Impact of GRIK4 gene polymorphisms on cognitive dysfunction in patients with major depression.

An increasing body of research has focused on the functions of the glutamate receptor ionotropic kainate 4 (GRIK4) gene in treatment for depression, memory, as well as neurodegenerative diseases. It is widely recognized that major depressive disorder (MDD) patients often display cognitive dysfunctions, which do not strictly correlate with the severity of depressive symptoms, and in some individuals persist after clinical remission. However, little is known regarding the particular role of GRIK4 in cognitive functions of patients suffering from a MDD. The current study therefore sought to examine the impact of GRIK4 polymorphism on cognitive functions in MDD patients. A total of 217 MDD patients participated in this study. Their depressive severity was determined with the 17-item Hamilton Depression Rating Scale, and cognitive functions were evaluated using the Stroop Neuropsychological Screening Test, tests of visual reproduction and immediate logical memory, and the verbal fluency test (VFT). All patients were genotyped to determine GRIK4 polymorphisms. Results of VFT revealed statistical differences among all single-nucleotide polymorphism (SNP) genotypes. In the Stroop-color-word test, only rs6589847 was discovered to be statistically different. No significant difference was found in the Stroop-color task scores, the visual reproduction test, or the immediate logical memory test. GRIK4 polymorphism exerted a significant effect on long-term memory retrieval and selective attention, but did not affect immediate memory.

Forward error correction supported 150 Gbit/s error-free wavelength conversion based on cross phase modulation in silicon.

We build a forward error correction (FEC) module and implement it in an optical signal processing experiment. The experiment consists of two cascaded nonlinear optical signal processes, 160 Gbit/s all optical wavelength conversion based on the cross phase modulation (XPM) in a silicon nanowire and subsequent 160 Gbit/s-to-10 Gbit/s demultiplexing in a highly nonlinear fiber (HNLF). The XPM based all optical wavelength conversion in silicon is achieved by off-center filtering the red shifted sideband on the CW probe. We thoroughly demonstrate and verify that the FEC code operates correctly after the optical signal processing, yielding truly error-free 150 Gbit/s (excl. overhead) optically signal processed data after the two cascaded nonlinear processes.

Nonlinear properties of and nonlinear processing in hydrogenated amorphous silicon waveguides.

We propose hydrogenated amorphous silicon nanowires as a platform for nonlinear optics in the telecommunication wavelength range. Extraction of the nonlinear parameter of these photonic nanowires reveals a figure of merit larger than 2. It is observed that the nonlinear optical properties of these waveguides degrade with time, but that this degradation can be reversed by annealing the samples. A four wave mixing conversion efficiency of + 12 dB is demonstrated in a 320 Gbit/s serial optical waveform data sampling experiment in a 4 mm long photonic nanowire.

Degradation of stimulus selectivity of visual cortical cells in senescent rhesus monkeys.

Human visual function declines with age. Much of this decline is probably mediated by changes in the central visual pathways. We compared the stimulus selectivity of cells in primary visual cortex (striate cortex or V1) in young adult and very old macaque monkeys using single-neuron in vivo electrophysiology. Our results provide evidence for a significant degradation of orientation and direction selectivity in senescent animals. The decreased selectivity of cells in old animals was accompanied by increased responsiveness to all orientations and directions as well as an increase in spontaneous activity. The decreased selectivities and increased excitability of cells in old animals are consistent with an age-related degeneration of intracortical inhibition. The neural changes described here could underlie declines in visual function during senescence.

[Screening of microRNAs targeting Notch signaling pathway implicated in inner ear development and the role of microRNA-384-5p].

Objective: To screen the key microRNAs targeting Notch signaling pathway in inner ear and investigate its potential regulating function. Methods: The interaction network and the Core-Notch network, involved with key genes in Notch signal pathway and differential-expressed microRNAs in inner ear, were constructed by bioinformatics methods. The important microRNAs in regulating Notch signaling pathway were screened via topological and GO analysis, followed by in vivo and in vitro investigation. Results: MiRNA-384-5p was identified as a key regulator specifically expressed in mouse brain and inner ear, which could down-regulate Notch1. The Notch1 expression was found significantly down-regulated in miRNA-384-5p-mimic-transfected HeLa cells. The dual-luciferase reporter gene assay further confirmed the effect of miRNA-384-5p on the down-regulation of Notch1 and Dll4 in Notch signaling pathway. Conclusions: The Core-Notch network is constructed to screen microRNAs implicated in inner ear development, and miRNA-384-5p is screened and verified to be target-regulating the Notch signaling pathway, which could be the potential target in the regeneration of impaired hair cells.

Evidence of a novel redox-linked activation mechanism for the Src kinase which is independent of tyrosine 527-mediated regulation.

The kinase activity of p60c-src has been shown to be basically regulated through phosphorylation and dephosphorylation of Y527. We found that catalytic activity of the immunoprecipitated c-Src kinase from NIH3T3 cells was elevated several folds by exposure to 0.5-50 microM of sulfhydryl-reactive Hg2+. Vmax of the kinase was increased whereas Km was decreased. N-acetylcysteine neutralized this Hg2+ effect, suggesting a critical role of the Hg2+-mediated sulfhydryl modification of the kinase in the mechanism. Addition of protein tyrosine phosphatase inhibitor Na3VO4 into the reaction mixture did not inhibit the Hg2+-mediated activation. Further study revealed that Hg2+ was capable of activating the v-Src kinase lacking Y527 and the c-Src kinase from mutant cells defective of the Y527-phosphorylating Csk kinase. Cyanogen bromide cleavage maps of radiolabeled Src proteins showed that Hg2+ selectively promoted the autophosphorylation at Y416 and that the previously in vivo radiolabeled phosphorous on Y527 was not deleted during the promotion of Y416 autophosphorylation by Hg2+. Phosphoamino acid analysis demonstrated selective promotion of phosphorylation at tyrosine but not at serine/threonine. Not like bivalent Hg2+, monovalent p-chloromercuribenzenesulfonic acid was incapable of activating c-Src kinase. These results suggest a novel Y416 phosphorylation-linked activation pathway for Src kinases which is initially triggered independent of Y527-mediated or serine/threonine phosphorylation-linked regulation, possibly through sulfhydryl-based protein structural modification for functional alteration.

Intraoperative validation of mitral inflow determination by transesophageal echocardiography: comparison of single-plane, biplane and thermodilution techniques.

OBJECTIVES: This study investigated the accuracy of mitral inflow quantification using biplane transesophageal echocardiography. BACKGROUND: Mitral stroke volume can be reliably quantified by transthoracic Doppler echocardiography, but previous studies involving monoplane transesophageal echocardiography have yielded mixed results. METHODS: Thirty patients without mitral regurgitation were prospectively examined immediately before cardiovascular surgery. Mitral annulus diameter was measured in the transverse (d1) and longitudinal views (d2) by biplane transesophageal echocardiography. Assuming an elliptic shape, the annular area was calculated as pi d1d2/4; area was also calculated from single-plane data assuming a circular annular shape as pi d2/4. The time-velocity integral of mitral annular Doppler velocity was then multiplied by annular area to yield stroke volume. These data were compared with simultaneous thermodilution measurements by linear regression. RESULTS: Good correlations were observed between thermodilution (x) and Doppler (y) measurements of stroke volume (SV) (r = 0.86, p < 0.01, delta SV [y-x] = 2.64 +/- 9.86 ml for single four-chamber view; r = 0.77, p < 0.01, delta SV = 1.82 +/- 12.59 ml for two-chamber view; r = 0.94, p < 0.001, delta SV = 1.78 +/- 5.90 ml for biplane measurements) with similar data for cardiac output (r = 0.82, r = 0.74 and r = 0.92, respectively). The biplane measurements were most accurate and had less variability in individual patients (p < 0.05). This finding was supported by a numerical model that demonstrated (for an ellipse of eccentricity 1.5:1) that even maximal misalignment of biplane diameters yielded only 8% area overestimation, whereas single-plane calculations assuming a circular shape produced a variation in area of 225%. CONCLUSIONS: This study validates the accuracy of measurements of mitral inflow using biplane transesophageal echocardiography with potential application for quantification of valvular regurgitation in the operating room. The results are further generalizable, indicating that orthogonal biplane measurements are both necessary and sufficient to ensure accuracy in area calculation for any elliptic structure.

Impact of wall constraint on velocity distribution in proximal flow convergence zone. Implications for color Doppler quantification of mitral regurgitation.

OBJECTIVES: This study sought to elevate the effect of proximal flow constraint induced by the left ventricular wall on the accuracy of calculated flow rates and to assess a possible correction factor to adjust the proximal convergence angle. We further defined under which hydrodynamic and geometric conditions it is necessary to apply the corrected convergence angle. BACKGROUND: The proximal flow convergence method has been proposed as a new approach to quantify valvular regurgitation. However, significant overestimation of the calculated regurgitant flow rate has been reported, particularly in patients with mitral valve prolapse and severe mitral regurgitation. METHODS: We used an in vitro flow model and induced various degrees of proximal flow constraint. The accuracy of the proposed convergence angle formula, alpha = tau + 2 tan-1 d/r (d = wall distance; r = isovelocity radius) was tested in vitro and in a three-dimensional numerical simulation. RESULTS: With a constraining wall near the orifice, overstimulation of regurgitant flow rates was noted and was most significant with the constraining wall positioned closest to the orifice (calculated flow rate [Qc]/true flow rate [Qo] = 1.85 +/- 0.55 [mean +/- SD]). These findings were similar to the results of the numerical simulation. Applying the correction factor nearly completely eliminated the overestimation of the calculated flow rates (cQc), with cQc/Qo = 1.13 +/- 0.25. CONCLUSIONS: In the presence of a constraining wall, significant overestimation of calculated flow rates is observed when hemispheric symmetry of the flow field is assumed. In this situation, it is necessary to apply the corrected convergence angle formula to improve the accuracy of the proximal flow convergence method.

Three-dimensional echocardiographic planimetry of maximal regurgitant orifice area in myxomatous mitral regurgitation: intraoperative comparison with proximal flow convergence.

OBJECTIVES: We sought to validate direct planimetry of mitral regurgitant orifice area from three-dimensional echocardiographic reconstructions. BACKGROUND: Regurgitant orifice area (ROA) is an important measure of the severity of mitral regurgitation (MR) that up to now has been calculated from hemodynamic data rather than measured directly. We hypothesized that improved spatial resolution of the mitral valve (MV) with three-dimensional (3D) echo might allow accurate planimetry of ROA. METHODS: We reconstructed the MV using 3D echo with 3 degrees rotational acquisitions (TomTec) using a transesophageal (TEE) multiplane probe in 15 patients undergoing MV repair (age 59 +/- 11 years). One observer reconstructed the prolapsing mitral leaflet in a left atrial plane parallel to the ROA and planimetered the two-dimensional (2D) projection of the maximal ROA. A second observer, blinded to the results of the first, calculated maximal ROA using the proximal convergence method defined as maximal flow rate (2pi(r2)va, where r is the radius of a color alias contour with velocity va) divided by regurgitant peak velocity (obtained by continuous wave [CW] Doppler) and corrected as necessary for proximal flow constraint. RESULTS: Maximal ROA was 0.79 +/- 0.39 (mean +/- SD) cm2 by 3D and 0.86 +/- 0.42 cm2 by proximal convergence (p = NS). Maximal ROA by 3D echo (y) was highly correlated with the corresponding flow measurement (x) (y = 0.87x + 0.03, r = 0.95, p < 0.001) with close agreement seen (AROA (y - x) = 0.07 +/- 0.12 cm2). CONCLUSIONS: 3D echo imaging of the MV allows direct visualization and planimetry of the ROA in patients with severe MR with good agreement to flow-based proximal convergence measurements.

Physiological response properties of cat retinal ganglion cells projecting to suprachiasmatic nucleus.

The aim of this experiment was to characterize the physiological properties of cat retinal ganglion cells that project to the suprachiasmatic nucleus (SCN). Retrogradely labeled SCN-projecting ganglion cells were recorded extracellularly in vitro. For the first time, this study provides crucial information on visual response properties of ganglion cells in the entrainment circuitry. All recorded cells gave sustained responses (n = 9). Although most of the cells (n = 8) had an "on" center receptive field, one cell showed "on-off" center receptive field properties. The range of receptive field sizes was 2 to 5 deg. For most of the cells tested, the spectral wavelength that evoked peak responses was 500 nm (3 out of 5 cells). All recorded cells (n = 9) preferred still or extremely slow-moving stimuli (3.3 deg/s). These results indicate that cat SCN-projecting cells receive inputs from conventional photoreceptors. The hypothesis that both conventional and cryptochromic photoreceptors are involved in transferring photic signals is discussed.

Redox-linked ligand-independent cell surface triggering for extensive protein tyrosine phosphorylation.

Exposure of lymphocytes to 0.2-2 mM HgCl2, a thiol-reactive heavy metal, induced extensive tyrosine phosphorylation of multiple cellular proteins. The phosphorylation started as quickly as 5 s after exposure to HgCl2, and was irreversible. Another 3 thiol-reactive chemicals also displayed similar, though less marked, actions, whereas dithiothreitol, a reducing agent, antagonized the HgCl2 action. The demonstrated new action of HgCl2 indispensably required membrane-intact cells as a target. Whereas exposure of lymphocytes to > 0.2 mM HgCl2 caused rapid cell death, 0.01-0.1 mM HgCl2 affected the cells so as to accelerate their c-fos transcription. These results suggest a novel redox-linked mechanism of cell surface triggering of intracellular protein kinase activity, which is independent of receptor-ligand interactions.

Direct evidence of involvement of glycosylphosphatidylinositol-anchored proteins in the heavy metal-mediated signal delivery into T lymphocytes.

The biological significance of the action of glycosylphosphatidylinositol (GPI)-anchored proteins in cell physiology and pathology when stimulated with their natural agonists is not known. Here we provide evidence that GPI-anchored proteins play a crucial role in the recently defined heavy metal (HgCl2)-triggered signal delivery to T lymphocytes. Thiol-reactive HgCl2, a multi-potent crosslinker of cell membrane proteins, induced heavy aggregation of Thy-1, a representative GPI-anchored protein, on murine thymocytes, and delivered a signal to induce heavy tyrosine phosphorylation of cellular proteins. This rather unusual signal delivery by HgCl2 is diminished by the pre-treatment of cells with phosphatidylinositol-specific phospholipase C, which partially cleaved GPI-anchored proteins from the cell surface. Direct evidence for the involvement of GPI or GPI-anchored proteins in the HgCl2-mediated signaling is provided by the loss of signaling in a mutant thymoma cell line defective in the phosphatidylinositol glycan-class A gene (PIG-A), and its restoration in a transfectant with PIG-A.

Delivery of an accessory signal for cell activation by exogenous phosphatidylinositol-specific phospholipase C.

Digestion of phosphatidylinositol (PI) or glycosylphosphatidylinositol (GPI) anchors of membrane proteins on the external cell surface with exogenous PI-specific phospholipase C (PIPLC) from Bacillus thuringiensis was shown to transmit a signal into the thymocyte to modulate the TCR/CD3 complex-induced signal delivery for cell activation. This was demonstrated for very early protein tyrosine phosphorylation, early c-fos transcription and late DNA synthesis. For this effect preincubation of the cells with PIPLC was required, but there was no evidence of involvement of any soluble products released from the cell surface by PIPLC in the signaling, suggesting a crucial role of the membrane-bound counterpart (diacylglycerol or diradylglycerol) of the PI/GPI hydrolysate. A possible role for this accessory signal in the microorganism-linked control of the (diacylglycerol or diradylglycerol) of the PI/GPI hydrolysate. A possible role for this accessory signal in the microorganism-linked control of the T cell receptor function is discussed.

Dendritic morphology of cat retinal ganglion cells projecting to suprachiasmatic nucleus.

The morphological properties of cat retinal ganglion cells projecting to the suprachiasmatic nucleus (SCN) of the hypothalamus were studied by using retrograde labeling, in vitro intracellular injection, confocal optical section, and computer three-dimensional reconstruction techniques. A total of 218 stained cells were studied. Neither the dendritic fields nor soma diameters of SCN-projecting cells varied with eccentricity. Approximately 50% of cells were concentrated not in the area centralis, but rather in the visual streak. SCN-projecting cells showed large and symmetrical dendritic fields (596 +/- 159 microm) and medium to small sized somas (17.2 +/- 3.3 microm). The ramification patterns of SCN-projecting cells were similar. Most cells primarily ramify in either sublamina A or B. Evidence from quantitatively analyzed cells (n = 39) suggests that these cells ramified more frequently in sublamina A (n = 17) than in sublamina B (n = 8). A large number of cells, on the other hand, showed diffuse ramification (n = 14) throughout the inner plexiform layer (IPL). The functional roles of these cells and the corresponding retinal neurocircuitry in circadian entrainment remain to be studied.

Dendritic morphologies of retinal ganglion cells projecting to the nucleus of the optic tract in the rabbit.

Focal injections of Rhodamine-latex microspheres or Fast Blue were made in the nucleus of the optic tract (NOT) of four rabbits. After survival times of 8-10 days, both dyes were retrogradely transported to medium to large sized ganglion cell somas in the retinas contralateral, but not ipsilateral, to the injected NOT. Most labelled cells were located in or near the visual streak, but a significant percentage were also found in the midperiphery of both the inferior and superior retina. One hundred fifteen labelled cells in four living superfused retinas were impaled under visual control and successfully injected with Lucifer Yellow. The dendritic arborizations of 60 of these were drawn from photographic montages for morphological identification and analysis. Nearly all the injected ganglion cells had large, relatively dense dendritic trees that stratified narrowly in the proximal inner plexiform layer. The dendritic field size and dendritic density of these cells varied with eccentricity, but at all eccentricities their anatomical characteristics closely resembled those of intracellularly stained On directionally selective ganglion cells. In three of the four experiments, a small percentage of ganglion cells were also labelled in the visual streak that had bistratified morphologies resembling those of On-Off directionally selective ganglion cells.

Dendritic morphologies of retinal ganglion cells projecting to the lateral geniculate nucleus in the rabbit.

Small injections of fluorescent Rhodamine-latex microspheres and Fast Blue were made into the dorsal lateral geniculate nucleus (dLGN) of fifteen rabbits. After 8-15 day survival times, the somas of projecting ganglion cells were found to be labelled in the contralateral retinas by retrograde transport. The dendritic morphologies of the labelled ganglion cells were revealed by intracellular injection of Lucifer Yellow or horseradish peroxidase while superfusing the retinas. At least ten distinct dendritic morphologies were observed among 161 injected ganglion cells. The three most commonly recovered dendritic morphologies were those of: (1) alpha-like cells; (2) large, complex dendritic field cells; and (3) cells with small, dense dendritic fields that resemble intracellularly identified brisk sustained cells (Amthor et al., J. Comp. Neurol. 1989; 280:72-96). Smaller percentages of cells whose dendritic morphologies resembled those of several physiologically identified sluggish and complex receptive field ganglion cell classes (Amthor et al., J. Comp. Neurol. 1989; 280:72-96, 97-21) were also recovered. Several morphological types were also found that were previously unknown or could not be confidently related to those of previously known classes. Most dLGN injections labelled many different types of ganglion cells, but restricted injections in some dLGN loci labelled only a limited number of ganglion cell classes.

Theta ganglion cell type of cat retina.

We define a new bistratified ganglion cell type of cat retina using intracellular staining in vitro. The theta cell has a small soma, slender axon, and delicate, highly branched dendritic arbor. Dendritic fields are intermediate in size among cat ganglion cells, with diameters typically two to three times those of beta cells. Fields increase in size with distance from the area centralis, ranging in diameter from 70 to 150 microns centrally to a maximum of 700 microns in the periphery. Theta cells have markedly smaller dendritic fields within the nasal visual streak than above or below it and smaller fields nasally than temporally. Dendritic arbors are narrowly bistratified. The outer arbor lies in the lower part of sublamina a (OFF sublayer) of the inner plexiform layer where it costratifies with the dendrites of OFF alpha cells. The inner arbor occupies the upper part of sublamina b (ON sublayer), where it costratifies with ON alpha dendrites. The outer and inner arbors are composed of many relatively short segments and are densely interconnected by branches that traverse the a/b sublaminar border. Experiments combining retrograde labeling with intracellular staining indicate that theta cells project to the superior colliculus and to two components of the dorsal lateral geniculate nucleus (the C laminae and medial interlaminar nucleus). Theta cells project contralaterally from the nasal retina and ipsilaterally from the temporal retina. They apparently correspond to a sluggish transient or phasic W-cell with an ON-OFF receptive field center.

The Eta ganglion cell type of cat retina.

We define a morphologic type of ganglion cell in cat retina by using intracellular staining in vitro. The eta cell has a small soma, slender axon, and delicate, highly branched dendritic arbor. Dendritic fields are intermediate in size among cat ganglion cells, with diameters typically two to three times those of beta cells. Fields increase in size as a function of distance from the area centralis, ranging in diameter from 90 microm to 200 microm centrally to a maximum of 600 microm in the periphery. This increase is unusually radially symmetric. By contrast with other cat ganglion cell types, eta cells do not have markedly smaller dendritic fields within the visual streak than above or below it nor much smaller fields nasally than temporally. Dendrites ramify broadly throughout sublamina a (OFF sublayer) of the inner plexiform layer. They arborize most densely in S2, where they costratify with dendrites of OFF alpha cells. There is apparently no matching ON variety of eta cell. Experiments combining retrograde labeling with intracellular staining indicate that eta cells project to the superior colliculus and to two components of the dorsal lateral geniculate nucleus (the C laminae and medial interlaminar nucleus). Eta cells apparently project contralaterally from the nasal retina and ipsilaterally from the temporal retina. The morphology and projection patterns of the eta cell suggest that its physiologic counterpart is a type of sluggish or W-cell with an OFF center, an ON surround, and possibly a transient light response.

The zeta cell: a new ganglion cell type in cat retina.

We define a new morphological type of ganglion cell in cat retina by using intracellular staining in vitro. The zeta cell has a small soma, slender axon, and compact, tufted, unistratified dendritic arbor. Dendritic fields were intermediate in size among cat ganglion cells, typically twice the diameter of beta cell fields. They were smallest in the nasal visual streak (<280 microm diameter), especially near the area centralis (60-150 microm diameter), and largest in the nonstreak periphery (maximum diameter 570 microm). Fields sizes were symmetric about the nasotemporal raphe except near the visual streak, where nasal fields were smaller than temporal ones. Zeta-cell dendrites ramified near the boundary between sublaminae a and b (OFF and ON sublayers) of the inner plexiform layer, occupying the narrow gap separating the dendrites of ON and OFF alpha cells. There was no evidence for separate ON and OFF types of zeta cell. Retrograde labeling studies revealed that both nasally and temporally located zeta cells project to the contralateral superior colliculus, whereas few project to the ipsilateral colliculus or to any subdivision of the dorsal lateral geniculate nucleus. The zeta cell's morphology and projection patterns suggest that it corresponds to the ON-OFF phasic W-cell (also known as the local edge detector) of physiological studies. Zeta cells have particularly small dendritic fields in the visual streak, presumably because they are disproportionately represented in the streak in comparison with other ganglion cell types. These conditions are consistent with optimal spatial resolution along the retinal projection of the visual horizon rather than principally at the center of gaze. Strong commonalities with similar ganglion cell types in ferret, rabbit, and monkey suggest that "zeta-like" cells may be a universal feature of the mammalian retina.

Correlation between the visual callosal connections and the retinotopic organization in striate-peristriate border region in the hamster: an anatomical and physiological study.

The correlation between the retinotopic organization of receptive fields in the striate-peristriate border region and the distribution pattern of the visual callosal projections was investigated in hamsters with corpus callosum transected 2 days before recording. The results showed that in all the animals studied, the V1/V2 border defined by reversal of receptive fields at the vertical meridian was located in the dense central portion of the visual callosal projection which terminated in cortical regions bordering areas 17 and 18a. These results indicate that there is a close relationship between the striate-peristriate border determined by anatomical and physiological methods. In addition, these data strengthen the suggestion that the pattern of visual callosal projections is a useful and reliable reference system for delineating boundaries of different visual areas in the golden hamster.