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Undergraduate Theses, Department of Biology, 2015-2016
Noncoding RNAs can orchestrate eukaryotic gene expression programs through diverse yet only partially understood mechanisms. One noncoding RNA in particular, 7SK, is known to repress mRNA transcription by blocking RNA polymerase II activity at gene promoters. Recent studies suggest that 7SK may be physically associated with chromatin, the target of RNA polymerase II, but the functional significance of this association has not been explored. Here we discover novel roles for 7SK at distinct genomic loci and find that it coordinates the functions of multiple protein complexes. 7SK binds both promoters and enhancers across the genome. At enhancers, mass spectrometry and co-immunoprecipitation reveal a direct, previously unknown interaction between 7SK and a major eukaryotic chromatin remodeling complex called BAF. Depletion of 7SK disrupts the BAF complex, causing aberrant transcription as well as increased DNA damage signaling at thousands of enhancers. These results suggest that 7SK has a multifaceted role in controlling gene regulation. By scaffolding at least two separate nuclear protein complexes at distinct genomic elements, 7SK provides a conceptual framework for how noncoding RNAs may operate as versatile regulators of information flow through the nucleus.
Collection
Undergraduate Theses, Department of Biology, 2015-2016
The Wnt pathway is an instructive signaling system in development, tissue homeostasis, and cancer. Although many core components of the canonical Wnt signaling cascade have been identified, additional layers of regulation likely remain undiscovered. To identify genes and regulatory elements involved in Wnt signaling, we performed unbiased forward genetic screens in a human haploid cell line using insertional mutagenesis with a retrovirus. The work in this thesis is divided into two experimental sections based on the analysis of these haploid genetic screens: 1) design and implementation of an improved and generally applicable computational pipeline to map the genomic insertion sites of the retroviral mutagen used in these screens and 2) the experimental analysis of a class of unexpected mutants we discovered using this pipeline. Analysis of insertional genetic screens in cultured cells has traditionally been “gene-centric”, focused on mapping the insertions in genomic regions with annotated, protein-coding transcripts. We hypothesized that recurrent insertions in non-protein coding regions or unexpected patterns of insertions in coding regions of the genome may identify regulatory elements or cryptic transcripts that regulate Wnt signaling. Therefore, we developed a bioinformatics pipeline designed to be “gene blind” by identifying recurrent insertions in one-thousand base-pair bins across the human genome, chosen consecutively across each chromosome without regard to gene boundaries. Using this pipeline, we found several genomic regions, including unannotated areas near the genes LRP6, TCF7L2, TFAP4 and APC, that are strong candidates to play important regulatory roles in Wnt responsiveness. These genomic regions may represent regulatory elements such as enhancers, promoters, or cis-acting non-coding RNAs (ncRNAs). A human tumor suppressor gene that is a central negative regulator of the Wnt pathway, the adenomatous polyposis coli (APC) gene is one of the most commonly mutated genes in colorectal cancer. Therefore, we designed a screen to search for genes that positively regulate the high-level oncogenic signaling observed when the APC gene is inactivated using CRISPR/Cas9 engineering. Our bioinformatics pipeline identified a perplexing pattern of retroviral insertions in the APC gene that were enriched for in cells selected for reduced Wnt signaling in the absence of APC. This was paradoxical since APC had already been engineered to contain a frameshift mutation in these cells. We found that these insertions somehow increase the level of APC protein, leading to the suppression of signaling in cells still containing a putatively inactivating lesion in the APC gene. In summary, the combined use of haploid screens and a custom bioinformatics pipeline has the potential to probe the genomic regulome of a signaling pathway that plays a central role in development and cancer. Future detailed understanding of these genetic elements and their mechanism of function may reveal new strategies that could be used to target human cancers resulting from deregulation of the Wnt pathway.
Collection
Undergraduate Theses, Department of Biology, 2015-2016
Autism spectrum disorders (ASDs) are fundamentally social and behavioral disorders with a range of comorbidities and social and financial impacts. Recent studies have estimated ASDs to have a heritability of around 50%, while indicating that there is also a significant environmental component. It is clear that neither genes nor environment in isolation can explain the etiology of autism. Large-scale genomics studies have identified a set of genes that have been shown to have a high association with ASDs. In addition, recent studies have identified certain environmental factors associated with an increased risk for developing ASDs, with pre- and perinatal hypoxia as one of the more salient factors. However, the interaction between genes and environment through the lens of hypoxia has yet to be evaluated. This study aimed to find and characterize the intersection between genes associated with autism and the genes associated with the cellular response to hypoxia. Every gene in a database of autism-associated genes was interrogated, through a thorough literature search and comparison with a set of microarray data, for evidence of its regulation by hypoxia. This process created a set of genes associated with both autism and the hypoxia response. A statistical test for overrepresentation indicated that hypoxia-regulated genes were overrepresented in the ASD database; the proportion of ASD genes also responsive to hypoxia was roughly twice what would be expected by chance. Functional and network analyses then showed that specific biological functions were overrepresented in the ASD/Hypoxia gene set, indicating that the number of hypoxia-regulated genes among all ASD genes, were indeed greater than would be expected by chance, and fell into specific networks and pathways. This lays the groundwork for functional characterization of variations in these genes in a population affected with autism as well as a neurotypical population. With a better understanding of how variations in certain genes can affect an individual’s response to a potential hypoxic event, researchers and medical professionals alike can open up better therapeutic avenues for children and adults affected by ASDs.
Collection
Undergraduate Honors Theses, Department of English
This paper analyzes recurring themes and patterns of thought in the nature poetry of W. H. Auden. This topic, typically neglected in most Auden criticism, focuses on the themes from Auden's nature poetry that persist throughout his poetic career. Divided into three sections--poetry about mines and mining, poetry about the body and the natural landscape, and poetry about places unknown--this paper argues that a more complete reading of Auden occurs when one examines his work in light of the subject, the natural world, rather than in a chronological way, as in most criticism. In combining the critical approaches of Edward Mendelson and John Fuller, this paper hopes to examine an atypical topic in a unique manner. In conclusion, Auden's poetry about the natural world keeps returning to the same concerns and anxieties. Though Auden is a poet characterized in part by the way that his poetry changes throughout his life, this paper examines how these recurring themes appear repeatedly in Auden's poetry about the natural world.
Collection
Undergraduate Theses, Department of Biology, 2015-2016
The microtubule cytoskeleton is spatially reorganized from the centrosomes to new subcellular sites during cell differentiation in many cell types, yet the importance of possessing distinct microtubule organizing centers (MTOCs) and the mechanisms governing MTOC reassignment remain poorly understood. Centrosomal and non-centrosomal microtubules are nucleated by a conserved nucleating complex, the γ-tubulin small complex (γ-TuSC), which is comprised of GIP-1/GCP3, GIP-2/GCP2, and TBG-1/γ-tubulin. Tissues of the nematode C. elegans display dualistic MTOC localization, in which γ-TuSC proteins are capable of localizing to both MTOCs, but do so at distinct times in development. This makes C. elegans an ideal system for studying the process of MTOC reassignment. We have proposed a model of MTOC reassignment whereby regulation of γ-TuSC protein localization dictates the sites of functional MTOCs. The gip-1 locus is predicted to encode multiple isoforms, presenting the possibility that differential expression of GIP-1 isoforms may play a role in this process. We therefore set out to investigate the role of GIP-1 in the developing C. elegans intestine. In this tissue, MTOC proteins are translocated from the centrosomes to the future apical cell membrane following their final round of divisions, resulting in a relatively simple dichotomy of MTOC function. Because a complete loss of functional MTOCs leads to an early arrest in embryonic development, we adapted an endogenous protein degradation pathway to deplete GIP-1 exclusively in the developing intestine around the time of MTOC reassignment. We found that GIP-1 is required for normal apical localization of GIP-2 and TBG-1, but not for apical localization of microtubules or the polarity protein PAR-3. Embryos depleted of intestinal GIP-1 have fewer and abnormally enlarged intestinal nuclei as compared to control embryos. Using a structure–function approach to identify GIP-1 domains required for MTOC localization and function, we have identified two domains (GIP-1[N], GIP-1a[G+C]) that localize to centrosomes but not apical membranes. Together, these results demonstrate that GIP-1 is vital for normal mitosis in the early embryonic intestine, and highlight the presence of redundant microtubule nucleating and anchoring mechanisms in this tissue. Furthermore, we provide the first evidence that GIP-1 may localize to centrosomal and apical membrane MTOCs through distinct protein domains. Future efforts focused on understanding the consequences of GIP-1 depletion for microtubule dynamics will greatly inform our understanding of the role of GIP-1 in regulating the microtubule cytoskeleton. With aberrant microtubule organization linked to some epithelial cancers and invasive cell behavior, understanding this basic cellular process may inform future efforts to inhibit cancer proliferation and metastasis.
Book
xiii, 205 pages : illustrations ; 23 cm.
Green Library
Book
1 online resource.
This doctoral dissertation analyzes the surprisingly common presence of Homer in imperial literary symposia, i.e. fictionalized dinner conversations in the early Roman Empire, where characters often cite the already ancient poetry. Unlike past studies of text reuse at these dinner parties, this dissertation takes the setting seriously and treats these quotations from the standpoint of performance. Through the societally approved use of Homer the elite justifies its privileged position and establishes a hierarchy within itself, and these texts either accept this ideology or reject it through parody. Such an approach not only explains the role of Homer at table, but also why learning how to present and interpret poetry is a vital skill cross-culturally.
Book
1 online resource.
Staphylococcus aureus is both a transient skin colonizer and a formidable human pathogen, ranking among the leading causes of skin and soft tissue infections as well as severe pneumonia. The secreted bacterial alpha-toxin is essential for S. aureus virulence in these epithelial diseases. To discover host cellular factors required for alpha-toxin cytotoxicity, we conducted a genetic screen using mutagenized haploid human cells. Our screen identified a cytoplasmic member of the adherens junctions, plekstrin-homology domain containing protein 7 (PLEKHA7), as the second most significantly enriched gene after the known alpha-toxin receptor, a disintegrin and metalloprotease 10 (ADAM10). Here we report a new, unexpected role for PLEKHA7 and several components of cellular adherens junctions in controlling susceptibility to S. aureus alpha-toxin. We find that despite being injured by alpha-toxin pore formation, PLEKHA7 knockout cells recover after intoxication. By infecting PLEKHA7−/− mice with methicillin-resistant S. aureus USA300 LAC strain, we demonstrate that this junctional protein controls disease severity in both skin infection and lethal S. aureus pneumonia. Our results suggest that adherens junctions actively control cellular responses to a potent pore-forming bacterial toxin and identify PLEKHA7 as a potential non-essential host target to reduce S. aureus virulence during epithelial infections.
Collection
Undergraduate Theses, Department of Biology, 2015-2016
Chronic wounds afflict over 6.5 million individuals and cost over $25 billion annually in the United States alone. These nonhealing wounds are caused in large part by impairments in neovascularization, the formation of new blood vessels. Stem cell therapies have emerged as a potentially viable approach to treat chronic wounds. In particular, adipose-derived mesenchymal stem cells (ASCs) are promising due to their ease of harvest and production of pro-regenerative molecules, including those that promote neovascularization. However, a challenge with stem cell therapies is maintaining cell survival in the harsh wound environment. Therefore, stem cell delivery to the wound must be optimized to make cell-based therapies for wound healing translatable. Previously, the Gurtner laboratory found that delivering ASCs by seeding these cells in a hydrogel composed of collagen and the polysaccharide pullulan and topically applying the ASC-seeded hydrogel to a cutaneous wound accelerated wound closure. This project focused on further elucidating how ASC-seeded hydrogels have this therapeutic effect. Specifically, we tested the hypothesis that ASC-seeded hydrogels increase the recruitment and heighten the functionality of endogenous progenitor cells that promote neovascularization. We used techniques including a model in vivo to study cell recruitment to cutaneous wounds, fluorescence activated cell sorting (FACS) of recruited cells, and in vitro measurement of recruited cell proliferation, migration, and expression of provascular genes. We found that application of ASC-seeded hydrogels to wounds in vivo, compared to injected ASCs or a saline control, increased the recruitment of circulating bone marrow-derived mesenchymal progenitor cells (BM-MPCs, p < 0.05), a population we previously found plays a role in neovascularization. In vitro, we found an increase in expression of genes related to angiogenesis, as well as BM-MPC proliferation, migration, and tubule formation, all of which play a role in neovascularization (p < 0.05 for all assays). These data support our hypothesis, demonstrating that treating cutaneous wounds with ASCs seeded in hydrogel increases recruitment of progenitor cells that contribute to neovascularization and improves recruited cell provascular functionality. Overall, this study demonstrates that our pullulan-collagen hydrogel can optimize delivery of ASCs to cutaneous wounds, underscoring the potential of ASC-seeded hydrogels to be used clinically in cell-based therapies for chronic wound healing.
Book
1 online resource.
We study two new cryptographic primitives inspired by recent advances in multilinear maps: private constrained pseudorandom functions (PRFs) and order-revealing encryption (ORE). We show how these primitives have direct applications in searchable symmetric encryption, watermarking, deniable encryption, private information retrieval, and more. To construct private constrained PRFs, we first demonstrate that our strongest notions of privacy and functionality can be achieved using indistinguishability obfuscation. Then, for our main constructions, we build private constrained PRFs for bit-fixing constraints and for puncturing constraints from concrete algebraic assumptions over multilinear maps. We also construct the first implementable ORE scheme that provides what is known as ``best-possible'' semantic security. In our scheme, there is a public algorithm that given two ciphertexts as input, reveals the order of the corresponding plaintexts and nothing else. Our constructions are inspired by obfuscation techniques, but do not use obfuscation. Finally, we also show how to build efficiently implementable ORE from PRFs, achieving a simulation-based security notion with respect to a leakage function that precisely quantifies what is leaked by the scheme.
Book
1 online resource.
\prefacesection{Abstract} The Boltzmann transport equation describes the macroscopic behavior of radiation particles such as neutrons, photons, and electrons as they travel through and interact with matter. The widely known Monte Carlo (MC) method is a general approach to obtaining open form solutions to the linearized Boltzmann transport equation. Monte Carlo algorithm is thte most accurate way to predict how dose is delivered inside a patient. However, the computation time inhibits its routine use in the clinic. For a patient, MC carlo simulation takes anywhere from 10 hours to several days. In this dissertation, we use the state-of-the-art cloud computing technology to accelerate Monte Carlo methods. The approach is evaluated for pencil beams and broad beams of high-energy electrons and photons. The cloud-based Monte Carlo simulation is compared to single-threaded implementation and demonstrates a 47x speed up. Current clinical treatment planning requires multiple trial-and-error adjustments of system model parameters. Producing a treatment plan is time consuming. A team of physician, dosimetrist, and physicist manually adjust parameters in a commercial planning environment. In this dissertation, an autonomous treatment planning technique is implemented in a clinical platform. An outer-loop decision function interacts on-the-fly with an inner-loop clinical treatment planning system (TPS). The approach is applied to 3 head and neck volumetric modulated arc therapy (VMAT) cases and one prostate intensity-modulated radiation therapy (IMRT) case. A strategy of using population-based prior patient data was explored. An upper and lower bound for the dose-volume segments are derived from a group of previously treated patients. The bounds are then used for new case to provide a dosimetric range for acceptability. An heuristic algorithm adjusts the constraints for the optimization using a stochastic approach. Rather than setting a deterministic value for each dose-volume segments, the constraint is changed during each iteration of the outer-loop optimization. The proposed algorithm is applied to a head and neck VMAT case and a prostate IMRT case on a clinical treatment planning system. Results obtained show a comparable dose volume histogram (DVH) compared to manual planning.
Book
1 online resource.
Beginning in 1986 with the discovery of LaBaCuO by Bednorz and Muller, the field of high temperature (high-Tc) superconductivity remains the biggest intellectual challenge in condensed matter physics, with theoretical (and sometimes experimental!) consensus being elusive for almost thirty years. The underlying problem of understanding how large numbers of interacting particles can form various ordered states is tremendously daunting. This thesis begins with a historical overview of superconductivity, beginning with experimental discoveries, followed by an introduction of some theoretical concepts. In particular we discuss some details about electron-phonon coupling. As the systems being studied become more complex, the tools needed to fabricate and study them must also increase in complexity. Pushing forward new experimental discoveries in high-Tc therefore requires advancing both materials growth and characterization. The characterization techniques we introduce in this thesis are angle resolved photoemission spectroscopy (ARPES) and resonant inelastic x-ray scattering (RIXS). We will discuss ARPES in detail, but present only a small work on RIXS in a later chapter, as a detailed treatment of the latter is beyond the scope of this thesis. Next we introduce the fabrication technique of molecular beam epitaxy (MBE), and discuss the design and implementation of an experimental chamber capable of performing in-situ ARPES studies of films grown via MBE. The capabilities of this chamber are demonstrated through growth and measurement of films from two classes of materials: topological insulators and iron-based superconductors. In topological insulators, we show the capability of using a thermal cracking chalcogenide source to grow intrinsically doped films, which may be useful for future studies and devices. Recently, it had been discovered that single-unit-cell-thick (1UC) iron selenide (FeSe) films grown on strontium titanate (STO) demonstrate a large increase in superconducting transition temperature compared to bulk iron selenide. We use our MBE-ARPES chamber to grow and study FeSe films of varying thicknesses down to 1UC. We then discuss spectroscopic signatures of cross-interfacial coupling between electrons in the 1UC iron selenide and the STO substrate. This electron-phonon coupling is unprecedented and until recently had not be resolved with such clarity in any other solid state system. It is furthermore unusual in that it can enhance superconductivity in many different channels. We calculate the enhancement of Tc in 1UC FeSe/STO due to this coupling and find good agreement with experimental results, and suggest that such coupling can be broadly used to enhance Tc in other films. The thesis concludes with some future prospects and directions for study. We make the case that MBE-ARPES, and more generally the improved fabrication and characterization allowed by it, will be important to definitively elucidate the interactions between particles that make up novel phases in the solid state. Lastly, in the appendix we discuss some properties of a new six-axis in-vacuum manipulator, as well as cover some theoretical details of the FeSe and RIXS experiments.
Book
1 online resource.
This thesis is organized into two primary areas of research: cis-regulatory evolution and genome engineering. It is now known that noncoding regions comprise the vast majority of genomic regions under selective constraint in mammals. Despite this, the ability to detect natural selection on noncoding regions has lagged behind the ability to detect selection on coding regions. In Chapter 1, we introduce a new test to detect selection on cis-regulatory elements, and demonstrate its utility on three mammalian transcriptional enhancers. In Chapter 2, we investigate the evolution of resistance to the mycotoxin citrinin by comparing two closely related species of budding yeast, Saccharomyces paradoxus and Saccharomyces cerevisiae. Applying a genome-wide test for selection on cis-regulation, we identified five genes involved in resistance in S paradoxus, four of which are necessary for resistance and increase resistance in S cerevisiae when over-expressed. In the second half of this dissertation, I discuss my work with genome engineering and CRISPR-Cas9. In Chapter 2, we build an improved CRISPR activator (CRISPRa) to simultaneously induce overexpression (in S cerevisiae) of the four genes identified to confirm their role in citrinin resistance. In Chapter 3, we build an inducible CRISPR interference (CRISPRi) system and and designed gRNA libraries to determine design rules for CRISPRi gRNA design in S cerevisiae. We determined that gRNAs targeted to a region with low nucleosome occupancy and high chromatin accessibility within a window of 0 to 200bp upstream of the transcription start site (TSS) are most likely to be effective. In Chapter 4 we confirm and refine these rules in a much larger library consisting of ~9000 unique strains. Additionally, we present a novel method for parsing complex oligonucleotide libraries into single, sequence verified DNA sequences using high throughput sequencing and yeast synthetic biology. We utilize this technology to create and characterize a collection of ~9000 individual inducible CRISPRi strains to the vast majority of essential and respiratory essential genes in S cerevisiae. In Chapter 5, we compare mismatch tolerance for Cas9 in vitro and in vivo (in S cerevisiae) and test a variety of truncated and full-length gRNAs (with 17, 18, and 20 nucleotides of complementarity sequence). We observed notable differences between in vitro and in vivo Cas9 cleavage specificity profiles, with in vivo cleavage being more sensitive/less tolerant to mismatches.
Book
1 online resource.
The diversity in the kinds of vehicles that are appearing in the commercial space transportation sector raises questions regarding the applicability of the licensing procedures and methodologies that are in place to protect public safety. These licensing procedures are designed to limit risks to public safety in case of a space vehicle explosion. Concerns arise because the methods currently used are derived from expendable launch vehicles (ELVs) developed during the Space Shuttle era, and thus they might not be fully applicable to future vehicles, which include new types of ELVs, suborbital vehicles, reusable launch vehicles (RLVs), and a number of hybrid configurations. This dissertation presents a safety analysis tool, called the Range Safety Assessment Tool (RSAT), that quantifies the risks to people on the ground due to a space vehicle explosion or breakup. This type of problem is characterized by the complexity and uncertainty in the physical modeling. RSAT has been used to analyze both launch and reentry scenarios and can be applied to many possible vehicle configurations. The Space Shuttle Columbia accident was modeled with RSAT, and the results were compared with simulations performed by the Columbia Accident Investigation Board (CAIB). A methodology to perform sensitivity and optimization studies is also presented. This methodology leverages previous work done in active subspaces and Gaussian process regression to generate surrogate models. The proposed sensitivity and optimization methodologies were used to analyze a commercial ELV. The results show that the methodology can handle a large number of stochastic inputs and identify opportunities to decrease risk.
Book
1 online resource.
Structure-based modeling, introduced by Kassinos and Reynolds (1995), uses one-point tensors to provide a more detailed description of the turbulent fluctuations. This thesis describes further developments to two structure-based models, namely the Algebraic Structure-based Model (ASBM), which belongs to the RANS category, and the Interacting Particle Representation Model (IPRM), which can been interpreted as a PDF model. The ASBM is an engineering model of turbulence for wall-bounded flows. A new variant of the model has been formulated, which exhibits (1) a segregated near-wall correction that leads to a new paradigm for model development and comparison, (2) a set of fully-explicit equations that replaces the original formulation and reveals the highly nonlinear nature of the ASBM, and (3) a new coupling with transport equations that improves the accuracy of the model. The original and newer variants of the ASBM are then applied in the simulation of separated flows, so as to obtain a comprehensive assessment of their predictive capabilities. This is then followed by a thorough study on the ability of the model to provide well-converged solutions. The IPRM is a stochastic structure-based model of homogeneous turbulence. This thesis documents a new formulation based on an Eulerian reference frame that replaces the original Lagrangian framework and thus avoids the slow convergence and bias of statistical estimators. The derivation of the Eulerian formulation, its solution through radial basis functions, and a comparison against the original solution methods are reported in detail. Taken together, the work performed on both models advances the applicability and understanding of structure-based modeling for turbulent flows.
Book
1 online resource.
Continuous monitoring of physiological parameters inside a living cell will lead to major advances in understanding of biology and complex diseases, such as cancer. It also enables us to develop new medical diagnostics and therapeutics. Here we propose a technique to measure the pH level inside a cell using a wireless implantable passive sensor, which consists of capacitive and inductive components. Even a slight change of cellular pH level can reveal substantial information about the health of a cell. Only a highly sensitive pH sensor can detect this slight variation. Building such a wireless implantable sensor platform is the main goal of this thesis. Our designed and fabricated pH sensor is basically an extended gate ISFET (Ion Sensitive Field Effect Transistor) structure. It is compatible with CMOS (Complementary Metal Oxide Silicon) fabrication processes and can be miniaturized as an implantable device. To fully understand the parameters that give rise to high pH sensitivity, we have investigated the effect of solution molecular size on enhancing the sensitivity of this type of sensor. Our simulation and experimental results show that buffered solutions with larger counter ion size can induce significantly higher hydrogen ion activity at the sensor surface. The larger buffer counter ion size results in higher externally measured sensitivity, which even exceeds the Nernst limit (59mV/pH). For each pH buffer solution there is a specific size of the counter ion, which is necessary to achieve this high sensitivity. In addition, progress in nanofabrication and wireless communication has opened up the potential of making our wireless chip small enough that it can be wholly inserted into a cell. To investigate how the chip could be internalized into the cell and how the chip would affect cell physiology, we designed and fabricated a series of 3D multilayer structures with different sizes as a potential RFID (Radio Frequency IDenentification) cell tracker. Our experiments show that the chips with smaller sizes than 21 µm × 9 µm × 1.5 µm can be easily internalized by various types of living cells, such as macrophages, cancer cells, and normal/healthy cells. The incubated cells with internalized chips stayed alive during the 7 days of monitoring. Also, we observed successful cell division from these incubated cells. These results are the first steps towards long-term, wireless, intracellular physiologic monitoring.
Book
1 online resource.
The frontier challenges that must be solved before brain-machine interfaces (BMIs) can be used as clinically useful motor prostheses differ depending on the degree of function being restored. Two-dimensional cursor control (i.e., for communication) has recently reached high levels of peak performance in pre-clinical studies, but translation is hampered by less than reliable performance due to unstable neural signals. Meanwhile, control of robotic arms remains poor, despite some impressive glimpses at what the future could be, because we lack fundamental understanding of how the brain incorporates the BMI into its motor schema. This hampers our ability to accurately decode intended arm movements. My dissertation focused on both sets of problems in pre-clinical macaque BMI studies. Chapters 2 and 3 provide solutions for improving BMI robustness. I first describe a machine learning approach to building decoder algorithms that are robust to the changing neural-to-kinematic mappings that plague translational BMI efforts. We developed a multiplicative recurrent neural network decoder that could exploit the large quantities of data generated by a chronic BMI — data that has heretofore gone unused. I then describe a neural engineering approach for increasing the device lifespan by providing high performance control even after losing spike signals. I developed a method for decoding local field potentials (LFPs) as a longer-lasting alternative or complimentary BMI control signal. This led to the highest-performing LFP-driven BMI and the first 'hybrid' BMI which decoded kinematics from spikes and LFPs together. Chapter 4 looks ahead to challenges that will be encountered when BMI-controlled limbs operate in the physical world by describing how error signals impact ongoing BMI control. I perturbing the kinematics of monkeys performing a BMI cursor task and found that visual feedback drove responses starting 70 ms later in the same motor cortical population driving the BMI. However, this initial response did not cause unwanted BMI output because it was limited to a decoder null space in which activity does not affect the BMI. When activity changed in output-potent dimensions starting 115 ms after perturbation, it caused corrective BMI movement. This elegant arrangement may hint at a broader computational strategy by which error processing is separated from output.
Book
1 online resource.
There is a strong consensus that the climate is changing, that human activities are the dominant cause of this change, and that continued climate change will have negative impacts on human societies. To analyze energy and climate policy remedies, researchers have developed a diverse collection of integrated assessment models (IAMs) that represent the linked energy, economic, and earth systems in an interdisciplinary framework. Some IAMs are cost-benefit models designed to compute optimal policy interventions, while others are cost-effectiveness models used to determine the technology pathways that enable an emissions or climate goal to be achieved at least cost. Although IAM representations of technological change are critical determinants of model outcomes, underlying processes are poorly understood and models typically feature fairly crude formulations. The goal of the three projects that constitute this dissertation is to develop more advanced representations of technological change that capture a wider range of endogenous drivers. Scenario analyses based on these representations reveal their implications for energy and climate policy, as well as technology transitions this century. Chapter 2 describes the development of a system of technology diffusion constraints that endogenously respects empirically observed spatial diffusion patterns. Technologies diffuse from an advanced core to less technologically adept regions, with adoption experiences in the former determining adoption possibilities in the latter. Endogenous diffusion constraints are incorporated into the MESSAGE framework and results suggest that IAMs based on standard exogenous diffusion formulations are overly optimistic about technology leapfrogging potential in developing countries. Findings also demonstrate that policies which stimulate initial deployment of low-carbon technologies in advanced economies can be justified from a global common goods perspective even if they fail the cost-benefit test domestically. In Chapter 3, learning-by-doing is formulated as a firm-level rather than an industry-level phenomenon. Wind and solar PV manufacturers strategically choose output levels in an oligopoly game with learning and inter-firm spillovers. This game-theoretic representation of renewable technology markets is coupled to MESSAGE so that the energy system planner can only invest in wind and solar PV capacity at the equilibrium prices the market would charge for the desired quantities. Findings illustrate that the most ambitious emissions reduction pathways include widespread solar PV diffusion, which only occurs if competitive markets and spillovers combine to reduce prices sufficiently. The relationship between price and cumulative capacity is similar to that between unit cost and cumulative capacity under competitive markets, but a combination of market power, strong climate policy, and weak spillovers can cause prices to rise with cumulative capacity even though unit costs decline. The bilevel modeling framework of Chapter 4 is built to determine the optimal combination of technology-push and demand-pull subsidies for a given technology policy application. Firms (inner agents) solve a two-stage stochastic profit maximization problem in which they choose process and product R& D investments in the first stage, then choose output levels in the second stage. The policymaker (outer agent) seeks to identify the combination of policies that induces the firms to reach an equilibrium with the highest possible expected welfare. Numerical simulation results show that technology policy can enhance welfare under a wide range of parameter settings. Spillovers reduce product R& D expenditures but generally improve welfare by making R& D more effective. Welfare decreases with competition in the no-policy case, but increases with competition if optimal technology policies can be imposed. Each of the three projects focuses on a distinct aspect of technological change, but the formulations developed for these studies reflect several important themes: endogenous mechanisms, multiple decision-making agents, game-theoretic interactions, market power, spillovers, regional heterogeneity, and uncertainty. While the research presented in this dissertation advances the modeling of technological change, a number of formidable challenges remain. The final chapter discusses some of these challenges and ideas for future research to address them.
Book
1 online resource.
"'Agents Wanted': Sales, Gender, and the Making of Consumer Markets in America, 1830-1930" is a history of capitalism and a gender history that explores both a business model and women's conflicted engagement with it. The agency method of distributing consumer goods became widespread during the nineteenth century. With a gathering force in the antebellum decades and real abandon after the Civil War, entrepreneurs recruited individuals into agency networks and assigned them territories in which to cultivate demand for new kinds of mass-produced consumer goods—lavishly illustrated books, family magazines, engravings, patent medicines, and more. Agents not only persuaded people to buy but as independent contractors they also shouldered risks and carried out quotidian economic practices that enabled businesses to function. This dissertation examines three sites where agency distribution was particularly visible—the periodical, subscription book, and patent medicine industries. The agency economy recruited diverse participants into the work of selling. It offered possibilities not only to men struggling to make their way in a changing economy but also to women. In the gender-segmented and highly unequal nineteenth-century labor market, it provided a rare venue that valued the labor of men and women equally. It kindled hopes for economic independence and offered a tool for salvaging a productive home-based family economy. While most agents were men, women's minority perspective illuminates how the system functioned and how appeals to older cultural values both facilitated new economic developments and came under pressure. Women found bridges into agency work in cultural practices of hospitality, patronage, and charity to widows and via fraternal networks. They experienced obstacles as well, including negative class and moral associations. After 1870, their selling coincided with increased agitation for woman suffrage and temperance and a movement towards a freer and more commodified sexuality. These historical conjunctions of politics, sexuality, and economics informed women's interaction with selling and entrepreneurs' efforts to attract sales workers. The agency model changed over time. In the periodical industry, distinct distribution channels developed, including a system of clubbing that rewarded women's sales labor with consumer goods. After the Civil War, entrepreneurs, including E.C. Allen, elaborated agency, using advertising, merchandise premiums, and inexpensive second-class postal rates to recruit masses of agents and transform their names into commodities. With agents' help, periodical publishers built nationwide readerships, platforms that other entrepreneurs used to fulfill distribution dreams. A case study of the Viavi Company shows a patent medicine concern and its female sales workers shaping agency into direct selling—the purview of companies like Avon Products, Inc.—and in the process forwarding a commercial maternalism. Cultural representations of sellers played a role in agency transformations. Stereotypes of male and female book agents informed women's approach to selling while working to limn sales as a male pathway to business success. The comedic trope of the female drummer, or commercial traveler, evolved in ways that helped to alleviate concerns about women's ability to balance work and domestic life. In revisiting this nearly forgotten business meaning of the word "agency, " this project makes gender central to the new history of capitalism and illuminates the importance of the small-scale actions of sometimes unlikely economic actors.
Book
1 online resource.
Bubble generation and air entrainment on ocean surfaces and behind ships are complex phenomena which usually accompany turbulent flows. Non-linear wave-breaking events entrain air and generate turbulence. Turbulence consequently fragments the entrained air into smaller bubbles. This process drastically increases the flux of air into the oceans and rivers, which is important for both aerating the water bodies and reducing greenhouse gases from the atmosphere. Wave breaking and bubble generation behind ships also have important effects on the hydrodynamics of ships and on their performance. The bubbly flow as a result of ship passage generates ship trails which remain for several minutes thereafter. Although turbulence is responsible for the fragmentation of larger bubbles into smaller ones, it cannot be the cause of the generation of micron-size bubbles. These bubbles are observed in ship wakes and natural waves and are associated with liquid-liquid impact events. These phenomena, due to their complexity, are far from being completely understood. In addition, there is missing quantitative connection between the large-scale non-linear wave-breaking events and the micron-size bubble generation as a result of impact events. There is a large-scale separation between these two phenomena which makes elucidation of the problem very challenging. The aim of this study is to use direct numerical simulations of turbulent hydraulic jumps as canonical representation of non-linear breaking waves, to study the air entrainment and large bubble generation. Furthermore, this study provides statistics of liquid-liquid impact events, which are precursors to micro-bubble generation in these flows. As far as we know, the present work is the first direct numerical simulation of turbulent hydraulic jumps, as well as the first attempt to obtain interface impact statistics in a stationary turbulent breaking wave. In addition to bubble generation, we investigate turbulence statistics such as mean and turbulent velocity fluctuations, Reynolds stress tensors, turbulence production terms, energy spectra and one-dimensional energy budget of the flow. Finally, we present investigation of the effect of relevant non-dimensional parameters such as Weber number and Reynolds number on both large bubbles and impact statistics in these flows.