Involvement of the proteasome and caspase activation in hippocampal long-term depression induced by the serine protease subtilisin

The serine protease subtilisin-A produces a long-term depression (LTD) of synaptic potentials in hippocampal slices which differs mechanistically from classical LTD. Since caspases have been implicated in hippocampal plasticity, this study examined a possible role for these enzymes in subtilisin-induced LTD. Subtilisin produced a concentration-dependent decrease in the size of field excitatory synaptic potentials (fEPSPs), which was not prevented or modified by the caspase inhibitors Z-VAD(OMe)-fmk and Z-DEVD-fmk. Similarly Z-VAD(OMe)-fmk did not modify the selective loss of protein expression produced by subtilisin. Subtilisin reduced the expression of procaspase-3 and caspase-9 but, while caspase-9 was converted to its conventionally activated form (39 kDa), caspase-3 was metabolised along a non-canonical pathway to a 29/30 kDa protein rather than the classical 17/19 kDa fragments. Both Z-VAD(OMe)-fmk and Z-DEVD-fmk were unable to prevent the reduced expression of Postsynaptic Density Protein-95, Vesicle-Associated Membrane Protein-1 and Unco-ordinated 5H3 proteins produced by subtilisin, although MG132 did produce partial recovery from subtilisin-induced depression of fEPSPs. When tested on long-term potentiation (LTP) induced by theta stimulation in the stratum radiatum, MG132 inhibited the immediate increase in fEPSP size but generated a higher plateau LTP. Twin LTP stimulation generated a further increase in LTP amplitude in control slices but not in slices exposed to MG132. The results indicate that subtilisin does produce caspase activation but that this does not contribute to its induction of LTD. However, activation of the proteasome does contribute to subtilisin-induced LTD and may also play a modulatory role in electrically induced LTP

Analysis and control of dual-output LCLC resonant converters with significant leakage inductance

The analysis, design and control of fourth-order LCLC voltage-output series-parallel resonant converters for the provision of multiple regulated outputs, is described. Specifically, state-variable concepts are developed to establish operating mode boundaries with which to describe the internal behavior and the impact of output leakage inductance. The resulting models are compared with those obtained from SPICE simulations and measurements from a prototype power supply under closed loop control to verify the analysis, modeling, and control predictions

New battery model and state-of-health determination through subspace parameter estimation and state-observer techniques

This paper describes a novel adaptive battery model based on a remapped variant of the well-known Randles' lead-acid model. Remapping of the model is shown to allow improved modeling capabilities and accurate estimates of dynamic circuit parameters when used with subspace parameter-estimation techniques. The performance of the proposed methodology is demonstrated by application to batteries for an all-electric personal rapid transit vehicle from the Urban Light TRAnsport (ULTRA) program, which is designated for use at Heathrow Airport, U. K. The advantages of the proposed model over the Randles' circuit are demonstrated by comparisons with alternative observer/estimator techniques, such as the basic Utkin observer and the Kalman estimator. These techniques correctly identify and converge on voltages associated with the battery state-of-charge (SoC), despite erroneous initial conditions, thereby overcoming problems attributed to SoC drift (incurred by Coulomb-counting methods due to overcharging or ambient temperature fluctuations). Observation of these voltages, as well as online monitoring of the degradation of the estimated dynamic model parameters, allows battery aging (state-of-health) to also be assessed and, thereby, cell failure to be predicted. Due to the adaptive nature of the proposed algorithms, the techniques are suitable for applications over a wide range of operating environments, including large ambient temperature variations. Moreover, alternative battery topologies may also be accommodated by the automatic adjustment of the underlying state-space models used in both the parameter-estimation and observer/estimator stages

Altered hippocampal plasticity by prenatal kynurenine administration, kynurenine-3-monoxygenase (KMO) deletion or galantamine

Glutamate receptors sensitive to N-methyl-d-aspartate (NMDA) are involved in embryonic brain development but their activity may be modulated by the kynurenine pathway of tryptophan metabolism which includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at these receptors. Our previous work has shown that prenatal inhibition of the pathway produces abnormalities of brain development. In the present study kynurenine and probenecid (both 100 mg/kg, doses known to increase kynurenic acid levels in the brain) were administered to female Wistar rats on embryonic days E14, E16 and E18 of gestation and the litter was allowed to develop to post-natal day P60. Western blotting revealed no changes in hippocampal expression of several proteins previously found to be altered by inhibition of the kynurenine pathway including the NMDA receptor subunits GluN1, GluN2A and GluN2B, as well as doublecortin, Proliferating Cell Nuclear Antigen (PCNA), sonic hedgehog and unco-ordinated (unc)-5H1 and 5H3. Mice lacking the enzyme kynurenine-3-monoxygenase (KMO) also showed no changes in hippocampal expression of several of these proteins or the 70-kDa and 100-kDa variants of Disrupted in Schizophrenia-1 (DISC1). Electrical excitability of pyramidal neurons in the CA1 region of hippocampal slices was unchanged, as was paired-pulse facilitation and inhibition. Long-term potentiation was decreased in the kynurenine-treated rats and in the KMO(−/−) mice, but galantamine reversed this effect in the presence of nicotinic receptor antagonists, consistent with evidence that it can potentiate glutamate at NMDA receptors. It is concluded that interference with the kynurenine pathway in utero can have lasting effects on brain function of the offspring, implying that the kynurenine pathway is involved in the regulation of early brain development

Methodologies for the design of LCC voltage-output resonant converters

Abstract: The paper presents five structured design methodologies for third-order LCC voltage output resonant converters. The underlying principle of each technique is based on an adaptation of a FMA equivalent circuit that accommodates the nonlinear behaviour of the converter. In contrast to previously published methods, the proposed methodologies explicitly incorporate the effects of the transformer magnetising inductance. Furthermore, a number of the methodologies allow the resonant-tank components to be specified at the design phase, thereby facilitating the use of standard off-the-shelf components. A procedure for sizing the filter capacitor is derived, and the use of error mapping, to identify parameter boundaries and provide the designer with a qualitative feel for the accuracy of a proposed converter design, is explored

Progress on the development of a three-dimensional capability for simulating large-scale complex geologic processes

Significant progress has been made in developing a three-dimensional capability for predicting the mechanical response of rock over spatial and time scales of geologic interest to the Oil and Gas industry. An Advanced Computational Technology Initiative (ACTI) initiated three years ago to achieve such a computational technology breakthrough has made significant progress towards its goal by adapting and improving the unique advanced quasistatic finite element technology developed by Sandia National Laboratories to the mechanics applications important to exploration and production (E and P). This capability now gives the industry a powerful tool to help reduce risk on prospects, improve pre-project initial reserve estimates, and lower operating costs. Progress to date on this program is reported herein by presenting and discussing the enhancements and adaptations that have been made to the technology, with specific examples to illustrate their use on large E and P geomechanics problems

Field theoretical approach to non-local interactions: 1d electrons and fermionic impurities

We apply a recently proposed path-integral approach to non-local bosonization to a Thirring-like system modeling non-relativistic massless particles interacting with localized fermionic impurities. We consider forward scattering processes described by symmetric potentials including interactions between charge, current, spin and spin-current densities. In the general (spin-flipping) problem we obtain an effective action for the collective modes of the model at T = 0, containing WZW-type terms. When spin-flipping processes are disregarded the structure of the action is considerably simplified, allowing us to derive exact expressions for the dispersion relations of collective modes and two point fermionic correlation functions as functionals of the potentials. Finally, as an example, we compute the momentum distribution for the case in which electrons and impurities are coupled through spin and spin-current densities only. The formulae we get suggest that our formalism could be useful in order to seek for a mechanism able to restore Fermi liquid behavior.Comment: 27 pages, Latex file, no figure

Changes in synaptic transmission and protein expression in the brains of adult offspring after prenatal inhibition of the kynurenine pathway

During early brain development, N-methyl-d-aspartate (NMDA) receptors are involved in cell migration, neuritogenesis, axon guidance and synapse formation, but the mechanisms which regulate NMDA receptor density and function remain unclear. The kynurenine pathway of tryptophan metabolism includes an agonist (quinolinic acid) and an antagonist (kynurenic acid) at NMDA receptors and we have previously shown that inhibition of the pathway using the kynurenine-3-monoxygenase inhibitor Ro61-8048 in late gestation produces rapid changes in protein expression in the embryos and effects on synaptic transmission lasting until postnatal day 21 (P21). The present study sought to determine whether any of these effects are maintained into adulthood. After prenatal injections of Ro61-8048 the litter was allowed to develop to P60 when some offspring were euthanized and the brains removed for examination. Analysis of protein expression by Western blotting revealed significantly reduced expression of the GluN2A subunit (32%) and the morphogenetic protein sonic hedgehog (31%), with a 29% increase in the expression of doublecortin, a protein associated with neurogenesis. No changes were seen in mRNA abundance using quantitative real-time polymerase chain reaction. Neuronal excitability was normal in the CA1 region of hippocampal slices but paired-pulse stimulation revealed less inhibition at short interpulse intervals. The amount of long-term potentiation was decreased by 49% in treated pups and recovery after low-frequency stimulation was delayed. The results not only strengthen the view that basal, constitutive kynurenine metabolism is involved in normal brain development, but also show that changes induced prenatally can affect the brains of adult offspring and those changes are quite different from those seen previously at weaning (P21). Those changes may be mediated by altered expression of NMDAR subunits and sonic hedgehog

Noise and Measurement Efficiency of a Partially Coherent Mesoscopic Detector

We study the noise properties and efficiency of a mesoscopic resonant-level conductor which is used as a quantum detector, in the regime where transport through the level is only partially phase coherent. We contrast models in which detector incoherence arises from escape to a voltage probe, versus those in which it arises from a random time-dependent potential. Particular attention is paid to the back-action charge noise of the system. While the average detector current is similar in all models, we find that its noise properties and measurement efficiency are sensitive both to the degree of coherence and to the nature of the dephasing source. Detector incoherence prevents quantum limited detection, except in the non-generic case where the source of dephasing is not associated with extra unobserved information. This latter case can be realized in a version of the voltage probe model.Comment: 15 pages, 5 figures; revised dicussion of voltage probe model

Time-delayed feedback control of unstable periodic orbits near a subcritical Hopf bifurcation

We show that Pyragas delayed feedback control can stabilize an unstable periodic orbit (UPO) that arises from a generic subcritical Hopf bifurcation of a stable equilibrium in an n-dimensional dynamical system. This extends results of Fiedler et al. [PRL 98, 114101 (2007)], who demonstrated that such feedback control can stabilize the UPO associated with a two-dimensional subcritical Hopf normal form. Pyragas feedback requires an appropriate choice of a feedback gain matrix for stabilization, as well as knowledge of the period of the targeted UPO. We apply feedback in the directions tangent to the two-dimensional center manifold. We parameterize the feedback gain by a modulus and a phase angle, and give explicit formulae for choosing these two parameters given the period of the UPO in a neighborhood of the bifurcation point. We show, first heuristically, and then rigorously by a center manifold reduction for delay differential equations, that the stabilization mechanism involves a highly degenerate Hopf bifurcation problem that is induced by the time-delayed feedback. When the feedback gain modulus reaches a threshold for stabilization, both of the genericity assumptions associated with a two-dimensional Hopf bifurcation are violated: the eigenvalues of the linearized problem do not cross the imaginary axis as the bifurcation parameter is varied, and the real part of the cubic coefficient of the normal form vanishes. Our analysis of this degenerate bifurcation problem reveals two qualitatively distinct cases when unfolded in a two-parameter plane. In each case, Pyragas-type feedback successfully stabilizes the branch of small-amplitude UPOs in a neighborhood of the original bifurcation point, provided that the phase angle satisfies a certain restriction.Comment: 35 pages, 19 figure