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Materials-based immune modulation to promote tissue repair and regeneration
No full textThe immune system plays a critical role in returning the body to homeostasis following tissue damage, quiescing inflammation and promoting healthy remodeling following injury. In cases of unresolved inflammation, the immune system may also exacerbate the issue and lead to chronic inflammation or adverse remodeling, leading to cycles of host tissue damage without resolution. This poses major societal, economic, and public health burdens as the incidence rates of such diseases continue to increase around the world. In this work, we explore materials-based strategies to tune the response of the immune system in order to promote inflammation resolution and reparative phenotypes. The immune system is composed of two major arms – the innate immune system which responds rapidly and serves as the first line of defense, and the adaptive immune system that ensures longer term protection against pathogens. We first explore recent biomaterials-based approaches that have leveraged both innate and adaptive immunity to drive tissue engineering and characterize four overarching mechanisms of action used in current materials systems. Next, we assess the immunomodulatory ability of bare hyaluronic acid microrods in the context of cardiac repair, exploring the ways in which macrophages interact with these microrods following myocardial infarction. We found that hyaluronic acid microrods, but not an equivalent dose of soluble hyaluronic acid, was able to promote the production of repair and remodeling proteins critical to improving cardiac function and minimize risk of heart failure. This mechanism of action was revealed to be driven through the CD44 receptor, suggesting potential routes to further modulate macrophages. Finally, we explored the tunability of conjugating antibody-based biologics to a material platform and assessed their ability to drive differential T cell phenotypes. We thoroughly characterized the conjugation reaction between antibodies and our polycaprolactone nanowire system and identified ways to tune conjugation efficiency and loading density of the antibody. When conjugated with an antibody/cytokine fusion protein designed to promote a regulatory T cell phenotype, these nanowire constructs successfully expanded and maintained T cells. By tuning the density of antibody presentation, we saw shifts towards a stronger effector phenotype at higher doses and densities, suggesting the potential for these systems to operate as local immunomodulatory depots. Collectively, these approaches highlight ways in which biomaterials-based therapeutics can tune the immune system to promote reparative phenotypes and help improve our understanding of biomaterials-immune cell interactions to better design the next generation of therapies.
Diabetes, Familial Bonds, and Emotional Experience: A Qualitative Study on Latinx Mothers with Type 2 Diabetes and the Mother-Child Relationship
Get PDFMy dissertation, entitled Diabetes, Familial Bonds, and Emotional Experience: A Qualitative Study on Latinx Mother-Adult Child Relationships, aims to understand the emotional journey of families living with Type 2 diabetes (T2D). This is an important topic because diabetes is a common chronic condition in the United States, including in the Latinx community. Over 30 million children and adults in the U.S. have been diagnosed with T2D; Latinx women represent 11.7% of those diagnosed. Diabetes is the seventh leading cause of death (101,209 per year) with healthcare to treat patients with diabetes currently at $412.9 billion per year (National Diabetes Statistics Report, 2024). Fortunately, this disease can be managed with healthy eating habits, daily exercise, and medicine, but not everyone is in an advantaged position to take these steps, with Black, Latinx, and lower-income groups facing structural barriers to effective diabetes management. When adults living with diabetes cannot practice the self-care needed to manage their disease, it can lead to long term complications such as eye blindness, kidney and liver failure, limb amputations, nerve damage, heart disease, and even death. Reflecting broader studies on health inequities, Latinx mothers living with T2D face challenges to diabetes management based on legal status, language barriers, lack of health insurance coverage, and lower paying jobs. As well, T2D brings with it significant social stigma, where those with the condition may be viewed by providers and even family members as committing personal and moral failures for not adhering to provider-recommended practices, particularly in minoritized and lower-income communities. Latinx mothers with T2D may also be expected to prioritize caregiving for others, even adult children, over their own self-care, making the structural and cultural barriers to diabetes management even more complex. But less is known about the experiences of Latinx mothers coping with T2D and how they navigate both their health condition and their relationships with their adult children. Therefore, in my dissertation project I look at the bi-directional relationship between mothers and their adult children as they navigate living with T2D. Applying at sociology of emotions framework, I examine the nature of their emotive experiences (their feelings over time, and the work they do to manage these emotions) and how these experiences may, in turn, affect diabetes management. More specifically, I ask: 1) What are the emotive experiences of Latinx mothers living with diabetes? 2) How do emotive experiences influence the way Latinx mothers living with diabetes manage their chronic illness?
3) What are the emotive experiences of their adult children as they witness their mother navigate diabetes?
4) How do these emotive experiences affect both Latinx mothers and their children? Using multiple in-depth interviews with 11 dyads of Latinx mothers between the ages of 51-83 with T2D and their adult children between the ages of 18-63 (n=22) in northern and southern California. I employ an interpretive an interpretive phenomenological (IP) methodology to answer these questions. Overall, I find that Latinx mothers with T2D face a triple burden when managing diabetes; they not only have to manage structural barriers and manage the social stigma of T2D, but they also feel they must hide their negative experiences to prioritize others and fulfill their social role as caregivers. Latinx mother see strong emotions as leading to diabetes diagnosis, as well as shaping their experiences after diagnosis and their ability to manage their condition. But they cannot fully manage their diabetes due to prioritizing childrearing and household tasks, often not sharing symptoms or when they feel ill so as not to worry their children. Additionally, food is laden with complex double meaning for both mothers and their children, as both a symbol of care (positive) as well as a moral failure (negative). For their part, adult children react when they view their mother not taking diabetes management “seriously,” try to step into the role of monitor and/or caregiver and often fear that they too will be diagnosed with diabetes in the future—witnessing and participating in the chronic illness journey. Overall, the project illuminates Latinx families’ emotive experience of diabetes and the additional relational barriers they face to diabetes management, with important implications for policymakers and providers seeking to mitigate health inequities in Latinx communities and lessen the barriers Latinx communities face in preventative care and diabetes management
Characterization of the alternative splicing landscape of the developing human cortex, its regulation, and tools to survey both, at single-cell resolution
No full textThe human brain utilizes alternative splicing to a degree greater than any other organ or tissue in all higher eukaryotes. Due to technological limitations, the full extent of this heterogeneity, its regulation, and the developmental transitions by which it’s established remain unmeasured. With this goal in mind, we developed a novel, high-throughput, single cell linked-read transcriptomic assay, capable of profiling alternative splicing across full-length RNA molecules. We utilized this method to profile alternative splicing in approximately 75,000 single cells across four gestational week ages from the developing human cortex, revealing the breadth of cell type specific splicing during corticogenesis. In order to define the regulatory syntax governing these differences, we trained deep learning models on our splicing data to comprehend the underlying RNA sequences as enhancing or suppressing and link these effects to known RNA binding proteins affinity motifs, revealing both established and novel regulatory patterns. Our results demonstrate the utility of our method for cell type resolved alternative splicing analysis and provide a blueprint for continued fine-grained profiling of alternative splicing across the human brain
Ovarian Aging at the Crossroads of Ovulation, Stress, and the Systemic Environment
No full textWhile the inverse relationship between maternal age and fertility is well established, developing therapies to slow the decline in ovarian function with age requires a deeper understanding of the molecular mechanisms driving ovarian aging. Ovarian aging is a dynamic, multifaceted process influenced by both intrinsic and extrinsic factors. In this body of work, we develop and apply novel whole-mount immunofluorescence staining and clearing techniques to enable high-resolution phenotyping of the ovary across the reproductive lifespan. Using follicle quantification, in vitro fertilization, and a dual-platform single-cell transcriptomics approach, we characterize the age-associated depletion of oocyte quantity and deterioration of oocyte quality in the C57BL/6 mouse ovary and compare these trajectories to human ovarian aging. Building on this foundation, we go on to demonstrate that reproductive history significantly shapes the rate of ovarian aging, implicating the cyclic nature of the ovary as an accelerant of ovarian functional decline. Extending beyond ovary-intrinsic mechanisms, we show using heterochronic parabiosis that the aging ovary remains selectively responsive to systemic pro-youth factors but is uniquely resistant to pro-aging signals. Finally, we investigate the impact of physiological stress, characterizing sexually dimorphic responses to glucocorticoid receptor signaling in the germline and identifying a role for Corticotropin-Releasing Factor Receptor 2 dysregulation in driving ovarian decline. Together, these studies illuminate conserved vulnerabilities in ovarian aging and identify potential strategies to preserve reproductive health across the lifespan
High-Resolution Multicolor Shortwave Infrared Dynamic In Vivo Imaging with Chromenylium Nonamethine Dyes.
Get PDFImaging in the shortwave infrared (SWIR) region offers fast, high-resolution visualization of in vivo targets in a multiplexed manner. These methods require bright, bathochromically shifted fluorescent dyes with sufficient emission at SWIR wavelengths-ideally above 1500 nm for high-resolution deep tissue imaging. Polymethine dyes are a privileged class of contrast agents due to their excellent absorption and high degree of modularity. In this work, we push flavylium and chromenylium dyes further into the SWIR region through polymethine chain extension. This panel of nonamethine dyes boasts absorbances as red as 1149 nm and tail emission beyond 1500 nm. These dyes are the brightest organic fluorophores at their respective bandgaps to date, with εmax ∼ 105 M-1 cm-1 and ΦF up to 0.5%. Using two nonamethine dyes, Chrom9 and JuloFlav9, we performed two-color all-SWIR multiplexed imaging (Excitation at 1060 and 1150 nm; Emission collection at >1500 nm), enhancing the depths and resolutions able to be obtained in multicolor SWIR imaging with small molecule contrast agents. Finally, we combine the nonamenthine dyes with other SWIR-emissive fluorophores and demonstrate five-color awake imaging in an unrestrained mouse, simultaneously pushing the multiplexing, resolution, and speed limits of in vivo optical imaging
The Global Arms Supply Constraint and Its Implications for Modern Conflicts
Get PDFModern International Relations theories of conflict largely relies on rationality-based arguments to explain the variance in interstate armed conflict. In this paper, I introduce a stricter logic, that of a global arms production constraint, to explain why conflicts between states of disparate military strengths are more likely to engage in militarized conflict in the post-World War II era. I argue that due to the increased complexity and specialization of arms production, the manufacture and supply of modern arms globally is highly concentrated and constrained. My results show that in the post-WWII period, states of disparate military strengths are 58.4\% more likely to engage in militarized conflict. This paper makes a methodological contribution by introducing a new measurement of military strength using a two-step Principal Component Analysis – Manhattan Distance (PCA-MD) technique and k-Means Clustering on comprehensive arsenal data from 1970 – 2014 to better reflect the effectiveness of combined arms capabilities in modern warfare
Forecasting Bitcoin Volatility: A Comparative Analysis of Statistical and Deep Learning Models
Get PDFThis study investigates the effectiveness of traditional econometric models and deep learning architectures in forecasting Bitcoin’s 7-day realized volatility over the period from 2021 to 2025. Four models, GARCH, ARIMA, LSTM, and CNN-LSTM, are evaluated using a combination of error-based metrics, information criteria, statistical tests, and visual diagnostics. The analysis highlights key trade-offs between model interpretability, complexity, and adaptability to market conditions. Rather than identifying a universally superior approach, the study emphasizes that model selection should be guided by the specific forecasting objectives, data characteristics, and application context
Estimating COVID-19 Deaths in Los Angeles Communities through a Hawkes Process Model
Get PDFThe COVID-19 pandemic presents a unique challenge in the field of epidemiology, due to the numerous transmission patterns of different variants, the diversity of virus symptoms, and reporting inconsistencies. Traditional models that assume a constant, homogeneous rate of transmission between the infected and non-infected are no longer accurate when predictingCOVID-19. In particular, for a region as densely populated and diverse as Los Angeles, the unique geographical and social characteristics of each region should be considered when analyzing the transmission patterns. This paper focuses on analyzing COVID-19 death counts in various Los Angeles communities using a Hawkes process model, which has the
ability to handle spatial-temporal data on events that occur at non-constant rates. Within the Hawkes model, there are various approaches to estimating the parameters, each of which satisfy different objectives. The paper explores three methods of parameter estimation in seven different communities, along with the effects of factors like time and age
Mechanism of enhancing chemotherapy efficacy in pancreatic ductal adenocarcinoma with paricalcitol and hydroxychloroquine
Get PDFPancreatic ductal adenocarcinoma (PDAC) has a minimal (<15%) 5-year existence, in part due to resistance to chemoradiotherapy. Previous research reveals the impact of paricalcitol (P) and hydroxychloroquine (H) on altering the lysosomal fusion, decreasing stromal burden, and triggering PDAC to chemotherapies. This investigation aims to elucidate the molecular properties of the H and P combination and their potential in sensitizing PDAC to gemcitabine (G). PH potentiates the effects of G in in vitro, orthotopic mouse models, and a patient-derived xenograft model of PDAC. Proteomic and single-cell RNA sequencing (RNA-seq) analyses reveal that GPH treatment upregulates autophagy and endoplasmic reticulum (ER) stress-related transcripts. GPH treatment decreases the number of Ki67, fibroblast-associated protein (FAP), and alpha-smooth muscle actin (SMA)-expressing fibroblasts with a decrease in autophagy-related transcripts. The GPH treatment increases M1 polarization and CD4+ and CD8+ T cells and reduces CD4+ and CD8+ regulatory T cells (Tregs). These effects of GPH were confirmed in paired biopsies obtained from patients treated in a clinical trial (NCT04524702)
One-Way Shear Strength of Large Beams and Foundation ElementsContaining High-Strength Longitudinal Reinforcement
Get PDFMat foundations for high-rise buildings have traditionally been constructed as relatively thick members without shear reinforcement and with relatively low longitudinal reinforcement ratio. Laboratory tests demonstrate that unit shear strength decreases with increasing depth and with decreasing longitudinal reinforcement. These effects are represented in the one-way shear strength design equations of ACI 318-19, which results in significantly reduced nominal strength compared with design strengths that were successfully used for foundation mats for decades. The introduction of high-strength longitudinal reinforcement raises further questions about the effects of increased longitudinal reinforcement strains on one-way shear strength. To explore the effects of depth, reinforcement ratio, and high-strength reinforcement on one-way shear strength, a series of seven one-way shear laboratory tests were conducted. The tests were supplemented by nonlinear finite element studies to extrapolate the test results to alternate member geometries and boundary conditions. Design recommendations are proposed based on the findings of the experimental and analytical studies