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Search Results: 1 - 10 of 154878 matches for " Elena B. Pasquale "
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Eph Receptors Are Involved in the Activity-Dependent Synaptic Wiring in the Mouse Cerebellar Cortex
Roberta Cesa,Federica Premoselli,Annamaria Renna,Iryna M. Ethell,Elena B. Pasquale,Piergiorgio Strata
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019160
Abstract: Eph receptor tyrosine kinases are involved in many cellular processes. In the developing brain, they act as migratory and cell adhesive cues while in the adult brain they regulate dendritic spine plasticity. Here we show a new role for Eph receptor signalling in the cerebellar cortex. Cerebellar Purkinje cells are innervated by two different excitatory inputs. The climbing fibres contact the proximal dendritic domain of Purkinje cells, where synapse and spine density is low; the parallel fibres contact the distal dendritic domain, where synapse and spine density is high. Interestingly, Purkinje cells have the intrinsic ability to generate a high number of spines over their entire dendritic arborisations, which can be innervated by the parallel fibres. However, the climbing fibre input continuously exerts an activity-dependent repression on parallel fibre synapses, thus confining them to the distal Purkinje cell dendritic domain. Such repression persists after Eph receptor activation, but is overridden by Eph receptor inhibition with EphA4/Fc in neonatal cultured cerebellar slices as well as mature acute cerebellar slices, following in vivo infusion of the EphA4/Fc inhibitor and in EphB receptor-deficient mice. When electrical activity is blocked in vivo by tetrodotoxin leading to a high spine density in Purkinje cell proximal dendrites, stimulation of Eph receptor activation recapitulates the spine repressive effects of climbing fibres. These results suggest that Eph receptor signalling mediates the repression of spine proliferation induced by climbing fibre activity in Purkinje cell proximal dendrites. Such repression is necessary to maintain the correct architecture of the cerebellar cortex.
Positrons from pulsar winds
Pasquale Blasi,Elena Amato
Physics , 2010,
Abstract: Pulsars, or more generally rotation powered neutron stars, are excellent factories of antimatter in the Galaxy, in the form of pairs of electrons and positrons. Electrons are initially extracted from the surface of the star by the intense rotation induced electric fields and later transformed into electron-positron pairs through electromagnetic cascading. Observations of Pulsar Wind Nebulae (PWNe) show that cascades in the pulsar magnetosphere must ensure pair multiplicities of order $10^{4}-10^{5}$. These pairs finally end up as part of the relativistic magnetized wind emanating from the pulsar. The wind is slowed down, from its highly relativistic bulk motion, at a termination shock, which represents the reverse shock due to its interaction with the surrounding ejecta of the progenitor supernova. At the (relativistic) termination shock, acceleration of the pairs occurs, as part of the dissipation process, so that the cold wind is transformed into a plasma of relativistic non-thermal particles, plus a potential thermal component, which however has never been observed. As long as the pulsar wind is embedded in the supernova remnant these pairs are forced to escavate a bubble and lose energy adiabatically (because of the expansion) and radiatively (because of magnetic and radiation fields). We discuss here the observational constraints on the energy and number content of such pairs and discuss the scenarios that may allow for the pairs to escape in the interstellar medium and possibly contribute to the positron excess that has recently been detected by the PAMELA satellite. Special attention is dedicated to the case of Pulsar Bow Shock Nebulae. The pairs produced in these objects may be effectively carried out of the Supernova Remnant and released in the Interstellar Medium. As a result, Bow Shock Pulsar Wind Nebulae might be the main contributors to the positron excess in the Galaxy.
Diffusive propagation of cosmic rays from supernova remnants in the Galaxy. II: anisotropy
Pasquale Blasi,Elena Amato
Physics , 2011, DOI: 10.1088/1475-7516/2012/01/011
Abstract: We investigate the effects of stochasticity in the spatial and temporal distribution of supernova remnants on the anisotropy of cosmic rays observed at Earth. The calculations are carried out for different choices of the diffusion coefficient D(E) for propagation in the Galaxy. The propagation and spallation of nuclei are taken into account. At high energies we assume that $D(E)\sim(E/Z)^{\delta}$, with $\delta=1/3$ and $\delta=0.6$ being the reference scenarios. The large scale distribution of supernova remnants in the Galaxy is modeled following the distribution of pulsars with and without accounting for the spiral structure of the Galaxy. Our calculations allow us to determine the contribution to anisotropy resulting from both the large scale distribution of SNRs in the Galaxy and the random distribution of the nearest remnants. The naive expectation that the anisotropy amplitude scales as D(E) is shown to be an oversimplification which does not reflect in the predicted anisotropy for any realistic distribution of the sources. The fluctuations in the anisotropy pattern are dominated by nearby sources, so that predicting or explaining the observed anisotropy amplitude and phase becomes close to impossible. We find however that the very weak energy dependence of the anisotropy amplitude below $10^{5}$ GeV and the rise at higher energies, can best be explained if the diffusion coefficient is $D(E)\sim E^{1/3}$. Faster diffusion, for instance with $\delta=0.6$, leads in general to an exceedingly large anisotropy amplitude. The spiral structure introduces interesting trends in the energy dependence of the anisotropy pattern, which qualitatively reflect the trend seen in the data. For large values of the halo size we find that the anisotropy becomes dominated by the large scale regular structure of the source distribution, leading indeed to a monotonic increase of $\delta_A$ with energy.
Diffusive propagation of cosmic rays from supernova remnants in the Galaxy. I: spectrum and chemical composition
Pasquale Blasi,Elena Amato
Physics , 2011, DOI: 10.1088/1475-7516/2012/01/010
Abstract: In this paper we investigate the effect of stochasticity in the spatial and temporal distribution of supernova remnants on the spectrum and chemical composition of cosmic rays observed at Earth. The calculations are carried out for different choices of the diffusion coefficient D(E) experienced by cosmic rays during propagation in the Galaxy. In particular, at high energies we assume that D(E)\sim E^{\delta}, with $\delta=1/3$ and $\delta=0.6$ being the reference scenarios. The large scale distribution of supernova remnants in the Galaxy is modeled following the distribution of pulsars, with and without accounting for the spiral structure of the Galaxy. We find that the stochastic fluctuations induced by the spatial and temporal distribution of supernovae, together with the effect of spallation of nuclei, lead to mild but sensible violations of the simple, leaky-box-inspired rule that the spectrum observed at Earth is $N(E)\propto E^{-\alpha}$ with $\alpha=\gamma+\delta$, where $\gamma$ is the slope of the cosmic ray injection spectrum at the sources. Spallation of nuclei, even with the small rates appropriate for He, may account for slight differences in spectral slopes between different nuclei, providing a possible explanation for the recent CREAM observations. For $\delta=1/3$ we find that the slope of the proton and helium spectra are $\sim 2.67$ and $\sim 2.6$ respectively at energies above 1 TeV (to be compared with the measured values of $2.66\pm 0.02$ and $2.58\pm 0.02$). For $\delta=0.6$ the hardening of the He spectra is not observed. We also comment on the effect of time dependence of the escape of cosmic rays from supernova remnants, and of a possible clustering of the sources in superbubbles. In a second paper we will discuss the implications of these different scenarios for the anisotropy of cosmic rays.
Unique Structure and Dynamics of the EphA5 Ligand Binding Domain Mediate Its Binding Specificity as Revealed by X-ray Crystallography, NMR and MD Simulations
Xuelu Huan, Jiahai Shi, Liangzhong Lim, Sayantan Mitra, Wanlong Zhu, Haina Qin, Elena B. Pasquale, Jianxing Song
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074040
Abstract: The 16 EphA and EphB receptors represent the largest family of receptor tyrosine kinases, and their interactions with 9 ephrin-A and ephrin-B ligands initiate bidirectional signals controlling many physiological and pathological processes. Most interactions occur between receptor and ephrins of the same class, and only EphA4 can bind all A and B ephrins. To understand the structural and dynamic principles that enable Eph receptors to utilize the same jellyroll β-sandwich fold to bind ephrins, the VAPB-MSP domain, peptides and small molecules, we have used crystallography, NMR and molecular dynamics (MD) simulations to determine the first structure and dynamics of the EphA5 ligand-binding domain (LBD), which only binds ephrin-A ligands. Unexpectedly, despite being unbound, the high affinity ephrin-binding pocket of EphA5 resembles that of other Eph receptors bound to ephrins, with a helical conformation over the J–K loop and an open pocket. The openness of the pocket is further supported by NMR hydrogen/deuterium exchange data and MD simulations. Additionally, the EphA5 LBD undergoes significant picosecond-nanosecond conformational exchanges over the loops, as revealed by NMR and MD simulations, but lacks global conformational exchanges on the microsecond-millisecond time scale. This is markedly different from the EphA4 LBD, which shares 74% sequence identity and 87% homology. Consequently, the unbound EphA5 LBD appears to comprise an ensemble of open conformations that have only small variations over the loops and appear ready to bind ephrin-A ligands. These findings show how two proteins with high sequence homology and structural similarity are still able to achieve distinctive binding specificities through different dynamics, which may represent a general mechanism whereby the same protein fold can serve for different functions. Our findings also suggest that a promising strategy to design agonists/antagonists with high affinity and selectivity might be to target specific dynamic states of the Eph receptor LBDs.
Attenuation of Eph Receptor Kinase Activation in Cancer Cells by Coexpressed Ephrin Ligands
Giulia Falivelli, Erika Mathes Lisabeth, Elena Rubio de la Torre, Gizeh Perez-Tenorio, Giovanna Tosato, Ombretta Salvucci, Elena B. Pasquale
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081445
Abstract: The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting “in trans” with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral “cis” associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans.
Spectral breaks as a signature of cosmic ray induced turbulence in the Galaxy
Pasquale Blasi,Elena Amato,Pasquale D. Serpico
Physics , 2012, DOI: 10.1103/PhysRevLett.109.061101
Abstract: We show that the complex shape of the cosmic ray (CR) spectrum, as recently measured by PAMELA and inferred from Fermi-LAT gamma-ray observations of molecular clouds in the Gould belt, can be naturally understood in terms of basic plasma astrophysics phenomena. A break from a harder to a softer spectrum at blue rigidity R\simeq 10 GV follows from a transition from transport dominated by advection of particles with Alfven waves to a regime where diffusion in the turbulence generated by the same CRs is dominant. A second break at R\simeq 200 GV happens when the diffusive propagation is no longer determined by the self-generated turbulence, but rather by the cascading of externally generated turbulence (for instance due to supernova (SN) bubbles) from large spatial scales to smaller scales where CRs can resonate. Implications of this scenario for the cosmic ray spectrum, grammage and anisotropy are discussed.
PEGylation Potentiates the Effectiveness of an Antagonistic Peptide That Targets the EphB4 Receptor with Nanomolar Affinity
Roberta Noberini, Sayantan Mitra, Ombretta Salvucci, Fatima Valencia, Srinivas Duggineni, Natalie Prigozhina, Ke Wei, Giovanna Tosato, Ziwei Huang, Elena B. Pasquale
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028611
Abstract: The EphB4 receptor tyrosine kinase together with its preferred ligand, ephrin-B2, regulates a variety of physiological and pathological processes, including tumor progression, pathological forms of angiogenesis, cardiomyocyte differentiation and bone remodeling. We previously reported the identification of TNYL-RAW, a 15 amino acid-long peptide that binds to the ephrin-binding pocked of EphB4 with low nanomolar affinity and inhibits ephrin-B2 binding. Although ephrin-B2 interacts promiscuously with all the EphB receptors, the TNYL-RAW peptide is remarkably selective and only binds to EphB4. Therefore, this peptide is a useful tool for studying the biological functions of EphB4 and for imaging EphB4-expressing tumors. Furthermore, TNYL-RAW could be useful for treating pathologies involving EphB4-ephrin-B2 interaction. However, the peptide has a very short half-life in cell culture and in the mouse blood circulation due to proteolytic degradation and clearance by the kidneys and reticuloendothelial system. To overcome these limitations, we have modified TNYL-RAW by fusion with the Fc portion of human IgG1, complexation with streptavidin or covalent coupling to a 40 KDa branched polyethylene glycol (PEG) polymer. These modified forms of TNYL-RAW all have greatly increased stability in cell culture, while retaining high binding affinity for EphB4. Furthermore, PEGylation most effectively increases peptide half-life in vivo. Consistent with increased stability, submicromolar concentrations of PEGylated TNYL-RAW effectively impair EphB4 activation by ephrin-B2 in cultured B16 melanoma cells as well as capillary-like tube formation and capillary sprouting in co-cultures of endothelial and epicardial mesothelial cells. Therefore, PEGylated TNYL-RAW may be useful for inhibiting pathological forms of angiogenesis through a novel mechanism involving disruption of EphB4-ephrin-B2 interactions between endothelial cells and supporting perivascular mesenchymal cells. Furthermore, the PEGylated peptide is suitable for other cell culture and in vivo applications requiring prolonged EphB4 receptor targeting.
EphA4 Activation of c-Abl Mediates Synaptic Loss and LTP Blockade Caused by Amyloid-β Oligomers
Lina M. Vargas, Nancy Leal, Lisbell D. Estrada, Adrian González, Felipe Serrano, Katherine Araya, Katia Gysling, Nibaldo C. Inestrosa, Elena B. Pasquale, Alejandra R. Alvarez
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0092309
Abstract: The early stages of Alzheimer's disease are characterised by impaired synaptic plasticity and synapse loss. Here, we show that amyloid-β oligomers (AβOs) activate the c-Abl kinase in dendritic spines of cultured hippocampal neurons and that c-Abl kinase activity is required for AβOs-induced synaptic loss. We also show that the EphA4 receptor tyrosine kinase is upstream of c-Abl activation by AβOs. EphA4 tyrosine phosphorylation (activation) is increased in cultured neurons and synaptoneurosomes exposed to AβOs, and in Alzheimer-transgenic mice brain. We do not detect c-Abl activation in EphA4-knockout neurons exposed to AβOs. More interestingly, we demonstrate EphA4/c-Abl activation is a key-signalling event that mediates the synaptic damage induced by AβOs. According to this results, the EphA4 antagonistic peptide KYL and c-Abl inhibitor STI prevented i) dendritic spine reduction, ii) the blocking of LTP induction and iii) neuronal apoptosis caused by AβOs. Moreover, EphA4-/- neurons or sh-EphA4-transfected neurons showed reduced synaptotoxicity by AβOs. Our results are consistent with EphA4 being a novel receptor that mediates synaptic damage induced by AβOs. EphA4/c-Abl signalling could be a relevant pathway involved in the early cognitive decline observed in Alzheimer's disease patients.
On the cosmic ray spectrum from type II Supernovae expanding in their red giant presupernova wind
Martina Cardillo,Elena Amato,Pasquale Blasi
Physics , 2015, DOI: 10.1016/j.astropartphys.2015.03.002
Abstract: While from the energetic point of view SNRs are viable sources of Galactic CRs, the issue of whether they can accelerate protons up to PeV remains unsolved. Here we discuss particle acceleration at the forward shock of SN and discuss the possibility that the escaping particle current may excite a non-resonant instability that in turn leads to the formation of resonant modes confining particles close to the shock and increasing the maximum energy. This mechanism works throughout the expansion of the SN explosion, from the ejecta dominated (ED) to the Sedov-Taylor (ST) phase. Because of their higher explosion rate,we focus on type II SNae expanding in the slow, dense red supergiant wind. When the explosion occurs in such winds, the transition between the ED and the ST phase is likely to take place within a few tens of years. As a result, the spectrum of accelerated particles shows a break in the slope, at the maximum energy (Em) achieved at the beginning of the ST phase. Above this energy, the spectrum becomes steeper but remains a power law than developing an exponential cutoff. We show that for type II SNae typical parameters, proton Em can easily reach PeV energies, confirming that type II SNRs are the best candidate sources for CRs at the knee. We have tried to fit KASCADE-Grande, ARGO -YBJ and YAC1-Tibet Array data with our model but we could not find any parameter combination that could explain all data sets. Indeed the recent measurement of the proton and helium spectra in the knee region, with the ARGO-YBJ and YAC1-Tibet Array, has made the situation very confused. These measurements suggest that the knee in the light component is at 650 TeV, appreciably below the overall spectrum knee. This finding would resolve the problem of reaching very high energies in SNae, but, on the other hand, it would open a critical issue in the transition region between Galactic and extragalactic CRs.
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