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DIVERGENT MECHANISMS UNDERLYING CELLULAR REGENERATION IN THE ZEBRAFISH RETINA
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Retinal neurodegenerative diseases lead to loss of vision in humans, with no cures in place to replace vision once it is lost. These diseases involve the loss of individual neural cell types, such as retinal ganglion cells (RGCs) in glaucoma. One transformative therapeutic approach being explored is to stimulate retinal Müller glia (MG) to act as stem cells that regenerate the lost neurons, a phenomenon that occurs naturally in zebrafish. Studies in zebrafish have proven useful to understand how MG achieve functional regeneration, but this has only been thoroughly characterized at the molecular level following widespread injury, in which all retinal neuron cell types much be regenerated. Thus, there is a knowledge gap in the field regarding MG regeneration following localized, cell-specific injuries.
Methods: To enhance knowledge of retinal regeneration in zebrafish, I employed the transgenic Nitroreductase (NTR) system of cell targeting to study “fate-biased” MG responses to cell-specific damage of RGCs, rods, and bipolar interneurons. I then employed a combination of genetic tools (multiple types of RNA sequencing, CRISPR/Cas9 mutagenesis), drug treatments, imaging and computational analyses to study how retinal regeneration is regulated in different models.
Results: I’ve identified and validated numerous transcriptomic regulators of regeneration across models and importantly shown that these processes are exquisitely specific to the injury sustained (i.e. what cell type(s) were damaged). Furthermore, comparative CRISPR/Cas9 mediated knockout (KO) experiments have shown unique effects on regeneration dependent on the cell type being regenerated. Of high interest to the field, KO of ascl1a, a highly studied gene required for tissue regeneration and being overexpressed in attempts to stimulate mammalian regeneration, surprisingly led to enhanced RGC regeneration by biasing the fates of MG-derived progenitor cells (MGPCs) toward RGCs.
Conclusions: It is abundantly clear that damage to different cell types, or to different scales (e.g. widespread vs. cellular damage) induces unique transcriptional responses underlying MG stem cell activation and subsequent MGPC behavior. This contrasts with a popular dogma in the field that “regeneration recapitulates development” and suggests cell-specific regeneration paradigms will help to advance strategies for regenerating disease-relevant cell types selectively
BEYOND THE CHECK: A MULTI METHODS STUDY OF CAREGIVER EXPERIENCES AND UNDERSTANDING OF THE EXPANDED CHILD TAX CREDIT
No full textThe COVID-19 pandemic revealed how close many U.S. households were to experiencing poverty. The federal government’s response included efforts to address poverty and alleviate its consequences like the expanded child tax credit (ECTC), which provided families with children cash assistance in 2021. Although research has evaluated the ECTC’s effects, more work is needed to examine how people experienced its implementation, as well as how alternative distributional structures of cash transfers during the pandemic impacted health.
This dissertation used multiple and mixed methods to examine the ECTC across multiple dimensions. The first and second studies leveraged the COVID-19 Family Study, a longitudinal study of families living in Maryland during the pandemic. Semi-structured interviews and thematic content analysis were used to describe caregivers’ experiences of the expansion. The first study found that the ECTC benefited caregivers and their families, across income levels. However, confusion regarding its financial implications contributed to financial anxiety and strain. As part of an explanatory sequential study of how caregivers used the ECTC and what factors shaped their use of the funds, the second study found that caregivers, across income levels, prioritized daily living expenses. However, lower-income caregivers experienced greater financial strain and were especially reliant on the ECTC to make ends meet. Decisions about how to use the funds were also highly contextual, reflecting diverse financial contexts, preferences, and knowledge.
The third study used the Household Pulse Survey to compare household food insufficiency among low-income households with and without children after the distribution of the third stimulus check and the ECTC. Notably, the analysis revealed that much of the third stimulus check’s benefits dissipated quickly after the checks were issued by the end of April 2021, while the benefits of the monthly expanded child tax credit payments persisted from July into December 2021.
Federal cash transfers improve well-being across diverse financial contexts, but poor understanding can limit their benefits, particularly if they are administered through the tax system. Smaller, monthly cash payments protected better against food insufficiency than larger one-time payments. Policymakers should consider continuing and expanding these models to other public assistance programs
Genetic Susceptibility to Enteric Infections and Diarrhea in Bangladeshi Infants
No full textEach year approximately 5 million children under the age of five die, many from preventable conditions including diarrhea. In addition to mortality, repeated infections in early childhood have lasting effects including reduced oral vaccine efficacy, linear growth faltering, and cognitive deficits. Risk factors for infection include limited access to clean water, poor sanitation, and overcrowding. Environmental risk factors do not explain observed heterogeneity in response to pathogens and we hypothesized that host genetics play a role in susceptibility to infection. We assessed this using data from 3 independent birth cohorts in Dhaka, Bangladesh: the Dhaka Birth Cohort, the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries study, and the Cryptosporidiosis Birth Cohort. First, we performed a genome-wide association study for Campylobacter-positive diarrheal episodes in the first year of life, using a nested case-control study design. We identified a protective locus on chromosome 8 (rs13281104, G allele OR = 0.41). Next, we investigated extreme diarrhea, comparing those with no diarrhea to those with an abundance, measured by frequency (6+ episodes) or duration (25+ days), all within the first year of life. For frequency, we identified two genome-wide significant loci associated with no diarrhea: rs2827548 on chromosome 21 (C allele OR = 0.31) and rs1915541 on chromosome 8 (T allele OR = 0.35). For duration we observed the same association with rs2827548, and an additional protective locus on chromosome 17 (rs5026214, C allele OR = 0.35). Finally, we leveraged the vast amount of genetic data on inflammatory bowel disease to learn more about the genetic underpinnings of diarrhea, identifying loci that were associated with both IBD and one or both of the extreme diarrhea phenotypes. We established an overall relationship using a genome-wide polygenic score, then found specific regions of shared genetics using both variant-level and gene-based approaches. Identifying genetic variants that are protective against enteric infection and diarrhea may provide insight into biological mechanisms and provide novel targets for therapeutics. Furthermore, understanding the shared etiology underlying both extreme diarrhea in the first year of life and inflammatory bowel disease may lead to better diagnostics and targeted approaches for treatment
GREENHOUSE GAS AND AIR POLLUTION EMISSIONS FROM FOSSIL FUEL EXTRACTION IN THE US AND CHINA
No full textMethane and other non-methane alkanes are important fugitive gas emissions from the energy sector. A large fraction of global methane emissions come from coal mining, oil activities, and natural gas. Another example is ethane, 80% to 90% of which is believed to come from oil and gas (O&G) reservoirs. In this thesis, I investigate emissions of light alkanes from the energy sector in both China and the U.S. using geostatistical inverse modeling (GIM) and global atmospheric chemistry models, such as GEOS-Chem.
Following a brief introduction in Ch. 1, I estimate the benefits of recovering coal methane as an alternative and cleaner fossil fuel energy source in China (Ch. 2). I find that China’s 2020 goals for coal methane recovery would decrease the country’s total carbon emissions by 2.3% in 2020, and these reductions are dominated by mitigated direct methane emissions and therefore confer a much larger climate benefit than conventional natural gas (Zhang et al., 2020a).
In Ch. 3, I present emissions estimates of ethane from the US for years 2015 - 2020. I do so by combining inverse modeling with observation data collected by NOAA and partner organizations. I find that U.S. ethane emissions are approximately three times those estimated by EPA’s 2017 NEI platform, and I observe a discrepancy between ethane emission trends and O&G gas activities, including ethane production.
Ch. 4 is a departure from the first three chapters and focuses on global carbon fluxes from the biosphere. In this chapter, I use inverse modeling to test the power of solar-induced fluorescence (SIF) to predict net biosphere exchange. SIF is radiation that is emitted by chloroplasts during photosyn- thesis, and it is now observed from space by several different satellites. SIF may therefore serve as an effective proxy of photosynthesis and net biosphere exchange at regional to global spatial scales. The results of this study highlight the enormous potential of SIF as a predictor of net biosphere exchange.
The dissertation closes with a discussion and conclusions chapter (Ch. 5). In this chapter, I discuss the broader policy implications of the work described in this thesis and identify several areas for future research
UTILITY-SCALE SOLAR ENERGY DEVELOPMENT ALONG THE COLORADO POWER PATHWAY: LAND-USE CODE ASSESSMENT
Get PDFUtility-scale solar energy system siting considers natural resources, interconnection feasibility, and regulatory implications, including land-use code and permitting requirements. County-level land-use codes can impact the time efficiency of the early project development process and cost throughout the lifespan of a project. This capstone project aims to assess landuse code throughout counties along the Colorado Power Pathway, a new transmission system being built in Eastern Colorado, to determine if the land-use code could have a supportive, neutral, or inhibitive impact on future utility-scale solar development. It also explores the potential relationship between land-use code and operating and planned solar capacity in the twelve impacted counties. The Energy Information Administration's Form EIA-860 was extrapolated and combined with information from Xcel's Clean Energy Plan to determine planned and operating utility-scale capacity. A literature review was conducted to develop the Land-Use Code Evaluation Tool (LUCET), and data collection was performed on the twelve counties. Comparative analysis was conducted to determine if the information outlined in the LUCET was supportive, neutral, or inhibitive to future development. Then, an impact weight was applied to these characteristics based on cost. After totaling the outcome, four counties were deemed to have supportive code, seven counties were deemed to have neutral code, and one county deemed to have inhibitive code. A possible relationship exists between land-use code and installed and planned capacity, but this is not the only influencing factor
PASS_E2E_TEST_SUBMISSION_JOURNAL:Tue May 07 2024 20:19:34 GMT+0000 (Coordinated Universal Time)
No full textSPATIALLY-RESOLVED TRANSCRIPTOMICS OF THE HUMAN DENTATE GYRUS ACROSS LIFESPAN
Get PDFThe hippocampus (HPC) is important for many human cognitive functions, including regulation of learning, memory, navigation, and mood. However, molecular signatures of development, aging, and activity in the human HPC have yet to be fully characterized in the same molecular and spatial detail as other species. Here, we survey the transcriptomic landscape of the human dentate gyrus (DG) to characterize its postnatal development, aging, and activity dependent expression. We found enriched expression of extracellular matrix markers during infancy and increased expression of several inhibitory markers after infancy, continued spatial enrichment of immature granule cell (imGC) markers, and regions with accelerated age based changes marked by age dependent increases in glial associated neuroinflammation. Following up by integrating snRNA-seq and SRT datasets with non-negative matrix factorization and cross-species comparisons, we improved detection of conserved markers for imGCs, and also found conserved expression patterns of activity regulated genes (ARGs) which predict neurons recently responding to excitatory input. We then used a rodent model of electroconvulsive shock to further explore transcriptional isoforms of BDNF, one of the conserved ARGs. Our findings suggest protracted development of certain cell types after infancy, accelerated aging in glial enriched tissue compared to neuronal enriched tissue, and finally the importance of transcriptional isoforms for ARGs with respect to activity dependent synaptic plasticity
Sumerian and Akkadian in Old Babylonian Incantation Tablets
Get PDFIncantations are magical recitations intended to manipulate reality for the benefit of the reciter or their client. Throughout the history of ancient Iraq, otherwise known as Mesopotamia, these recitations were inscribed onto clay tablets and performed for a variety of cultic, medical, and private functions, such as consecrating ritual implements for the king, aiding in childbirth, or taking control over a lover. While Sumerian incantations are found from sites belonging to all periods of Mesopotamian history, from the earliest periods onwards, Akkadian incantations only began to appear in significant numbers during the first half of the second millennium; thus, the Old Babylonian period (ca. 2003 – 1595 BCE) marks a time when textual genres are multilingual and consist of contemporaneous texts written in two languages: Sumerian and Akkadian.
While there have been recent advances in the study of Old Babylonian incantations, research on these difficult texts remains divided by the researcher’s language specialization, either Akkadian or Sumerian, despite the multilingualism of the textual genre. This investigation takes a new approach and provides a comprehensive survey of virtually all published Sumerian and Akkadian incantation tablets dating to the Old Babylonian period. Through an in-depth analysis of all 777 of the incantation texts and 61 non-incantation texts inscribed upon the 322 incantation tablets included in the corpus for this project, this investigation attempts to clarify the relationship between language and function in the Sumerian and Akkadian incantations that date to the first half of the second millennium BCE, put a spotlight on the shifting linguistic landscape of southern Mesopotamia in the Old Babylonian period, and provide insight into magical practice and ritual in one of the earliest and most well-documented periods of recorded history
Mechanisms of Adverse Maternal and Fetal Outcomes From Viral Infections in Pregnant Mice
Get PDFViral infections during pregnancy are associated with significant adverse maternal and fetal outcomes. Pregnancy is a unique immunologic and physiologic state, which can influence control of virus replication, severity of disease, and vertical transmission. Animal models are instrumental to understanding the pathogenesis of viral infections during pregnancy and identification of targetable treatments to improve health outcomes of pregnant individuals and their offspring. The three aims of this dissertation each characterize a mouse model of viral infection during pregnancy with significant public health importance. First, using an immunocompetent mouse model of transplacental Zika virus (ZIKV) transmission and adverse pregnancy outcomes, we found that placental IL-1β was increased at 3 hours post ZIKV infection in the absence of NLRP3 inflammasome activation. ZIKV infection and placental IL-1β were associated with profound downregulation of host gene expression, indicating that ZIKV infection disrupts pathways associated with adverse fetal outcomes in the placenta. Second, we developed a novel mouse model of SARS-CoV-2 infection during pregnancy with gestational age–dependent adverse maternal and fetal outcomes including greater morbidity, reduced antiviral immunity, greater viral titers, and greater adverse fetal outcomes with infection at embryonic day (E) 16 than with infection at either E6 or E10. Further, we treated E16-infected dams with mouse-equivalent dosing of ritonavir-boosted nirmatrelvir and observed that treatment reduced pulmonary viral titers, decreased maternal morbidity, and prevented offspring growth restriction and neurodevelopmental impairments. Finally, using an outbred mouse model of influenza A virus (IAV) infection during pregnancy, we investigated the role of progesterone in mediating adverse maternal and fetal outcomes. IAV infection suppressed circulating and placental progesterone concentrations and caused placental cell death and inflammation. IAV-induced upregulation of pulmonary cyclooxygenase (COX)-1, but not COX-2-, dependent synthesis and secretion of prostaglandin F2α caused progesterone suppression. Treatment with 17-α-hydroxyprogesterone caproate (17-OHPC), a synthetic progestin that is safe to use in pregnancy, ameliorated the adverse fetal outcomes and prevented placental cell death and inflammation. Taken together, these data highlight the value of mouse models of viral infection during pregnancy, adding to the mechanistic understanding of pathogenesis and proving a system for testing novel therapeutic strategies during pregnancy
DEVELOPING A TASK MANAGEMENT TOOL FOR DEPARTMENTAL RESEARCH ADMINISTRATION
Get PDFResearch conducted at institutions of higher education is often led by faculty working in specific subject matter areas within a department. Consistent changes in research policy at the government and institutional levels necessitate partnerships with skilled administrators, who can support and advise these faculty as business partners in the research enterprise. The specialty area of departmental research administration has formed over time to address this need. Compared with other administrative roles, departmental administrators work most closely with researchers. They must leverage job knowledge specific to the subject matter in their department, on top of skills to navigate larger frameworks for research operations. Finding an effective way to
understand and manage workflow in this environment can be challenging.
The objective of this project is to create a task management tool to more effectively guide the workflow of one such departmental role at a specific institution. In conducting the project, the author relied on a variety of resources such as applicable literature, personal job knowledge, and feedback from other members of the research community. The tool scopes the departmental role into major task areas, condensing and illuminating information necessary for task efficiency, including key logistical information and informal job knowledge. The result of the project was the first version of a task management tool to support workflow and onboarding for this departmental role