Performance on a visual discrimination task shows long-term improvement after a single training session. When tested within 24 hr of training, improvement was not observed unless subjects obtained at least 6 hr of posttraining sleep prior to retesting, in which case improvement was proportional to the amount of sleep in excess of 6 hr. For subjects averaging 8 hr of sleep, overnight improvement was proportional to the amount of slow wave sleep (SWS) in the first quarter of the night, as well as the amount of rapid eye movement sleep (REM) in the last quarter. REM during the intervening 4 hr did not appear to contribute to improvement. A two-step process, modeling throughput as the product of the amount of early SWS and late REM, accounts for 80 percent of intersubject variance. These results suggest that, in the case of this visual discrimination task, both SWS and REM are required to consolidate experience-dependent neuronal changes into a form that supports improved task performance.

The emergence of drug resistance is a major limitation of current antimalarials. The discovery of new druggable targets and pathways including those that are critical for multiple life cycle stages of the malaria parasite is a major goal for the development of the next-generation of antimalarial drugs. Using an integrated chemogenomics approach that combined drug-resistance selection, whole genome sequencing and an orthogonal yeast model, we demonstrate that the cytoplasmic prolyl-tRNA synthetase (PfcPRS) of the malaria parasite Plasmodium falciparum is a biochemical and functional target of febrifugine and its synthetic derivatives such as halofuginone. Febrifugine is the active principle of a traditional Chinese herbal remedy for malaria. We show that treatment with febrifugine derivatives activated the amino acid starvation response in both P. falciparum and a transgenic yeast strain expressing PfcPRS. We further demonstrate in the P. berghei mouse model of malaria that halofuginol, a new halofuginone analog that we developed, is highly active against both liver and asexual blood stages of the malaria parasite. Halofuginol, unlike halofuginone and febrifugine, is well tolerated at efficacious doses, and represents a promising lead for the development of dual-stage next generation antimalarials.

A library of approximately 2000 small molecules biased toward inhibition of histone deacetylases was assayed for antimalarial activity in a high-throughput P. falciparum viability assay. Active compounds were cross-analyzed for induction of histone hyperacetylation in a human myeloma cell line to identify HDAC inhibitors with selectivity for P. falciparum over the human host. To verify on-target selectivity, pfHDAC-1 was expressed and purified and a biochemical assay for pfHDAC-1 activity was established.