Sleep is regulated by a homeostatic process that determines its need and by a circadian process that determines its timing. By using sleep deprivation and transcriptome profiling in inbred mouse strains, we show that genetic background affects susceptibility to sleep loss at the transcriptional level in a tissue-dependent manner. In the brain, Homer1a expression best reflects the response to sleep loss. Timecourse gene expression analysis suggests that 2,032 brain transcripts are under circadian control. However, only 391 remain rhythmic when mice are sleep-deprived at four time points around the clock, suggesting that most diurnal changes in gene transcription are, in fact, sleep-wake-dependent. By generating a transgenic mouse line, we show that in Homer1-expressing cells specifically, apart from Homer1a, three other activity-induced genes (Ptgs2, Jph3, and Nptx2) are overexpressed after sleep loss. All four genes play a role in recovery from glutamate-induced neuronal hyperactivity. The consistent activation of Homer1a suggests a role for sleep in intracellular calcium homeostasis for protecting and recovering from the neuronal activation imposed by wakefulness.homeostasis ͉ microarray ͉ mRNA tagging ͉ sleep deprivation ͉ sleep function T wo main processes regulate sleep. A homeostatic process regulates sleep need and intensity according to the time spent awake or asleep. A circadian process regulates the appropriate timing of sleep and wakefulness across the 24-h day. A highly reliable index of the homeostatic process is provided by the amplitude and prevalence of delta (1-to 4-Hz) oscillations in the electroencephalogram (EEG) of nonrapid eye movement (NREM) sleep (hereafter, ''delta power''). Delta power is high at sleep onset and decreases during sleep, in parallel with sleep depth. Sleep deprivations and naps induce a predictable increase or decrease, respectively, in delta power during subsequent sleep. The interaction between homeostatic and circadian processes is mathematically described in the two-process model of sleep regulation, which provides a framework for prediction and interpretation of a large body of experimental data (1).Among hypotheses concerning the physiological function of waking-induced changes in sleep, the most compelling suggests that sleep plays a key role in synaptic plasticity (2, 3). More specifically, EEG delta power during NREM sleep has been shown to play a critical role in learning-induced plasticity (4-6). In general, the prediction is that local neural activation due to specific behavioral (cognitive) demands imposes a burden on the brain which necessitates sleep and which is reflected by the EEG delta power.On the basis of mathematical modeling and experimental data, we have shown that sleep need, as indexed by the EEG delta power, is under genetic control (7), which is of direct relevance for explaining the interindividual vulnerability to sleep loss in human subjects (8, 9). However, deciphering the molecular bases of sleep need is rendered difficult because the contr...

Cortical development involves synaptic formation and elimination. While synaptogenesis predominates earlier and pruning later, the two processes are thought to happen concurrently. Since in adults synaptic strength is modulated by behavioral state, we asked if synaptic remodeling may be affected by sleep and wake. Using two-photon microscopy in adolescent mice, we found that wake results in a net increase in cortical spines, whereas sleep is associated with net spine loss.

Previous studies of differential gene expression in sleep and wake pooled transcripts from all brain cells and showed that several genes expressed at higher levels during sleep are involved in the synthesis/maintenance of membranes in general and of myelin in particular, a surprising finding given the reported slow turnover of many myelin components. Other studies showed that oligodendrocyte precursor cells (OPCs) are responsible for the formation of new myelin in both the injured and the normal adult brain, and that glutamate released from neurons, via neuron-OPC synapses, can inhibit OPC proliferation and affect their differentiation into myelin-forming oligodendrocytes. Because glutamatergic transmission is higher in wake than in sleep, we asked whether sleep and wake can affect oligodendrocytes and OPCs. Using the translating ribosome affinity purification technology combined with microarray analysis in mice, we obtained a genome-wide profiling of oligodendrocytes after sleep, spontaneous wake, and forced wake (acute sleep deprivation). We found that hundreds of transcripts being translated in oligodendrocytes are differentially expressed in sleep and wake: genes involved in phospholipid synthesis and myelination or promoting OPC proliferation are transcribed preferentially during sleep, while genes implicated in apoptosis, cellular stress response, and OPC differentiation are enriched in wake. We then confirmed through BrdU and other experiments that OPC proliferation doubles during sleep and positively correlates with time spent in REM sleep, whereas OPC differentiation is higher during wake. Thus, OPC proliferation and differentiation are not perfectly matched at any given circadian time but preferentially occur during sleep and wake, respectively.

SummaryTwo field studies in Kenya and an experimental challenge study in the USA were done to assess the accuracy of a dipstick antigen-capture assay based on qualitative detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP-2) in peripheral blood for diagnosis of P falciparum infection.In these studies, the assay was 96·5-100% sensitive for detection of greater than 60 P falciparum asexual parasites/ µL blood, 70-81% sensitive for 11-60 parasites/µL blood, and 11-67% sensitive for 10 parasites or less/µL blood. Specificity was 95% (95% Cl 85-105%; n = 20) among naive American volunteers, 98% (96-101%; n=112) among volunteers exposed to the bite of P falciparium-infected mosquitoes, and 88% (84-92%; n=285) among Kenyans living in an area with holoendemic malaria. Our results also indicated that PfHRP-2 antigen was not detectable in blood 6 days after initiation of curative chemotherapy, and suggest that such circulating antigens rarely lead to false-positive tests.The dipstick assay's sensitivity, specificity, simplicity, and speed may make it an important tool in the battle against malaria.

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.

Candida enolase antigenemia is a novel marker for invasive candidiasis. It may be a useful indicator of deep infection in patients with cancer and neutropenia and may complement the diagnostic usefulness of blood cultures.

Delta oscillations, characteristic of the electroencephalogram (EEG) of slow wave sleep, estimate sleep depth and need and are thought to be closely linked to the recovery function of sleep. The cellular mechanisms underlying the generation of delta waves at the cortical and thalamic levels are well documented, but the molecular regulatory mechanisms remain elusive. Here we demonstrate in the mouse that the gene encoding the retinoic acid receptor beta determines the contribution of delta oscillations to the sleep EEG. Thus, retinoic acid signaling, which is involved in the patterning of the brain and dopaminergic pathways, regulates cortical synchrony in the adult.

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