Comment on "Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2".

Did hypocretin receptor 2 autoantibodies cause narcolepsy with hypocretin deficiency in Pandemrix-vaccinated children, as suggested by Ahmed et al.? Using newly developed mouse models to report and inactivate hypocretin receptor expression, Vassalli et al. now show that hypocretin neurons (whose loss causes narcolepsy) do not express hypocretin autoreceptors, raising questions to the interpretation of Ahmed et al.'s findings

Reconstructing the free energy landscape of a polyprotein by single-molecule experiments

The mechanical unfolding of an engineered protein composed of eight domains of Ig27 is investigated by using atomic force microscopy. Exploiting a fluctuation relation, the equilibrium free energy as a function of the molecule elongation is estimated from pulling experiments. Such a free energy exhibits a regular shape that sets a typical unfolding length at zero force of the order of 20 nm. This length scale turns out to be much larger than the kinetic unfolding length that is also estimated by analyzing the typical rupture force of the molecule under dynamic loading

Novel Insights on Nitric Oxide Synthase and NO Signaling in Ascidian Metamorphosis

Nitric oxide (NO) is a pivotal signaling molecule involved in a wide range of physiological and pathological processes. We investigated NOS/NO localization patterns during the different stages of larval development in the ascidia Ciona robusta and evidenced a specific and temporally controlled pattern. NOS/NO expression starts in the most anterior sensory structures of the early larva and progressively moves towards the caudal portion as larval development and metamorphosis proceeds. We here highlight the pattern of NOS/NO expression in the central and peripheral nervous system of Ciona larvae which precisely follows the progression of neural signals of the central pattern generator necessary for the control of the movements of the larva towards the substrate. This highly dynamic localization profile perfectly matches with the central role played by NO from the first phase of settlement induction to the next control of swimming behavior, adhesion to substrate and progressive tissue resorption and reorganization of metamorphosis itself

Bidirectional and context-dependent changes in theta and gamma oscillatory brain activity in noradrenergic cell-specific Hypocretin/Orexin receptor 1-KO mice.

Noradrenaline (NA) and hypocretins/orexins (HCRT), and their receptors, dynamically modulate the circuits that configure behavioral states, and their associated oscillatory activities. Salient stimuli activate spiking of locus coeruleus noradrenergic (NA <sup>LC</sup> ) cells, inducing NA release and brain-wide noradrenergic signalling, thus resetting network activity, and mediating an orienting response. Hypothalamic HCRT neurons provide one of the densest input to NA <sup>LC</sup> cells. To functionally address the HCRT-to-NA connection, we selectively disrupted the Hcrtr1 gene in NA neurons, and analyzed resulting (Hcrtr1 <sup>Dbh-CKO</sup> ) mice', and their control littermates' electrocortical response in several contexts of enhanced arousal. Under enforced wakefulness (EW), or after cage change (CC), Hcrtr1 <sup>Dbh-CKO</sup> mice exhibited a weakened ability to lower infra-θ frequencies (1-7 Hz), and mount a robust, narrow-bandwidth, high-frequency θ rhythm (~8.5 Hz). A fast-γ (55-80 Hz) response, whose dynamics closely parallelled θ, also diminished, while β/slow-γ activity (15-45 Hz) increased. Furthermore, EW-associated locomotion was lower. Surprisingly, nestbuilding-associated wakefulness, inversely, featured enhanced θ and fast-γ activities. Thus HCRT-to-NA signalling may fine-tune arousal, up in alarming conditions, and down during self-motivated, goal-driven behaviors. Lastly, slow-wave-sleep following EW and CC, but not nestbuilding, was severely deficient in slow-δ waves (0.75-2.25 Hz), suggesting that HCRT-to-NA signalling regulates the slow-δ rebound characterizing sleep after stress-associated arousal