The hangover gene defines a stress pathway required for ethanol tolerance development.

Repeated alcohol consumption leads to the development of tolerance, simply defined as an acquired resistance to the physiological and behavioural effects of the drug. This tolerance allows increased alcohol consumption, which over time leads to physical dependence and possibly addiction. Previous studies have shown that Drosophila develop ethanol tolerance, with kinetics of acquisition and dissipation that mimic those seen in mammals. This tolerance requires the catecholamine octopamine, the functional analogue of mammalian noradrenaline. Here we describe a new gene, hangover, which is required for normal development of ethanol tolerance. hangover flies are also defective in responses to environmental stressors, such as heat and the free-radical-generating agent paraquat. Using genetic epistasis tests, we show that ethanol tolerance in Drosophila relies on two distinct molecular pathways: a cellular stress pathway defined by hangover, and a parallel pathway requiring octopamine. hangover encodes a large nuclear zinc-finger protein, suggesting a role in nucleic acid binding. There is growing recognition that stress, at both the cellular and systemic levels, contributes to drug- and addiction-related behaviours in mammals. Our studies suggest that this role may be conserved across evolution.

Hangover Links Nuclear RNA Signaling to cAMP Regulation via the Phosphodiesterase 4d Ortholog dunce.

The hangover gene defines a cellular stress pathway that is required for rapid ethanol tolerance in Drosophila melanogaster. To understand how cellular stress changes neuronal function, we analyzed Hangover function on a cellular and neuronal level. We provide evidence that Hangover acts as a nuclear RNA binding protein and we identified the phosphodiesterase 4d ortholog dunce as a target RNA. We generated a transcript-specific dunce mutant that is impaired not only in ethanol tolerance but also in the cellular stress response. At the neuronal level, Dunce and Hangover are required in the same neuron pair to regulate experience-dependent motor output. Within these neurons, two cyclic AMP (cAMP)-dependent mechanisms balance the degree of tolerance. The balance is achieved by feedback regulation of Hangover and dunce transcript levels. This study provides insight into how nuclear Hangover/RNA signaling is linked to the cytoplasmic regulation of cAMP levels and results in neuronal adaptation and behavioral changes.

Long term monitoring of three automated HIV 4th generation combined antibody/antigen screening assays.

In a diagnostic laboratory performing analyses for about 40 hospitals and 2,000 physicians treating outpatients results of HIV 4th generation combined antibody/antigen screening assays were monitored over a period of 50 months. In period A (Jan 2007 - Mar 2009) 37,986 serum samples were examined by Architect and in period B (Apr 2009 - Feb 2011) 38,178 samples by Modular system. In period B1 (Apr 2009 - Jun 2010) 24,756 samples were analyzed only by Modular system while in period B2 (July 2010 - February 2011) 13,422 samples were examined in parallel by Modular and Axsym system. Sensitivity and negative predictive value of each was 100%. Specificities ranged from 99.69-99.88% and positive predictive values (ppv) from 35.1-65.9%. Architect test results obtained a better reliability than Modular test results while Axsym test results were similar to that of Architect system. However, specificity and ppv of Modular system was markedly improved in period B2. In summary our study shows that long term monitoring of HIV combined antibody/antigen screening test results allows discovering of impairment and improvement of HIV testing quality. We also show that in a low prevalence region specificities of > 99% are accompanied by relatively low ppv. Increase of cut off values to define reactivity of the tests will increase specificities and ppv without affecting sensitivity.