Doctor of Philosophy

dissertationThe nervous system is comprised of an estimated 100 billion individual neurons, which are connected to one another to form a network that senses environmental stimuli and coordinates the organism's behavior. Because of the complexity of the nervous system, deciphering the developmental processes and adult wiring diagram has proved challenging. A number of axon guidance molecules have been identified; however, the means by which they guide billions of axons to their target cells in vivo remains poorly understood. Several axon guidance molecules have been found to be bifunctional, meaning they can elicit different growth cone responses depending on the presence or absence of other molecules, such as growth cone receptors, intracellular signal transduction molecules, or extracellular modulators. Axon sorting within axon tracts is perhaps a means by which axons are presorted to make a precise connection on their target cells. The zebrafish, Danio rerio, is an ideal model organism to study vertebrate axon guidance and axon sorting due to its external fertilization, optical transparency, amenability to forward genetics, and ease of making transgenic lines. In order to study axon guidance within the zebrafish retinotectal system, I developed a new method of misexpressing genes. Local misexpression can be induced by using a modified soldering iron in transgenic zebrafish in which a gene of interest is driven by a heat shock promoter. This method allowed me to examine the mechanisms by which Slit1a and Slit2 guide axons from the retina to the optic tectum. I determined the expression pattern of Slits in the zebrafish and used antisense morpholino technology to knock down Slit1a. The iv resultant axon guidance errors indicated that Slit1a acts to guide retinal axons through the optic tract. I then misexpressed Slit1a and Slit2 near the optic tract to observe their effect on axons. I found that both proteins appeared to attract retinal axons. Additionally, I saw that Slit2 seems to attract retinal axons earlier in the retinotectal pathway, at the optic chiasm. I also report on a new method, to whose development I contributed, for automated tracking of axons through electron microscopy datasets. Taken together, my results add new methods to the endeavor of mapping neural connectivity and development, and suggest a new role for Slits in axon guidance

Establishing Frameworks of Contentment: Income Satisfaction in Germany

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Principal Leadership in a Virtual Environment

Commissioned by The Wallace Foundation, which supports efforts to promote effective school leadership, this report sets out to define what high-quality, equitable learning looks like in a virtual environment. It poses questions for school district leaders to ask if they want to develop principals who can lead their schools to this type of learning. It also describes strategies for districts to consider in efforts to develop a whole pipeline of principals adept at high-quality, equitable virtual learning—using a definition of an "aligned, comprehensive principal pipeline" that emerged through research and field work funded by The Wallace Foundation. The report is based on an examination of research literature supplemented by interviews with 11 principals and administrators knowledgeable about virtual learning. It also draws on Digital Promise's experience in working with schools and school districts. The final chapter looks at topics that merit further exploration in the areas of virtual learning, equity, and school leadership

How well are Australian infants and children aged 4 to 5 years doing?

This report presents an analysis of the data from the first wave of the Longitudinal Study of Australian Children (LSAC) to explore the wellbeing of over 10,000 Australian infants and children. This report presents an analysis of the data from the first wave of the Longitudinal Study of Australian Children (LSAC) to explore the wellbeing of 5,107 children in the infant cohort of the study and the 4,983 children, aged 4 to 5 years, in the child cohort. Wave 1 of LSAC includes measures of multiple aspects of children\u27s early development. These developmental measures are summarised in the LSAC Outcome Index, a composite measure which includes an overall index as well as three separate domain scores, tapping physical development, social and emotional functioning, and learning and cognitive development. This report explores five specific aspects of infants\u27 and children\u27s experiences, exposures and environments in relation to their Outcome Index scores: * key sociodemographic characteristics covering the child, mother, family and neighbourhood * non-parental care experiences * child health—prenatal and postnatal experiences and exposures * maternal physical and mental health * the early educational experiences of the child cohort in the home and out-of-home contexts. This paper is by Melissa Wake, Ann Sanson, Donna Berthelsen, Pollyanna Hardy, Sebastian Misson, Katherine Smith, Judy Ungerer and the LSAC Research Consortium

A Chromosome-Scale Assembly of the Axolotl Genome

The axolotl (Ambystoma mexicanum) provides critical models for studying regeneration, evolution, and development. However, its large genome (∼32 Gb) presents a formidable barrier to genetic analyses. Recent efforts have yielded genome assemblies consisting of thousands of unordered scaffolds that resolve gene structures, but do not yet permit large-scale analyses of genome structure and function. We adapted an established mapping approach to leverage dense SNP typing information and for the first time assemble the axolotl genome into 14 chromosomes. Moreover, we used fluorescence in situ hybridization to verify the structure of these 14 scaffolds and assign each to its corresponding physical chromosome. This new assembly covers 27.3 Gb and encompasses 94% of annotated gene models on chromosomal scaffolds. We show the assembly\u27s utility by resolving genome-wide orthologies between the axolotl and other vertebrates, identifying the footprints of historical introgression events that occurred during the development of axolotl genetic stocks, and precisely mapping several phenotypes including a large deletion underlying the cardiac mutant. This chromosome-scale assembly will greatly facilitate studies of the axolotl in biological research

Distribution of cardiovascular health by individual- and neighborhood-level socioeconomic status: Findings from the Jackson Heart Study

BACKGROUND: Data demonstrate a positive relationship between socioeconomic status (SES) and cardiovascular health (CVH). OBJECTIVE: To assess the association between individual- and neighborhood-level SES and CVH among participants of the JHS (Jackson Heart Study), a community-based cohort of African Americans in Jackson, Mississippi. METHODS: We included all JHS participants with complete SES and CVH information at the baseline study visit (n = 3,667). We characterized individual- and neighborhood-level SES according to income (primary analysis) and education (secondary analysis), respectively. The outcome of interest for these analyses was a CVH score, based on 7 modifiable behaviors and factors, summed to a total of 0 (worst) to 14 (best) points. We utilized generalized estimating equations to account for the clustering of participants within the same residential areas to estimate the linear association between SES and CVH. RESULTS: The median age of the participants was 55 years, and 64% were women. Nearly one-third of eligible participants had individual incomes \u3c$20,000 and close to 40$25,480). Adjusted for age, sex, and neighborhood SES, there was an average increase in CVH score of 0.31 points associated with each 1-category increase in individual income. Similarly, each 1-category increase in neighborhood SES was associated with a 0.19-point increase in CVH score. These patterns held for our secondary analyses, which used educational attainment in place of income. These data did not suggest a synergistic effect of individual- and neighborhood-level SES on CVH. CONCLUSIONS: Our findings suggest a potential causal pathway for disparities in CVH among vulnerable populations. These data can be useful to the JHS community to empower public health and clinical interventions and policies for the improvement of CVH

Dichloroacetate prevents cisplatin-induced nephrotoxicity without compromising cisplatin anticancer properties

Cisplatin is an effective anticancer drug; however, cisplatin use often leads to nephrotoxicity, which limits its clinical effectiveness. In this study, we determined the effect of dichloroacetate, a novel anticancer agent, in a mouse model of cisplatin-induced AKI. Pretreatment with dichloroacetate significantly attenuated the cisplatin-induced increase in BUN and serum creatinine levels, renal tubular apoptosis, and oxidative stress. Additionally, pretreatment with dichloroacetate accelerated tubular regeneration after cisplatin-induced renal damage. Whole transcriptome sequencing revealed that dichloroacetate prevented mitochondrial dysfunction and preserved the energy-generating capacity of the kidneys by preventing the cisplatin-induced downregulation of fatty acid and glucose oxidation, and of genes involved in the Krebs cycle and oxidative phosphorylation. Notably, dichloroacetate did not interfere with the anticancer activity of cisplatin in vivo. These data provide strong evidence that dichloroacetate preserves renal function when used in conjunction with cisplatin