Melatonin pretreatment alleviates the long-term synaptic toxicity and dysmyelination induced by neonatal Sevoflurane exposure via MT1 receptor-mediated Wnt signaling modulation.

Sevoflurane (Sev) is one of the most widely used pediatric anesthetics. The major concern of neonatal repeated application of Sev is its potential long-term impairment of cognition and learning/memory, for which there still lacks effective treatment. At the cellular level, Sev exerts toxic effects in multiple aspects, making it difficult for effective interference. Melatonin is a pineal hormone regulated by and feedbacks to biological rhythm at physiological condition. Recent studies have revealed significant neuroprotective effects of exogenous melatonin or its agonists under various pathological conditions. Whether melatonin could prevent the long-term toxicity of Sev remains elusive. Here, we report that neonatal repeated Sev exposure up-regulated MT1 receptor in hippocampal neurons and oligodendrocytes. Pretreatment with melatonin significantly alleviated Sev-induced synaptic deficiency, dysmyelination, and long-term learning impairment. Both MT1-shRNA and MT1 knockout effectively blocked the protective effects of melatonin on synaptic development, myelination, and behavior performance. Interestingly, long-lasting suppression of Wnt signaling, instead of cAMP/PKA signaling, was observed in hippocampal neurons and oligodendrocytes after neonatal Sev exposure. Pharmacologically activating Wnt signaling rescued both the long-term synaptic deficits and dysmyelination induced by Sev. Further analysis showed that MT1 receptor co-expressed well with ß-catenin and Axin2 and bound to ß-catenin by its C-terminal. Melatonin pretreatment effectively rescued Sev-induced Wnt suppression. Wnt signaling inhibitor XAV939 significantly compromised the protective effects of melatonin. Taken together, our data demonstrated a beneficial effect of melatonin pretreatment on the long-term synaptic impairment and dysmyelination induced by neonatal Sev exposure, and a novel MT1 receptor-mediated interaction between melatonin and canonical Wnt signaling, indicating that melatonin may be clinically applied for improving the safety of pediatric Sev anesthesia.

Perfectly matched layer absorbing boundary conditions for Euler equations with oblique mean flows modeled with smoothed particle hydrodynamics.

Absorbing boundary conditions (ABCs) play a critical role in the simulation of sound or wave propagation problems. This paper proposes a technique of space-time transformed perfectly matched layer (PML) boundary condition implemented in a widely used mesh-free method called smoothed particle hydrodynamic (SPH) method, to absorb the outgoing sound waves with oblique shear mean flow. Special consideration is given to the particle features of the SPH, and the PMLs are formulated to correct the truncation error of SPH and absorb the outgoing wave at the same time, aiming to reduce the storage and computational cost in the infinite computational domain. Because the group velocity and phase velocity of the outgoing sound waves in the PMLs may be in different directions, exponentially growing pseudo reflections can result. The authors thus employ space-time transformation to eliminate the reflections effectively in PML boundaries for stable solutions. Moreover, a uniform framework of PML absorbing boundary conditions for Euler equations in the cases of arbitrary oblique mean flow and static media is derived. Finally, the present PML-SPH method with this stable absorbing boundary is applied to simulate sound waves propagating with mean flow. The obtained numerical results agree very well with the reference results.