Fetal alcohol exposure (FAE) can lead to a variety of behavioral and physiological disturbances later in life. Understanding how alcohol (ethanol, EtOH) affects fetal brain development is essential to guide the development of better therapeutics for FAE. One of EtOH's many pharmacological targets is the c-aminobutyric acid type A receptor (GABA A R), which plays a prominent role in early brain development. Acute EtOH potentiates inhibitory currents carried by certain GABA A R subtypes, whereas chronic EtOH leads to persistent alterations in GABA A R subunit composition, localization and function. We recently introduced a flavonoid compound, dihydromyricetin (DHM), which selectively antagonizes EtOH's intoxicating effects in vivo and in vitro at enhancing GABA A R function as a candidate for alcohol abuse pharmacotherapy. Here, we studied the effect of FAE on physiology, behavior and GABA A R function of early adolescent rats and tested the utility of DHM as a preventative treatment for FAE-induced disturbances. Gavage administration of EtOH (1.5, 2.5, or 5.0 g/kg) to rat dams on day 5, 8, 10, 12, and 15 of pregnancy dose-dependently reduced female/male offspring ratios (largely through decreased numbers of female offspring) and offspring body weights. FAE (2.5 g/kg) rats tested on postnatal days (P) 25-32 also exhibited increased anxiety and reduced pentylenetetrazol (PTZ)-induced seizure threshold. Patchclamp recordings from dentate gyrus granule cells (DGCs) in hippocampal slices from FAE (2.5 g/kg) rats at P25-35 revealed reduced sensitivity of GABAergic miniature inhibitory postsynaptic currents (mIPSCs) and tonic current (I tonic ) to potentiation by zolpidem (0.3 lM). Interestingly, potentiation of mIPSCs by gaboxadol increased, while potentiation of I tonic decreased in DGCs from FAE rats. Coadministration of EtOH (1.5 or 2.5 g/kg) with DHM (1.0 mg/kg) in pregnant dams prevented all of the behavioral, physiological, and pharmacological alterations observed in FAE offspring. DHM administration alone in pregnant rats had no adverse effect on litter size, progeny weight, anxiety level, PTZ seizure threshold, or DGC GABA A R function. Our results indicate that FAE induces long-lasting alterations in physiology, behavior, and hippocampal GABA A R function and that these deficits are prevented by DHM co-treatment of EtOH-exposed dams. The absence of adverse side effects and the ability of DHM to prevent FAE consequences suggest that DHM is an attractive candidate for development as a treatment for prevention of fetal alcohol spectrum disorders.
A procedure for automatic numerical generation of a structured grid system with coordinate lines coinciding with all boundaries of a general two-dimensional region containing a body of arbitrary shape is presented. The solution procedure incorporated the method of false transients and the approximate factorisation algorithm, where a sequence of time steps is cycled in a geometric fashion with repeated endpoints, and has a capability for clustering grid lines close to the body. The procedure requires significantly much less computational effort to obtain a converged solution than a point or line successive over-relaxation iterative scheme. Although, the superiority of the presented algorithm has been demonstrated for the grid generation problem, it can be utilised for other problems requiring the solution of a set of elliptic partial differential equations of similar nature.
A finite difference method based scheme incorporating a method of false transients and an approximate factorisation technique is presented for solution of a system of Poisson's equations used for grid generation. A time step cycling process with repeated endpoints enhances the convergence rate. The scheme required much less computational effort than that required by other numerical schemes. High quality grid systems over an aircraft tailplane are presented. Although, the superiority of the scheme is illustrated for the grid generation problem, it can be employed for other problems requiring the solution of a set of similar elliptic partial differential equations.
Incidents involving low speed flutter of the wing-flaperon configured Government Aircraft Factories Nomad N22 and N24 have been reported. Wind tunnel experiments are unable to reproduce the effect.To better understand what could have caused the reported flutter, a computational fluid dynamics based investigation was undertaken, employing a complex commercial simulation software, with the aim to study the local flowfield structures around this configuration, focusing specifically on turbulence effects. Inviscid and viscous flows incorporating the Spalart-Allmaras and rng k-turbulence models were computed. Comparisons with experimental data showed excellent agreement among the results, with the predicted section lift coefficients being within 10% of the measured values.
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