Faculty Bibliography

Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-D-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91(phox) and p47(phox), both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91(phox) and p47(phox) mutant mice have mild impairments in hippocampus-dependent memory. The gp91(phox) mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47(phox) mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD

While the classical pathway of NF-kappaB activation plays critical roles in a wide range of biological processes, the more recently described 'non-canonical' NF-kappaB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-kappaB pathway, based on processing of the nf-kappab2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-kappaB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions

Speckle-field long- and short-exposure spatial correlation characteristics for target-in-the-loop (TIL) laser beam propagation and scattering in atmospheric turbulence are analyzed through the use of two different approaches: the conventional Monte Carlo (MC) technique and the recently developed brightness function (BF) method. Both the MC and the BF methods are applied to analysis of speckle-field characteristics averaged over target surface roughness realizations under conditions of 'frozen' turbulence. This corresponds to TIL applications where speckle-field fluctuations associated with target surface roughness realization updates occur within a time scale that can be significantly shorter than the characteristic atmospheric turbulence time. Computational efficiency and accuracy of both methods are compared on the basis of a known analytical solution for the long-exposure mutual correlation function. It is shown that in the TIL propagation scenarios considered the BF method provides improved accuracy and requires significantly less computational time than the conventional MC technique. For TIL geometry with a Gaussian outgoing beam and Lambertian target surface, both analytical and numerical estimations for the speckle-field long-exposure correlation length are obtained. Short-exposure speckle-field correlation characteristics corresponding to propagation in 'frozen' turbulence are estimated using the BF method. It is shown that atmospheric turbulence-induced static refractive index inhomogeneities do not significantly affect the characteristic correlation length of the speckle field, whereas long-exposure spatial correlation characteristics are strongly dependent on turbulence strength

This essay looks at the historical significance of three APS classic papers that are freely available online: Naka K-I and Nye PW. Role of horizontal cells in organization of the catfish retinal receptive field. J. Neurophysiol 34:785-801, 1971. Marmarelis PZ and Naka K-I. Nonlinear analysis and synthesis of receptive-field responses in the catfish retina. II. One-input white-noise analysis. J. Neurophysiol 36: 619-633, 1973. Naka K-I, Marmarelis PZ, and Chan RY. Morphological and functional identifications of catfish retinal neurons. III. Functional identification. J. Neurophysiol 38: 92-131, 1975

Brain-derived neurotrophic factor (BDNF) has been implicated in higher-order cognitive functions and in psychiatric disorders such as depression and schizophrenia. BDNF modulates synaptic transmission and plasticity primarily through the TrkB receptor, but the molecules involved in BDNF-mediated synaptic modulation are largely unknown. Myosin VI (Myo6) is a minus end-directed actin-based motor found in neurons that express Trk receptors. Here we report that Myo6 and a Myo6-binding protein, GIPC1, form a complex that can engage TrkB. Myo6 and GIPC1 were necessary for BDNF-TrkB-mediated facilitation of long-term potentiation in postnatal day 12-13 (P12-13) hippocampus. Moreover, BDNF-mediated enhancement of glutamate release from presynaptic terminals depended not only upon TrkB but also upon Myo6 and GIPC1. Similar defects in basal synaptic transmission as well as presynaptic properties were observed in Myo6 and GIPC1 mutant mice. Together, these results define an important role for the Myo6-GIPC1 motor complex in presynaptic function and in BDNF-TrkB-mediated synaptic plasticity

Extracorporeal elimination of drugs and toxins is a critical component in the management of poisonings, though specific techniques and indications remain a matter of debate. Conventional hemodialysis is frequently the treatment of choice because of its widespread availability and proven effectiveness for certain drugs and toxins. With the increased availability of continuous renal replacement therapy (CRRT) modalities, there is yet another therapeutic option, but one that has yet to find a definitive role in this field. The continuous nature of these therapies is attractive for the management of acute renal failure, but the relatively slower clearance rates as compared to conventional hemodialysis is a distinct drawback in patients with acute xenobiotic-induced toxicity. There are abundant case reports as well as a few small case series in the medical literature documenting the use of CRRT, but specific techniques and the clinical outcomes vary considerably. Therefore one cannot draw definitive conclusions regarding benefit. Some patients, particularly those who are hemodynamically unstable and are not candidates for conventional hemodialysis, may warrant a trial of CRRT. However, at the present time, routine use for the treatment of poisoning is not supported. Controlled trials to better clarify its role would be beneficial, though such studies would be extremely difficult to conduct in this field. We believe that the intelligent application of extracorporeal modalities requires a thorough knowledge of drug pharmacokinetics, of the techniques utilized, and a skeptical analysis of the available literature

Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by excessive inattention, hyperactivity, and impulsivity, either alone or in combination. Neuropsychological findings suggest that these behaviors result from underlying deficits in response inhibition, delay aversion, and executive functioning which, in turn, are presumed to be linked to dysfunction of frontal-striatal-cerebellar circuits. Over the past decade, magnetic resonance imaging (MRI) has been used to examine anatomic differences in these regions between ADHD and control children. In addition to quantifying differences in total cerebral volume, specific areas of interest have been prefrontal regions, basal ganglia, the corpus callosum, and cerebellum. Differences in gray and white matter have also been examined. The ultimate goal of this research is to determine the underlying neurophysiology of ADHD and how specific phenotypes may be related to alterations in brain structure

Chitosan is a positively charged non-absorbable cellulose-like fibrillar biopolymer derived from shellfish which forms films with negatively charged surfaces. We hypothesized that negatively charged oxalate in the intestinal lumen could attach to the positively charged tertiary amino group of chitosan. We studied the effects of chitosan on intestinal oxalate absorption by measuring urinary oxalate excretion following an oral oxalate load with and without accompanying oral chitosan. The subjects consumed a fixed diet and collected urine for 24 h, in divided periods, during control and experimental protocols. Urine was collected with HCl and thymol as a preservative. For the control period, the subjects consumed an oxalate load, 50 g of cooked spinach, with water for lunch; the post-prandial urine collection was divided into three periods of 2 h. For the experimental period, 1 week later, the subjects consumed the same diet as that during the control period, but added 2 g of chitosan to the oxalate load. Post-prandial urinary oxalate excretion was expressed as mg oxalate/g creatinine. The spinach load was associated with a significant post-prandial increase in urinary oxalate during the control period of 25.7+/-12.8 mg/g creatinine. Accompanying the oxalate load with chitosan was well tolerated. There was no decrease in post-prandial urinary oxalate excretion during the experimental period: oxalate excretion rose by 31.3+/-16.9 mg/g creatinine (P=0.57, NS). We conclude that chitosan does not reduce acute intestinal oxalate absorption and therefore does not affect post-prandial urinary oxalate excretion

Fast neurotransmitter release at presynaptic terminals occurs at specialized transmitter release sites where docked secretory vesicles are triggered to fuse with the membrane by the influx of Ca2+ ions that enter through local N type (CaV2.2) calcium channels. Thus, neurosecretion involves two key processes: the docking of vesicles at the transmitter release site, a process that involves the scaffold protein RIM (Rab3A interacting molecule) and its binding partner Munc-13, and the subsequent gating of vesicle fusion by activation of the Ca2+ channels. It is not known, however, whether the vesicle fusion complex with its attached Ca2+ channels and the vesicle docking complex are parts of a single multifunctional entity. The Ca2+ channel itself and RIM were used as markers for these two elements to address this question. We carried out immunostaining at the giant calyx-type synapse of the chick ciliary ganglion to localize the proteins at a native, undisturbed presynaptic nerve terminal. Quantitative immunostaining (intensity correlation analysis/intensity correlation quotient method) was used to test the relationship between these two proteins at the nerve terminal transmitter release face. The staining intensities for CaV2.2 and RIM covary strongly, consistent with the expectation that they are both components of the transmitter release sites. We then used immunoprecipitation to test if these proteins are also parts of a common molecular complex. However, precipitation of CaV2.2 failed to capture either RIM or Munc-13, a RIM binding partner. These findings indicate that although the vesicle fusion and the vesicle docking mechanisms coexist at the transmitter release face they are not parts of a common stable complex.

We studied by immunocytochemistry and Western blots the identity and cellular distribution of voltage-gated calcium channels within dopaminergic neurons of the rat retina. The aim was to associate particular calcium channel subtypes with known activities of the neuron (e.g., transmitter release from axon terminals). Five voltage-gated calcium channels were identified: alpha1A, alpha1B, alpha1E, alpha1F, and alpha1H. All of these, except the alpha1B subtype, were found within dopaminergic perikarya. The alpha1B channels were concentrated at axon terminal rings, together with alpha1A calcium channels. In contrast, alpha1H calcium channels were most abundant in the dendrites, and alpha1F calcium channels were restricted to the perikaryon. The alpha1E calcium channel was present at such a low density that its cellular distribution beyond the perikaryon could not be determined. Our findings are consistent with the available pharmacological data indicating that alpha1A and alpha1B calcium channels control the major fraction of dopamine release in the rat retina