Laura Binkley

NSDHL is a 3β-hydroxysterol dehydrogenase that is involved in the removal of two C-4 methyl groups in one of the later steps of cholesterol biosynthesis. Mutations in the gene encoding the enzyme are responsible for the X-linked, male lethal mouse mutations bare patches and striated, as well as most cases of human CHILD syndrome. Rare, hypomorphic NSDHL mutations are also associated with X-linked intellectual disability in males with CK syndrome. Since hemizygous male mice with Nsdhl mutations die by midgestation, we generated a conditional targeted Nsdhl mutation (Nsdhl(tm1.1Hrm)) to investigate the essential role of cholesterol in the early postnatal CNS. Ablation of Nsdhl in radial glia using GFAP-cre resulted in live-born, normal appearing affected male pups. However, the pups develop overt ataxia by postnatal day 8-10 and die shortly thereafter. Histological abnormalities include progressive loss of cortical and hippocampal neurons, as well as deficits in the proliferation and migration of cerebellar granule precursors and subsequent massive apoptosis of the cerebellar cortex. We replicated the granule cell precursor proliferation defect in vitro and demonstrate that it results from defective signaling by SHH. Furthermore, this defect is almost completely rescued by supplementation of the culture media with exogenous cholesterol, while methylsterol accumulation above the enzymatic block appears to be associated with increased cell death. These data support the absolute requirement for cholesterol synthesis in situ once the blood-brain-barrier forms and cholesterol transport to the fetus is abolished. They further emphasize the complex ramifications of cholesterogenic enzyme deficiency on cellular metabolism.

Rabies, a multi-host pathogen responsible for the loss of roughly 59,000 human lives each year worldwide, continues to impose a significant burden of disease despite control efforts, especially in Ethiopia. However, how species other than dogs contribute to rabies transmission throughout Ethiopia remains largely unknown. In this study, we quantified interactions among wildlife species in Ethiopia with the greatest potential for contributing to rabies maintenance. We observed wildlife at supplemental scavenging sites across multiple landscape types and quantified transmission potential. More specifically, we used camera trap data to quantify species abundance, species distribution, and intra- and inter-species contacts per trapping night over time and by location. We derived a mathematical expression for the basic reproductive number (R0) based on within- and between-species contract rates by applying the next generation method to the susceptible, exposed, infectious, removed model. We calculated R0 for transmission within each species and between each pair of species using camera trap data in order to identify pairwise interactions that contributed the most to transmission in an ecological community. We estimated which species, or species pairs, could maintain transmission ( R 0 > 1 ${R_0} > 1$ ) and which species, or species pairs, had contact rates too low for maintenance ( R 0 < 1 ${R_0} < 1$ ). Our results identified multiple urban carnivores as candidate species for rabies maintenance throughout Ethiopia, with hyenas exhibiting the greatest risk for rabies maintenance through intra-species transmission. Hyenas and cats had the greatest risk for rabies maintenance through inter-species transmission. Urban and peri-urban sites posed the greatest risk for rabies transmission. The night-time hours presented the greatest risk for a contact event that could result in rabies transmission. Overall, both intra- and inter-species contacts posed risk for rabies maintenance. Our results can be used to target future studies and inform population management decisions.

Risk-based food safety systems are recognized as the best way to address food safety in an effective and efficient manner. Central to risk-based food safety systems is an assessment, ranking, and prioritization of risks associated with foodborne hazards that informs objective, evidence-based decisions on risk mitigation in a systematic and transparent manner. While the importance of such approaches is well recognized, many governments struggle with where to begin. We adapted and implemented a framework for risk-based decision-making in low-resource settings using Ethiopia as an example, engaging Ethiopian stakeholders in a multiphase process to identify food safety priorities. First, stakeholder representatives were engaged to define statements of concern and purpose; identify foodborne hazards of public health relevance in Ethiopia; and select appropriate risk metrics for risk ranking and prioritization. Second, estimates for each risk metric were calculated for selected foodborne hazards using World Health Organization (WHO) data and expert elicitation. Third, stakeholder representatives were engaged in ranking the hazards as High, Medium, or Low risk; notably, mortality was the preferred risk metric in decision-making. Fourth, attribution estimates to food groups were developed for hazards ranked as High risk using expert elicitation to supplement WHO data. Lastly, stakeholder representatives were engaged in a risk prioritization exercise that identified key control points in four food supply chains and quantified their impact on risk through mitigation of hazards or prevention of contamination. Our proposed framework provides a systematic, evidence-based, and adaptable method for prioritizing the allocation of public sector resources. The process can generate the evidence needed to strengthen regulatory systems and support the efficient implementation of national-level food safety strategies that span from farm to fork to improve public health.