Tetramethylenedisulfotetramine alters Ca²⁺ dynamics in cultured hippocampal neurons: mitigation by NMDA receptor blockade and GABA(A) receptor-positive modulation.

Tetramethylenedisulfotetramine (TETS) is a potent convulsant that is considered a chemical threat agent. We characterized TETS as an activator of spontaneous Ca²⁺ oscillations and electrical burst discharges in mouse hippocampal neuronal cultures at 13-17 days in vitro using FLIPR Fluo-4 fluorescence measurements and extracellular microelectrode array recording. Acute exposure to TETS (≥ 2 µM) reversibly altered the pattern of spontaneous neuronal discharges, producing clustered burst firing and an overall increase in discharge frequency. TETS also dramatically affected Ca²⁺ dynamics causing an immediate but transient elevation of neuronal intracellular Ca²⁺ followed by decreased frequency of Ca²⁺ oscillations but greater peak amplitude. The effect on Ca²⁺ dynamics was similar to that elicited by picrotoxin and bicuculline, supporting the view that TETS acts by inhibiting type A gamma-aminobutyric acid (GABA(A)) receptor function. The effect of TETS on Ca²⁺ dynamics requires activation of N-methyl-D-aspartic acid (NMDA) receptors, because the changes induced by TETS were prevented by MK-801 block of NMDA receptors, but not nifedipine block of L-type Ca²⁺ channels. Pretreatment with the GABA(A) receptor-positive modulators diazepam and allopregnanolone partially mitigated TETS-induced changes in Ca²⁺ dynamics. Moreover, low, minimally effective concentrations of diazepam (0.1 µM) and allopregnanolone (0.1 µM), when administered together, were highly effective in suppressing TETS-induced alterations in Ca²⁺ dynamics, suggesting that the combination of positive modulators of synaptic and extrasynaptic GABA(A) receptors may have therapeutic potential. These rapid throughput in vitro assays may assist in the identification of single agents or combinations that have utility in the treatment of TETS intoxication

Antillatoxin is a sodium channel activator that displays unique efficacy in heterologously expressed rNav1.2, rNav1.4 and rNav1.5 alpha subunits

<p>Abstract</p> <p>Background</p> <p>Antillatoxin (ATX) is a structurally unique lipopeptide produced by the marine cyanobacterium <it>Lyngbya majuscula</it>. ATX activates voltage-gated sodium channel α-subunits at an undefined recognition site and stimulates sodium influx in neurons. However, the pharmacological properties and selectivity of ATX on the sodium channel α-subunits were not fully characterized.</p> <p>Results</p> <p>In this study, we characterized the pharmacological properties and selectivity of ATX in cells heterologously expressing rNa_v1.2, rNa_v1.4 or rNa_v1.5 α-subunits by using the Na⁺selective fluorescent dye, sodium-binding benzofuran isophthalate. ATX produced sodium influx in cells expressing each sodium channel α-subunit, whereas two other sodium channel activators, veratridine and brevetoxin-2, were without effect. The ATX potency at rNa_v1.2, rNa_v1.4 and rNa_v1.5 did not differ significantly. Similarly, there were no significant differences in the efficacy for ATX-induced sodium influx between rNa_v1.2, rNa_v1.4 and rNa_v1.5 α-subunits. ATX also produced robust Ca²⁺influx relative to other sodium channel activators in the calcium-permeable DEAA mutant of rNa_v1.4 α-subunit. Finally, we demonstrated that the 8-demethyl-8,9-dihydro-antillatoxin analog was less efficacious and less potent in stimulating sodium influx.</p> <p>Conclusions</p> <p>ATX displayed a unique efficacy with respect to stimulation of sodium influx in cells expressing rNa_v1.2, rNa_v1.4 and rNa_v1.5 α-subunits. The efficacy of ATX was distinctive inasmuch as it was not shared by activators of neurotoxin sites 2 and 5 on VGSC α-subunits. Given the unique pharmacological properties of ATX interaction with sodium channel α-subunits, decoding the molecular determinants and mechanism of action of antillatoxin may provide further insight into sodium channel gating mechanisms.</p

Accelerated Particle Swarm Optimization for Photovoltaic Maximum Power Point Tracking under Partial Shading Conditions

This paper presents an accelerated particle swarm optimization (PSO)-based maximum power point tracking (MPPT) algorithm to track global maximum power point (MPP) of photovoltaic (PV) generation under partial shading conditions. Conventional PSO-based MPPT algorithms have common weaknesses of a long convergence time to reach the global MPP and oscillations during the searching. The proposed algorithm includes a standard PSO and a perturb-and-observe algorithm as the accelerator. It has been experimentally tested and compared with conventional MPPT algorithms. Experimental results show that the proposed MPPT method is effective in terms of high reliability, fast dynamic response, and high accuracy in tracking the global MPP

Design and Assessment of an Electric Vehicle Powertrain Model Based on Real-World Driving and Charging Cycles

In this paper, an advanced analytical model for an electric vehicle (EV) powertrain has been developed to illustrate the vehicular dynamics by combining electrical and mechanical models in the analysis. This study is based on a Nissan Leaf EV. In the electrical system, the powertrain has various components including a battery pack, a battery management system, a dc/dc converter, a dc/ac inverter, a permanent magnet synchronous motor, and a control system. In the mechanical system, it consists of power transmissions, axial shaft, and vehicle wheels. Furthermore, the driving performance of the Nissan Leaf is studied through the real-world driving tests and simulation tests in MATLAB/Simulink. In the analytical model, the vehicular dynamics is evaluated against changes in the vehicle velocity and acceleration, state of charge of the battery, and the motor power. Finally, a number of EVs involved in the power dispatch is studied. The greenhouse gas emissions of the EV are analyzed according to various energy power and driving features, and compared with the conventional internal combustion engine vehicle. In this case, Nissan Leaf is a pure EV. For a given drive cycle, Nissan Leaf can reduce CO2 emissions by 70%, depending on the way electricity is generated and duty cycles

Discovery of Dermorphin-Based Affinity Labels with Subnanomolar Affinity for Mu Opioid Receptors+

A series of potent electrophilic affinity labels (IC50 = 0.1-5 nM) containing either a bromoacetamide or isothiocyanate based on the mu opioid receptor (MOR) selective peptide dermorphin were prepared. All four analogs exhibited wash resistant inhibition of [3H]DAMGO binding at subnanomolar to nanomolar concentrations, suggesting that these analogs bind covalently to MOR. To our knowledge these peptides are the highest affinity peptide-based affinity labels for MOR reported to date

Design of a high speed 18/12 switched reluctance motor drive with an asymmetrical bridge converter for electric vehicles

The application of permanent magnet free motors have gained a huge attention for pure electric and hybrid electric vehicles. This paper proposed the design of 20-kW switched reluctance motor having 18 stator poles and 12 rotor poles by using finite element analysis machine design software Infolytica magnet and the main focus is to achieve the high speed, torque with adequate performance for electric vehicles. The asymmetric bridge converter has been used and the series of varying the excitation voltage, slot fill factor with respect to the number of turns and stranded area of the conductor has been analysed. Additionally, in order to the electromagnetic force vector, the switching sequence is examined. The simulation results show the great potential of the suggested motor and can provide a good starting torque with high speed and can be suitable to achieve the freedom Car 2020 electric vehicle target

Credneramides A and B: Neuromodulatory Phenethylamine and Isopentylamine Derivatives of a Vinyl Chloride-Containing Fatty Acid from cf. Trichodesmium sp. nov.

Credneramides A (1) and B (2), two vinyl chloride-containing metabolites, were isolated from a Papua New Guinea collection of cf. Trichodesmium sp. nov. and expand a recently described class of vinyl chloride-containing natural products. The precursor fatty acid, credneric acid (3), was isolated from both the aqueous and organic fractions of the parent fraction as well as from another geographically and phylogenetically distinct cyanobacterial collection (Panama). Credneramides A and B inhibited spontaneous calcium oscillations in murine cerebrocortical neurons at low micromolar concentrations (1, IC 50 4.0 μM; 2, IC 50 3.8 μM).Credneramides A (1) and B (2), two vinyl chloride-containing metabolites, were isolated from a Papua New Guinea collection of cf. Trichodesmium sp. nov. and expand a recently described class of vinyl chloride-containing natural products. The precursor fatty acid, credneric acid (3), was isolated from both the aqueous and organic fractions of the parent fraction as well as from another geographically and phylogenetically distinct cyanobacterial collection (Panama). Credneramides A and B inhibited spontaneous calcium oscillations in murine cerebrocortical neurons at low micromolar concentrations (1, IC 50 4.0 μM; 2, IC 50 3.8 μM)