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Search Results: 1 - 10 of 318853 matches for " Robert J Gasperini "
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TRPM8 and Nav1.8 sodium channels are required for transthyretin-induced calcium influx in growth cones of small-diameter TrkA-positive sensory neurons
Robert J Gasperini, Xu Hou, Helena Parkington, Harry Coleman, David W Klaver, Adele J Vincent, Lisa C Foa, David H Small
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-19
Abstract: Levels of intracellular cytosolic calcium were monitored in dorsal root ganglion (DRG) neurons isolated from embryonic rats using the calcium-sensitive fluorescent indicator Fluo4. An amyloidogenic mutant form of TTR, L55P, induced calcium influx into the growth cones of DRG neurons, whereas wild-type TTR had no significant effect. Atomic force microscopy and dynamic light scattering studies confirmed that the L55P TTR contained oligomeric species of TTR. The effect of L55P TTR was decreased by blockers of voltage-gated calcium channels (VGCC), as well as by blockers of Nav1.8 voltage-gated sodium channels and transient receptor potential M8 (TRPM8) channels. siRNA knockdown of TRPM8 channels using three different TRPM8 siRNAs strongly inhibited calcium influx in DRG growth cones.These data suggest that activation of TRPM8 channels triggers the activation of Nav1.8 channels which leads to calcium influx through VGCC. We suggest that TTR-induced calcium influx into DRG neurons may contribute to the pathophysiology of FAP. Furthermore, we speculate that similar mechanisms may mediate the toxic effects of other amyloidogenic proteins such as the β-amyloid protein of Alzheimer's disease.Protein misfolding is a common feature of many neurodegenerative diseases. In some of these diseases, such as the synucleinopathies and the tauopathies, cytoplasmic proteins aggregate to form intracellular deposits. However, in the amyloidoses, which include Alzheimer's disease (AD), prion diseases and the British and Danish familial dementias, proteinaceous aggregates are observed extracellularly [1-4]. There is increasing evidence that the mechanism of neurotoxicity in these amyloidoses is similar and that it is the conformation of the aggregated protein, rather than its specific amino acid sequence which results in altered membrane permeability to calcium [5]. Therefore, studies on the mechanism of neurotoxicity in one disease may provide insights into the mechanisms involved in other
Boosting Away Singularities from Conformal String Backgrounds
M. Gasperini,J. Maharana,G. Veneziano
Physics , 1992, DOI: 10.1016/0370-2693(92)90802-B
Abstract: Generalizing our previous work, we show how $O(d,d)$ transformations can be used to "boost away" in new dimensions the physical singularities that occur generically in cosmological and/or black-hole string backgrounds. As an example, we show how a recent model by Nappi and Witten can be made singularity-free via $O(3,3)$ boosts involving a fifth dimension.
Graceful exit in quantum string cosmology
M. Gasperini,J. Maharana,G. Veneziano
Physics , 1996, DOI: 10.1016/0550-3213(96)00201-5
Abstract: We write an O(d,d)-covariant Wheeler-De Witt equation in the ($d^2+1$)-dimensional minisuperspace of low-energy cosmological string backgrounds. We discuss explicit examples of transitions between two duality-related cosmological phases, and we find a finite quantum transition probability even when the two phases are classically separated by a curvature singularity. This quantum approach is completely free from operator ordering ambiguities as a consequence of the duality symmetries of the string effective action.
Gravitational waves in non-singular string cosmologies
C. Cartier,E. J. Copeland,M. Gasperini
Physics , 2001, DOI: 10.1016/S0550-3213(01)00182-1
Abstract: We study the evolution of tensor metric fluctuations in a class of non-singular models based on the string effective action, by including in the perturbation equation the higher-derivative and loop corrections needed to regularise the background solutions. We discuss the effects of such higher-order corrections on the final graviton spectrum, and we compare the results of analytical and numerical computations.
Homer regulates calcium signalling in growth cone turning
Robert Gasperini, Derek Choi-Lundberg, Michael JW Thompson, Camilla B Mitchell, Lisa Foa
Neural Development , 2009, DOI: 10.1186/1749-8104-4-29
Abstract: Homer1 knockdown reversed growth cone turning from attraction to repulsion in response to the calcium-dependent guidance cues brain derived neurotrophic factor and netrin-1. Conversely, Homer1 knockdown had no effect on repulsion to the calcium-independent guidance cue Semaphorin-3A. This reversal of attractive turning suggested a requirement for Homer1 in a molecular switch. Pharmacological experiments confirmed that the operational state of a calcium-calmodulin dependent protein kinase II/calcineurin phosphatase molecular switch was dependent on Homer1 expression. Calcium imaging of motile growth cones revealed that Homer1 is required for guidance-cue-induced rise of cytosolic calcium and the attenuation of spontaneous cytosolic calcium transients. Homer1 knockdown-induced calcium transients and turning were inhibited by antagonists of store-operated channels. In addition, immunocytochemistry revealed the close association of Homer1 with the store-operated proteins TRPC1 and STIM1 within dorsal root ganglia growth cones.These experiments provide evidence that Homer1 is an essential component of the calcium signalling repertoire within motile growth cones, regulating guidance-cue-induced calcium release and maintaining basal cytosolic calcium.Deciphering the cell signalling events that control growth cone navigation and, hence, axon guidance is crucial to our understanding of the development of functional neural circuitry. Cytosolic calcium ([Ca++]i) is a key signalling molecule that regulates growth cone motility [1,2]. The release of calcium from intracellular stores or influx via receptor-mediated or voltage-gated channels leads to discrete localised transients and/or global changes in [Ca++]i [3]. The frequency and magnitude of these [Ca++]i changes correlates with overall axon growth and extension as well as responses to soluble and contact-mediated guidance cues [2,4-6]. These changes in [Ca++]i can be of the order of milliseconds or quite persistent, lasting
Higher-dimensional perturbations of the vacuum energy density
M. Gasperini
Physics , 2008, DOI: 10.1088/1126-6708/2008/06/009
Abstract: The vacuum energy density arising from the broken supersymmetry of the (standard-model) fields living on a brane cannot be fully "off-loaded" to the bulk: even assuming the existence of an effective "self-tuning" mechanism, a small fraction of the transferred energy "bunces back" to the brane, as a backreaction of the supersymmetry breaking gravitationally transmitted to the bulk. In that case the SUSY scale of the brane has to be bounded, to guarantee the consistency of such a residual energy density with current large-scale phenomonological constraints. This effect is illustrated by computing the zero-point energies of the tower of (higher-dimensional) massive states associated to tensor metric fluctuations on a brane embedded in a warped bulk geometry, and it is shown to be independent of the number of compact or non-compact extra dimensions.
Why supersymmetry should be restored at the TeV scale
M. Gasperini
Physics , 2008, DOI: 10.1142/S0218271808014023
Abstract: It is explained why the curvature associated to the vacuum energy density arising from SUSY breaking cannot be completely transferred to the extra spatial dimensions of a bulk space-time manifold, and it is shown -- without using hierarchy arguments but only the results of current large-scale observations -- why the Tev scale should correspond to the maximal allowed SUSY-breaking scale.
Status of String Cosmology: Phenomenological Aspects
M. Gasperini
Physics , 1995,
Abstract: I report recent studies on the evolution of perturbations in the context of the ``pre-big-bang" scenario typical of string cosmology, with emphasis on the formation of a stochastic background of relic photons and gravitons, and its possible direct/indirect observable consequences. I also discuss the possible generation of a thermal microwave background by using, as example, a simple gravi-axio-dilaton model whose classical evolution connects smoothly inflationary expansion to decelerated contraction. By including the quantum back-reaction of the produced radiation the model eventually approaches the standard radiation-dominated (constant dilaton) regime.
Towards a future singularity?
M. Gasperini
Physics , 2004, DOI: 10.1142/S0218271804006310
Abstract: We discuss whether the future extrapolation of the present cosmological state may lead to a singularity even in case of "conventional" (negative) pressure of the dark energy field, namely $w=p/\rho \geq -1$. The discussion is based on an often neglected aspect of scalar-tensor models of gravity: the fact that different test particles may follow the geodesics of different metric frames, and the need for a frame-independent regularization of curvature singularities.
Amplification of Vacuum Fluctuations in String Cosmology Backgrounds
M. Gasperini
Physics , 1995,
Abstract: Inflationary string cosmology backgrounds can amplify perturbations in a more efficient way than conventional inflationary backgrounds, because the perturbation amplitude may grow - instead of being constant - outside the horizon. If not gauged away, the growing mode can limit the range of validity of a linearized description of perturbations. Even in the restricted linear range, however, this enhanced amplification may lead to phenomenological consequences unexpected in the context of the standard inflationary scenario. In particular, the production of a relic graviton background strong enough to be detected in future by LIGO, and/or the generation of a stochastic electromagnetic background strong enough to seed the cosmic magnetic fields and to be responsible for the observed large scale anisotropy.
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