Nijmegen breakage syndrome (NBS) is characterized by extreme radiation sensitivity, chromosomal instability and cancer. The phenotypes are similar to those of ataxia telangiectasia mutated (ATM) disease, where there is a deficiency in a protein kinase that is activated by DNA damage, indicating that the Nbs and Atm proteins may participate in common pathways. Here we report that Nbs is specifically phosphorylated in response to gamma-radiation, ultraviolet light and exposure to hydroxyurea. Phosphorylation of Nbs mediated by gamma-radiation, but not that induced by hydroxyurea or ultraviolet light, was markedly reduced in ATM cells. In vivo, Nbs was phosphorylated on many serine residues, of which S343, S397 and S615 were phosphorylated by Atm in vitro. At least two of these sites were underphosphorylated in ATM cells. Inactivation of these serines by mutation partially abrogated Atm-dependent phosphorylation. Reconstituting NBS cells with a mutant form of Nbs that cannot be phosphorylated at selected, ATM-dependent serine residues led to a specific reduction in clonogenic survival after gamma-radiation. Thus, phosphorylation of Nbs by Atm is critical for certain responses of human cells to DNA damage.

No abstract

Nijmegen breakage syndrome (NBS) is a rare human disease displaying chromosome instability, radiosensitivity, cancer predisposition, immunodeficiency, and other defects [1, 2]. NBS is complexed with MRE11 and RAD50 in a DNA repair complex [3-5] and is localized to telomere ends in association with TRF proteins [6, 7]. We show that blood cells from NBS patients have shortened telomere DNA ends. Likewise, cultured NBS fibroblasts that exhibit a premature growth cessation were observed with correspondingly shortened telomeres. Introduction of the catalytic subunit of telomerase, TERT, was alone sufficient to increase the proliferative capacity of NBS fibroblasts. However, NBS, but not TERT, restores the capacity of NBS cells to survive gamma irradiation damage. Strikingly, NBS promotes telomere elongation in conjunction with TERT in NBS fibroblasts. These results suggest that NBS is a required accessory protein for telomere extension. Since NBS patients have shortened telomeres, these defects may contribute to the chromosome instability and disease associated with NBS patients.

No abstract

Action potentials were recorded from rat retinal ganglion cell fibers in the presence of a uniform field and the maintained discharge pattern was characterized. Spike trains recorded under ketamine/ xylazine anesthesia were generally stationary, while those recorded under urethane anesthesia often showed slow, undriven, quasi-periodic fluctuations in firing rate. In light of these non-stationarities, interspike interval distributions and power spectral densities are reported for data collected primarily under ketamine/xylazine. The majority of cells had multi-modal interval distributions, with the first peak in the range of 25.0-38.5ms and the subsequent peaks occurring at integer multiples of the first peak. Cells with unimodal distributions were fit well by a gamma distribution function. Interval and spike count statistics showed that ON cells tended to fire faster than OFF cells and that cells with higher rates fired in a more regular manner, with the coefficient of variation covering a wide range of values across all cells (0.43-0.97). Both ON and OFF cells show serial correlations between adjacent interspike intervals, while ON cells also showed 2 nd order correlations. Cells with multimodal interval distribution showed a strong peak at high frequencies in the power spectra in the range of 28.9-41.4Hz. Oscillations were present under both anesthetic conditions and persisted in the dark at a slightly lower frequency, implying that the oscillations are generated independent of any light stimulus but can be modulated by light level. The oscillation frequency varied slightly between cells of the same type and in the same eye, suggesting that multiple oscillatory generating mechanisms exist within the retina. Cells with high frequency oscillations were described well by an integrateand-fire model with the input consisting of Gaussian noise plus a sinusoid where the phase was jittered randomly to account for the bandwidth present in the oscillations.

The rat is a popular animal model for vision research, yet there is little quantitative information about the physiological properties of the cells that provide its brain with visual input, the retinal ganglion cells. It is not clear whether rats even possess the full complement of ganglion cell types found in other mammals. Since such information is important for evaluating rodent models of visual disease and elucidating the function of homologous and heterologous cells in different animals, we recorded from rat ganglion cells in vivo and systematically measured their spatial receptive field (RF) properties using spot, annulus, and grating patterns. Most of the recorded cells bore likeness to cat X and Y cells, exhibiting brisk responses, center-surround RFs, and linear or nonlinear spatial summation. The others resembled various types of mammalian W cell, including local-edge-detector cells, suppressed-by-contrast cells, and an unusual type with an ON–OFF surround. They generally exhibited sluggish responses, larger RFs, and lower responsiveness. The peak responsivity of brisk-nonlinear (Y-type) cells was around twice that of brisk-linear (X-type) cells and several fold that of sluggish cells. The RF size of brisk-linear and brisk-nonlinear cells was indistinguishable, with average center and surround diameters of 5.6 ± 1.3 and 26.4 ± 11.3 deg, respectively. In contrast, the center diameter of recorded sluggish cells averaged 12.8 ± 7.9 deg. The homogeneous RF size of rat brisk cells is unlike that of cat X and Y cells, and its implication regarding the putative roles of these two ganglion cell types in visual signaling is discussed.

Purpose: High-density EEG (HD-EEG) systems and electrical source imaging techniques have revolutionized our ability to assess the potential sources of epileptiform activity and other EEG features. Nonetheless, clinical use of HD-EEG is hampered by the lack of a standardized electrode nomenclature system and the inherent difficulties encountered in visually reviewing recordings. Inefficient visual review of HD-EEG remains a major barrier to incorporating these techniques into routine clinical care. Methods: Extension of the 10-10 is first defined by the addition of 2 reference curves: the −10% and −20% axial reference curves. Electrode positions over the face are named based on facial bony structures (N = nasion, Z = zygomatic prominence, M = mandible) and over the back of the head on posterior landmarks (I = inion, S = subinion, B = Base). Then, following the 10% incremental distance rule, we define additional electrode positions. Electrodes with nonstandard positions are clustered around the closest 10-10 electrode, deemed their cardinal point. Results: The 256-electrode Geodesic Sensor Net mapped to 96 of the 120 extended 10-10 cardinal electrodes. Conclusions: Electrode position nomenclature that builds upon the international standard 10-10 system allows electroencephalographers to identify spatial areas of interest in HD-EEG relative to positions in routine use. A standard viewing montage for HD-EEG and its application with electrical source imaging boost efficiency when reviewing data and improve accuracy in recognizing epileptiform discharges. Additionally, our proposed system is not limited to a specific HD-EEG system, electrode count, or electrode layout.

No abstract