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

Effects of ethylenediamine – a putative GABA-releasing agent – on rat hippocampal slices and neocortical activity in vivo

The simple diamine diaminoethane (ethylenediamine, EDA) has been shown to activate GABA receptors in the central and peripheral nervous systems, partly by a direct action and partly by releasing endogenous GABA. These effects have been shown to be produced by the complexation of EDA with bicarbonate to form a carbamate. The present work has compared EDA, GABA and [beta]-alanine responses in rat CA1 neurons using extracellular and intracellular recordings, as well as neocortical evoked potentials in vivo. Superfusion of GABA onto hippocampal slices produced depolarisation and a decrease of field epsps, both effects fading rapidly, but showing sensitivity to blockade by bicuculline. EDA produced an initial hyperpolarisation and increase of extracellular field epsp size with no fade and only partial sensitivity to bicuculline, with subsequent depolarisation, while [beta]-alanine produces a much larger underlying hyperpolarisation and increase in fepsps, followed by depolarisation and inhibition of fepsps. The responses to [beta]-alanine, but not GABA or EDA, were blocked by strychnine. In vivo experiments, recording somatosensory evoked potentials, confirmed that EDA produced an initial increase followed by depression, and that this effect was not fully blocked by bicuculline. Overall the results indicate that EDA has actions in addition to the activation of GABA receptors. These actions are not attributable to activation of [beta]-alanine-sensitive glycine receptors, but may involve the activation of sites sensitive to adipic acid, which is structurally equivalent to the dicarbamate of EDA. The results emphasise the complex pharmacology of simple amines in bicarbonate-containing solution

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

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

Performance of the LHCb Vertex Detector Alignment Algorithm determined with Beam Test Data

LHCb is the dedicated heavy flavour experiment at the Large Hadron Collider at CERN. The partially assembled silicon vertex locator (VELO) of the LHCb experiment has been tested in a beam test. The data from this beam test have been used to determine the performance of the VELO alignment algorithm. The relative alignment of the two silicon sensors in a module and the relative alignment of the modules has been extracted. This alignment is shown to be accurate at a level of approximately 2 micron and 0.1 mrad for translations and rotations, respectively in the plane of the sensors. A single hit precision at normal track incidence of about 10 micron is obtained for the sensors. The alignment of the system is shown to be stable at better than the 10 micron level under air to vacuum pressure changes and mechanical movements of the assembled system.Comment: accepted for publication in NIM

QED3 theory of underdoped high temperature superconductors

Low-energy theory of d-wave quasiparticles coupled to fluctuating vortex loops that describes the loss of phase coherence in a two dimensional d-wave superconductor at T=0 is derived. The theory has the form of 2+1 dimensional quantum electrodynamics (QED3), and is proposed as an effective description of the T=0 superconductor-insulator transition in underdoped cuprates. The coupling constant ("charge") in this theory is proportional to the dual order parameter of the XY model, which is assumed to be describing the quantum fluctuations of the phase of the superconducting order parameter. The principal result is that the destruction of phase coherence in d-wave superconductors typically, and immediately, leads to antiferromagnetism. The transition can be understood in terms of the spontaneous breaking of an approximate "chiral" SU(2) symmetry, which may be discerned at low enough energies in the standard d-wave superconductor. The mechanism of the symmetry breaking is analogous to the dynamical mass generation in the QED3, with the "mass" here being proportional to staggered magnetization. Other insulating phases that break chiral symmetry include the translationally invariant "d+ip" and "d+is" insulators, and various one dimensional charge-density and spin-density waves. The theory offers an explanation for the rounded d-wave-like dispersion seen in ARPES experiments on Ca2CuO2Cl2 (F. Ronning et. al., Science 282, 2067 (1998)).Comment: Revtex, 20 pages, 5 figures; this is a much extended follow-up to the Phys. Rev. Lett. vol.88, 047006 (2002) (cond-mat/0110188); improved presentation, many additional explanations, comments, and references added, sec. IV rewritten. Final version, to appear in Phys. Rev.

Computational Physics on Graphics Processing Units

The use of graphics processing units for scientific computations is an emerging strategy that can significantly speed up various different algorithms. In this review, we discuss advances made in the field of computational physics, focusing on classical molecular dynamics, and on quantum simulations for electronic structure calculations using the density functional theory, wave function techniques, and quantum field theory.Comment: Proceedings of the 11th International Conference, PARA 2012, Helsinki, Finland, June 10-13, 201

Compressibility Effect on the Rayleigh–Taylor Instability with Sheared Magnetic Fields

We study the effect of plasma compressibility on the Rayleigh–Taylor instability of a magnetic interface with a sheared magnetic field. We assume that the plasma is ideal and the equilibrium quantities are constant above and below the interface. We derive the dispersion equation. Written in dimensionless variables, it contains seven dimensionless parameters: the ratio of plasma densities above and below the interface ζζ, the ratio of magnetic field magnitude squared χχ, the shear angle αα, the plasma beta above and below the interface, β2β2 and β1β1, the angle between the perturbation wave number and the magnetic field direction above the interface ϕϕ, and the dimensionless wave number κκ. Only six of these parameters are independent because χχ, β1β1, and β2β2 are related by the condition of total pressure continuity at the interface. Only perturbations with the wave number smaller than the critical wave number are unstable. The critical wave number depends on ϕϕ, but it is independent of β1β1 and β2β2, and is the same as that in the incompressible plasma approximation. The dispersion equation is solved numerically with ζ=100ζ=100, χ=1χ=1, and β1=β2=ββ1=β2=β. We obtain the following results. When ββ decreases, so does the maximum instability increment. However, the effect is very moderate. It is more pronounced for high values of αα. We also calculate the dependence on ϕϕ of the maximum instability increment with respect to κκ. The instability increment takes its maximum at ϕ=ϕmϕ=ϕm. Again, the decrease of ββ results in the reduction of the instability increment. This reduction is more pronounced for high values of |ϕ−ϕm||ϕ−ϕm|. When both αα and |ϕ−ϕm||ϕ−ϕm| are small, the reduction effect is practically negligible. The theoretical results are applied to the magnetic Rayleigh–Taylor instability of prominence threads in the solar atmosphere