Investigation of the effects of the novel anticonvulsant compound carisbamate(RWJ-333369) on rat piriform cortical neurones in vitro

Background and purpose: Carisbamate is being developed for adjuvant treatment of partial onset epilepsy. Carisbamate produces anticonvulsant effects in primary generalized, complex partial and absence-type seizure models, and exhibits neuroprotective and antiepileptogenic properties in rodent epilepsy models. Phase IIb clinical trials of carisbamate demonstrated efficacy against partial onset seizures; however, its mechanisms of action remain unknown. Here, we report the effects of carisbamate on membrane properties, evoked and spontaneous synaptic transmission and induced epileptiform discharges in layer II-III neurones in piriform cortical brain slices. Experimental approach: Effects of carisbamate were investigated in rat piriform cortical neurones by using intracellular electrophysiological recordings. Key results: Carisbamate (50–400 mmol·L-1) reversibly decreased amplitude, duration and rise-time of evoked action potentials and inhibited repetitive firing, consistent with use-dependent Na+ channel block; 150–400 mmol·L-1 carisbamate reduced neuronal input resistance, without altering membrane potential. After microelectrode intracellular Cl- loading, carisbamate depolarized cells, an effect reversed by picrotoxin. Carisbamate (100–400 mmol·L-1) also selectively depressed lateral olfactory tract-afferent evoked excitatory synaptic transmission (opposed by picrotoxin), consistent with activation of a presynaptic Cl conductance. Lidocaine (40–320 mmol·L-1) mimicked carisbamate, implying similar modes of action. Carisbamate (300–600 mmol·L-1) had no effect on spontaneous GABAA miniature inhibitory postsynaptic currents and at lower concentrations (50–200 mmol·L-1) inhibited Mg2+-free or 4-aminopyridine-induced seizure-like discharges. Conclusions and implications: Carisbamate blocked evoked action potentials use-dependently, consistent with a primary action on Na+ channels and increased Cl- conductances presynaptically and, under certain conditions, postsynaptically to selectively depress excitatory neurotransmission in piriform cortical layer Ia-afferent terminals.

The role of voltage gated T-type Ca2+ channel isoforms in mediating "capacitative" Ca2+ entry in cancer cells

The mechanism by which Ca2+ enters electrically non-excitable cells is unclear. The sensitivity of the Ca2+ entry pathway in electrically non-excitable cells to inhibition by extracellular Ni2+ was used to direct the synthesis of a library of simple, novel compounds. These novel compounds inhibit Ca2+ entry into and, consequently, proliferation of several cancer cell lines. They showed stereoselective inhibition of proliferation and Ca2+ influx with identical stereoselective inhibition of heterologously expressed Cav3.2 isoform of T-type Ca2+ channels. Proliferation of human embryonic kidney (HEK)293 cells transfected with the Cav3.2 Ca2+ channel was also blocked. Cancer cell lines sensitive to our compounds express message for the Cav3.2 T-type Ca2+ channel isoform, its delta25B splice variant, or both, while a cell line resistant to our compounds does not. These observations raise the possibility that clinically useful drugs can be designed based upon the ability to block these Ca2+ channels.

Performance of GPRS coding scheme detection under severe multipath and co-channel interference as a function of soft-bit width

The General Packet Radio Service (GPRS) has been developed for the mobile radio environment to allow the migration from the traditional circuit switched connection to a more efficient packet based communication link particularly for data transfer. GPRS requires the addition of not only the GPRS software protocol stack, but also more baseband functionality for the mobile as new coding schemes have be en defined, uplink status flag detection, multislot operation and dynamic coding scheme detect. This paper concentrates on evaluating the performance of the GPRS coding scheme detection methods in the presence of a multipath fading channel with a single co-channel interferer as a function of various soft-bit data widths. It has been found that compressing the soft-bit data widths from the output of the equalizer to save memory can influence the likelihood decision of the coding scheme detect function and hence contribute to the overall performance loss of the system. Coding scheme detection errors can therefore force the channel decoder to either select the incorrect decoding scheme or have no clear decision which coding scheme to use resulting in the decoded radio block failing the block check sequence and contribute to the block error rate. For correct performance simulation, the performance of the full coding scheme detection must be taken into account.

A block coprocessor for user data rate improvements to GPRS coding scheme 4

The general packet radio service (GPRS) has been developed to allow packet data to be transported efficiently over an existing circuit-switched radio network, such as GSM. The main application of GPRS are in transporting Internet protocol (IP) datagrams from web servers (for telemetry or for mobile Internet browsers). Four GPRS baseband coding schemes are defined to offer a trade-off in requested data rates versus propagation channel conditions. However, data rates in the order of > 100 kbits/s are only achievable if the simplest coding scheme is used (CS-4) which offers little error detection and correction (EDC) (requiring excellent SNR) and the receiver hardware is capable of full duplex which is not currently available in the consumer market. A simple EDC scheme to improve the GPRS block error rate (BLER) performance is presented, particularly for CS-4, however gains in other coding schemes are seen. For every GPRS radio block that is corrected by the EDC scheme, the block does not need to be retransmitted releasing bandwidth in the channel and improving the user's application data rate. As GPRS requires intensive processing in the baseband, a viable field programmable gate array (FPGA) solution is presented in this paper.

Signal detection for orthogonal space-time block coding over time-selective fading channels: the H(i) systems

One major assumption in all orthogonal space-time block coding (O-STBC) schemes is that the channel remains static over the length of the code word. However, time-selective fading channels do exist, and in such case conventional O-STBC detectors can suffer from a large error floor in the high signal-to-noise ratio (SNR) cases. As a sequel to the authors' previous papers on this subject, this paper aims to eliminate the error floor of the H(i)-coded O-STBC system (i = 3 and 4) by employing the techniques of: 1) zero forcing (ZF) and 2) parallel interference cancellation (PIC). It is. shown that for an H(i)-coded system the PIC is a much better choice than the ZF in terms of both performance and computational complexity. Compared with the, conventional H(i) detector, the PIC detector incurs a moderately higher computational complexity, but this can well be justified by the enormous improvement.

Signal detection for orthogonal space-time block coding over time-selective fading channels: a PIC approach for the Gi Systems

One major assumption in all orthogonal space-time block coding (O-STBC) schemes is that the channel remains static over the entire length of the codeword. However, time selective fading channels do exist, and in such case the conventional O-STBC detectors can suffer from a large error floor in the high signal-to-noise ratio (SNR) cases. This paper addresses such an issue by introducing a parallel interference cancellation (PIC) based detector for the Gi coded systems (i=3 and 4).

Orthogonal space-time block coding over time-selective fading channels: a PIC detector for the Gi systems

All the orthogonal space-time block coding (O-STBC) schemes are based on the following assumption: the channel remains static over the entire length of the codeword. However, time selective fading channels do exist, and in many cases the conventional O-STBC detectors can suffer from a large error floor in the high signal-to-noise ratio (SNR) cases. This paper addresses such an issue by introducing a parallel interference cancellation (PIC) based detector for the Gi coded systems (i=3 and 4).

A robust non-orthogonal space-time block code for four transmit antennas

Several non-orthogonal space-time block coding (NO-STBC) schemes have recently been proposed to achieve full rate transmission. Some of these schemes, however, suffer from weak robustness: their channel matrices will become ill conditioned in the case of highly correlated channels (HCC). To address this issue, this paper derives a family of robust NO-STBC schemes for four Tx antennas based on the worst case of HCC. These codes turned out to be a superset of Jafarkhani's quasi-orthogonal STBC codes. A computationally affordable linear decoder is also proposed. Although these codes achieve a similar performance to the non-robust schemes under normal channel conditions, they offer a strong robustness against HCC (although possibly yielding a poorer performance). Finally, computer simulations are presented to verify the algorithm design.

Space-time block coding for four transmit antennas over time-selective fading channels: orthogonal or non-orthogonal design?

The paper deals with an issue in space time block coding (STBC) design. It considers whether, over a time-selective channel, orthogonal STBC (O-STBC) or non-orthogonal STBC (NO-STBC) performs better. It is shown that, under time-selectiveness, once vehicle speed has risen above a certain value, NO-STBC always outperforms O-STBC across the whole SNR range. Also, considering that all existing NO-STBC schemes have been investigated under quasi-static channels only, a new simple receiver is derived for the NO-STBC system under time-selective channels.

Hepatitis C virus NS5A inhibits mixed lineage kinase 3 to block apoptosis

Hepatitis C virus (HCV) infection results in the activation of numerous stress responses including oxidative stress, with the potential to induce an apoptotic state. Previously we have shown that HCV attenuates the stress-induced, p38MAPK-mediated up-regulation of the K+ channel Kv2.1, to maintain the survival of infected cells in the face of cellular stress. We demonstrated that this effect was mediated by HCV non-structural 5A (NS5A) protein, which impaired p38MAPK activity through a polyproline motif dependent interaction, resulting in reduction of phosphorylation activation of Kv2.1. In this study, we investigated the host cell proteins targeted by NS5A in order to mediate Kv2.1 inhibition. We screened a phage-display library expressing the entire complement of human SH3 domains for novel NS5A-host cell interactions. This analysis identified mixed lineage kinase 3 (MLK3) as a putative NS5A interacting partner. MLK3 is a serine/threonine protein kinase that is a member of the MAPK kinase kinase (MAP3K) family and activates p38MAPK. An NS5A-MLK3 interaction was confirmed by co-immunoprecipitation and western blot analysis. We further demonstrate a novel role of MLK3 in the modulation of Kv2.1 activity, whereby MLK3 overexpression leads to the up-regulation of channel activity. Accordingly, coexpression of NS5A suppressed this stimulation. Additionally we demonstrate that overexpression of MLK3 induced apoptosis which was also counteracted by NS5A. We conclude that NS5A targets MLK3 with multiple downstream consequences for both apoptosis and K+ homeostasis.

Voronoi, Delaunay, and Block-Structured Mesh Refinement for Solution of the Shallow-Water Equations on the Sphere

Alternative meshes of the sphere and adaptive mesh refinement could be immensely beneficial for weather and climate forecasts, but it is not clear how mesh refinement should be achieved. A finite-volume model that solves the shallow-water equations on any mesh of the surface of the sphere is presented. The accuracy and cost effectiveness of four quasi-uniform meshes of the sphere are compared: a cubed sphere, reduced latitude–longitude, hexagonal–icosahedral, and triangular–icosahedral. On some standard shallow-water tests, the hexagonal–icosahedral mesh performs best and the reduced latitude–longitude mesh performs well only when the flow is aligned with the mesh. The inclusion of a refined mesh over a disc-shaped region is achieved using either gradual Delaunay, gradual Voronoi, or abrupt 2:1 block-structured refinement. These refined regions can actually degrade global accuracy, presumably because of changes in wave dispersion where the mesh is highly nonuniform. However, using gradual refinement to resolve a mountain in an otherwise coarse mesh can improve accuracy for the same cost. The model prognostic variables are height and momentum collocated at cell centers, and (to remove grid-scale oscillations of the A grid) the mass flux between cells is advanced from the old momentum using the momentum equation. Quadratic and upwind biased cubic differencing methods are used as explicit corrections to a fast implicit solution that uses linear differencing.

Salt marsh morphodynamics: An investigation of tidal flows and marsh channel equilibrium

Although numerous field studies have evaluated flow and transport processes in salt marsh channels, the overall role of channels in delivering and removing material from salt marsh platforms is still poorly characterised. In this paper, we consider this issue based on a numerical hydrodynamic model for a prototype marsh system and on a field survey of the cross-sectional geometry of a marsh channel network. Results of the numerical simulations indicate that the channel transfers approximately three times the volume of water that would be estimated from mass balance considerations alone. Marsh platform roughness exerts a significant influence on the partitioning of discharge between the channel and the marsh platform edge, alters flow patterns on the marsh platform due to its effects on channel-to-platform transfer and also controls the timing of peak discharge relative to marsh-edge overtopping. Although peak channel discharges and velocities are associated with the flood tide and marsh inundation, a larger volume of water is transferred by the channel during ebb flows, a portion of which transfer takes place after the tidal height is below the marsh platform. Detailed surveys of the marsh channels crossing a series of transects at Upper Stiffkey Marsh, north Norfolk, England, show that the total channel cross-sectional area increases linearly with catchment area in the inner part of the marsh, which is consistent with the increase in shoreward tidal prism removed by the channels. Toward the marsh edge, however, a deficit in the total cross-sectional area develops, suggesting that discharge partitioning between the marsh channels and the marsh platform edge may also be expressed in the morphology of marsh channel systems.