Neuroactive Steroids Reverse Tonic Inhibitory Deficits in Fragile X Syndrome Mouse Model

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. A reduction in neuronal inhibition mediated by γ-aminobutyric acid type A receptors (GABAARs) has been implicated in the pathophysiology of FXS. Neuroactive steroids (NASs) are known allosteric modulators of GABAAR channel function, but recent studies from our laboratory have revealed that NASs also exert persistent metabotropic effects on the efficacy of tonic inhibition by increasing the protein kinase C (PKC)-mediated phosphorylation of the α4 and β3 subunits which increase the membrane expression and boosts tonic inhibition. We have assessed the GABAergic signaling in the hippocampus of fragile X mental retardation protein (FMRP) knock-out (Fmr1KO) mouse. The GABAergic tonic current in dentate gyrus granule cells (DGGCs) from 3- to 5-week-old (p21–35) Fmr1KO mice was significantly reduced compared to WT mice. Additionally, spontaneous inhibitory post synaptic inhibitory current (sIPSC) amplitudes were increased in DGGCs from Fmr1 KO mice. While sIPSCs decay in both genotypes was prolonged by the prototypic benzodiazepine diazepam, those in Frm1-KO mice were selectively potentiated by RO15-4513. Consistent with this altered pharmacology, modifications in the expression levels and phosphorylation of receptor GABAAR subtypes that mediate tonic inhibition were seen in Fmr1 KO mice. Significantly, exposure to NASs induced a sustained elevation in tonic current in Fmr1 KO mice which was prevented with PKC inhibition. Likewise, exposure reduced elevated membrane excitability seen in the mutant mice. Collectively, our results suggest that NAS act to reverse the deficits of tonic inhibition seen in FXS, and thereby reduce aberrant neuronal hyperexcitability seen in this disorder

Analyzing Contract Robustness through a Model of Commitments

Commerce is driven by business contracts. Here, each party to such a contract must be assured that it is robust, fulfilling its goals and avoiding undesirable outcomes. However, real-life business contracts tend to be complex and unamenable both to manual scrutiny and domain- independent scientific methods, making it difficult to provide automated support for determining or improving their robustness. As a result, establishing a contract is nontrivial and adds significantly to the transaction costs of conducting business. If the adoption of multi-agent systems approaches in supporting business interactions is to be viable, we need to develop appropriate techniques to allow such software to reason about contracts in relation to their robustness. To this end, in this paper we propose a powerful approach to assessing the robustness of contracts, and make three main contributions. First, we demonstrate a novel commitment-based formal model for contracts. Second, we define rules to evaluate the robustness of contracts. Third, we offer a methodology for modeling contracts to enable checking them for robustness. We validate these contributions via real-world contracts

Angiotensin (1-7) Attenuates the Chronotropic Response to Angiotensin II via Stimulation of PTEN in Spontaneously Hypertensive Rat Brain

The pathogenesis of hypertension and its mode of progression are complex, multifactorial and incompletely understood. Several studies have focused on the beneficial effects of peripheral Ang (1-7) in the regulation of cardiovascular functions, showing the counter-regulatory effects of Ang (1-7) against the actions of Ang II in the periphery. However, its actions in the central nervous system are not completely understood. In the present study, our main goal was to determine the central action of Ang (1-7) and its interaction with Ang II in the blood pressure control. Previous studies reported that Ang II produces a greater degree of activation of neuronal cells from brainstem/hypothalamus cultures of SHR versus WKY rats. Our present findings showed that this enhanced action of Ang II was attenuated in co-presence of either Ang (1-7) or PI3-kinase inhibitor. These counter-regulatory effects of Ang (1-7) on Ang II action in SHR neurons were abolished by co-treatment with either A-779, a Mas-R antagonist, or bisperoxovanadium (BPV), a PTEN inhibitor. In addition, incubation of WKY and SHR neurons with Ang (1-7) significantly increased PTEN activity. Chronic treatment with Ang (1-7) or chronic inhibition of PI3K using lentiviral vector significantly abolished the enhanced chronotroic response to Ang II in SHR neurons and significantly enhanced PTEN protein and mRNA expression levels in both WKY and SHR neuronal cultures. To further check the functional implications of our in vitro data, we further studied the interaction between Ang II and Ang (1-7) in the central control of cardiovascular functions. RVLM microinjection of Ang (1-7) or LY-294002 alone did not alter MAP, but reduced the pressor response to Ang II in SHR. Moreover, in compliance with our in vitro data, the inhibitory effect of Ang (1-7) on the pressor response to Ang II in SHR was abolished when co-administered together with A-779 or BPV. The data demonstrated that Ang (1-7) induce PTEN activity and expression via Mas-R, and depresses PI3-kinase-PKB/Akt signal transduction pathway, which lead to the counter-regulatory effect of Ang (1-7) on Ang II induced chronotropic and pressor effect on neuronal activity and cardiovascular functions including MAP and HR in SHR

Performance modeling and optimization for complex repairable system of paint manufacturing unit using a hybrid BFO-PSO algorithm

Purpose The purpose of this paper is to optimize the performance for complex repairable system of paint manufacturing unit using a new hybrid bacterial foraging and particle swarm optimization (BFO-PSO) evolutionary algorithm. For this, a performance model is developed with an objective to analyze the system availability. Design/methodology/approach In this paper, a Markov process-based performance model is put forward for system availability estimation. The differential equations associated with the performance model are developed assuming that the failure and repair rate parameters of each sub-system are constant and follow the exponential distribution. The long-run availability expression for the system has been derived using normalizing condition. This mathematical framework is utilized for developing an optimization model in MATLAB 15 and solved through BFO-PSO and basic particle swarm optimization (PSO) evolutionary algorithms coded in the light of applicability. In this analysis, the optimal input parameters are determined for better system performance. Findings In the present study, the sensitivity analysis for various sub-systems is carried out in a more consistent manner in terms of the effect on system availability. The optimal failure and repair rate parameters are obtained by solving the performance optimization model through the proposed hybrid BFO-PSO algorithm and hence improved system availability. Further, the results obtained through the proposed evolutionary algorithm are compared with the PSO findings in order to verify the solution. It can be clearly observed from the obtained results that the hybrid BFO-PSO algorithm modifies the solution more precisely and consistently. Research limitations/implications There is no limitation for implementation of proposed methodology in complex systems, and it can, therefore, be used to analyze the behavior of the other repairable systems in higher sensitivity zone. Originality/value The performance model of the paint manufacturing system is formulated by utilizing the available uncertain data of the used manufacturing unit. Using these data information, which affects the performance of the system are parameterized in the input failure and repair rate parameters for each sub-system. Further, these parameters are varied to find the sensitivity of a sub-system for system availability among the various sub-systems in order to predict the repair priorities for different sub-systems. The findings of the present study show their correspondence with the system experience and highlight the various availability measures for the system analyst in maintenance planning. </jats:sec

Behavioral analysis and availability optimization of complex repairable industrial system using particle swarm optimization

Abstract The complexity in industrial system design under specific practical constraints has a great impact on the range of prediction in system behavior. The data collected in such conditions lead to the high range of uncertainties and the consequence is a possibility of low system performance. Thus, the main objective of the present study is to analyze the system behavior and remove the uncertainties up to the desired accuracy. For this, the mathematical formulation of the system is carried out using probabilistic approach i. e. Markov process. The input failure and repair rate parameters of various sub-systems used in the mathematical expression are considered as constant and statistically independent. Further, the particle swarm optimization (PSO) technique has been used to optimize the system performance in order to improve the system efficiency. A complex repairable system of ton container manufacturing plant has been considered to demonstrate the effectiveness of proposed methodology.</jats:p

Apelin-13 inhibits large-conductance Ca2+-activated K+ channels in cerebral artery smooth muscle cells via a PI3-kinase dependent mechanism.

Apelin-13 causes vasoconstriction by acting directly on APJ receptors in vascular smooth muscle (VSM) cells; however, the ionic mechanisms underlying this action at the cellular level remain unclear. Large-conductance Ca(2+)-activated K(+) (BKCa) channels in VSM cells are critical regulators of membrane potential and vascular tone. In the present study, we examined the effect of apelin-13 on BK(Ca) channel activity in VSM cells, freshly isolated from rat middle cerebral arteries. In whole-cell patch clamp mode, apelin-13 (0.001-1 μM) caused concentration-dependent inhibition of BK(Ca) in VSM cells. Apelin-13 (0.1 µM) significantly decreased BK(Ca) current density from 71.25 ± 8.14 pA/pF to 44.52 ± 7.10 pA/pF (n=14 cells, P<0.05). This inhibitory effect of apelin-13 was confirmed by single channel recording in cell-attached patches, in which extracellular application of apelin-13 (0.1 µM) decreased the open-state probability (NPo) of BK(Ca) channels in freshly isolated VSM cells. However, in inside-out patches, extracellular application of apelin-13 (0.1 µM) did not alter the NPo of BK(Ca) channels, suggesting that the inhibitory effect of apelin-13 on BKCa is not mediated by a direct action on BK(Ca). In whole cell patches, pretreatment of VSM cells with LY-294002, a PI3-kinase inhibitor, markedly attenuated the apelin-13-induced decrease in BK(Ca current density. In addition, treatment of arteries with apelin-13 (0.1 µM) significantly increased the ratio of phosphorylated-Akt/total Akt, indicating that apelin-13 significantly increases PI3-kinase activity. Taken together, the data suggest that apelin-13 inhibits BK(Ca) channel via a PI3-kinase-dependent signaling pathway in cerebral artery VSM cells, which may contribute to its regulatory action in the control of vascular tone