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Contributions Of Ca1 Inhibitory Interneurons To Cerebello-Hippocampal Communication
(2024-04) Froula, Jessica
The cerebellum is classically considered a motor structure, but the “little brain” is now being much more widely accepted for its roles in cognition, both in its own right and via communications with other brain regions like the hippocampus (a brain region chiefly known for its roles in learning, memory and spatial processing). Our lab terms the bidirectional connectivity between these two regions the ‘hippobellum’. The two structures interact in both healthy brains and in pathological states such as in Temporal Lobe Epilepsy. The focus of this dissertation is to assess the contributions of inhibitory cells within hippocampal CA1 to cerebello-hippocampal communication. We find that the cerebellum bidirectionally affects interneurons, increasing activity in some while decreasing activity in others. We also found some interneurons are modulated during object exploration. Highlighting the coordination between the cerebellum and the hippocampus in spatial processing, interneurons modulated during object investigations are also modulated by cerebellar stimulation. We also characterized interneurons in accordance with their activity during locomotion and rest; a subset of these neurons, too, are modulated by cerebellar stimulation. Our functional characterizations revealed specific patterns of interneuron responses to cerebellar stimulation: interneurons that increased their activity with cerebellar stimulation also tended to increase their activity with locomotion and during object investigations. Conversely, interneurons that decreased their activity with cerebellar stimulation tended to be more active during rest and also decreased their activity during object investigations. Similar results were found using different stimulation parameters within the cerebellum and when stimulating a different cerebellar location, showing multiple ways the cerebellum can influence hippocampal interneurons and that it can do so in a bidirectional, coordinated fashion – according to the roles of those interneurons during behavior. In another experiment, we used common molecular markers of interneurons in conjunction with cFOS (a proxy for neuronal activity) to label hippocampal neurons activated by cerebellar stimulation ex vivo. We found that cerebellar stimulation increases cFOS expression in both CCK-expressing and SOM-expressing cells in hippocampal CA1. Overall. our results support the notion that CA1 inhibitory neurons play a role in cerebello-hippocampal interactions and prompt exciting new directions in this field.
Hybrid Peptide-Specific T Cells Incite Islet Inflammation And Autoimmune Diabetes
(2022-04) Dwyer, Alexander
Autoimmune diabetes (AD) is a disease characterized by T cell-mediated destruction of the insulin-producing β cells within the islets of Langerhans of the endocrine pancreas. Upon recognition of β cell-specific autoantigen, self-reactive T cells of various specificities expand and migrate to pancreatic islets. Recently, a hybrid peptide derived from the insulin C-chain and chromogranin A (InsC-ChgA) was identified as the cognate antigen for the non-obese diabetic (NOD) mouse-derived diabetogenic BDC-2.5 CD4+ T cell clone, suggesting InsC-ChgA-specific T cells may contribute to disease. Epifluorescent microscopy of pancreatic islets is one approach by which islet T cell inflammation can be assessed in the course of disease altering therapies targeting InsC-ChgA-specific cells, yet most analytical techniques rely upon cumbersome manual estimation of islet infiltration. Importantly, little is known regarding the pathogenicity of InsC-ChgA-specific CD4+ T cells in NOD mice and how selective inhibition of these cells impacts cross-sectional T cell infiltrate area within the pancreatic islets. Here, we first describe a novel approach to achieve rapid, automated, unbiased, and quantifiable data regarding the distribution of islet infiltrating CD4+ and CD8+ T cells in NOD mice. We demonstrate the accurate detection of islet borders using convex hull islet modeling and quantification of T cell infiltrate by writing a macro using the freeware ImageJ. With this method, we assessed CD4+ and CD8+ T cell inflammation within the islets of different age groups of NOD mice progressing towards AD. As proof of technique, we identified significantly more T cell infiltration within convex hull-defined islets of non-diabetic 13-week and 17-week diabetic NOD mice compared to 4-week mice. Second, we focused on the InsC-ChgA-specific CD4+ T cell response in NOD mice and show rapid activation and expansion in neonates. We found that expansion of InsC-ChgA-specific cells requires early interactions with XCR1+ type 1 conventional dendritic cells, and InsC-ChgA-specific cells are clonally restricted with bias towards TRBV15 usage. We also show that adoptive transfer of polyclonal InsC-ChgA-specific cells into NOD.Rag1-/- mice induces AD. Further, spontaneous disease can be suppressed through weekly administration of an InsC-ChgA:I-Ag7-specific monoclonal antibody (mAb). Using the convex hull approach for quantification of T cell infiltration, we identified a substantial decrease in both CD4+ and CD8+ intra-islet infiltration in the nominally pre-diabetic period following InsC-ChgA:I-Ag7 mAb treatment. This thesis describes a novel methodology for the quantifiable assessment of T cell islet infiltration in NOD mice. Additionally, the data here establish the pathogenicity of InsC-ChgA-specific CD4+ T cells, and that immune responses to InsC-ChgA antigen are both necessary and sufficient for AD induction. These results form a framework for future interrogation of other hybrid peptide-specific T cell contributions to AD development in both mice and humans.
Strain-Tuned Pr-Based Cobaltite Thin Films: Electronic Ground State Control And Strain Relaxation Effects
(2023-03) Dewey, John
Perovskite cobalt oxides, e.g., LaCoO3, have long been understood to display intriguing phenomena known as spin-state crossovers—changes in the cobalt ion spin-state in response to temperature, pressure, or other stimuli. More recently, a very different situation was uncovered in perovskite cobaltites containing praseodymium (e.g., Pr0.5Ca0.5CoO3). In these materials, a remarkable praseodymium valence transition drives a coupled, first-order spin-state/structural/metal-insulator transition. Such a valence transition, especially when coupled to spin-state and metal-insulator transitions, offers highly appealing material functionality, but has thus far been confined to cryogenic temperatures in bulk materials (e.g., 90 K in Pr1-xCaxCoO3). This thesis demonstrates that thin-film heteroepitaxial strain enables wide control over the electronic and magnetic ground states of such Pr-based cobaltites, and provides a facile path to boosting their valence transition temperatures to a practical range.It is first shown that in thin films of (Pr1-yYy)1-xCaxCoO3-δ, heteroepitaxial strain tuning enables stabilization of the valence-driven spin-state/structural/metal-insulator transition to at least 291 K, i.e., room temperature, with broad technological implications. Wide control of the electronic ground state is demonstrated, from ferromagnetic metal under epitaxial tension to nonmagnetic insulator under compression, thereby exposing a potential novel quantum critical point in this material’s epitaxial strain “phase diagram.” These achievements then motivate a study of strain relaxation in thin film (Pr0.85Y0.15)0.7Ca0.3CoO3-δ. It is shown that, contrary to conventional strain relaxation theory, films grown under large compression beyond a critical thickness develop an anomalous, two-layered structure, exhibiting “fully-strained” and “strain-relaxed” properties simultaneously. The underlying mechanism of strain relaxation has not been previously observed, and this work therefore adds an entry to the growing list of “alternative” mechanisms of strain relaxation in oxide thin films. Intriguing ultrathin-film behavior is also described, specifically the suppression of the high-temperature metallic state without a change in metal-insulator transition temperature, generating new knowledge related to interfacial “dead layers” in epitaxial perovskite oxide films. With the basic shape of the (Pr1-yYy)1-xCaxCoO3-δ epitaxial strain phase diagram established, finally it is shown that the phase space between the discrete strains imposed by commercially-available substrates can be explored using partially-strain-relaxed films. In the compressive-to-tensile transition region of the strain phase diagram, it is demonstrated that the uniform nonmagnetic insulator ground state gives way to phase coexistence with an emergent ferromagnetic metallic phase as compressive strain is relaxed. Such electronic phase coexistence evidences a first-order transition between this material’s two disparate, strain-stabilized ground states as a function of epitaxial strain, in contrast to a quantum critical point scenario, of broad scientific interest.
Integrating Care And Paid Work – The Career Development Of Parents Of People With Disabilities In Brazil
(2024-04) Dalla Martha Rodriguez, Ana Carolina
Parenting a person with disabilities (PWD) is an experience that transforms one’s beliefs, family relationships, social connections, financial stability, and professional trajectory. Parents of PWD engage in what scholars call exceptional care – intense, lifelong, cyclical, and crisis-driven care. For them, caring is a central part of their lives, crossing boundaries between family and work domains and driving most of these parents’ career decisions. Studies show that parents of PWD often experience heightened work-family conflict and physical, emotional, and financial stress. Significantly, individuals identifying as women are disproportionally impacted as they assume most of the care work. Nevertheless, employment is critical for these parents’ financial and mental health, as work provides necessary income and personal fulfillment. This study applied a grounded theory methodology to investigate how Brazilian parents of PWD make career decisions to accommodate care and paid work, also examining the systemic factors that influence these decisions. In-depth interviews were conducted with 27 college-educated mothers and fathers of PWD to map their career trajectories and main career decisions. The findings of this study contribute to advancing and integrating career development and work-life theories, highlighting the importance of social identities and organizational and social dynamics. New frameworks are proposed to explain how parents of PWD, and potentially other caregivers, make ongoing career decisions and manage their family and work arrangements to attain more satisfactory work-life relationships. Additionally, this study offers practical implications for career development professionals, HRD practitioners in organizations, and public policymakers on how to support the professional development of caregivers.
Development And Statistical Analysis Of Graphene-Based Gas Sensors
(2024-03) Capman, Nyssa
The use of graphene in gas sensors has been increasing in recent years, as graphene has many attractive properties including high carrier mobility, excellent conductivity, and high surface-area-to-volume ratio. Both individual graphene sensors and “electronic nose” (e-nose) sensor arrays have been applied to detecting many gaseous chemicals involved in indoor and outdoor air pollution, food quality, and disease detection in breath. Volatile organic compounds (VOCs) are one important category of chemicals in all of these applications. While graphene sensors have been shown to be effective at detecting and discriminating between VOCs, limitations still exist. This dissertation will describe solutions to two of these problems: Improving selectivity through functionalization and detecting target analytes in the presence of a background interferant.A graphene-based e-nose comprised of 108 sensors functionalized with 36 different chemical receptors was applied to sensing 5 VOCs at 4 concentrations each. The 5 analytes (ethanol, hexanal, methyl ethyl ketone, toluene, and octane) were chosen based on their importance as indicators of diseases such as lung cancer, since disease diagnosis in exhaled breath is one possible application of these arrays. The VOC discrimination ability of the sensor arrays was found to be near-perfect (98%) when using a Bootstrap Aggregated Random Forest classifier. Even with the addition of 1-octene, a compound highly similar to octane and therefore likely to cause high numbers of misclassifications, the sensors still achieved high classification accuracy (89%). The behavior of individual, unfunctionalized graphene varactors was also examined in the presence of VOCs mixed with oxygen. Response signal patterns unique to each VOC + oxygen mixture were revealed. As these patterns developed over the entire gas exposure period, a Long Short-Term Memory (LSTM) network was chosen to classify the gas mixtures as this algorithm utilizes the entire time series. Even in the presence of varying levels of oxygen, three VOCs (ethanol, methanol, and methyl ethyl ketone) at 5 concentrations each could be classified with 100% accuracy, and the VOC concentration could be resolved within approximately 100-200 ppm. This discrimination success was also possible despite the sensors exhibiting varied drift patterns typical of graphene sensors.
Improved Methods Of Transgenic And Viral Reagent Delivery For Genome Engineering In Plants
(2023-01) Chamness, James
Plant genetic improvement is a crucial lever to increase the productivity and sustainability of agricultural systems in the face of manifold economic and environmental challenges. The previous decade has witnessed burgeoning molecular technologies and genomic targets for directed modification, with the potential to underpin both incremental and radical genetic gains. The use of such technologies for plant breeding, however, depends on robust delivery and activity of molecular reagents into and within regenerable cells, in order to produce stably modified germplasm. This remains a significant barrier for the majority of plants. In this thesis, I present research at the intersection of reagent design and delivery for genome modification in plants. This work includes development of practical methods for the assembly and cloning of transformation constructs, guidance on transgene expression strategies to effect desired outcomes in planta, and a particular focus on the roles engineered plant viruses can play as augmenting or primary vectors to address specific challenges in transformation and gene editing. Three manuscripts constituting the primary chapters include a comprehensive historical review of viral vector development in plants; a methods paper advancing the design and assembly of transformation constructs; and a research paper describing an improved viral delivery system for site specific recombinases. In the conclusion, I consider perspectives for the broader field and prospects for future research.
Essays On Racial Inequality In The Labor Market
(2024-04) Treanor, Caitlin
This dissertation studies issues related to racial inequality in the labor market. The first two chapters focus on the impact of racially segregated referral networks on inequality and aggregate welfare, while the final chapter focuses on differences in returns to work experience and the supply of labor between black and white workers in recent decades. The first chapter shows that there are racial differences in the composition of referral networks and the use of referral networks by occupation. In particular, non-college black and white workers in the United States who obtain a job via referral display substantial social segregation, using same-race contacts around 90% of the time. While non-college black and white workers use referrals at a similar rate overall, black workers use referrals for higher-skill and higher-paying occupations at a lower rate than white workers. I also document racial differences in occupational choice, with white workers sorting into higher-skill occupations. The following chapter connects and rationalize these observations by incorporating a referral-based matching function into a standard search and match model with occupational choice, heterogeneous ability levels, free entry, and wages determined by Nash bargaining. Social segregation can lead to differences in occupational choice by race, and thus wage and employment inequality, in the steady state. After calibrating the model to examine black and white workers in the United States, the estimates show that racially biased networks alone can generate a black-white wage gap of 1.66 percent and an employment gap of 0.74 percentage points. Moving from the segregated to the desegregated steady state harms the majority white workers while helping the minority black workers, resulting in a decrease in aggregate welfare. In the final chapter I utilize individual fixed effects combined with an instrumental variables approach to document the extent to which returns to work experience differ for black and white workers; I then use a life-cycle model with a learning-by-doing human capital production function to assess the consequences of these differences for the supply of labor. Returns to an extra thousand hours of work experience for the typical white worker are 23 cents per hour in 2012 USD (amounting to an additional $478 per year of full time work), compared to 12 cents for an otherwise identical black worker (amounting to an additional $250 per year). Using a life-cycle model, differences in returns to experience combined with simulated differences in choices of hours worked can account for approximately 10 percent of the measured difference in average wages over the life-cycle between black and white workers.
Nonthermal Plasma Synthesis Of Nanoparticles And Double Probe Diagnostic
(2023-04) Xiong, Zichang
Nanoparticles are tiny particles that range in size from 1 to 100 nanometers. Their large surface area-to-volume ratio allows them to interact with their surroundings in unique ways. Nonthermal plasmas are particularly attractive sources for nanoparticle synthesis. In these plasmas, energetic plasma electrons decompose molecular gaseous precursors, producing radicals, which lead to the nucleation and growth of nanoparticles. This thesis investigates the feasibility of double probe measured in nonthermal dusty plasma and the mechanism of particle trapping and heating in nonthermal plasma synthesis of nanoparticles. This thesis also studies ICP synthesized size-tunable y-Al2O3 nanocrystals and reducing iron oxide particles by a MW hydrogen plasma. Double probes are utilized to diagnose the plasma properties of an argon:silane plasma containing nanoparticles. We demonstrate good stability of current-voltage characteristics over several minutes of operation. In addition, we developed a zero-dimensional global model to investigate the effect of the presence of nanoparticles on the plasma properties. Critical processes were investigated in nonthermal plasma synthesis of nanoparticles. We present experimental and computational evidence that, during their growth in the plasma, sub-10 nm silicon particles become temporarily confined in an electrostatic trap in radio-frequency excited plasmas until they grow to a size at which the increasing drag force imparted by the flowing gas entrains the particles, carrying them out of the trap. Furthermore, a nanoparticle heating model was used to study the temperature increase of a particle exposed to a plasma by exothermic surface reactions. y-Al2O3 is widely used as a catalyst and catalytic support due to its high specific surface area and porosity. We report a single-step synthesis of size-controlled and monodisperse, facetted y-Al2O3 nanocrystals in an inductively coupled nonthermal plasma reactor using trimethylaluminum and oxygen as precursors. Nanocrystal size tuning was achieved by varying the total reactor pressure yielding particles as small 3.5 nm, below the predicted thermodynamic stability limit for y-Al2O3. CO2 emissions from the steel production account for 8% of the global anthropogenic CO2 emissions and are a key challenge towards achieving a carbon-neutral future. We report an electrified process for reducing iron ore particles using atmospheric pressure hydrogen plasma powered by microwave energy. Iron ore particles were reduced steadily on a mesh exposed to the plasma. Moreover, in-flight iron ore reduction was achieved using the atmospheric pressure hydrogen microwave plasma, which is more than 100 times faster than the previously reported flash in-flight iron ore reduction by a thermal hydrogen technique.
Experimental Investigation Of Disks Settling In Quiescent And Turbulent Air
(2024-04) Tinklenberg, Amy
We experimentally investigate the settling of millimeter-sized disks in quiescent air and in homogeneous turbulence, as turbulence can have a strong effect on the fall speed of snowflakes and ice crystals. The range of physical parameters is chosen to be relevant to plate crystals settling in the atmosphere: Disks range in diameter from 0.3 to 3 mm, with diameter-to-thickness aspect ratios of χ = 5 − 60, inertia ratios of I∗ ≈ O(1), and Reynolds numbers from Re = 10 − 663. Both solid and perforated disk geometries are considered, with area ratios in the range AR = 0.73 − 1. Velocity fluctuations of the turbulence are comparable to the disk terminal velocities. Thousands of trajectories are captured and reconstructed for each disk type by planar high-speed imaging, using the method developed by Baker & Coletti (J. Fluid Mech., vol. 943, 2022, A27). This allows for statistical analysis of the translational dynamics in 2D and the rotational dynamics in 3D. In quiescent air, most disks either fall straight vertically with their maximum projected area normal to gravity or tumble while drifting laterally at an angle <20°. Two of the three disk sizes considered exhibit bimodal behavior, with both non-tumbling and tumbling modes occurring with significant probabilities, which stresses the need for a statistical characterization of the process. The smaller disks (1 mm in diameter, Re = 96) have stronger tendency to tumble than the larger disks (3 mm in diameter, Re = 360), at odds with the diffused notion that Re = 100 is a threshold below which falling disks remain horizontal. Larger fall speeds (and thus smaller drag coefficients) are found with respect to existing correlations based on experiments in liquids, demonstrating the role of the density ratio in setting the vertical velocity. The data supports a simple scaling of the rotational frequency based on the equilibrium between drag and gravity, which remains to be tested in further studies where disk thickness and density ratio are varied. Air turbulence reduces the disk terminal velocities by up to 35%, with the largest diameters most significantly influenced, which is primarily attributed to drag nonlinearity. This is evidenced by large lateral excursions of the trajectories, which correlate with cross-flow-induced drag enhancement as previously reported for falling spheres and rising bubbles. As the turbulent intensity is increased, flat-falling behavior is progressively eliminated and tumbling becomes prevalent. The rotation rates of the tumbling disks, however, remain similar to those displayed in still air. This is due to their large moment of inertia compared to the surrounding fluid, in stark contrast with studies conducted in water. In fact, the observed reduction of settling velocity is opposite to previous findings on disks falling in turbulent water. This emphasizes the importance of the solid-to-fluid density ratio in analogous experiments that aim to mimic the behavior of frozen hydrometeors. The velocities estimated by the empirical model of Heymsfield & Westbrook (2010) for both the solid and perforated geometries match quite well with the measured velocities in quiescent air, with an average error of < 20%. This model consistently underestimates the terminal velocities, but is an improvement on the estimates from Bohm (1989). The perforated disk geometries experience a velocity reduction due to the turbulence, of similar magnitude to the solid disk. A stabilizing effect due to the perforations is present for the four quadrant and single hole geometries, which manifests as a larger percentage of steady falling trajectories than for the solid. This result is robust in quiescent air and homogeneous turbulence. In turn, lateral motion induced by the turbulent forcing is less than for the solid disk. A distinct bimodality is present for the angular velocity of the solid disk, directly correlated to the falling style. In the perforated case, the tumbling angular velocity measured is half of that for the solid disk, and thus becomes indistinguishable from the angular velocity in a fluttering descent.
Why Don’T Girls Think They’Re Good At Physics? Recognition In A High School Classroom
(2024-04) Stoeckel, Marta
Women, especially Black and Latina women, are marginalized in physics, including in high school classrooms. Recognition is one of the ways women and girls experience marginalization in physics. This dissertation is comprised of three distinct but related studies examining how students experience recognition in an AP Physics 1 classroom. The first study is a mixed-methods study examining students’ sense of self-efficacy using a sequential explanatory design. This study first examined the relationship between students’ self-assessments and actual quiz scores and found no statistically significant difference between boys and girls in this class. I next used open-ended self-assessment prompts and semi-structured student interviews to identity classroom experiences that students felt contributed to or detracted from their sense of self-efficacy. While boys and girls talked about many experiences, such as the way labs in the course were structured, in very similar ways, only boys clearly discussed receiving consistent recognition from their peers, leading to the research questions in the subsequent studies. The second study examined how students provided each other with recognition, what kinds of contributions they recognized, and how peer recognition interacted with students’ sense of physics identity using small group video and student interviews. Recognition fell into two major categories: explicit, where students directly recognized a peer, and implicit, where the recognition was provided indirectly. Explicit recognition was primarily connected to correct answers while implicit recognition was connected to a much broader range of contributions. During interviews, when students discussed their personal physics identity, they primarily discussed correct answers and explicit recognition they had received, suggesting that their personal identity was primarily connected to explicit recognition. When discussing their conceptions of what it means to hold a physics identity, students referenced not only correct answers, but the much broader range of contributions connected to implicit recognition. They also described giving both explicit and implicit recognition. This suggests that students connected both categories of recognition to their conceptions of a physics identity. Third, I analyzed exchanges in which students positioned each other in terms of physics ability without directly referencing physics using video of a mixed-gender group and an all-boy group. The mixed-gender group engaged in many of these exchanges and primarily used them when the girl contributed a correct answer with the boys taking authoritative positions. Rather than providing the girl with recognition, these exchanges served to devalue her contribution. The all-boy group, by contrast, only had one of these exchanges and neither was clearly established as more authoritative. Together, these studies provide insights into the gendered dynamics of the recognition that students give and receive in physics classrooms with implications for instructional practice. There is a clear need for teachers to structure group work in ways that ensure all students are recognized by their peers for a wide range of contributions and to disrupt gendered patterns in the classroom.
Modeling And Design Of Hydraulic Power Take-Offs For Ocean Wave-Powered Reverse Osmosis Desalination
(2024-04) Simmons, Jeremy
Ocean wave-powered desalination of seawater using reverse osmosis (RO) presents an important opportunity for coastal communities as an economical and clean source of fresh water. However, the breadth and depth of study in the design of hydraulic power take-offs (PTOs) for ocean wave-powered RO is not sufficient for reliable high-performance. This work introduces several novel PTO architectures for wave-powered RO systems that take the approach of pressurizing seawater directly using a pump that is driven by the wave energy converter (WEC). These architectures include co-generation of electricity with fresh water to support the system without reliance on a local electrical grid. These architectures are modeled and compared in terms of the size of the WEC-driven pump, the RO membrane module, high-pressure accumulator volume, and the yearly average rate of permeate production. Results show that a parallel-type PTO architecture that closely resembles the state-of-the-art is consistently outperformed by series-type architectures. The series-type architecture, which is examined with and without an integrated switch-mode power transformer, produces as much fresh water as the parallel-type architecture while (1) using a WEC-driven pump that is 30–74 percent smaller without the switch-mode power transformer and 70–92 percent smaller with the switch-mode power transformer and (2) requiring 75 percent less high-pressure accumulator volume. Results also show that varying the active RO membrane area as a function of sea conditions can improve performance in terms of WEC-driven pump size, RO membrane module size, and permeate production, by 7–41 percent. Using model predictive control as an optimal load control method, this work also finds that a variable displacement WEC-driven pump can enhance productivity by 11–29 percent. Pipeline modeling methods are also examined for their use in wave energy systems and results show that a lumped parameter pipeline model that represents a pipeline in multiple segments is sufficient for the design of these systems, subject to a constraint on the length of pipe each segment represents. As a whole, this work provides guidance to the design of PTOs in future projects with insight into selecting the architecture of the PTO, formulation of multi-objective design problems, and models that can be usedeffectively for model-based design.
Network Topology And Causal Structure Recovery In Linear Dynamical Systems
(2024-04) Shaikh Veedu, Mishfad
Modeling and representing complex systems by a network of interacting agents provide cost-effective and efficient ways to simulate, design, and test the solutions to real-world problems in science and engineering. Applications such as finance, neuroscience, climate science, power grids, etc. involve modeling the agents and states that interact and evolve dynamically and can contain feedback loops. Most existing literature assumes a static relationship between the agents, which fails to capture the dependencies across time. Learning the interdependency (topology) and cause-and-effect structure among the agents is therefore of importance and having an active interest in the graphical network representation and effective modeling of the dynamical systems. Identifying the unknown interaction structure can in general be classified into active and passive techniques. The active techniques involve intervention in the normal operation of the system by injecting external signals and/or modifying agents in the system. Critical applications in financial markets, power grids, meteorological systems, etc. do not allow active intervention in the system. In such critical applications passive methods, which infer the information from the observed time-series measurements, are applied. In the passive techniques, the evolution of the underlying system is mathematically modeled using a generative model, where the agents are excited with a disturbance signal. In this thesis, we study passive techniques to identify the interdependency and the influence pathways in the dynamical systems, where the agents interact linearly. Further, in practice, it might not be viable to observe all the states in the system. Thus, it is imperative to identify the influence structure (network topology) when the system involves hidden/latent states, which is a challenging problem. In Chapter 2, we provide a novel algorithm to identify the interdependency structure, including the dependency among the latent nodes, when only a subset of the nodes/agents provide the time-series measurements. In many applications, the proposed algorithm retrieves the exact influence pathways, with partial directions, including that of the latent nodes. Another practical issue is that some of the disturbances at the agents themselves can be correlated, which renders the agents' influence structure indistinguishable from passive observations. Examples of such systems are observable in applications such as power grids and stock markets. Learning the network topology in the presence of such correlated disturbances is difficult as it is required to extract the dependency between the disturbances first. In Chapter 3, we show that the correlation between the disturbances is equivalent to the dependency induced by the latent nodes. The network topology only provides the correlation structure of the network of agents. It is well known that correlation is not equivalent to causation and the cause-effect structure contains more information than the correlation structure. In many applications in medicine, biology, and statistics the correlation structure might not be sufficient. Here, it is necessary to know the causal structure of the underlying dynamics. In Chapter 4, we provide an algorithm to learn the causal structure of a linear dynamical system when the agents are excited by identical noise sources. Further, a sample complexity analysis is provided, which finds matching upper and lower bounds on the number of samples required to obtain a given error performance. In general, without intervention and assumptions on the generative models, it is impossible to identify a complete causal structure. The best one can identify without further restriction is an equivalent set of graphs with the same conditional correlation structure, Essential Graphs. In Chapter 5, we provide algorithms to estimate the essential graph in linear dynamical systems using the Wiener filter (WF). The conventional time-domain approach to computing WF is computationally expensive. To speed up the calculation, we propose a fast Fourier transform-based computationally efficient approach to estimate the Wiener filter. The conventional probability notion of CI fails to capture the CI notion in a stochastic process. To tackle this problem, we propose a novel probability notion of CI for stochastic processes in the frequency domain. This notion is used to extend the notions of the front-door and the back-door criterion from static graphical models to linear dynamical systems, where the nodal states are stochastic processes.
Astrocyte Pathophysiology In Huntington’S Disease: Characterization Of Spatial Distribution, Organization, And Function Of Distinct Populations Of Astrocytes
(2024-04) Brown, Taylor
Huntington’s disease (HD) is a devastating neurodegenerative disease that manifests as motor, cognitive, and psychiatric impairments. HD is caused by a poly-glutamine expansion in exon 1 of the huntingtin (HTT) gene, which results in misfolding and aggregation of the mutant HTT protein (mHTT). HD preferentially affects medium spiny neurons of the striatum, causing a severe and progressive loss of striatal cells, while other areas of the brain, such as the cortex, are affected to a lesser degree. Interestingly, degeneration of neurons in the striatum is accompanied by striatal astrogliosis and astrocytic dysfunction. However, the mechanisms by which mHTT induces striatal astrocyte pathology and its association with neuronal degeneration and behavioral deficits in HD is still unclear. This gap in knowledge has hindered the development of effective therapies to ameliorate disease progression. Here, we sought to characterize how HD affects astrocyte abundance, diversity, and distribution within the striatum using the zQ175 mouse model of HD. We focused on three types of astrocytes characterized by the expression of specific protein markers, GS+, S100B+, and GFAP+. We found that S100B+ astrocytes and GFAP+ astrocytes were more abundant in the striatum of zQ175 mice compared to WT. However, while S100B+ astrocytes were increased throughout different striatal domains, GFAP+ astrocytes were only increased in the most dorsomedial region. Additionally, we found that GFAP+ astrocytes appeared in clusters whereas S100B+ astrocytes were more homogenously distributed. Spatial clustering of astrocytes has been reported in other neurodegenerative diseases and can indicate areas of cell death, inflammation, or aggregation of toxic proteins. We found that the spatial distribution of GFAP+ astrocytes in zQ175 mice surprisingly reflected areas of low HTT aggregate load and corresponded to white matter fascicles passing through the striatum. Intriguingly, we also found that GFAP+ astrocytes only accumulated around a specific subset of fascicles in the dorsomedial striatum. To determine the origin of those fascicles, we utilized the Allen Mouse Brain Connectivity Atlas and conducted viral tracing experiments. We determined that the secondary motor area (MOs), a cortical region involved in motor actions and decision making, sends fascicles through the dorsomedial region of the striatum. We then confirmed that GFAP+ astrocytes are specifically associated with fascicles originating in the MOs and looked for pathology in the MOs as a reason for this interaction. We saw a significant increase in GFAP+ astrocytes in the MOs of zQ175 mice compared to WT. Taken together, this research demonstrates that HD differentially affects the abundance and distribution of distinct types of astrocytes in the striatum. This information is vital to understanding the contribution of astrocytes to HD pathology. In fact, we show that an increase in number of S100B+ astrocytes in the striatum likely reflects the response of protoplasmic astrocytes to striatal gray matter pathology. In contrast, an increase in number of GFAP+ astrocytes in the striatum is probably a response to pathology of cortical neurons or white matter. Astrocyte heterogeneity and the MOs are two understudied areas of research in HD and our work emphasizes the importance of further research into these topics with the hope of uncovering the distinct roles of each in disease pathogenesis.
On The Allosteric Mechanisms Of Paradoxical Activation By Raf Inhibitors
(2024-04) Rasmussen, Damien
The type II class of RAF inhibitors currently in clinical trials paradoxically activate BRAF at subsaturating concentrations. Activation is mediated by induction of BRAF dimers, but why activation rather than inhibition occurs remains unclear. Using biophysical methods tracking BRAF dimerization and conformation we built an allosteric model of inhibitor-induced dimerization that resolves the allosteric contributions of inhibitor binding to the two active sites of the dimer, revealing key differences between type I and type II RAF inhibitors. For type II inhibitors the allosteric coupling between inhibitor binding and BRAF dimerization is distributed asymmetrically across the two dimer binding sites, with binding to the first site dominating the allostery. This asymmetry results in efficient and selective induction of dimers with one inhibited and one catalytically active subunit. Our allosteric models quantitatively account for paradoxical activation data measured for 11 RAF inhibitors. Unlike type II inhibitors, type I inhibitors lack allosteric asymmetry and do not activate BRAF homodimers. Finally, NMR data reveal that BRAF homodimers are dynamically asymmetric with only one of the subunits locked in the active αC-in state. This provides a structural mechanism for how binding of only a single αC-in inhibitor molecule can induce potent BRAF dimerization and activation.
Autoregulation Of G Protein-Coupled Receptor Signaling Through The Third Intracellular Loop
(2023-04) Sadler, Fredrik
The third intracellular loop (ICL3) of the G protein-coupled receptor (GPCR) fold is important for the signal transduction process downstream of receptor activation. Despite this, ICL3’s lack of defined structure, combined with its high sequence divergence among GPCRs, obfuscates characterization of its involvement in receptor signaling. Previous studies focusing on the β2 adrenergic receptor (β2AR) suggest that ICL3 is involved in the structural process of receptor activation and signaling. We derive mechanistic insights into ICL3s role in β2AR signaling, finding that ICL3 autoregulates receptor activity through a dynamic conformational equilibrium between states that block or expose the receptor’s G protein binding site. We demonstrate the importance of this equilibrium for receptor pharmacology, finding that G protein-mimetic effectors bias ICL3’s exposed states to allosterically activate the receptor. Our findings additionally reveal that ICL3 tunes signaling specificity by inhibiting receptor coupling to G protein subtypes that weakly couple to the receptor. Despite the sequence diversity of ICL3, we demonstrate that this negative G protein selection mechanism through ICL3 extends to GPCRs across the superfamily, expanding upon the framework for how receptors mediate G protein subtype selective signaling. Furthermore, our collective findings motivate ICL3 as an allosteric site for receptor and signaling pathway specific ligands.
Trem2 Regulates Foamy Macrophage Function In Atherosclerosis
(2024-04) Patterson, Michael
Implementation Of Ćuk Converter With Integrated Magnetics For Residential Solar Applications
(2020-05) Ramanath, Anushree
Rooftop solar is becoming a popular source of energy for electricity generation. An optimal photovoltaic interface has ripple-free terminal currents and compact system design along with a high step-up ratio. The Ćuk converter is an ideal choice for such applications due to its unique quality of continuous current flow at both the terminals and the wide operating range. This reduces the noise, need for filtering, and electromagnetic interference issues. With the use of coupled inductor, the Ćuk converter can adequately operate with ripple-free input or output current. With the use of additional windings along with the coupled inductor, either in the form of inductor or isolation transformer, ripple-free currents can be obtained at both input and output terminals. However, only a minority of the users easily adapt Ćuk converter and its variants for their needs due to the complications in terms of the design method and absence of a rational design strategy for obtaining the suitable magnetics design that yields 'zero-ripple' terminal currents. This thesis presents an innovative, definitive method with an analytical basis for determining the component values that cater to a broad range of applications for a Ćuk converter with integrated magnetics and compares it with the basic and coupled inductor based Ćuk converter topologies. The descriptive analysis is carried out with the aid of the MATLAB scripts developed and the theoretical results are validated with the help of simulation models created using the PLECS software platform. Analysis-Led Design (ALD) tool has been developed for facilitating parameter estimation for critical topologies using MATLAB and Excel spreadsheets. This serves as an initial framework and can be utilized for the parameter estimation of other topologies with integrated magnetics. The design of the magnetic components and equivalent modeling is carried out using ANSYS and the designed converter has been implemented for experimental validation. Traditionally, control of the Ćuk converter has been extremely complicated due to unstable higher-order transfer function and non-minimum phase behavior. For the chosen topology with integrated magnetics, control techniques have been investigated and performance analysis is carried out on a system level.
Speculating Abolition: Alternatives Models Of Redress In Black And Indigenous Feminist Speculative Fiction
(2024-04) Ornelas, E.
Policing and prisons don’t solve the problems of interpersonal and institutional violence and harm, and in fact fail those most vulnerable to violence. Speculating Abolition: Alternative Forms of Redress in Black and Indigenous Feminist Speculative Fiction, analyzes contemporary North American Anglophone fiction from Black and Indigenous women, queer, trans, and Two Spirit people in order to conceive of a world free of the carceral settler state. In the hands of Black and Indigenous peoples, speculating as a gerundive verb form—rather than an adjective—is a distinct practice of reading and creating, defined by its promise of imagining otherwise. Hence, I ask: How do these works help envision alternatives to forms of redress like the criminal punishment system? What do literary texts illustrate as possible options for and limits to resistance in the face of gendered, racialized, and colonial interpersonal and institutional violence? And how can these speculative visions transform broader debates about models of justice? The arc of this project traces ways to enact redress without policing and prisons, instead moving toward healing and away from harm. The introduction grounds the work in an abolitionist feminism that takes seriously the critiques of traditional Western forms of “justice.” My first chapter asks necessary questions of the place of punishment in lieu of the carceral settler state, particularly in the case of egregious crimes like sexual assault witnessed within Octavia Butler’s novel Dawn. The second chapter argues that a crucial part of addressing interpersonal and institutional violence without state apparatuses is to directly confront those who are causing harm, like in Mariame Kaba’s short story “Justice” as well as Cherie Dimaline’s (Métis) The Marrow Thieves. When facing conflict head-on isn’t effective or feasible, my third chapter encourages a turn inward towards those most affected by violence, through the fugitivity, generative refusal, and cultural reclamation seen in Rivers Solomon’s An Unkindness of Ghosts and Adam Garnet Jones’s (Cree/Métis) short story “The History of the New World.” Finally, the conclusion speculates about the application of these lessons for scholars and activists to prefigure abolition. Ultimately, I present a case against punitive measures for those who commit harm, by asserting that more restorative and transformative options are reflected in Black and Indigenous feminist literature.
Ready Or Not: On The Climate Vulnerability Of Sport Organizations
(2020-05) Orr, Madeleine
Since the 1970s, North America has experienced warmer and wetter winters, and more frequent extreme weather events such as hurricanes and heat waves. These climate shifts have carried consequences for the business and performance of sport at all levels, such as event cancellations, decreased participation rates, and facility damages. In the format of three articles, this dissertation examines sport organizations’ climate vulnerability. The first article (Chapter 2) reviews the extant literature on sport and the natural environment, advances two sport-specific constructs for climate vulnerability: climate impacts on organizations (CIO) and organizational climate capacity (OCC), and proposed a framework that graphically represents the various states of vulnerability an organization may face based on the organization’s exposure to hazards, sensitivity to hazards, and capacity to respond. The second article (Chapter 3) presents a qualitative study using 16 semi-structured interviews with sport practitioners whose organizations have recently faced climate hazards, to determine dimensions for OCC. Findings revealed the dimensions of OCC are infrastructural resources, natural resources, planning and development resources, human resources, financial resources, and network and relationship resources. These dimensions bear resemblance to the dimensions of organizational capacity and adaptive capacity, adopting five dimensions from organizational capacity and the natural environment focus of adaptive capacity. In the third article (Chapter 4), the construct of OCC is operationalized beyond a set of dimensions into a list of 77 indicators, organized by dimensions. This list of indicators was developed through an online Delphi study involving 25 academic experts in sport management, and represents an important step in rendering the construct more applicable and understandable for sport managers.
Applications Of Nanotechnology For Microbial Diagnostics To Combat Infectious Diseases
(2024-03) Novi Thekkudan, Vinni
Various pathogens cause disease outbreaks in plants, animals and humans that have led to fatalities and economic losses. To effectively prevent these outbreaks, disease surveillance and early diagnosis is crucial. While there are some standard detection methods used currently, they are expensive and suffer from long turnaround times that delay treatment and disease control actions. Since nucleic acid detection techniques are preferred as they offer target gene specific diagnosis, significant research has been directed to simplifying them for faster and more accurate identification. Several isothermal amplification methods have been explored for this purpose, among which loop mediated isothermal amplification (LAMP) offers a simple, cost-effective, and reliable approach for rapid onsite pathogen detection. This study discusses the design and optimization of a LAMP assay for the detection of the oak wilt fungus, Bretziella fagacearum, as the model organism. Oak wilt disease is a significant threat to oak (Quercus spp.) tree health in the United States and eastern Canada. Without management the disease may cause dramatic changes to natural and urban ecosystems. Early and accurate diagnosis is necessary for timely treatment. The LAMP assay developed for oak wilt takes 30 min to complete and shows 100% sensitivity and specificity. Recent studies have investigated colorimetric visualization of LAMP products for their adaptability to onsite microbial detection, but they suffer from reproducibility and varied perceptions of color change. Therefore, this study also discusses the development of a novel LAMP visualization method by exploiting the optical properties of gold nanoparticles (AuNPs) to overcome those challenges. Oligonucleotide-coated AuNPs (AuNP-oligos) hierarchically assemble on DNA networks in positive samples to form globular nanostructures, that settle into a visible red pellet upon inducing precipitation whereas, the negative samples do not show this. This LAMP assay coupled with AuNP-oligos visualization is a promising method for accurate and rapid molecular-based diagnosis in field settings.Additionally, other applications of nanomaterials in combating infectious diseases are also discussed. This includes the study of zinc oxide nanoparticle coated textiles for their antimicrobial activity against human bacterial and fungal pathogens, Pseudomonas aeruginosa, methicillin resistant Staphylococcus aureus, Klebsiella pneumoniae and Candida albicans.