Challenging the catechism of therapeutics for chronic neuropathic pain: targeting CaV2.2 interactions with CRMP2 peptides

Chronic neuropathic pain management is a worldwide concern. Pharmaceutical companies globally have historically targeted ion channels as the therapeutic catechism with many blockbuster successes. Remarkably, no new pain therapeutic has been approved by European or American regulatory agencies over the last decade. This article will provide an overview of an alternative approach to ion channel drug discovery: targeting regulators of ion channels, specifically focusing on voltage-gated calcium channels. We will highlight the discovery of an anti-nociceptive peptide derived from a novel calcium channel interacting partner – the collapsin response mediator protein 2 (CRMP2). In vivo administration of this peptide reduces pain behavior in a number of models of neuropathic pain without affecting sympathetic-associated cardiovascular activity, memory retrieval, sensorimotor function, or depression. A CRMP2-derived peptide analgesic, with restricted access to the CNS, represents a completely novel approach to the treatment of severe pain with an improved safety profile. As peptides now represent one of the fastest growing classes of new drugs, it is expected that peptide targeting of protein interactions within the calcium channel complex may be a paradigm shift in ion channel drug discovery

Morphological Phase Separation in Unstable Thin Films: Pattern Formation and Growth

We present results from a comprehensive numerical study of {\it morphological phase separation} (MPS) in unstable thin liquid films on a 2-dimensional substrate. We study the quantitative properties of the evolution morphology via several experimentally relevant markers, e.g., correlation function, structure factor, domain-size and defect-size probability distributions, and growth laws. Our results suggest that the late-stage morphologies exhibit dynamical scaling, and their evolution is self-similar in time. We emphasize the analogies and differences between MPS in films and segregation kinetics in unstable binary mixtures.Comment: 17 pages, 6 figures; Accepted for publication in Physical Chemistry Chemical Physic

Specific binding of lacosamide to collapsin response mediator protein 2 (CRMP2) and direct impairment of its canonical function: implications for the therapeutic potential of lacosamide

The novel antiepileptic drug lacosamide (LCM; SPM927, Vimpat®) has been heralded as having a dual-mode of action through interactions with both the voltage-gated sodium channel and the neurite outgrowth-promoting collapsin response mediator protein 2 (CRMP2). Lacosamide's ability to dampen neuronal excitability through the voltage-gated sodium channel likely underlies its efficacy in attenuating the symptoms of epilepsy (i.e., seizures). While the role of CRMP2 in epilepsy has not been well studied, given the proposed involvement of circuit reorganization in epileptogenesis, the ability of lacosamide to alter CRMP2 function may prove disease modifying. Recently, however, the validity of lacosamide's interaction with CRMP2 has come under scrutiny. In this review, we address the contradictory reports concerning the binding of lacosamide to CRMP2 as well as the ability of lacosamide to directly impact CRMP2 function. Additionally, we address similarly the contradicting reports regarding the potential disease-modifying effect of lacosamide on the development and progression of epilepsy. As the vast majority of antiepileptic drugs influences only the symptoms of epilepsy, the ability to hinder disease progression would be a major breakthrough in efforts to cure or prevent this debilitating syndrome

Spinodal Phase Separation in Liquid Films with Quenched Disorder

We study spinodal phase separation in unstable thin liquid films on chemically disordered substrates via simulations of the thin-film equation. The disorder is characterized by immobile patches of varying size and Hamaker constant. The effect of disorder is pronounced in the early stages (amplification of fluctuations), remains during the intermediate stages and vanishes in the late stages (domain growth). These findings are in contrast to the well-known effects of quenched disorder in usual phase-separation processes, viz., the early stages remain undisturbed and domain growth is slowed down in the asymptotic regime. We also address the inverse problem of estimating disorder by thin-film experiments.Comment: 12 pages, 7 figure

Development of Single layered, Wide angle, Polarization insensitive Metamaterial Absorber

The simultaneous achievement of multiband absorption, polarisation-insensitive, and angularly stable absorber is a difficult job. Therefore, in this article, an efficient single-layered absorber is designed, critically analysed, fabricated, and experimentally validated. The proposed model incorporates eight sectors loaded a circle inside the square. The four discrete absorption peaks are observed at 4.4 GHz, 6.0 GHz, 14.1 GHz, and 16.0 GHz manifesting absorption intensities of 94%, 84%, 82%, and 92%, respectively. Parametric studies have been also exercised to investigate the influence of discrete geometrical design variables on the proposed absorber. The proposed structure is symmetrical in geometry, consequence in polarisation-independent behaviour. The absorption mechanism is also explained by analysing the surface current, electric field, and magnetic field distributions. Besides, the complex electromagnetic parameters are extracted to realise the absorption phenomenon. Additionally, to validate the simulated results, an optimal sample is fabricated and the measured response is well-matched with simulated ones

Kinetics of Spinodal Phase Separation in Unstable Thin Liquid Films

We study universality in the kinetics of spinodal phase separation in unstable thin liquid films, via simulations of the thin film equation. It is shown that in addition to morphology and free energy,the number density of local maxima in the film profile can also be used to identify the early, intermediate and late stages of spinodal phase separation. A universal curve between the number density of local maxima and rescaled time describes the kinetics of early stage in d = 2, 3. The Lifshitz-Slyozov exponent of -1/3 describes the kinetics of the late stage in d = 2 even in the absence of coexisting equilibrium phases.Comment: 5 figure

Comparative Analysis of Control Techniques for PWM Rectifiers in Grid Connected Distributed Generation Systems Based on VOC and DPC

This paper presents Virtual flux based and Voltage based control schemes for PWM rectifiers in grid connected distributed generation systems from renewable sources are presented. In particular, the so-called Voltage Oriented Control (VOC), Direct Power Control (DPC), two DPC based techniques to minimize the Common Mode (CM) emissions called DPC-EMC1 and DPC-EMC2 set up by the authors and their versions based on virtual flux. All the described techniques have been implemented using MATLAB/Simulink® (Classic version 8.2 Release name (R2013b)) and compared with each other. Theoretical background with results of simulations is provided. The advantages and disadvantages of the individual control strategies are documented

Analysis of Magneto-inductive System for Rocket Sled Velocity Measurement Beyond Mach 1.5

The rail track rocket sled (RTRS) national test facility at Terminal Ballistics Research Laboratory (TBRL) has been established to provide simulated flight environment for carrying out aero dynamic studies, terminal studies and kinematic studies of variety of test articles. The sled velocity is a critical parameter in evaluation trials.  This velocity is also used to ensure that the maximum speed and allowable g loading does not exceed the value which the test article will experience under free flight in air1. Overseas, the facilities have been set up to attain velocities ranging from sub-sonic to hypersonic2. The rocket sled at TBRL can be presently accelerated to travel along the rail track at velocities up to 500 m/s and capability is being built to increase velocity beyond 500 m/s. Signals acquired from existing magneto-inductive arrangement have been analysed in the present work. The experiments indicate that with increase in velocity the rate of change of flux increases, the amplitude of induced emf also increases but terminal voltage decreases and shape of the acquired pulse gets distorted. The parameters of magneto-inductive pick up have been modified in such a way that there is improvement in amplitude and shape of the received pulse with increase in velocity. The improved signals have been analysed and simulation results validated with feasible experiments. This paper also discusses issues, challenges and proposes recommendations in improving the sensor for measurement of velocity beyond Mach 1.5. It has been found that it is prudent to reduce the inductance by reducing the number of turns and changing the core from soft iron core to air core which will improve the response of inductive pick up coil at high velocity.Defence Science Journal, 2014, 64(2), pp. 143-151. DOI: http://dx.doi.org/10.14429/dsj.64.503