Exploring Mechanisms by Which CodY Regulate the Activity of the Sae Two-Component System to Control Virulence in Staphylococcus aureus

Ph.D.Staphylococcus aureus is a ubiquitous Gram-positive bacterium that colonizes up to 30% of the human population. As an opportunistic human pathogen, the bacterium is a leading cause of skin and soft tissue infections, endocarditis, and bacteremia. Drug resistance compounds the problem, and the lack of an efficacious vaccine emphasizes the need for new therapies to combat staphylococcal infections. One exciting approach is to target the regulation of virulence genes. Virulence genes are often regulated by multiple factors that respond to different environmental cues. Some of the factors act directly on virulence genes; others control virulence indirectly by controlling the expression or activity of other regulators. My dissertation research focuses on CodY, an amino acid- and GTP-responsive global transcriptional regulator of many metabolic pathways, and the mechanism by which it funnels nutrient depletion signals through a major regulator of virulence-the SaeR/S two-component system. Previous work by others and I in the Brinsmade lab and elsewhere showed that overexpressing the sensor kinase gene saeS and the response regulator gene saeR does not increase the expression of the Sae regulon genes. To explain this surprising result, my thesis provides experimental support for the hypothesis that CodY controls the cellular fraction of activated SaeR (SaeR~P) to adjust the expression of virulence factor genes. In Chapter II, I show that transcriptional regulation of the sae locus is dispensable for CodY-dependent upregulation of the Sae regulon. Moreover, CodY-deficient S. aureus strains have higher SaeS kinase activity, correlating with increased membrane branch- chain fatty acids derived from isoleucine. In chapter III, I show that CodY regulates SaeS kinase activity during periods of nutrient sufficiency by repressing the genes that code for enzymes and proteins that catalyze branched-chain fatty acid synthesis. Additional work herein focuses on the molecular mechanism by which the branched-chain fatty acids alter the SaeS signaling complex. My work contributes to the elucidation of a novel method of post-transcriptional virulence regulation by branched-chain fatty acids. Understanding the molecular basis of this regulation is an important first step in characterizing potentially new anti-virulence targets with therapeutic potential

Racial and Ethnic Disparities in Vaccination Coverage across Thirteen States: A County-Level Analysis

M.S.Despite significant strides in vaccine development and dissemination during the COVID-19 pandemic, limited and patchy vaccine uptake highlights a critical public health challenge for future pandemics. However, the inadequacy of detailed data has hampered our ability to understand the ethnic and racial disparities in COVID-19 vaccinations Previous research has primarily focused on national or state-level disparities, highlighting the need for county-level analyses. This study aims to bridge this gap by analyzing disparities at the county level, providing a more accurate assessment of COVID-19 vaccination inequities. Specifically, we investigate the geographic distribution of COVID-19 vaccination disparities for Black and Hispanic populations, whether there are disparities between urban and rural counties, and whether significant differences exist in racial/ethnic disparity in vaccination rates when analyzed at the county level compared to state and national rates. Data was collected from 13 state health departments between June 22, 2021, and July 22, 2021, and included COVID vaccination counts disaggregated by county and race/ethnicity group. The findings reveal significant spatial heterogeneity in both Black and Hispanic vaccination disparity. Urban areas exhibited higher levels of Black disparity. Rural areas exhibited higher levels of Hispanic disparity. It was also determined that state-level analyses significantly obscure true disparities, highlighting the importance of county-level data. The findings from this study underscore the importance of targeted interventions tailored to specific geographic contexts and emphasize the imperative forpolicymakers and public health officials to prioritize the collection and utilization of granular county-level data to effectively address racial and ethnic disparities in vaccination efforts, thereby fostering more equitable health outcomes for all communities

Semi-Annual Report to Congress, April 1, 2023 – September 30, 2023

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Budgeting the Blaze: An Analysis of the Relationship Between Prescribed Burns and Wildfire Suppression Costs

M.P.P.Federal wildland firefighting agencies spend billions each year to contain and manage wildfires. These costs have grown exponentially as wildfire seasons have grown more severe. Unfortunately, climate scientists anticipate that the frequency and scope of these disasters will continue to grow over the next several decades as temperatures increase. It is crucial to understand how fuel reduction strategies can mitigate these effects. This thesis paper draws upon wildfire incident data from the National Geographic Area Coordination Center (GACCC) and prescribed fire data from the US Forest Service to examine the impact of prescribed burns in previous years on reducing wildfire suppression costs. This relationship analysis occurs on a county-level basis across the continental United States. Additionally, the wildfire data covers the years 2020 through 2023, and the prescribed fire data covers the years 2015 through 2023. This leaves 2,243 observations of counties that experienced wildfires and 3779 county observations that were treated with a prescribed burn. By evaluating the economic effects of prescribed burns by year on future wildfire suppression costs, this paper seeks to add to the existing literature on mitigation and serve as a reference for better financial management of the growing wildfire crisis

Environmental Woes and Their Economic Echoes

Ph.D.This dissertation is a compilation of three essays on the economic consequences of environmental shocks.In the first chapter, No Point Crying over Spilled Oil: Impact of Crude Oil Spills on Out-Migration in Nigeria, I study adaptation measures adopted by households in the face of land pollution shocks, namely crude oil spills. I use a staggered difference-in-differences framework to find that exposure to crude oil spills increases the likelihood of out-migration. A sub-group analysis helps me investigate the causal mechanism driving my results. I find that oil spills are linked to migration only for those who resided in households that practiced agriculture at baseline. They report fewer hours worked in cultivation and weak evidence suggests that rural household members migrate to urban areas as a consequence of oil spill exposures, indicating a substitution away from their farms. Reported short-term migration responses to oil spill exposure are often marriage-related, while longer-term migrations are reportedly driven by work and education pursuits, predominantly among female members. Thus, persistent exposure to land pollution shocks can prompt agriculture-dependent households to resort to out-migration as a coping strategy.The second chapter, High Temperature and Learning Outcomes: Evidence from Ethiopia, ---co-authored with Kibrom Tafere and A. Patrick Behrer--- investigates the impact of high temperatures on the test scores of students in high-stakes examinations in Ethiopia. We rely on quasi-random variation in daily temperature during the year preceding an exam for identification. Our results indicate that an additional day with maximum temperature exceeding 33°C leads to a significant decrease in students' total test scores by 0.009 standard deviations. We also find meaningful heterogeneity in effects based on the gender of students. Specifically, female students' exam scores appear to be less influenced by high temperatures, implying that climate change has differential impacts by gender. Additionally, we find that students from schools located in hotter regions can better cope with higher temperatures as compared to their counterparts from cooler regions. We posit this as suggestive evidence of heat acclimatization since Ethiopian schools have negligible adoption of cooling technologies.In the third chapter, Agriculture Production Potential of Groundwater Irrigation in Sub-Saharan Africa, ---co-authored with Ifeanyi N. Edochie, Aparajita Goyal, and Andrew Dabalen--- we investigate the potential of the vast under-utilized groundwater reserves available in Sub-Saharan African countries to increase agricultural production and resilience. By combining a novel groundwater aquifer database with geo-spatial agriculture productivity data, we simulate the gains from expanding groundwater access-- ensuring access is kept within sustainable limits-- on agriculture productivity and production and find substantial gains. This analysis is particularly relevant against the backdrop of climate change and the impending disruption to rain-fed agriculture

Youth Mainstreaming in Small Arms and Light Weapons Control

This essay examines the critical issue of youth exclusion and its impact on global peace and security, focusing on the inordinate effects of armed violence on youth and the challenges hindering their integration into decision-making spheres. Despite being disproportionately affected by armed violence, youth find themselves marginalized in discussions that directly impact their lives and futures. Through an exploration of grassroots initiatives and governmental actions, the essay highlights the importance of youth mainstreaming in small arms control efforts. It proposes recommendations for research, funding, and inclusion measures to ensure meaningful youth participation in policymaking and implementation processes. Hence, the essay underscores the necessity of incorporating youth perspectives and leadership in small arms and light weapons control initiatives to foster sustainable peace and security worldwide