Faculty Bibliography

A key component of eukaryotic lipid homeostasis is the esterification of sterols with fatty acids by sterol O-acyltransferases (SOATs). The esterification reactions are allosterically activated by their sterol substrates, the majority of which accumulate at the plasma membrane. We demonstrate that in yeast, sterol transport from the plasma membrane to the site of esterification is associated with the physical interaction of the major SOAT, acyl-coenzyme A:cholesterol acyltransferase (ACAT)-related enzyme (Are)2p, with 2 plasma membrane ATP-binding cassette (ABC) transporters: Aus1p and Pdr11p. Are2p, Aus1p, and Pdr11p, unlike the minor acyltransferase, Are1p, colocalize to sterol and sphingolipid-enriched, detergent-resistant microdomains (DRMs). Deletion of either ABC transporter results in Are2p relocalization to detergent-soluble membrane domains and a significant decrease (53-36%) in esterification of exogenous sterol. Similarly, in murine tissues, the SOAT1/Acat1 enzyme and activity localize to DRMs. This subcellular localization is diminished upon deletion of murine ABC transporters, such as Abcg1, which itself is DRM associated. We propose that the close proximity of sterol esterification and transport proteins to each other combined with their residence in lipid-enriched membrane microdomains facilitates rapid, high-capacity sterol transport and esterification, obviating any requirement for soluble intermediary proteins.-Gulati, S., Balderes, D., Kim, C., Guo, Z. A., Wilcox, L., Area-Gomez, E., Snider, J., Wolinski, H., Stagljar, I., Granato, J. T., Ruggles, K. V., DeGiorgis, J. A., Kohlwein, S. D., Schon, E. A., Sturley, S. L. ATP-binding cassette transporters and sterol O-acyltransferases interact at membrane microdomains to modulate sterol uptake and esterification.

OBJECTIVE: The recent Ebola virus disease (EVD) outbreak in 2014-2015 has been the largest and longest lasting to date. Media coverage about the outbreak has been extensive, but there are large gaps in our understanding of the ways in which widely accessed social media sites are used during times of public health crisis. The purpose of this study was to analyze widely viewed videos about EVD on the YouTube video-sharing site. METHODS: We coded the source, content, and characteristics of the 100 most widely viewed videos about EVD on YouTube. RESULTS: The videos included in the sample were viewed more than 73 million times. The death toll in West Africa was mentioned in nearly one-third of the videos. Over one-third of the videos mentioned how EVD was generally transmitted. There was little mention of treatment and no mention of the need for US funding of disaster preparedness; coordination between local, state, and federal governments; or beds ready for containment. No significant differences in the number of views were identified between video sources with the exception of a significantly higher number of views for "consumer videos" compared with "commercial television videos." CONCLUSIONS: With 1 billion unique users a month, YouTube has potential for both enhancing education and spreading misinformation. (Disaster Med Public Health Preparedness. 2015;0:1-5).

BACKGROUND: The purpose of this study was to describe the prevalence of aggressive and violent behaviors in the context of the school environment in a nationally representative sample of adolescent youth and to illustrate these patterns during 2001-2011. METHODS: We analyzed data from 84,734 participants via the Youth Risk Behavior Surveillance System (YRBSS). Frequencies were visualized using heatmaps. One-way analyses of variance and corresponding post hoc tests helped to identify if differences in prevalence fluctuated significantly across all years. RESULTS: Rates of youth feeling unsafe in their school environment, bringing weapons to school, and engaging in physical fighting on school property continue to persist. Findings illustrated that Hispanic youth and youth classified as "other" have emerged as particularly high-risk demographic subgroups over the past decade. Peer victimization and sexual victimization continue to affect girls disproportionately. CONCLUSIONS: Though some variation within demographic subgroups exists, rates of aggressive and violent behaviors in the context of the school environment continue to persist. Implications for the coordinated prevention of aggressive and violent behaviors among adolescent youth are discussed and recommendations for school-based prevention efforts are identified.

We describe integrated strategies that employ both translation of ENCODE data and major proteomic technology pillars to improve the identification of the missing proteins, protein isoforms, and PTMs. The results from proteoENCODEdb searches with experimental mass spectral data indicate that some novel splice forms detected at the transcript level are in fact translated to proteins. Our results provide a step toward the directives of the C-HPP initiative and related biomedical research.

OBJECTIVE: To apply discovery-based computational methods to nationally representative data from the Centers for Disease Control and Preventions' Youth Risk Behavior Surveillance System to better understand and visualize the behavioral factors associated with gun possession among adolescent youth. RESULTS: Our study uncovered the multidimensional nature of gun possession across nearly five million unique data points over a ten year period (2001-2011). Specifically, we automated odds ratio calculations for 55 risk behaviors to assemble a comprehensive table of associations for every behavior combination. Downstream analyses included the hierarchical clustering of risk behaviors based on their association "fingerprint" to 1) visualize and assess which behaviors frequently co-occur and 2) evaluate which risk behaviors are consistently found to be associated with gun possession. From these analyses, we identified more than 40 behavioral factors, including heroin use, using snuff on school property, having been injured in a fight, and having been a victim of sexual violence, that have and continue to be strongly associated with gun possession. Additionally, we identified six behavioral clusters based on association similarities: 1) physical activity and nutrition; 2) disordered eating, suicide and sexual violence; 3) weapon carrying and physical safety; 4) alcohol, marijuana and cigarette use; 5) drug use on school property and 6) overall drug use. CONCLUSIONS: Use of computational methodologies identified multiple risk behaviors, beyond more commonly discussed indicators of poor mental health, that are associated with gun possession among youth. Implications for prevention efforts and future interdisciplinary work applying computational methods to behavioral science data are described.

The toxic subcellular accumulation of lipids predisposes several human metabolic syndromes, including obesity, type 2 diabetes, and some forms of neurodegeneration. To identify pathways that prevent lipid-induced cell death, we performed a genome-wide fatty acid sensitivity screen in Saccharomyces cerevisiae. We identified 167 yeast mutants as sensitive to 0.5 mm palmitoleate, 45% of which define pathways that were conserved in humans. 63 lesions also impacted the status of the lipid droplet; however, this was not correlated to the degree of fatty acid sensitivity. The most liposensitive yeast strain arose due to deletion of the "ARE2 required for viability" (ARV1) gene, encoding an evolutionarily conserved, potential lipid transporter that localizes to the endoplasmic reticulum membrane. Down-regulation of mammalian ARV1 in MIN6 pancreatic beta-cells or HEK293 cells resulted in decreased neutral lipid synthesis, increased fatty acid sensitivity, and lipoapoptosis. Conversely, elevated expression of human ARV1 in HEK293 cells or mouse liver significantly increased triglyceride mass and lipid droplet number. The ARV1-induced hepatic triglyceride accumulation was accompanied by up-regulation of DGAT1, a triglyceride synthesis gene, and the fatty acid transporter, CD36. Furthermore, ARV1 was identified as a transcriptional of the protein peroxisome proliferator-activated receptor alpha (PPARalpha), a key regulator of lipid homeostasis whose transcriptional targets include DGAT1 and CD36. These results implicate ARV1 as a protective factor in lipotoxic diseases due to modulation of fatty acid metabolism. In conclusion, a lipotoxicity-based genetic screen in a model microorganism has identified 75 human genes that may play key roles in neutral lipid metabolism and disease.

Adolescents are particularly vulnerable to engaging in poor skin-protection behaviors. The objective of this study was to examine use of sunscreen and indoor tanning devices among a nationally representative sample of high school students during a 10-year period (2001-2011) using data from the Youth Risk Behavior Surveillance System. The percentage of youth who reported using sunscreen declined from 67.7% in 2001 to 56.1% in 2011. The prevalence of using indoor tanning devices was highest among white females: 37.4% in 2009 and 29.3% in 2011. These findings indicate the need for prevention efforts aimed at adolescents to reduce risks for skin cancer.

Consistency, quality, and duration of sleep are important determinants of health. We describe sleep patterns among demographically defined subgroups from the Youth Risk Behavior Surveillance System reported in 4 successive biennial representative samples of American high school students (2007 to 2013). Across the 4 waves of data collection, 6.2% to 7.7% of females and 8.0% to 9.4% of males reported obtaining 9 or more hours of sleep. Insufficient duration of sleep is pervasive among American high school students. Despite substantive public health implications, intervention research on this topic has received little attention.