310 research outputs found

    Kidins220/ARMS Is a Novel Modulator of Short-Term Synaptic Plasticity in Hippocampal GABAergic Neurons

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    Kidins220 (Kinase D interacting substrate of 220 kDa)/ARMS (Ankyrin Repeat-rich Membrane Spanning) is a scaffold protein highly expressed in the nervous system. Previous work on neurons with altered Kidins220/ARMS expression suggested that this protein plays multiple roles in synaptic function. In this study, we analyzed the effects of Kidins220/ARMS ablation on basal synaptic transmission and on a variety of short-term plasticity paradigms in both excitatory and inhibitory synapses using a recently described Kidins220 full knockout mouse. Hippocampal neuronal cultures prepared from embryonic Kidins220−/− (KO) and wild type (WT) littermates were used for whole-cell patch-clamp recordings of spontaneous and evoked synaptic activity. Whereas glutamatergic AMPA receptor-mediated responses were not significantly affected in KO neurons, specific differences were detected in evoked GABAergic transmission. The recovery from synaptic depression of inhibitory post-synaptic currents in WT cells showed biphasic kinetics, both in response to paired-pulse and long-lasting train stimulation, while in KO cells the respective slow components were strongly reduced. We demonstrate that the slow recovery from synaptic depression in WT cells is caused by a transient reduction of the vesicle release probability, which is absent in KO neurons. These results suggest that Kidins220/ARMS is not essential for basal synaptic transmission and various forms of short-term plasticity, but instead plays a novel role in the mechanisms regulating the recovery of synaptic strength in GABAergic synapses

    NuSTAR and XMM-Newton observations of NGC 1365: Extreme absorption variability and a constant inner accretion disk

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    We present a spectral analysis of four coordinated NuSTAR+XMM-Newton observations of the Seyfert galaxy NGC 1365. These exhibit an extreme level of spectral variability, which is primarily due to variable line-of-sight absorption, revealing relatively unobscured states in this source for the first time. Despite the diverse range of absorption states, each of the observations displays the same characteristic signatures of relativistic reflection from the inner accretion disk. Through time-resolved spectroscopy we find that the strength of the relativistic iron line and the Compton reflection hump relative to the intrinsic continuum are well correlated, as expected if they are two aspects of the same broadband reflection spectrum. We apply self-consistent disk reflection models to these time-resolved spectra in order to constrain the inner disk parameters, allowing for variable, partially covering absorption to account for the vastly different absorption states observed. Each of the four observations is treated independently to test the consistency of the results obtained for the black hole spin and the disk inclination, which should not vary on observable timescales. We find both the spin and the inclination determined from the reflection spectrum to be consistent, confirming NGC 1365 hosts a rapidly rotating black hole; in all cases the dimensionless spin parameter is constrained to be a* > 0.97 (at 90% statistical confidence or better)

    Plasmodium vivax but not Plasmodium falciparum blood-stage infection in humans is associated with the expansion of a CD8+ T cell population with cytotoxic potential

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    P. vivax and P. falciparum parasites display different tropism for host cells and induce very different clinical symptoms and pathology, suggesting that the immune responses required for protection may differ between these two species. However, no study has qualitatively compared the immune responses to P. falciparum or P. vivax in humans following primary exposure and infection. Here, we show that the two species differ in terms of the cellular immune responses elicited following primary infection. Specifically, P. vivax induced the expansion of a subset of CD8+ T cells expressing the activation marker CD38, whereas P. falciparum induced the expansion of CD38+ CD4+ T cells. The CD38+ CD8+ T cell population that expanded following P. vivax infection displayed greater cytotoxic potential compared to CD38- CD8+ T cells, and compared to CD38+ CD8+ T cells circulating during P. falciparum infection. We hypothesize that P. vivax infection leads to a stronger CD38+ CD8+ T cell activation because of its preferred tropism for MHC-I-expressing reticulocytes that, unlike mature red blood cells, can present antigen directly to CD8+ T cells. This study provides the first line of evidence to suggest an effector role for CD8+ T cells in P. vivax blood-stage immunity. It is also the first report of species-specific differences in the subset of T cells that are expanded following primary Plasmodium infection, suggesting that malaria vaccine development may require optimization according to the target parasite

    Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development

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    The growth factor family of neurotrophins has major roles both inside and outside the nervous system. Here, we report a detailed histological analysis of key phenotypes generated by the ablation of the Kinase D interacting substrate of 220 kDa/Ankyrin repeat-rich membrane spanning (Kidins220/ARMS) protein, a membrane-anchored scaffold for the neurotrophin receptors Trk and p75NTR. Kidins220 is important for heart development, as shown by the severe defects in the outflow tract and ventricle wall formation displayed by the Kidins220 mutant mice. Kidins220 is also important for peripheral nervous system development, as the loss of Kidins220 in vivo caused extensive apoptosis of DRGs and other sensory ganglia. Moreover, the neuronal-specific deletion of this protein leads to early postnatal death, showing that Kidins220 also has a critical function in the postnatal brain

    Contribution of limbic norepinephrine to cannabinoid-induced aversion

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    RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007)

    Improved Search for νˉμνˉe\bar ν_μ\rightarrow \bar ν_e Oscillations in the MiniBooNE Experiment

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    Submitted to PRL. Further information provided in arXiv:1207.4809Submitted to PRL. Further information provided in arXiv:1207.4809The MiniBooNE experiment at Fermilab reports results from an analysis of νˉe\bar \nu_e appearance data from 11.27×102011.27 \times 10^{20} protons on target in antineutrino mode, an increase of approximately a factor of two over the previously reported results. An event excess of 78.4±28.578.4 \pm 28.5 events (2.8σ2.8 \sigma) is observed in the energy range 200<EνQE<1250200<E_\nu^{QE}<1250 MeV. If interpreted in a two-neutrino oscillation model, νˉμνˉe\bar{\nu}_{\mu}\rightarrow\bar{\nu}_e, the best oscillation fit to the excess has a probability of 66% while the background-only fit has a χ2\chi^2-probability of 0.5% relative to the best fit. The data are consistent with antineutrino oscillations in the 0.01<Δm2<1.00.01 < \Delta m^2 < 1.0 eV2^2 range and have some overlap with the evidence for antineutrino oscillations from the Liquid Scintillator Neutrino Detector (LSND). All of the major backgrounds are constrained by in-situ event measurements so non-oscillation explanations would need to invoke new anomalous background processes. The neutrino mode running also shows an excess at low energy of 162.0±47.8162.0 \pm 47.8 events (3.4σ3.4 \sigma) but the energy distribution of the excess is marginally compatible with a simple two neutrino oscillation formalism. Expanded models with several sterile neutrinos can reduce the incompatibility by allowing for CP violating effects between neutrino and antineutrino oscillations

    Using L/E Oscillation Probability Distributions

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    This paper explores the use of L/EL/E oscillation probability distributions to compare experimental measurements and to evaluate oscillation models. In this case, LL is the distance of neutrino travel and EE is a measure of the interacting neutrino's energy. While comparisons using allowed and excluded regions for oscillation model parameters are likely the only rigorous method for these comparisons, the L/EL/E distributions are shown to give qualitative information on the agreement of an experiment's data with a simple two-neutrino oscillation model. In more detail, this paper also outlines how the L/EL/E distributions can be best calculated and used for model comparisons. Specifically, the paper presents the L/EL/E data points for the final MiniBooNE data samples and, in the Appendix, explains and corrects the mistaken analysis published by the ICARUS collaboration

    Lovastatin Modulates Glycogen Synthase Kinase-3β Pathway and Inhibits Mossy Fiber Sprouting after Pilocarpine-Induced Status Epilepticus

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    This study was undertaken to assay the effect of lovastatin on the glycogen synthase kinase-3 beta (GSK-3β) and collapsin responsive mediator protein-2 (CRMP-2) signaling pathway and mossy fiber sprouting (MFS) in epileptic rats. MFS in the dentate gyrus (DG) is an important feature of temporal lobe epilepsy (TLE) and is highly related to the severity and the frequency of spontaneous recurrent seizures. However, the molecular mechanism of MFS is mostly unknown. GSK-3β and CRMP-2 are the genes responsible for axonal growth and neuronal polarity in the hippocampus, therefore this pathway is a potential target to investigate MFS. Pilocarpine-induced status epilepticus animal model was taken as our researching material. Western blot, histological and electrophysiological techniques were used as the studying tools. The results showed that the expression level of GSK-3β and CRMP-2 were elevated after seizure induction, and the administration of lovastatin reversed this effect and significantly reduced the extent of MFS in both DG and CA3 region in the hippocampus. The alteration of expression level of GSK-3β and CRMP-2 after seizure induction proposes that GSK-3β and CRMP-2 are crucial for MFS and epiletogenesis. The fact that lovastatin reversed the expression level of GSK-3β and CRMP-2 indicated that GSK-3β and CRMP-2 are possible to be a novel mechanism of lovatstain to suppress MFS and revealed a new therapeutic target and researching direction for studying the mechanism of MFS and epileptogenesis
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