Altered Kv2.1 functioning promotes increased excitability in hippocampal neurons of an Alzheimer's disease mouse model.

Altered neuronal excitability is emerging as an important feature in Alzheimer's disease (AD). Kv2.1 potassium channels are important modulators of neuronal excitability and synaptic activity. We investigated Kv2.1 currents and its relation to the intrinsic synaptic activity of hippocampal neurons from 3xTg-AD (triple transgenic mouse model of Alzheimer's disease) mice, a widely employed preclinical AD model. Synaptic activity was also investigated by analyzing spontaneous [Ca(2+)]i spikes. Compared with wild-type (Non-Tg (non-transgenic mouse model)) cultures, 3xTg-AD neurons showed enhanced spike frequency and decreased intensity. Compared with Non-Tg cultures, 3xTg-AD hippocampal neurons revealed reduced Kv2.1-dependent Ik current densities as well as normalized conductances. 3xTg-AD cultures also exhibited an overall decrease in the number of functional Kv2.1 channels. Immunofluorescence assay revealed an increase in Kv2.1 channel oligomerization, a condition associated with blockade of channel function. In Non-Tg neurons, pharmacological blockade of Kv2.1 channels reproduced the altered pattern found in the 3xTg-AD cultures. Moreover, compared with untreated sister cultures, pharmacological inhibition of Kv2.1 in 3xTg-AD neurons did not produce any significant modification in Ik current densities. Reactive oxygen species (ROS) promote Kv2.1 oligomerization, thereby acting as negative modulator of the channel activity. Glutamate receptor activation produced higher ROS levels in hippocampal 3xTg-AD cultures compared with Non-Tg neurons. Antioxidant treatment with N-Acetyl-Cysteine was found to rescue Kv2.1-dependent currents and decreased spontaneous hyperexcitability in 3xTg-AD neurons. Analogous results regarding spontaneous synaptic activity were observed in neuronal cultures treated with the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Our study indicates that AD-related mutations may promote enhanced ROS generation, oxidative-dependent oligomerization, and loss of function of Kv2.1 channels. These processes can be part on the increased neuronal excitability of these neurons. These steps may set a deleterious vicious circle that eventually helps to promote excitotoxic damage found in the AD brain

GRB 970228 Revisited: Evidence for a Supernova in the Light Curve and La te Spectral Energy Distribution of the Afterglow

At the time of its discovery, the optical and X-ray afterglow of GRB 970228 appeared to be a ringing endorsement of the previously untried relativistic fireball model of gamma-ray burst (GRB) afterglows, but now that nearly a dozen optical afterglows to GRBs have been observed, the wavering light curve and reddening spectrum of this afterglow make it perhaps the most difficult of the observed afterglows to reconcile with the fireball model. In this Letter, we argue that this afterglow's unusual temporal and spectral properties can be attributed to a supernova that overtook the light curve nearly two weeks after the GRB. This is the strongest case yet for a GRB/supernova connection. It strengthens the case that a supernova also dominated the late afterglow of GRB 980326, and the case that GRB 980425 is related to SN 1998bw.Comment: Accepted to The Astrophysical Journal (Letters), 14 pages, LaTe

Metal abundances in extremely distant Galactic old open clusters. II. Berkeley 22 and Berkeley 66

We report on high resolution spectroscopy of four giant stars in the Galactic old open clusters Berkeley~22 and Berkeley~66 obtained with HIRES at the Keck telescope. We find that $[Fe/H]=-0.32\pm0.19$ and $[Fe/H]=-0.48\pm0.24$ for Berkeley~22 and Berkeley~66, respectively. Based on these data, we first revise the fundamental parameters of the clusters, and then discuss them in the context of the Galactic disk radial abundance gradient. We found that both clusters nicely obey the most updated estimate of the slope of the gradient from \citet{fri02} and are genuine Galactic disk objects.Comment: 20 pages, 6 eps figures, accepted for publication in the Astronomical Journa

Involvement of caspace-3 in the cleavage of terminal transferase.

To investigate the in vivo role of caspase-3 in Terminal Transferase metabolism DMSO-treated RPMI-8402, a human pre-T cell line was used. In DMSO treated samples3H-dGTP incorporation and TdT phosphorylation occurs after 4 hours of treatment. After 8 hours cells undergo TdT proteolysis in addition to its inactivation. The cleavage of TdT into 32- and 58-KDa proteolytic fragments occurred simultaneously with the activation of Caspase-3, but preceded changes associated with the apoptotic process described after 48 hours of treatment. The Caspase-3 peptide inhibitor V, used as a specific inhibitor, prevented TdT proteolysis prolonging its activity and rescued cells from apoptosis. Our experiments suggest that TdT is a nuclear substrate for Caspase-3, the main apoptotic effector protease in many cell types, and that the cleavage of TdT represents a primary step in a signal cascade leading to pre-T cell apoptosis

A Photometric Investigation of the GRB970228 Afterglow and the Associated Nebulosity

We carefully analyze the WFPC2 and STIS images of GRB970228. We measure magnitudes for the GRB970228 point source component in the WFPC2 images of $V=26.20^{+0.14}_{-0.13}$, $I_c=23.94^{+0.10}_{-0.09}$ and $V=26.52^{+0.16}_{-0.18}$, $I_c=24.31^{+0.15}_{-0.11}$ on March 26 and April 7, respectively; and $R_c=27.09^{+0.14}_{-0.14}$ on September 4 in the STIS image. For the extended component, we measure magnitudes of $R_c=25.48^{+0.22}_{-0.20}$ in the combined WFPC2 images and $R_c=25.54^{+0.33}_{-0.22}$ in the STIS image, which are consistent with no variation. This value is fainter than previously reported (Galama et al. 98) and modifies the previously assumed magnitudes for the optical transient when it faded to a level where the extended source component contribution was not negligible, alleviating the discrepancy to a power-law temporal behavior. We also measure a color of $V_{606}-I_{814}=-0.18^{+0.51}_{-0.61}$ for the extended source component. Taking into account the extinction measured in this field (Castander & Lamb 1998), this color implies that the extended source is most likely a galaxy with ongoing star formation.Comment: 21 pages, including 8 figures. Submitted to Ap

Solution of the Fokker-Planck equation with a logarithmic potential and mixed eigenvalue spectrum

Motivated by a problem in climate dynamics, we investigate the solution of a Bessel-like process with negative constant drift, described by a Fokker-Planck equation with a potential V(x) = - [b \ln(x) + a\, x], for b>0 and a<0. The problem belongs to a family of Fokker-Planck equations with logarithmic potentials closely related to the Bessel process, that has been extensively studied for its applications in physics, biology and finance. The Bessel-like process we consider can be solved by seeking solutions through an expansion into a complete set of eigenfunctions. The associated imaginary-time Schroedinger equation exhibits a mix of discrete and continuous eigenvalue spectra, corresponding to the quantum Coulomb potential describing the bound states of the hydrogen atom. We present a technique to evaluate the normalization factor of the continuous spectrum of eigenfunctions that relies solely upon their asymptotic behavior. We demonstrate the technique by solving the Brownian motion problem and the Bessel process both with a negative constant drift. We conclude with a comparison with other analytical methods and with numerical solutions.Comment: 21 pages, 8 figure