networked Stackelberg model considering network constraints and producer anticipation. We provide insights on limiting manipulation under these constrained networked marketplaces with nodal prices, and show that demand management mechanisms that traditionally aid system stability also help plays a vital role economically. In particular, we show that demand management empower consumers and give them "market power" to counter that of producers, limiting the impact of their anticipation and their potential for manipulation. Lastly, we study how participants (e.g., drivers on Uber) make competitive real-time production (driving) decisions. To that end, we design a novel pursuit algorithm for making online optimization under limited inventory constraints. Our analysis yields an algorithm that is competitive and applicable to achieve optimal results in the well known one-way trading problem, and new variants of the original problem.</p
Nuclearity and π-π Interaction Effects on Olefin Polymerization and Coordination Chemistry
Get PDFThis thesis details work performed on the use of secondary coordination sphere effects to impact olefin polymerization activity and tacticity control and the coordination chemistry of Y, Fe, and Cu. Chapter One provides a general introduction and summary of each chapter. Chapter Two describes work in collaboration with KFUPM on nuclearity effects in Zr bisamine bisphenolate complexes. Chapter Three describes the coordination chemistry of arene-appended Y di(pyridyl) pyrrolide complexes and the olefin polymerization activity of tris(dimethylamido) Ti, Zr, and Hf di(pyridyl) pyrrolide complexes. Appendix A describes the effects of bulky trialkylsilyl, triphenylsilyl, and diphenyl(alkyl)silyl substituents on the tacticity control of monozirconium amine bis(phenolate) complexes in 1-hexene polymerization. Appendix B describes the synthesis and structures of miscellaneous dizirconium amine bis(phenolate) complexes which could not be isolated in sufficient purity for olefin polymerization tests. Appendix C describes the synthesis, electrochemistry, and reduction of mesityl-substituted di(pyridyl) NHC supported Fe complexes. Appendix D describes the preparation, solid-state structures, and electrochemistry of di(pyridyl) pyrrolide and di(pyridyl) NHC Cu(I) and Cu(II) complexes displaying π-π interactions in the solid state. Appendix E describes work towards the synthesis of di(pyridyl) guanidinate proligands and metal complexes supported by di(pyridyl) urea, monopyridyl and di(pyridyl) N-heterocyclic olefin and N-heterocyclic vinylidene ligands for use in Lewis acid assisted olefin polymerization. Appendix F includes relevant spectra.</p
Multi-Contrast Photoacoustic Computed Tomography
Get PDFImaging of small animals has played an indispensable role in preclinical research by providing high dimensional physiological, pathological, and phenotypic insights with clinical relevance. Yet pure optical imaging suffers from either shallow penetration (up to ~1–2 mm) or a poor depth-to-resolution ratio (~3), and non-optical techniques for whole-body imaging of small animals lack either spatiotemporal resolution or functional contrast. A stand-alone single-impulse photoacoustic computed tomography (PACT) system has been built, which successfully mitigates these limitations by integrating high spatiotemporal resolution, deep penetration, and full-view fidelity, as well as anatomical, dynamical, and functional contrasts. Based on hemoglobin absorption contrast, the whole-body dynamics and large scale brain functions of rodents have been imaged in real time. The absorption contrast between cytochrome and lipid has enabled PACT to resolve MRI-like whole brain structures. Taking advantage of the distinct absorption signature of melanin, unlabeled circulating melanoma cells have been tracked in real time in vivo.
Assisted by near-infrared dyes, the perfusion processes have been visualized in rodents. By localizing single-dyed droplets, the spatial resolution of PACT has been improved by six-fold in vivo. The migration of metallic-based microrobots toward the targeted regions in the intestines has been monitored in real time. Genetically encoded photochromic proteins benefit PACT in detection sensitivity and specificity. The unique photoswitching characteristics of different photochromic proteins allow quantitative multi-contrast imaging at depths. A split version of the photochromic protein has permitted PA detection of protein-protein interactions in deep-seated tumors. The photochromic behaviors have also been utilized to guide photons to form an optical focus inside live tissue. As a rapidly evolving imaging technique, PACT promises pre-clinical applications and clinical translation.</p
Copper and Nickel Catalysis for the Construction of Novel C−N and C−C Bonds
Get PDFFirst-row transition-metals such as nickel and copper have revolutionized cross-coupling chemistry. Their propensity to form radical intermediates from alkyl electrophiles has greatly expanded the scope of traditional cross-coupling reactions. Alkyl radicals can be recaptured by a chiral transition-metal catalyst allowing for enantioselective bond formation. In general, alkyl radicals rapidly epimerize, and thus both enantiomers of a racemic mixture of an alkyl electrophile can be processed into the same enantiomer of product, rendering the overall process enantioconvergent. Herein, the development of basic bond constructions and the development of asymmetric reactions leveraging alkyl radical intermediates for carbon-nitrogen and carbon-carbon bond formations are discussed. Reaction development is the primary focus of this work, though mechanistic insights discovered along the way are also detailed within.
Chapter 2 describes the development of an enantioconvergent alkylation of amine nucleophiles with alkyl electrophiles. Carbazole and indole derivatives are employed as nucleophiles to undergo copper-catalyzed cross-coupling with tertiary α-chloroamide electrophiles under visible light irradiation. Reaction optimization, scope of reactivity, inorganic synthesis, and mechanistic insights are described within.
Chapter 3 details the development of a non-asymmetric copper-catalyzed alkylation of aliphatic amines with unactivated alkyl electrophiles under visible light irradiation. The development of a novel catalytic system to circumvent the issues with the photophysical properties of aliphatic amine-copper complexes is discussed. Scope of reactivity and mechanistic investigations are detailed within. Additionally, our efforts to develop an asymmetric variant of this reaction are enclosed.
Chapter 4 discusses the development of a copper-catalyzed alkylation of N-heterocycles with α-halolactams in the absence of light. The scope of the reactivity is detailed within. Mechanistic studies contained in this section suggest a unique and interesting reaction pathway—one that does not proceed through a radical intermediate.
Chapter 5 presents a novel class of organosilane electrophiles employed in an enantioconvergent nickel-catalyzed cross-coupling reaction. Here, the development of the reaction, scope of reactivity, and initial mechanistic insights are discussed.</p