High‐Throughput Screen of Natural Product Extracts in A Yeast Model of Polyglutamine Proteotoxicity

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106714/1/cbdd12259.pd

Factors associated with AIDS risk behaviors among high school students in an AIDS epicenter.

BACKGROUND. A greater understanding of the determinants of risky behaviors is an essential precursor to the development of successful AIDS prevention programs for adolescents. METHODS. A survey measuring AIDS-related behaviors, beliefs, and knowledge was administered to a sample of 531 10th-grade students residing in an AIDS epicenter. RESULTS. Of the 56.8% of students reporting past-year involvement in sexual intercourse, 67.3% reported unprotected intercourse with low-risk partners, 1.3% reported unprotected intercourse with high-risk partners, and 6.6% reported a past-year history of a sexually transmitted disease. Students whose friends had intercourse and never or inconsistently used condoms, who personally sanctioned intercourse involvement, who believed that the majority of their peers had intercourse, and who perceived low preventive action self-efficacy, were 5.1, 3.0, 2.1, 3.7, and 2.8 times more likely, respectively, to score in the riskier categories of an AIDS behavior index. CONCLUSIONS. These findings suggest that addressing socioenvironmental influences on risky and preventive behaviors may prove to be the most effective AIDS prevention strategy among adolescents

Factors Associated with AIDS-Related Behavioral Intentions Among High School Students in An AIDS Epicenter

Using data from a cross-sectional survey of 531 predominantly black and Hispanic 10th graders in two New York City schools, the explanatory power of predictors of intentions to engage in sexual intercourse, to have multiple intercourse partners, and to use condoms was compared. Theoretically derived predictor variables (i.e., susceptibility, severity, benefits, barriers, self-efficacy, values, norms) were derived from the health belief model, social cognitive theory, and a model of social influence. One half of sampled students definitely intended to have sexual intercourse in the next year, one tenth definitely intended to have multiple partners, and two thirds definitely intended to use condoms. In multivariate analyses, variables derived from the model of social influence and from social cognitive theory were most strongly associated with the three investigated behavioral intentions; however, certain background and health belief variables also contributed to the explained variance in intercourse and multiple partner intentions

Pharmacological Tuning of Heat Shock Protein 70 Modulates Polyglutamine Toxicity and Aggregation

Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential therapeutic target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70 ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify the role of Hsp70 as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic

Pharmacological Tuning of Heat Shock Protein 70 Modulates Polyglutamine Toxicity and Aggregation

Nine neurodegenerative disorders are caused by the abnormal expansion of polyglutamine (polyQ) regions within distinct proteins. Genetic and biochemical evidence has documented that the molecular chaperone, heat shock protein 70 (Hsp70), modulates polyQ toxicity and aggregation, yet it remains unclear how Hsp70 might be used as a potential target in polyQ-related diseases. We have utilized a pair of membrane-permeable compounds that tune the activity of Hsp70 by either stimulating or by inhibiting its ATPase functions. Using these two pharmacological agents in both yeast and PC12 cell models of polyQ aggregation and toxicity, we were surprised to find that stimulating Hsp70 solubilized polyQ conformers and simultaneously exacerbated polyQ-mediated toxicity. By contrast, inhibiting Hsp70’s ATPase activity protected against polyQ toxicity and promoted aggregation. These findings clarify Hsp70’s role as a possible drug target in polyQ disorders and suggest that Hsp70 uses ATP hydrolysis to help partition polyQ proteins into structures with varying levels of proteotoxicity. Our results thus support an emerging concept in which certain kinds of polyQ aggregates may be protective, while more soluble polyQ species are toxic