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A model of Type Theory in Groupoid Assemblies
Get PDFWe consider the category \GrpA{A} of groupoids defined internally to the category of assemblies on a partial combinatory algebra . In this thesis we exhibit the structure of a -tribe on \GrpA{A} showing the category to be a model of type theory. We also show that \GrpA{A} has -types with reductions and univalent object classifier for assemblies and modest assemblies, where the latter is an impredicative object classifier. Using the -types with reductions, we show that \GrpA{A} has a model structure. Finally, we construct \pGrA{A}, the full subcategory of partitioned groupoid assemblies, and show that \pGrA{A} has finite bilimits and bicolimits as well as showing that the homotopy category of the full subcategory of the -types of \pGrA{A} is \RT{A}, the realizability topos of
Pleiotropic Functions of WIDE AWAKE in Circadian and Non-Circadian Regulation of Behavior
Get PDFConditioned fear learning is crucial for survival, as it enables animals to anticipate and react to potential threats based on past experiences. In this thesis, I investigate the role of mWAKE, previously studied as a clock-output molecule, in this process. First, I focus on mWAKE in the central amygdala (CeA) and characterize its expression and projections. These data revealed that mWAKE is expressed in multiple clusters of defined CeA neurons, including those that play key roles in fear learning and memory. Although conditioned fear learning has previously been described as a circadian-dependent process, I unexpectedly found that neither mWAKE, nor the core clock molecules PER2 or BMAL1, exhibit rhythmic expression in the CeA. Knockout of mWAKE in the CeA impairs fear learning and memory, indicating that mWAKE function is necessary for this process. Moreover, my data suggest that, while mWAKE is not under circadian control in the CeA, its expression is dependent on fear learning. Next, I examine the function of mWAKE in the suprachiasmatic nucleus (SCN) by conditionally knocking it out in this region. These data suggest that mWAKE is not required in the SCN for robust circadian rhythms. In collaboration with a labmate, I helped examine the function of the mWAKE in the lateral amygdala (LA). We found that mWAKE exhibits rhythmic expression in the LA and labels a local circadian oscillator in this brain region. These findings demonstrate that mWAKE plays a critical role in modulating emotion-dependent responses, in a circadian- or non-circadian manner. Overall, this study provides new insights into the functional significance of mWAKE in the amygdala and its broader implications for the temporal regulation of fear- and anxiety-related processes
Approximation Algorithms for New Problems in Network Design
Get PDFDue to the ubiquity of graphs and networks in real-world settings, an important and
thus well-studied class of problems in combinatorial optimization are network design
problems; these are problems that deal with the efficient design of networks. We
introduce new, well-motivated network design problems and develop approximation
algorithms for each.
Many of the most important network design problems ask for the preservation of graph connectivity, which is a measure of the fault-tolerance of a network. A weakness of these classical problems, though, is that we are not able to ask for any fault-tolerance that is larger than the connectivity. We introduce and study new variants of these problems under a notion of relative fault-tolerance. Informally, we require not that two nodes are connected if there are a bounded number of faults (as in the classical setting), but that two nodes are connected if there are a bounded number of faults and the two nodes are connected in the underlying graph post-faults. That is, the subgraph we build must “behave” identically to the underlying graph with respect to connectivity after bounded faults.
We also study hopsets, another network design object. Hopsets are edge sets that, when added to a particular graph, introduce low-hop paths that approximately preserve the distances of the original graph. For decades, hopsets have found a wide range of applications for distance-based problems in various computational models. More recently, there has been significant interest in understanding these fundamental objects from an existential and structural perspective. All of this work, however, takes a worst-case (or existential) point of view: How many edges do we need to add to satisfy a given hopbound and stretch requirement for any input graph? We initiate the study of the natural optimization variant of this problem: Given a specific graph instance, what is the minimum number of edges that satisfy the hopbound and stretch requirements
Molecular Determinants of Calcium-Induced Aggregation in Cryptococcus neoformans: A Biological and Theoretical Investigation
No full textCryptococcus neoformans is a pathogenic yeast causing upwards of 200,000 deaths each year globally, with most of them occurring in Sub-Saharan Africa. People most at risk for cryptococcosis are individuals with weakened immune systems, such as those living with HIV. A weakened immune system makes it difficult for the immune system to effectively clear infectious propagules of C. neoformans, resulting with the yeast causing disseminated cryptococcosis. It is critical for the immune system to be able to control cryptococcus. Understanding how the capsule of cryptococcus mediates interactions with host cells and adheres to surfaces is a critical link to understanding how persistent cryptococcal infections may be more effectively targeted.
In the presence of high extracellular CaCl2 and phosphate anions we observed a new aggregation phenomenon unlike any type of aggregation previously reported. Magnesium did not produce this aggregation. Analysis of capsule polysaccharide from cryptococcal cells showed that calcium and calcium phosphate altered the structural properties of the polymers, influencing biophysical properties like size and polydispersity, diffusion, and absorption of circularly polarized light. Additionally, it was discovered that calcium phosphate mediated cell aggregation influenced the interactions between macrophages and cryptococcus.
To understand the molecular nature of metal-mediated Cryptococcal aggregation, we modelled interactions between cryptococcal polysaccharides and metals. Nuclear magnetic resonance (NMR) Diffusion-Ordered Spectroscopy (DOSY) and Fourier Transform Infrared Spectroscopy (FTIR) experiments showed that D-Glucuronic acid (D-GlcA) is the interaction point of cryptococcal polysaccharide glucuronoxylomannan (GXM) with dication metals, indicating that calcium interactions are the strongest. Electronic structure theory calculations were used to model dication interactions with negatively charged D-GlcA. We explored the energetics of D-GlcA to form multidentate structures with dication metals of similar ionic radii. Our results suggest that the glucuronic acid-calcium bond is remarkably strong with energies that approach that of covalent bonds.
This study provides atomic and cellular level information on the mechanism involved in dication-mediated aggregation of C. neoformans cells. One prediction from this work is that given the essentiality of the D-GlcA for metal ion binding that this sugar is essential for capsule construction and that no encapsulated mutant lacking this residue in GXM can exist
Drug Resistance Mechanisms in the Pathogenic Yeast Candida glabrata
No full textCandida glabrata (also known as Nakaseomyces glabratus) is a pathogenic yeast that is rising in prevalence due to increasing numbers of immunocompromised patients and rapidly acquired resistance to antifungal drugs. Genetic screens for genes involved in drug resistance have been limited by incomplete genome coverage and low sensitivity to phenotypic differences. Recent advances in transposon insertion profiling followed by next-generation DNA sequencing (Tn-seq) have revolutionized genetic screens, especially in non-model organisms with limited genetic tools. This study builds on previous work aimed at identifying genetic responses to fluconazole treatment by expanding Tn-seq to other C. glabrata strains and antifungal drugs. In Chapter One of this dissertation, I review fungal pathogens and diseases, antifungal drugs and drug resistance mechanisms, and the utility of transposon mutagenesis in genetic screens that can shed light on C. glabrata drug resistance mechanisms.
In Chapter Two, I utilized Tn-seq to compare gene essentiality in two well-studied C. glabrata isolates to uncover differences in gene essentiality and chromatin architecture. I found that a derivative of the type strain CBS138 contains a tandem duplication on chromosome K that can be detected by an increased transposon density in the duplicated region. Analyzing the rest of the genome, I uncovered a defect in CBS138 subtelomere silencing as well as differences in chromatin accessibility between the strains. In addition, I treated pools of insertion mutants with the antifungal drug micafungin to reveal genes involved in drug resistance and sensitivity.
In Chapter Three, I used another well-studied C. glabrata strain (BG2) to elucidate genetic differences between strains during micafungin treatment. I then compared the genetic resistance profiles of BG2 to the other glucan synthase inhibitors caspofungin, anidulafungin, rezafungin, and ibrexafungerp. These screens revealed that there are key differences in drug resistance spectra including lipid biosynthesis genes and mitochondria. These discoveries highlight the utility of the Tn-seq method to explore genetic diversity and drug resistance and the portability to other strains and organisms.
In Chapter Four, I discuss the overall significance of this study and how the main conclusions presented herein contribute to our understanding of C. glabrata drug resistance. I reveal important and unexpected differences between common laboratory isolates and unique mechanisms underlying resistance to echinocandin-class drugs. I also offer interpretations of these findings and how they may lead to the development of new antifungal drugs, improve patient outcomes, and inform future studies
Stories of the St. Ursin: Unraveling the Last Slave Voyage to French Colonial Louisiana
No full textThis dissertation examines the last slave voyage brought from Africa to French-controlled Louisiana. Arriving in Louisiana in late August of 1743 twelve years after the arrival of the previous slave voyage to the colony, the ship the St. Ursin became the only slave ship brought to the colony for at least the next thirty years until the Spanish reopened the slave trade in the 1770s after assuming control of Louisiana in the Seven Years’ War. Approximately one hundred and ninety people from the Senegambian region of West Africa survived the journey incarcerated below the deck of the St. Ursin. When the Company of the Indies retroceded the Louisiana colony to France in 1731, the slave trade to Louisiana ceased. The slave ship the St. Ursin became the only slave voyage in the history of the French colony to be financed and organized by enslavers living in Louisiana rather than a monopoly company.
“Stories of the St. Ursin” untangles the 1743 slave voyage through a thematic rather than chronological focus. The picture that emerges is a transatlantic history shaped by local factors emerging across New Orleans, the lands stewarded by the Chickasaw nation in present-day Mississippi, Tennessee, Alabama, and Kentucky, Saint Malo and La Rochelle in France, Saint Louis, Gajaaga, Gambia, and Gorée in Senegambia and Cap Français in Saint Domingue. In the current historiography, historians credit an enslaver named Claude Joseph Dubreuil for financing and organizing the St. Ursin. By navigating the history of the St. Ursin thematically, this dissertation decenters Dubreuil to reveal a wider network of catalysts for the last slave voyage to French colonial Louisiana from catastrophic military losses to the Chickasaw nation to the white women enslavers who helped fund the voyage. Concurrently, the dissertation investigates how the archive shapes our knowledge of the St. Ursin and the people who experienced it
Oral history of Tanika Paxton, Leslie Sherrod, and Hamilton Johns
No full textIn this interview, Dr. Warren Hayman spoke with several members of the Dunbar Hopkins program, including Tanika Paxton, Leslie Sherrod, and Hamilton Johns. This focus group centered on individuals who ended up in health professions more broadly defined.
Tanika graduated from Dunbar in 1992 and worked as a paramedic firefighter for 25 years with the Baltimore County Fire Department. She retired and started her second career as a nurse in critical care at Sinai Hospital. She reflects that the Hopkins Dunbar program was a good starting point for her to mentally prepare for the educational expectations in high school and beyond. She speaks about the lasting bonds formed with other students in the program and reflects on how differently her life could have turned out considering growing up in Baltimore.
Leslie graduated from Dunbar in 1994, then went to the University of Maryland, College Park. She also attended the University of Maryland, Baltimore, earning her master's degree in social work. She currently works as a licensed clinical social worker and has her own private practice. She has worked in maternal and child health but now focuses on geriatrics. Leslie shares that she felt blessed and privileged to have been a part of the Hopkins Dunbar program. She speaks of three key factors – exposure to the medical/health fields, the resources provided, and the support of its teachers. She mentions Stacy Smith Cannon as a teacher who went above and beyond, in particular to help her get into UMD.
Hamilton graduated from Dunbar in 1996 and went on to Johns Hopkins University, majoring in public health studies. He then studied Health Policy and Management at the Johns Hopkins Bloomberg School of Public Health. Hamilton currently works for Medicare and Medicaid under the Department of Health and Human Services as an analyst. Hamilton reflects that the Hopkins Dunbar program gave him a good foundation for pursuing higher education. He also reflected that it exposed him to different careers in health, not just the role of a doctor or nurse.
All three interviewees shared that being on a college campus gave them a sense of independence and excellence, opened opportunities for summer jobs, volunteering, and traveling. They spoke about being exposed to the sciences in a broader sense and emphasized that seeing faces that looked like theirs in leadership roles contributed to their journey in understanding what was possible for themselves. Each reflected on their professional careers and offered advice for current Dunbar students. They reminded the students to seek mentors in different fields, to keep their options open, to be flexible, and to let their minds be spongelike. Lastly, the interviewees express gratitude for Dr. Hayman, indicating that their success was a direct result of the labor he put in the program
Fungal-Environmental and Host-Pathogen Interactions in Cryptococcus spp.
No full textCryptococcus is a fungal genus in which two species complexes, C. neoformans and C. gattii, cause pulmonary and neurologic infections in humans and animals. The majority of agents responsible for systemic mycoses are environmental saprophytes, with mammalian infection occurring following exposure to environmental sources, such as inhalation of spores or yeasts aerosolized from soil. These fungi thus spend most of their life cycle, and most of evolutionary time, coping with selective pressures exerted by chronic environmental stressors. There is mounting evidence that adaptation driven by environmental conditions, such as resistance to temperature, osmotic stress, and amoeba predation, fortuitously improve the competence of fungi as pathogens of mammalian cells in what has been termed “cross-adaptation.” Nonetheless, the fungi-environmental axis has yet to be comprehensively explored. This thesis explores mechanisms by which pathogenic species of Cryptococcus respond to environmental stressors, how these pathogen-environment interactions inform subsequent host-pathogen interactions, and the role of environmental conditions in mediating fungal transport and ecological niche expansion. Chapter I explores mechanisms that govern thermotolerance in Cryptococcus spp. and how deficits in thermotolerance pathways impact host-pathogen interactions, with a focus on fungi-initiated events that facilitate immune evasion. Chapter II investigates the effect incubation in saltwater, which is nutrient-poor and hyperosmolar, on cell and capsule dimensions, infectivity for mammalian cells, and biofilm formation. Chapter III studies factors contributing to buoyancy of cryptococcal cells in an aqueous environment and proposes a model by which cryptococci may utilize natural ecological phenomena to enhance transport between ecological niches
CHARACTERIZATION OF THE MURINE IMMUNE RESPONSE TO AAV-VECTORED HUMAN CHIMERIC ANTIBODIES
Get PDFCryptococcus neoformans is a pathogenic fungus that primarily infects immunocompromised individuals, such as organ transplant recipients and people living with untreated HIV. Mortality rates can be as high as 60%. There are no FDA-approved vaccines for C. neoformans and standard-of-care antifungals, such as Amphotericin B, have a high toxicity profile. Climate change is leading to an increased prevalence of fungal infections, creating an urgent need for novel therapeutics. Vectored Immunoprophylaxis (VIP) is a gene delivery mechanism that uses an adeno-associated virus (AAV) to insert genes encoding for an antibody protective against an infectious disease of interest into the host nucleus. These genes are then transcribed and translated by the host’s cellular machinery. To date, VIP has been demonstrated as safe and efficacious against HIV and malaria in immunocompetent animal models. The goal of the work presented in this thesis was to test the safety of AAV-vectored VIP in the A/J mouse strain, an immunocompromised animal model.
A/J mice were transduced into the intracranial thigh muscle with AAV genetically modified to express genes encoding for one of two antibodies with specificity to surface-associated epitopes on C. neoformans (2H1 and 18B7) or to a protective epitope on the malaria circumsporozoite antigen (2A10). Weekly blood draws were obtained and the degree to which the A/J mice reacted to the AAV exposure was measured by assessing the levels of cytokines produced, as well as by the magnitude of the anti-AAV antibody responses. Cytokine and antibody responses were measured using a highly sensitive multiplex electrochemiluminescence assay.
Results demonstrate that A/J mice did not produce an elevated cytokine profile in response to the VIP, nor was there statistically significant evidence of increased antibodies against the AAV capsid protein compared to controls. These results suggest that preclinical models using strains of mice with selective defects in immune regulation will be useful and that VIP is a potentially safe intervention in immunocompromised humans. However, due to a confounding pinworm outbreak in the animal facility, as well as low serum volumes, additional trials should be conducted to further validate the safety of the VIP intervention
Enhancing Model Based Value-Based Care for Surgical Treatment of Claudication
No full textPeripheral artery disease (PAD) affects over 8.5 million Americans and remains a major source of morbidity. Its prevalence continues to rise due to aging populations and increasing rates of diabetes and smoking. Claudication, the hallmark symptom of PAD, presents a key opportunity for intervention to improve mobility, quality of life, and long-term vascular outcomes.
Over the last decade, peripheral vascular interventions (PVIs) for claudication have grown markedly. However, this growth has come with increased practice variation, overuse of low-value interventions, and concerns about patient outcomes and healthcare costs. Studies have shown that early invasive treatment, unwarranted tibial procedures, and underuse of supervised exercise therapy contribute to inefficient and inequitable care. Meanwhile, value-based care models are gaining momentum, underscoring the need for better evidence to guide appropriate intervention use.
Modeling is a cornerstone of biomedical informatics and supports evidence-based decisions by simulating clinical pathways, estimating treatment outcomes, and informing guidelines. In vascular care, models can integrate patient characteristics, treatment strategies, and outcomes data to optimize care and evaluate the value of interventions.
This dissertation leverages national administrative claims data and advanced decision modeling to enhance value-based surgical care for claudication. The work is organized into three aims:
Aim 1 characterizes trends, regional variation, and system-level factors associated with PVI use from 2011 to 2022. Sub-analyses explore how market dynamics influence early and tibial interventions, and the persistent underuse of supervised exercise therapy.
Aim 2 evaluates the clinical and economic outcomes of early PVI versus initial non-invasive management using decision analysis applied to real-world data.
Aim 3 extends the analysis internationally, comparing PVI trends across countries to identify policy implications and structural differences in care delivery.
A concluding discussion highlights the broader role of informatics in transforming surgical care through decision modeling and systems thinking. Together, these studies provide a comprehensive, data-driven assessment of current practices and offer pathways to more effective, patient-centered, and cost-efficient vascular care