In vivo vitamin C supplementation increases phosphoinositol transfer protein expression in peripheral blood mononuclear cells from healthy individuals

Ascorbate can act as both a reducing and oxidising agent in vitro depending on its environment. It can modulate the intracellular redox environment of cells and therefore is predicted to modulate thiol-dependent cell signalling and gene expression pathways. Using proteomic analysis of vitamin C-treated T cells in vitro, we have previously reported changes in expression of five functional protein groups associated with signalling, carbohydrate metabolism, apoptosis, transcription and immune function. The increased expression of the signalling molecule phosphatidylinositol transfer protein (PITP) was also confirmed using Western blotting. Herein, we have compared protein changes elicited by ascorbate in vitro, with the effect of ascorbate on plasma potassium levels, on peripheral blood mononuclear cell (PBMC) apoptosis and PITP expression, in patients supplemented with vitamin C (0-2 g/d) for up to 10 weeks to investigate whether in vitro model systems are predictive of in vivo effects. PITP varied in expression widely between subjects at all time-points analysed but was increased by supplementation with 2 g ascorbate/d after 5 and 10 weeks. No effects on plasma potassium levels were observed in supplemented subjects despite a reduction of K+ channel proteins in ascorbate-treated T cells in vitro. Similarly, no effect of vitamin C supplementation on PBMC apoptosis was observed, whilst ascorbate decreased expression of caspase 3 recruitment domain protein in vitro. These data provide one of the first demonstrations that proteomics may be valuable in developing predictive markers of nutrient effects in vivo and may identify novel pathways for studying mechanisms of action in vivo.

Effects of metformin on BRIN-BD11 beta-cell insulin secretory desensitization induced by prolonged exposure to sulphonylureas

Aims: Prolonged exposure of pancreatic beta-cells in vitro to the sulphonylureas tolbutamide and glibenclamide induces subsequent desensitization of insulinotropic pathways. Clinically, the insulin-sensitizing biguanide drug metformin is often administered alongside sulphonylurea as antidiabetic therapy. The present study examines the functional effects of metformin (200 ��M) on tolbutamide- and glibenclamide-induced desensitisation. Methods: Acute and prolonged (18 h) effects of exposure to tolbutamide and glibenclamide alone, or in the presence of metformin, were examined in insulin-secreting BRIN-BD11 cells. Results: In acute 20 min incubations at 1.1 mM glucose, metformin increased (1.2-1.7-fold; p <0.001) the insulin-releasing actions of tolbutamide and glibenclamide. At 16.7 mM glucose, metformin significantly enhanced glibenclamide-induced insulin release at all concentrations (50-400 ��M) examined, but tolbutamide-stimulated insulin secretion was only augmented at higher concentrations (300-400 ��M). Exposure for 18 h to 100 ��M tolbutamide or glibenclamide significantly impaired insulin release in response to glucose and a broad range of insulin secretagogues. Concomitant culture with metformin (200 ��M) prevented or partially reversed many of the adverse effects on K channel dependent and independent insulinotropic pathways. Beneficial effects of metformin were also observed in cells exposed to glibenclamide for 18 h with significant improvements in the insulin secretory responsiveness to alanine, GLP-1 and sulphonylureas. The decrease of viable cell numbers observed with glibenclamide was reversed by co-culture with metformin, but cellular insulin content was depressed. Conclusions: The results suggest that metformin can prevent the aspects of sulphonylurea-induced beta-cell desensitization. �� 2010 Blackwell Publishing Ltd.

Modulation of a calcium-sensitive nonspecific cation channel by closely associated protein kinase and phosphatase activities

Regulation of nonspecific cation channels often underlies neuronal bursting and other prolonged changes in neuronal activity. In bag cell neurons of Aplysia, it recently has been suggested that an intracellular messenger-induced increase in the activity of a nonspecific cation channel may underlie the onset of a 30-min period of spontaneous action potentials referred to as the ���afterdischarge.��� In patch clamp studies of the channel, we show that the open probability of the channel can be increased by an average of 10.7-fold by application of ATP to the cytoplasmic side of patches. Duration histograms indicate that the increase is primarily a result of a reduction in the duration and percentage of channel closures described by the slowest time constant. The increase in open probability was not observed using 5���-adenylylimidodiphosphate, a nonhydrolyzable ATP analog, and was blocked in the presence of H7 or the more specific calcium/phospholipid-dependent protein kinase C (PKC) inhibitor peptide(19���36). Because the increase in activity observed in response to ATP occurred without application of protein kinase, our results indicate that a kinase endogenous to excised patches mediates the effect. The effect of ATP could be reversed by exogenously applied protein phosphatase 1 or by a microcystin-sensitive phosphatase also endogenous to excised patches. These results, together with work demonstrating the presence of a protein tyrosine phosphatase in these patches, suggest that the cation channel is part of a regulatory complex including at least three enzymes. This complex may act as a molecular switch to activate the cation channel and, thereby, trigger the afterdischarge.

A practical phase sensitive amplification scheme for two channel phase regeneration

A "black-box" phase sensitive amplifier is presented achieving simultaneous suppression of deterministic phase distortion on two independent 42.66 Gbit/s DPSK modulated signal wavelengths.

The development of planar high-K/III-V p-channel MOSFETs for post-silicon CMOS

Conventional Si complementary-metal-oxide-semiconductor (CMOS) scaling is fast approaching its limits. The extension of the logic device roadmap for future enhancements in transistor performance requires non-Si materials and new device architectures. III-V materials, due to their superior electron transport properties, are well poised to replace Si as the channel material beyond the 10nm technology node to mitigate the performance loss of Si transistors from further reductions in supply voltage to minimise power dissipation in logic circuits. However several key challenges, including a high quality dielectric/III-V gate stack, a low-resistance source/drain (S/D) technology, heterointegration onto a Si platform and a viable III-V p-metal-oxide-semiconductor field-effect-transistor (MOSFET), need to be addressed before III-Vs can be employed in CMOS. This Thesis specifically addressed the development and demonstration of planar III-V p-MOSFETs, to complement the n-MOSFET, thereby enabling an all III-V CMOS technology to be realised. This work explored the application of InGaAs and InGaSb material systems as the channel, in conjunction with Al2O3/metal gate stacks, for p-MOSFET development based on the buried-channel flatband device architecture. The body of work undertaken comprised material development, process module development and integration into a robust fabrication flow for the demonstration of p-channel devices. The parameter space in the design of the device layer structure, based around the III-V channel/barrier material options of In_{x���0.53}Ga_1-xAs/In_0.52Al_0.48As and In_{x���0.1}Ga_1-xSb/AlSb, was systematically examined to improve hole channel transport. A mobility of 433 cm²/Vs, the highest room temperature hole mobility of any InGaAs quantum-well channel reported to date, was obtained for the In_0.85Ga_0.15As (2.1% strain) structure. S/D ohmic contacts were developed based on thermally annealed Au/Zn/Au metallisation and validated using transmission line model test structures. The effects of metallisation thickness, diffusion barriers and de-oxidation conditions were examined. Contacts to InGaSb-channel structures were found to be sensitive to de-oxidation conditions. A fabrication process, based on a lithographically-aligned double ohmic patterning approach, was realised for deep submicron gate-to-source/drain gap (L_side) scaling to minimise the access resistance, thereby mitigating the effects of parasitic S/D series resistance on transistor performance. The developed process yielded gaps as small as 20nm. For high-k integration on GaSb, ex-situ ammonium sulphide ((NH₄)₂S) treatments, in the range 1%-22%, for 10min at 295K were systematically explored for improving the electrical properties of the Al₂O₃/GaSb interface. Electrical and physical characterisation indicated the 1% treatment to be most effective with interface trap densities in the range of 4 - 10��10¹²cm^-2eV^-1 in the lower half of the bandgap. An extended study, comprising additional immersion times at each sulphide concentration, was further undertaken to determine the surface roughness and the etching nature of the treatments on GaSb. A number of p-MOSFETs based on III-V-channels with the most promising hole transport and integration of the developed process modules were successfully demonstrated in this work. Although the non-inverted InGaAs-channel devices showed good current modulation and switch-off characteristics, several aspects of performance were non-ideal; depletion-mode operation, modest drive current (I_d,sat=1.14mA/mm), double peaked transconductance (g_m=1.06mS/mm), high subthreshold swing (SS=301mV/dec) and high on-resistance (R_on=845k���.��m). Despite demonstrating substantial improvement in the on-state metrics of I_d,sat (11��), g_m (5.5��) and R_on (5.6��), inverted devices did not switch-off. Scaling gate-to-source/drain gap (L_side) from 1��m down to 70nm improved I_d,sat (72.4mA/mm) by a factor of 3.6 and gm (25.8mS/mm) by a factor of 4.1 in inverted InGaAs-channel devices. Well-controlled current modulation and good saturation behaviour was observed for InGaSb-channel devices. In the on-state In_0.3Ga_0.7Sb-channel (I_d,sat=49.4mA/mm, g_m=12.3mS/mm, R_on=31.7k���.��m) and In_0.4Ga_0.6Sb-channel (I_d,sat=38mA/mm, g_m=11.9mS/mm, R_on=73.5k���.��m) devices outperformed the InGaAs-channel devices. However the devices could not be switched off. These findings indicate that III-V p-MOSFETs based on InGaSb as opposed to InGaAs channels are more suited as the p-channel option for post-Si CMOS.

Interference Alignment Algorithms for the K User Constant MIMO Interference Channel

This paper considers the degrees of freedom (DOF) for a K user multiple-input multiple-output (MIMO) M x N interference channel using interference alignment (IA). A new performance metric for evaluating the efficacy of IA algorithms is proposed, which measures the extent to which the desired signal dimensionality is preserved after zero-forcing the interference at the receiver. Inspired by the metric, two algorithms are proposed for designing the linear precoders and receive filters for IA in the constant MIMO interference channel with a finite number of symbol extensions. The first algorithm uses an eigenbeamforming method to align sub-streams of the interference to reduce the dimensionality of the interference at all the receivers. The second algorithm is iterative, and is based on minimizing the interference leakage power while preserving the dimensionality of the desired signal space at the intended receivers. The improved performance of the algorithms is illustrated by comparing them with existing algorithms for IA using Monte Carlo simulations.

On the generalized degrees of freedom of the K-user symmetric MIMO Gaussian interference channel

This work derives inner and outer bounds on the generalized degrees of freedom (GDOF) of the K-user symmetric MIMO Gaussian interference channel. For the inner bound, an achievable GDOF is derived by employing a combination of treating interference as noise, zero-forcing at the receivers, interference alignment (IA), and extending the Han-Kobayashi (HK) scheme to K users, depending on the number of antennas and the INR/SNR level. An outer bound on the GDOF is derived, using a combination of the notion of cooperation and providing side information to the receivers. Several interesting conclusions are drawn from the bounds. For example, in terms of the achievable GDOF in the weak interference regime, when the number of transmit antennas (M) is equal to the number of receive antennas (N), treating interference as noise performs the same as the HK scheme and is GDOF optimal. For K >; N/M+1, a combination of the HK and IA schemes performs the best among the schemes considered. However, for N/M <; K ��� N/M+1, the HK scheme is found to be GDOF optimal.

Physical Layer Network Coding for the K-User Multiple Access Relay Channel

We propose a Physical layer Network Coding (PNC) scheme for the K-user wireless Multiple Access Relay Channel, in which K source nodes want to transmit messages to a destination node D with the help of a relay node R. The proposed scheme involves (i) Phase 1 during which the source nodes alone transmit and (ii) Phase 2 during which the source nodes and the relay node transmit. At the end of Phase 1, the relay node decodes the messages of the source nodes and during Phase 2 transmits a many-to-one function of the decoded messages. To counter the error propagation from the relay node, we propose a novel decoder which takes into account the possibility of error events at R. It is shown that if certain parameters are chosen properly and if the network coding map used at R forms a Latin Hypercube, the proposed decoder offers the maximum diversity order of two. Also, it is shown that for a proper choice of the parameters, the proposed decoder admits fast decoding, with the same decoding complexity order as that of the reference scheme based on Complex Field Network Coding (CFNC). Simulation results indicate that the proposed PNC scheme offers a large gain over the CFNC scheme.

On Precoding for Constant K-User MIMO Gaussian Interference Channel With Finite Constellation Inputs

This paper considers linear precoding for the constant channel-coefficient K-user MIMO Gaussian interference channel (MIMO GIC) where each transmitter-i (Tx-i) requires the sending of d(i) independent complex symbols per channel use that take values from fixed finite constellations with uniform distribution to receiver-i (Rx-i) for i = 1, 2, ..., K. We define the maximum rate achieved by Tx-i using any linear precoder as the signal-to-noise ratio (SNR) tends to infinity when the interference channel coefficients are zero to be the constellation constrained saturation capacity (CCSC) for Tx-i. We derive a high-SNR approximation for the rate achieved by Tx-i when interference is treated as noise and this rate is given by the mutual information between Tx-i and Rx-i, denoted as I(X) under bar (i); (Y) under bar (i)]. A set of necessary and sufficient conditions on the precoders under which I(X) under bar (i); (Y) under bar (i)] tends to CCSC for Tx-i is derived. Interestingly, the precoders designed for interference alignment (IA) satisfy these necessary and sufficient conditions. Furthermore, we propose gradient-ascentbased algorithms to optimize the sum rate achieved by precoding with finite constellation inputs and treating interference as noise. A simulation study using the proposed algorithms for a three-user MIMO GIC with two antennas at each node with d(i) = 1 for all i and with BPSK and QPSK inputs shows more than 0.1-b/s/Hz gain in the ergodic sum rate over that yielded by precoders obtained from some known IA algorithms at moderate SNRs.

Inner Bound on the GDOF of the K-User MIMO Gaussian Symmetric Interference Channel

The K-user multiple input multiple output (MIMO) Gaussian symmetric interference channel where each transmitter has M antennas and each receiver has N antennas is studied from a generalized degrees of freedom (GDOF) perspective. An inner bound on the GDOF is derived using a combination of techniques such as treating interference as noise, zero forcing (ZF) at the receivers, interference alignment (IA), and extending the Han-Kobayashi (HK) scheme to K users, as a function of the number of antennas and the log INR/log SNR level. Several interesting conclusions are drawn from the derived bounds. It is shown that when K > N/M + 1, a combination of the HK and IA schemes performs the best among the schemes considered. When N/M < K <= N/M + 1, the HK-scheme outperforms other schemes and is found to be GDOF optimal in many cases. In addition, when the SNR and INR are at the same level, ZF-receiving and the HK-scheme have the same GDOF performance.

Outer Bounds on the Sum Rate of the K-User MIMO Gaussian Interference Channel

This paper derives outer bounds on the sum rate of the K-user MIMO Gaussian interference channel (GIC). Three outer bounds are derived, under different assumptions of cooperation and providing side information to receivers. The novelty in the derivation lies in the careful selection of side information, which results in the cancellation of the negative differential entropy terms containing signal components, leading to a tractable outer bound. The overall outer bound is obtained by taking the minimum of the three outer bounds. The derived bounds are simplified for the MIMO Gaussian symmetric IC to obtain outer bounds on the generalized degrees of freedom (GDOF). The relative performance of the bounds yields insight into the performance limits of multiuser MIMO GICs and the relative merits of different schemes for interference management. These insights are confirmed by establishing the optimality of the bounds in specific cases using an inner bound on the GDOF derived by the authors in a previous work. It is also shown that many of the existing results on the GDOF of the GIC can be obtained as special cases of the bounds, e. g., by setting K = 2 or the number of antennas at each user to 1.

Origin of flat-band voltage sharp roll-off in metal gate/high-k/ultrathin- SiO2/Si p-channel metal-oxide-semiconductor stacks

The origin of the flat band voltage roll-off (V-FB roll-off) in metal gate/high-k/ultrathin-SiO2/Si metal-oxide-semiconductor stacks is analyzed and a model describing the role of the dipoles at the SiO2/Si interface on the V-FB sharp roll-off is proposed. The V-FB sharp roll-off appears when the thickness of the SiO2 interlayer diminishes to below the oxygen diffusion depth. The results derived using our model agree well with experimental data and provide insights to the mechanism of the V-FB sharp roll-off.

64������������������������������������������������������������������������A 64-Channel Position Sensitive Current Distribution Detector with Data Acquisition System

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Optimisation of source/drain extension region profile for suppression of short channel effects in sub-50 nm DG SOI MOSFETs with high- k gate dielectrics

Novel technology dependent scaling parameters i.e. spacer to gradient ratio and effective channel length (Leff) are proposed for source/drain engineered DG MOSFET, and their significance in minimizing short channel effects (SCES) in high-k gate dielectrics is discussed in detail. Results show that a high-k dielectric should be associated with a higher spacer to gradient ratio to minimise SCEs The analytical model agrees with simulated data over the entire range of spacer widths, doping gradients, high-k gate dielectrics and effective channel lengths.

Isoform-specific inhibition of TRPC4 channel by phosphatidylinositol 4,5-bisphosphate.

Full-length transient receptor potential (TRP) cation channel TRPC4alpha and shorter TRPC4beta lacking 84 amino acids in the cytosolic C terminus are expressed in smooth muscle and endothelial cells where they regulate membrane potential and Ca(2+) influx. In common with other "classical" TRPCs, TRPC4 is activated by G(q)/phospholipase C-coupled receptors, but the underlying mechanism remains elusive. Little is also known about any isoform-specific channel regulation. Here we show that TRPC4alpha but not TRPC4beta was strongly inhibited by intracellularly applied phosphatidylinositol 4,5-bisphosphate (PIP(2)). In contrast, several other phosphoinositides (PI), including PI(3,4)P(2), PI(3,5)P(2), and PI(3,4,5)P(3), had no effect or even potentiated TRPC4alpha indicating that PIP(2) inhibits TRPC4alpha in a highly selective manner. We show that PIP(2) binds to the C terminus of TRPC4alpha but not that of TRPC4beta in vitro. Its inhibitory action was dependent on the association of TRPC4alpha with actin cytoskeleton as it was prevented by cytochalasin D treatment or by the deletion of the C-terminal PDZ-binding motif (Thr-Thr-Arg-Leu) that links TRPC4 to F-actin through the sodium-hydrogen exchanger regulatory factor and ezrin. PIP(2) breakdown appears to be a required step in TRPC4alpha channel activation as PIP(2) depletion alone was insufficient for channel opening, which additionally required Ca(2+) and pertussis toxin-sensitive G(i/o) proteins. Thus, TRPC4 channels integrate a variety of G-protein-dependent stimuli, including a PIP(2)/cytoskeleton dependence reminiscent of the TRPC4-like muscarinic agonist-activated cation channels in ileal myocytes.