SUMMARY Reduced insulin/IGF-1-like signaling (IIS) extends C. elegans lifespan by upregulating stress response (Class I) and downregulating other (Class II) genes through a mechanism that depends on the conserved transcription factor DAF-16/FOXO. By integrating genomewide mRNA expression responsiveness to DAF-16 with genomewide in vivo binding data for a compendium of transcription factors, we discovered that PQM-1 is the elusive transcriptional activator that directly controls development (Class II) genes by binding to the DAF-16 associated element (DAE). DAF-16 directly regulates Class I genes only, through the DAF-16 binding element (DBE). Loss of PQM-1 suppresses daf-2 longevity and further slows development. Surprisingly, the nuclear localization of PQM-1 and DAF-16 is controlled by IIS in opposite ways, and was also found to be mutually antagonistic. We observe progressive loss of nuclear PQM-1 with age, explaining declining expression of PQM-1 targets. Together, our data suggest an elegant mechanism for balancing stress response and development.

Accurate and comprehensive information about the nucleotide sequence specificity of trans-acting factors (TFs) is essential for computational and experimental analyses of gene regulatory networks. We present the Yeast Transfactome Database, a repository of sequence specificity models and condition-specific regulatory activities for a large number of DNA- and RNA-binding proteins in Saccharomyces cerevisiae. The sequence specificities in TransfactomeDB, represented as position-specific affinity matrices (PSAMs), are directly estimated from genomewide measurements of TF-binding using our previously published MatrixREDUCE algorithm, which is based on a biophysical model. For each mRNA expression profile in the NCBI Gene Expression Omnibus, we used sequence-based regression analysis to estimate the post-translational regulatory activity of each TF for which a PSAM is available. The trans-factor activity profiles across multiple experiments available in TransfactomeDB allow the user to explore potential regulatory roles of hundreds of TFs in any of thousands of microarray experiments. Our resource is freely available at http://bussemakerlab.org/TransfactomeDB/

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By means of a partial extracorporeal bypass, incorporating a bubble counting chamber, measured quantities of oxygen and of air microbubbles, having average diameters of 100 and 76 µ, respectively, were introduced into the carotid arteries of dogs. The desired number of bubbles was produced by varying the blood level and gas flow in the bubble oxygenator. Eighty per cent of dogs receiving oxygen in volumes up to 0.43 cc/kg (approximately 12.5 million microbubbles) survived without evidence of neurologic abnormalities. Seventy per cent of the control group, which received no microbubbles, survived. Of those perfused with air, all animals receiving up to 0.19 cc/kg (9.1 million bubbles) survived with no neurologic sequelae. Those perfused with air volumes greater than 0.19 cc/kg died within 24 hours, many exhibiting evidence of neurologic damage. The emphasis upon the introduction of oxygen microbubbles as the major fault of bubble oxygenators may be unwarranted. Air microbubbles are more deleterious than are oxygen microbubbles.

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