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Charles the Bald: the Story of an Epithet
Get PDFFor centuries, historians have followed the lead of their forebears by using standardized names to refer to people and events. The use of 'Charles the Bald' to refer to Charlemagne's grandson has been reinforced via centuries of copying, paraphrasing, and citing historical documents. The sobriquet is now inextricably linked to the man. But in the simple process of writing the epithet, it is easy to forget how much complexity is distilled into one word. Any sophisticated metaphors or hidden meanings have been nearly erased by time. But, this one word carries a wealth of nuance in meaning and intentions. Any analysis of this nickname must attempt to reconnect with the medieval mindset and understand how to reconcile the simplicity of the epithet with the complexity of the man. The investigation of Carolus Calvus (Charles the Bald) must consider not only Charles' own legacy and physical reality, but also evaluate the nickname as part of a larger naming phenomenon. Furthermore, understanding the way the medieval mind saw hair and baldness is instrumental in understanding the possible deeper meanings behind Charles' epithet.
Was Charles the Bald actually bald? Here are the facts: first, the true origin of Carolingian epithets (nicknames given to the kings of Charles' dynasty) will never be known, but their use and proliferation were certainly fueled by the need to distinguish between the overlapping names of the Carolingians. Second, the alliterative nickname Carolus Calvus, could come from as early as 869 or as late as the 10th century. The earliest written use of the epithet appears in a manuscript dated to the 10th century. However, the document is a copy of a text originally drafted before 869. Thus, the nickname could either be contemporary with Charles as a part of the original text or created up to a century after his death and added for clarity in the tenth century copy. Third, Hucbald's incredible alliterative poem on baldness, his Ecloga de Calvus (In Praise of Bald Men), was not written for Charles, as many historians once believed, but it does demonstrate that bald men were ridiculed in the ninth century and symbolically ties baldness to virtue and holiness. Fourth, Charles' grandson, Baldwin II of Flanders was known as 'the bald' by the 11th century; he seemingly inherited the nickname despite not being bald himself.
In their analysis of Charles' nickname, many historians conclude that the meaning is obvious and undeniable, that Charles was simply bald. Regardless of how much time these scholars spend analyzing other Carolingian epithets such as Charlemagne (Charles the Great), Louis the Pious, or Charles the Simple, Charles the Bald was 'obviously' bald. From the facts and theories cultivated during this thesis, however, there is no reason to believe that Charles was truly bald. There are no images or descriptions of a bald king and a significant lack of mocking from Charles' enemies and detractors. Furthermore, Charles certainly had hair into his early adulthood and the poet Hucbald, who lived in Charles' court for a time, does not address the king directly in his poem praising of bald men. Charles may have been called the bald in his lifetime, as the adoption of the epithet by his grandson would suggest, yet the nickname's earliest recorded use can only be certainly dated to the late tenth century. It is entirely possible that Charles' byname and its use by his grandson were invented by post-contemporary historians looking to distinguish between the Carolingians and make their mark on Charles' legacy. A non-physical baldness could symbolize any number of things via its negative associations with old-age, immorality, and low status or positive associations with humility, piety, and prudence. For Charles, it likely referenced a symbolic infertility tied to Charles' difficulty in producing a suitable male heir as well as the subsequent sunset of the Carolingian dynasty.</p
The Evolution of Dragons: From Living Serpents to Mythical Beasts
Get PDFWe, at least in the modern West, tend to think of dragons as mythical beasts; they inhabit medieval epics and romances, as well as the modern fantasy stories and movies inspired by them. As such, they have been around for centuries. However, at the beginning of their life dragons were not mythical; they were in fact quite real. But the original dragons were not dragons at all – they were serpents. The modern image of dragons with legs, wings, and fire-breathing capabilities emerged in the course of the European Middle Ages. It has no place in the Classical world and would have been unrecognizable to the ancient Romans or Greeks. The evolution of dragons from simple snakes did not happen all at once. It occurred slowly over the course of three thousand years (~900BC-1700AD). Further, it did not even happen in the same order everywhere. Dragons were associated with fire and venom in ancient Greek myths and stories but lacked wings until Roman late antiquity. They failed to have their fire-breathing powers confirmed in natural history until the seventeenth century. And across the board, the number of legs attributed to dragons varied greatly between time periods, and even between different depictions in the same time period. Natural histories did not describe dragons as quadrupeds until Athanasius Kircher in the seventeenth century.
That dragons existed, however, remained uncontested until the Early Modern period, and believers persisted well into the eighteenth century. Carl Linnaeus, the father of modern taxonomy, was the person to finally cast them from the real world and firmly trap them in the realm of folklore and legends. It was their strong connection with the world of the gods, a connection that they had enjoyed from the beginning, that led dragons to develop from the real to the unreal, and finally allowed Linnaeus to slay them. Nevertheless, though the dragons that Linnaeus actually met – and he did meet some – were undoubtebly the stuff of myth, the dragons of Ancient Greece were as real as Linnaeus’ dragons were fake.</p
The Molecular Biophysics of Evolutionary and Physiological Adaptation
Get PDFCentral to any definition of Life is the ability to sense changes in one’s environment and respond in kind. Adaptive phenomena can be found across the biological scales ranging from the nanosecond-scale conformational changes of proteins, to temporary rewiring of metabolic networks, to the 3.5 billion years of evolution that produced the enormous biodiversity we see today. This thesis presents a body of work which attempts to examine the overlap between these three scales of adaptation through the quantitative lens of statistical physics. Namely, we examine how molecular, physiological, and evolutionary adaptation governs a feature common to all life – the regulation of gene expression.
We begin by examining the phenomenon of molecular adaptation in the context of allostery, specifically in the context of allosteric transcriptional repressors. Using simple tools of quasi-equilibrium thermodynamics, we derive and experimentally dissect a quantitative model of how such a repressor adapts to different concentrations of an extracellular inducer molecule, modulating the repressors activity and thereby gene expression. While the model is relatively simple, it is remarkably powerful in its ability to draw concrete, quantitative predictions about not only the level of gene expression at a given concentration of inducer, but details of how the repressor responds to changes in the inducer concentration. With a few lines of simple mathematics, we are able to use this model to derive a state variable of the simple repression motif which we term the free energy of the regulatory architecture. This permits us to collapse nearly 500 distinct measurements of the level of gene expression onto a master curve defined by this free energy.
We leverage this feature of the model and use data collapse as a method to identify the effects of mutation, a strong evolutionary force responsible for much of the genetic diversity in bacteria. In Chapter 3, we examine how mutations within the allosteric repressor itself can be mapped to changes in the free energy. The precise value of these free energy shifts and their dependence on the inducer concentration reveal different classes of mutations with one class affecting only the DNA-repressor interaction and another class governing the allosteric nature of the repressor. We test these pen-and-paper predictions experimentally and illustrate that given sufficient knowledge of how single mutants behave, the complete phenotypic response of pairwise double mutants can be predicted with quantitative accuracy.
With this framework in hand, we turn to exploring how changes in the physiological state of the cell influence the molecular biophysics of the regulatory architecture. We hypothesize that changes in the source of carbon in the growth medium or changes in the growth temperature can be accounted for by the existing model without any additional parameters. We experimentally show that the parameter values determined in one physiological state are inherited when the available carbon source is verified, but changes in the growth temperature require some additional considerations. Chapter 4 as a whole reveals that, while there remains work to be done both theoretically and experimentally when it comes to temperature variation, thermodynamic models can remain powerful tools to draw predictions of gene expression in different physiological contexts.
Finally, in Chapter 5, we explore physiological adaptation and cellular decision making where it counts – in the survival of cells to environmental insults. We turn our focus beyond transcriptional regulation and consider the relationship between osmotic shocks, the abundance of mechanosensitive channels, and cellular survival with single cell resolution. Using a combination of quantitative microscopy and tricks of statistical inference, we infer how the probability of a cell surviving an osmotic shock scales as a function of the cell’s number of mechanosensitive channels.</p
New Electrolytic Media and Methods for Energy Storage and Conversion
Get PDFNew electrolytic media and methods for energy storage and conversion are needed to fully realize the sustained use of renewable energy and complete removal of dependence on fossil fuels. Motivated by this urgency, researchers today are heavily invested in developing new electrocatalytic systems for carbon dioxide sequestration to reduce greenhouse gas emissions and new battery architectures, such as non-aqueous redox flow batteries, to keep solar energy at our disposal during peak times of energy consumption. Chapter 1 provides an overview of the conceptual frameworks for these two alternative energy technologies and a literature review of relevant work and inspiration in these fields. Chapter 2 demonstrates one of the first examples of ionic liquid voltammetry of a molecular species, namely (tpfc)Mn, and its electron transfer reactivity in ionic liquids with varying solvent viscosity, effective electrolyte concentration, and donor strength. As well as showing the non-unity diffusional properties of molecular species in ionic liquids and the capability of ionic liquid anions to coordinate to molecular species, these studies suggest the viability of ionic liquids as conductive media for energy storage and conversion. Chapter 3 introduces methods for immobilization of molecular catalysts in polymeric ion gels, a general strategy that bridges the divide between homogeneous solution-state catalysis and heterogeneous solid-state catalysis. These results provide insight into how environment, catalyst concentration, catalyst mobility, substrate availability, and dielectric properties of a medium all affect the catalytic response and overpotential for CO2 reduction. Further implementation of these ion gel composites in solid-state devices, in aqueous environments, and in gas diffusion electrodes is also discussed. In Chapter 4, a brief overview of the use of boranes as capping ligands for cyanide is provided. The synthesis, electronic properties, and theoretical calculations of homoleptic, boronated Fe(II) hexacyanoferrates are reported. Addition of borane to cyanometallates dramatically alters electronic structures and is a novel method for permanent modification of formal potentials while simultaneously maintaining or improving electrochemical reversibility and ambient stability. These complexes are characterized and studied by cyclic and differential pulse voltammetry, UV-vis, IR, and Raman spectroscopy, and flash-quench photolysis. Chapter 5 extends the unique reactivity of borane adducts to the characterization of a full series of hexaisocyanoboratometallates (Cr, Mn, Fe, Ru, Os), compounds which demonstrate the concept of cyanide as a “variable-field” ligand, including magnetic circular dichroism spectroscopy, electron paramagnetic resonance spectroscopy, luminescence studies, excited-state lifetime studies, and electrochemistry. As electrolytes for non-aqueous redox flow batteries, these species exhibit excellent Coulombic and voltage efficiencies and fast electron transfer rates. The highly oxidizing species will also find use as reversible oxidants for chemical oxidations. Chapter 6 extends the concept of modifying formal potentials to heteroleptic cyanometallates (M = Fe, Ru) with diimine ligands (L = bipyridine, phenanthroline, 4,4’-trifluoromethylbipyridine). These species are shown to be potent excited-state reductants and oxidants, strong and long-lived phosphors, and promising electrolytes for symmetric, non-aqueous redox flow batteries. These data also demonstrate improved excited-state lifetimes for borane-appended species, likely due to inhibition of non-radiative decay pathways. Chapter 7 focuses on the generation of a solution stable, square pyramidal Co(II) species, which is studied by electrochemistry, UV-vis-NIR spectroscopy, X-band and Q-band CW EPR, and pulsed EPR techniques (HYSCORE, ENDOR). These studies demonstrate that boronation of cyanide differentially affects the energies of ligand field transitions based on π backbonding ability
Investigating the Functional Significance of O-GlcNAc Substrate/Interactor Networks
Get PDFO-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is a dynamic, inducible post-translational modification (PTM) of thousands of intracellular proteins. There are only two enzymes responsible for O-GlcNAc cycling in higher eukaryotes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which catalyze addition and removal, respectively. We hypothesized that constructing OGT substrate/interactor networks could serve as a useful foundation for understanding the functions of O-GlcNAcylation. Moreover, this approach might reveal novel insights into how OGT is able to coordinate the specific modification of thousands of proteins in response to individual stimuli.
Here, we first sought to validate interactor-substrate relationships suggested by these networks. Specifically, we found that knockdown (KD) of OGT interacting proteins was sufficient to disrupt O-GlcNAcylation of non-interacting OGT substrates. KD of the OGT interacting protein BAP1 changed the O-GlcNAcylation of several of its interactor proteins, many of which do not themselves interact with OGT. This KD strategy was attempted with other potential adaptor proteins such as WDR5 and CDK9, but KD was unsuccessful. KD of the OGT interacting protein GIT1 lead to intriguing changes in the O-GlcNAcylation of liprin-α1. Both of these proteins are vital for synaptic function in excitatory neurons. This result appears significant to the latter protein’s function as it changes with neuronal activity. The aforementioned two findings suggest that association between OGT and its interactors may allow OGT to engage different sets of substrates in different contexts.
Further, we investigated whether modulating global O-GlcNAcylation can affect peroxisome and lipid droplet biogenesis and function, a potentially novel role for O-GlcNAcylation revealed by our network. Together, these studies demonstrate that our networking approach highlights functional connections between OGT interactors and substrates.</p
Hunting for Hidden Explosions: Exploring the Transient Infrared Sky with the Spitzer Space Telescope
Get PDFThe study of time-variable astronomical phenomena is undergoing an explosive renaissance ushered in by recent advancements in capabilities to monitor the sky from radio to gamma rays. The infrared region of the electromagnetic spectrum provides a unique window to uncover a vast array of stellar eruptions and explosions that are otherwise obscured; however, the dynamic infrared sky has remained largely unexplored.
To uncover these hidden cosmic explosions, I undertook a systematic search in the infrared with the Spitzer Space Telescope called SPIRITS — the SPitzer InfraRed Intensive Transients Survey. Targeting a specially chosen sample of nearby galaxies, the search revealed a bounty of exceptionally red events, and may have discovered entirely new and diverse populations, including deeply embedded supernovae, catastrophic stellar mergers, and giant eruptions of massive, violently unstable stars. Providing a first census of stellar infrared transients, SPIRITS has paved the way for new and upcoming surveys to further expand our exploration of the dynamic infrared sky.</p
Investigating the Evolution of Surface Water on Mars through Spectroscopy of Secondary Minerals
Get PDFDespite its current arid climate, Mars’ surface preserves a wide variety of morphologies and minerals that point to a water-rich past. However, the mechanisms and timing of this environmental change are not yet well understood. In this dissertation, we explore a variety of water-related minerals through visible-shortwave infrared (VSWIR) reflectance spectroscopy to better understand the environmental conditions at the time of their formation, and trace the evolution of surface water on Mars over time. We also demonstrate the capabilities of VSWIR spectroscopy at laboratory and field scales in a Mars analogue environment (Samail Ophiolite, Oman)—an emerging technique for use on future landed missions that enables us to differentiate between spectrally-similar minerals and spot rare minerals that help to constrain environmental conditions and better understand the geologic context of samples. On Mars, we use orbital datasets (predominantly CRISM, the Compact Reconnaissance Imaging Spectrometer for Mars) to investigate secondary minerals in the southern highlands of Mars, focusing on perchlorate, chloride, and sulphate minerals. We identify a previously unknown artifact in the CRISM dataset, which mimics perchlorate absorptions; previous orbital perchlorate detections (including those associated with recurring slope lineae) are not robust when data are reprocessed, suggesting that there may not be orbitally-detectable reservoirs of perchlorate on Mars, which would enable liquid brines to exist at the surface today. A detailed investigation of chloride deposits across the southern highlands of Mars points to an episodic surface-runoff water source rather than upwelling groundwater, a process which continued to create chloride deposits into the Amazonian era. Where chloride and sulphate deposits are in close proximity (Terra Sirenum, Mars), they do not appear to be genetically related as they often are on Earth; instead, they point to chemically distinct groundwater vs. surface water reservoirs in Terra Sirenum through the Hesperian and into the Amazonian. Together, these studies indicate that briny and/or acidic volumes of water at the surface capable of creating mineral deposits continued to exist — at least episodically — on Mars into the Amazonian, rather than ceasing much earlier in Mars’ history.</p
Mechanics of Ultra-Thin Composite Coilable Structures
Get PDFCoilable structures are thin-shell structures that can be coiled around a hub by flattening their cross-section. They are attractive for multiple space applications as they allow efficient packaging and deployment of large planar structures. Reducing the shell thickness enables smaller coiling radius and more efficient packaging.
This thesis investigates TRAC structures, a type of coilable structure, made of ultra-thin composite materials. A design using a laminate made of glass fiber plainweave fabric and carbon fiber unidirectional tape is proposed, leading to a shell thickness of 0.08 mm. An in-autoclave, two-cure manufacturing process is presented, and a shape measurement method is used to mitigate post-cure shape changes due to residual stresses.
A study of the structure behavior in its deployed configuration is performed. First, the behavior when subjected to pure bending is investigated experimentally for structures with a length of 575 mm. Two regimes are observed, with a pre-buckling phase transitioning to a stable post-buckling phase after an initial buckling event. The ultimate buckling moment following the stable post-buckling regime can be as high as four times the initial buckling moment. A finite element model is developed and is able to reproduce all the features observed experimentally, except the ultimate buckling. This simulation model is used to study the effect of varying the structure length from 300 mm to 5000 mm on the initial buckling moment. Results show that nonlinearities in the pre-buckling deformations of the flanges under compression lead to a constant wavelength lateral-torsional buckling mode for which the critical moment is mostly constant across the range of length. The torsional behavior of the TRAC structure is also investigated. Good agreement is obtained between experiments and numerical simulations, and initial twist in the structure is shown to have little effect on the overall behavior due to the small torsional stiffness in the underformed configuration.
An analytical method to predict the buckling load of a TRAC structure under pure bending is presented. It is achieved by considering only one flange of the structure and solving the problem of a cylindrical shell panel with a longitudinal free edge under non-uniform axial compression. Partially uncoupled stability equations for a balanced laminate are derived and are used in conjunction with the Rayleigh-Ritz method to approximate the buckling load. This method overestimates the buckling load by 44% in the case of a 500 mm TRAC structure made with ultra-thin composite materials.
A study of the coiling behavior is also presented. High localized curvature in the transition region between the coiled and deployed regions is observed in experiments, leading to material failure for a structure made only of carbon fiber unidirectional tape. A numerical framework is developed and reproduces the localized curvature observed in experiments, predicting stress concentration at this location. The study shows that changing the laminate to a a single ply of carbon fiber unidirectional tape sandwiched between plies of glass fiber plainweave fabrics reduces significantly the maximum stress in the transition region, to the extent that the highest stress is now in the fully coiled region and can be accurately predicted using simple equations based on the change of curvatures due to the coiling process.</p
Acoustic Reporter Genes for Noninvasive Imaging of Cellular Function
Get PDFThe study of cellular function within the context of intact living organisms is a grand challenge in biological research. Addressing this challenge requires imaging tools that can visualize cells inside the body. If successful, this would greatly increase our ability to study a battery of processes from brain development to tumorigenesis, to monitoring cell-based therapeutics. To date, most common methods for imaging cellular processes such as gene expression have relied on optical reporters, such as fluorescent or luminescent proteins, which provide high molecular precision for studies in petri dishes and transparent organisms, but have limited performance in large animals due to the poor penetration of light in biological tissue. Conversely, magnetic resonance imaging (MRI) and ultrasound can image tissues at depth with high spatial and temporal resolution, but they lack molecular reporters analogous to the green fluorescent protein (GFP). As a result, they have made limited impact on biological research. To address this, we focus on developing biomolecular reporters for MRI and ultrasound — based on a unique class of air-filled protein nanostructures called gas vesicles — using them to image the location and function of cells deep inside the body.
This thesis begins with a brief review of genetically encoded materials for noninvasive imaging, highlighting key advances over the past two decades and providing context for the work below. We discuss the development of increasingly sophisticated tools starting from early efforts to engineer single molecule reporters to recent work on multi-component genetic machinery (including gas vesicles) with multi-modality capabilities. In Chapter 2, we present a platform for engineering the surface of gas vesicles to modulate their acoustic, surface charge, and molecular- targeting properties as injectable acoustic biomolecules. In Chapter 3, we present the recombinant expression of gas vesicles as injectable contrast agents in common lab strain bacteria to facilitate the genetic engineering of the entire gas vesicle gene cluster and to assist this technology’s adoption by other (non-specialist) research groups. This work characterized the ultrasound and hyperpolarized 129Xenon-MRI contrast of gas vesicles as nanoscale contrast agents.
In a parallel effort, we developed a hybrid gene cluster that when introduced to microbes enables the imaging of their gene expression using ultrasound. These bacterial acoustic reporter genes were used to image the location of probiotic cells inside the gastrointestinal tract of mice. However, the ability for these genes to be expressed in mammalian cells had not been demonstrated and presented a major challenge in synthetic biology. In Chapter 4, we addressed this by introducing the first mammalian acoustic reporter genes — a genetic program whose introduction to mammalian cells resulted in the expression of gas vesicles that can be visualized by ultrasound. These mammalian acoustic reporter genes will enable previously impossible approaches to monitoring the location, viability and function of mammalian cells in vivo.
In Chapter 5, we explore a new paradigm in MRI by taking advantage of the acousto-magnetic property of gas vesicles. Here, we present background-free MRI to address a longstanding challenge in untangling the signal of exogenous contrast agents from the endogenous MRI contrast produced by biological tissues. Chapter 6 explores the optical properties of gas vesicles as genetically encodable phase contrast agents in digital holographic imaging. Chapter 7 is a brief discussion of the potential future directions for this work.
The data presented in this thesis lays the ground for exciting new research on developing noninvasive biomolecular tools that will enable the discovery of novel biological processes.</p
Processing at Primary Chemosensory Neurons
Get PDFChemosensory perception involves the detection of chemical compounds. In animals, there are 2 chemical senses: taste, and olfaction. The two are related in that they utilize ligand-gated receptors, expressed in primary sensory neurons, to detect chemical stimuli from the surrounding environment. However, the processing of these inputs is quite different in the two systems, leading to divergent roles for olfaction and taste in sensory perception. This dissertation highlights some of these differences, by looking at processing of ethologically relevant stimuli at the very peripheral receptor neurons. The work is divided into 2 parts: water sensing by the mammalian taste system, and CO₂ sensing by the Drosophila olfactory system.
In Chapter 1, I talk about water sensing in the mammalian taste system. Initiation of drinking behavior relies on peripheral water detection. It is likely that this detection is mediated, at least in part, by the taste system. Here, I have shown that acid-sensing taste receptor cells (TRCs) that were previously suggested as the sensors for sour taste, also respond to water. This response is mediated by a bicarbonate-dependent molecular mechanism, likely involving the Carbonic Anhydrase enzyme family. Furthermore, optogenetic stimulation of the acid-sensing TRCs in thirsty animals induces robust licking responses towards the light source, even in the absence of water. Conversely, thirsty animals lacking functional acid-sensing TRCs show compromised discrimination between water and non-aqueous fluids. Taken together, this work reveals the cellular mechanism of water detection by the mammalian taste system.
In chapter 2, I talk about CO₂ sensing in the fruit fly. The Drosophila olfactory system responds to most odors with the activation of a large subset of its olfactory receptors (ORs). This broad activation is a consequence of the ORs having affinity to multiple chemical compounds. In contrast, a small number of odors, like CO₂, elicit responses in only single ORs. These ORs are, in contrast to most ORs, very narrowly tuned, generally responding only to that one odor. It has been assumed up until now that the specificity of these unique ORs is inherited by the olfactory receptor neurons (ORNs) they are expressed in, and even in the projection neurons (PNs), that the ORNs synapse onto. I show here that CO₂, though it activates only a single OR, the GR63a/GR21a hetero-dimer complex, actually activates multiple ORN axon terminals. This activation is due to lateral excitatory connections between axon terminals of the GR63a/GR21a expressing ORNs, and at least 4 other ORN types. Focusing on one of these ORNs, Ab1B, I show the lateral connections bypass the ORN cell bodies, only driving responses at the axon terminals. Consequently, Ab1B ORN axon terminals receive 2 sources of excitatory input, a feed-forward excitation from its endogenous OR, and a lateral excitation from GR63a/GR21a. This effectively divides the ORN into 2 compartments, distinct in their odor tuning. Finally, I show that lateral excitation is a general feature of the ORN circuit by silencing the feed-forward input of another ORN class, Ab1A. The Ab1A cell body is completely silent, but the axon terminals retain odor responses from lateral excitatory inputs. Thus, there is a lateral flow of odor information between multiple ORNs of the Drosophila olfactory system.</p