Faculty Bibliography

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.

Protein abundance and phosphorylation convey important information about pathway activity and molecular pathophysiology in diseases including cancer, providing biological insight, informing drug and diagnostic development, and guiding therapeutic intervention. Analyzed tissues are usually collected without tight regulation or documentation of ischemic time. To evaluate the impact of ischemia, we collected human ovarian tumor and breast cancer xenograft tissue without vascular interruption and performed quantitative proteomics and phosphoproteomics after defined ischemic intervals. While the global expressed proteome and most of the >25,000 quantified phosphosites were unchanged after 60 minutes, rapid phosphorylation changes were observed in up to 24% of the phosphoproteome, representing activation of critical cancer pathways related to stress response, transcriptional regulation and cell death. Both pan-tumor and tissue-specific changes were observed. The demonstrated impact of pre-analytical tissue ischemia on tumor biology mandates caution in interpreting stress-pathway activation in such samples, and motivates reexamination of collection protocols for phosphoprotein analysis.

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.

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 esterification of amphiphilic alcohols with fatty acids is a ubiquitous strategy implemented by eukaryotes and some prokaryotes to conserve energy and membrane progenitors and simultaneously detoxify fatty acids and other lipids. This key reaction is performed by at least four evolutionarily unrelated multigene families. The synthesis of this "neutral lipid" leads to the formation of a lipid droplet, which despite the clear selective advantage it confers is also a harbinger of cellular and organismal malaise. Neutral lipid deposition as a cytoplasmic lipid droplet may be thermodynamically favored but nevertheless is elaborately regulated. Optimal utilization of these resources by lipolysis is similarly multigenic in determination and regulation. We present here a perspective on these processes that originates from studies in model organisms, and we include our thoughts on interventions that target reductions in neutral lipids as therapeutics for human diseases such as obesity and diabetes.

The PAH1-encoded phosphatidate (PA) phosphatase in Saccharomyces cerevisiae is a pivotal enzyme that produces diacylglycerol for the synthesis of triacylglycerol (TAG) and simultaneously controls the level of PA used for phospholipid synthesis. Quantitative lipid analysis showed that the pah1Delta mutation caused a reduction in TAG mass and an elevation in the mass of phospholipids and free fatty acids, changes that were more pronounced in the stationary phase. The levels of unsaturated fatty acids in the pah1Delta mutant were unaltered, although the ratio of palmitoleic acid to oleic acid was increased with a similar change in the fatty acid composition of phospholipids. The pah1Delta mutant exhibited classic hallmarks of apoptosis in stationary phase and a marked reduction in the quantity of cytoplasmic lipid droplets. Cells lacking PA phosphatase were sensitive to exogenous fatty acids in the order of toxicity palmitoleic acid > oleic acid > palmitic acid. In contrast, the growth of wild type cells was not inhibited by fatty acid supplementation. In addition, wild type cells supplemented with palmitoleic acid exhibited an induction in PA phosphatase activity and an increase in TAG synthesis. Deletion of the DGK1-encoded diacylglycerol kinase, which counteracts PA phosphatase in controlling PA content, suppressed the defect in lipid droplet formation in the pah1Delta mutant. However, the sensitivity of the pah1Delta mutant to palmitoleic acid was not rescued by the dgk1Delta mutation. Overall, these findings indicate a key role of PA phosphatase in TAG synthesis for protection against fatty acid-induced toxicity.

Behavioural decisions involving foraging, mate choice and habitat selection are complex and difficult to evaluate experimentally. Web abandonment by orb spiders is a complex decision that is experimentally tractable. For females of the golden orb spider, Nephila clavipes, the web is a microhabitat that serves as a prey capture device, a mating site and a habitat for parasites. Thus, the web embodies the complexity of a bird territory or mammal home range, but is spatially compact and amenable to experimental manipulation. We used both field census data and field experimental manipulations to address the importance of prey capture rate, kleptoparasite load and male presence for web tenure (the time spent at a web site) in both mature and immature female N. clavipes. No factor explained variation in web tenure for immature females, although census data suggested that increased kleptoparasite load decreased web tenure. For mature females, increased male presence decreased web tenure, while increased prey capture rate, condition and body size all increased web tenure. Web tenure also decreased over the course of the season. Females integrate multiple cues to make web movement decisions. One of these cues is male presence, which detracts from the quality of a web site, suggesting that mate harassment might affect females' web movement decisions. Insight into this seemingly simple behaviour contributes to a growing understanding of how and when animals integrate multiple cues into behavioural decisions. (C) 2010 The Association for the Study of Animal Behaviour. Published by Elsevier Ltd. All rights reserved.

Deletion of the acyltransferases responsible for triglyceride and steryl ester synthesis in Saccharomyces cerevisiae serves as a genetic model of diseases where lipid overload is a component. The yeast mutants lack detectable neutral lipids and cytoplasmic lipid droplets and are strikingly sensitive to unsaturated fatty acids. Expression of human diacylglycerol acyltransferase 2 in the yeast mutants was sufficient to reverse these phenotypes. Similar to mammalian cells, fatty acid-mediated death in yeast is apoptotic and presaged by transcriptional induction of stress-response pathways, elevated oxidative stress, and activation of the unfolded protein response. To identify pathways that protect cells from lipid excess, we performed genetic interaction and transcriptional profiling screens with the yeast acyltransferase mutants. We thus identified diacylglycerol kinase-mediated phosphatidic acid biosynthesis and production of phosphatidylcholine via methylation of phosphatidylethanolamine as modifiers of lipotoxicity. Accordingly, the combined ablation of phospholipid and triglyceride biosynthesis increased sensitivity to saturated fatty acids. Similarly, normal sphingolipid biosynthesis and vesicular transport were required for optimal growth upon denudation of triglyceride biosynthesis and also mediated resistance to exogenous fatty acids. In metazoans, many of these processes are implicated in insulin secretion thus linking lipotoxicity with early aspects of pancreatic beta-cell dysfunction, diabetes, and the metabolic syndrome.