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PubMed1988

Benzodiazepines modulate voltage-sensitive calcium channels in GH3 pituitary cells at sites distinct from thyrotropin-releasing hormone receptors.

Benzodiazepines (BZs) have been shown to modulate voltage-sensitive Ca2+ channels in a number of neuronal and nonneuronal cell types and to competitively antagonize TRH binding to receptors on cells of the nervous system and anterior pituitary gland. Because interaction of TRH with its receptor is known to cause enhanced influx of Ca2+ through voltage-sensitive channels in rat pituitary GH3 cells, it was determined whether BZs and TRH were interacting with the same binding site on these cells. The potencies of three BZs, Ro5-4864, diazepam (DZP), and chlordiazepoxide (CDE), were compared as modulators of Ca2+ channels and as inhibitors of TRH binding in GH3 cells. Modulation of Ca2+ channel activity was measured as the inhibition by BZs of K+ depolarization-induced Ca2+ influx using intracellularly trapped quin 2 or 45Ca2+ uptake. The three BZs caused dose-dependent inhibition of Ca2+ influx with an order of potency of Ro 5-4864 greater than DZP greater than CDE. In contrast, the order of potency of the three BZs to inhibit [3H]TRH binding was CDE greater than DZP much greater than Ro 5-4864. The concentrations of BZs needed to inhibit Ca2+ influx and TRH binding were in the micromolar range. These data show that BZs can modulate Ca2+ channel activity in endocrine cells and that these sites are distinct from those that modulate TRH binding on pituitary cells.

Animals↗
PubMed1996

Effect of sodium valproate on luteinizing hormone secretion in pre- and postmenopausal women and its modulation by naloxone infusion.

The synchronized activity of the GnRH neurons can be modulated through both excitatory and inhibitory circuits: one such inhibitory modulator is gamma-aminobutyric acid (GABA), but this has been little studied in humans. The aim of this study was to examine whether acute or chronic modulation of the GABA-ergic system with the drug sodium valproate (VPA) affects gonadotropin secretory frequency and/or amplitude in a steroid-dependent manner, and whether any such modulation might interact with endogenous opioids. Sixty postmenopausal women (age range 50-60 yr, group I), 50 postmenopausal women who had been on estrogen replacement therapy (group II), and 30 women in the luteal phase of their regular menstrual cycle (age range 25-40 yr, group III) were studied. VPA was administered acutely using doses of 300, 600, and 1200 mg orally. Samples for serum gonadotropins were taken at intervals over 24 h. Each dose of VPA caused significant LH suppression in group I. The maximum degree of suppressibility was the same with the three doses of VPA (14-20%). However, no dose had any effect on gonadotropin levels in group II. In group III, the single high dose of 1200 mg VPA significantly suppressed serum LH levels. The efficacy of chronic VPA administration in the three groups studied was assessed by measuring LH pulsatility (10-min samples) over 6 h, before and after 1 month's treatment with VPA. No change in either mean basal LH or in the LH pulsatility parameters was found. Naloxone infusion (1.6 mg/h for 6 h) had no effect on LH pulsatility in group I. When 1200 mg of VPA was administered before naloxone infusion, the level of LH suppression was 18% and was associated with a significant decrease in LH pulse frequency (P < 0.01). Naloxone infusion alone significantly increased mean serum LH and LH pulse frequency in group II patients (P < 0.01), and this elevation was antagonized by VPA pretreatment. Naloxone infusion alone significantly increased mean LH levels and LH pulse frequency in patients in group III, and this was also blocked by VPA pretreatment. These results suggest that an acute increase in GABA-ergic tone may inhibit gonadotropin secretion in the estrogen-deprived state, or when endogenous opioid inhibition is blocked in postmenopausal women on estrogens, as well as during the luteal phase of the menstrual cycle. It is possible that GABA-ergic pathways interact with opioids in the inhibitory modulation of gonadotropins in the human female.

Adult↗
PubMed2005

Nonpeptide and peptide growth hormone secretagogues act both as ghrelin receptor agonist and as positive or negative allosteric modulators of ghrelin signaling.

Two nonpeptide (L692,429 and MK-677) and two peptide [GH-releasing peptide (GHRP)-6 and ghrelin] agonists were compared in binding and in signal transduction assays: calcium mobilization, inositol phosphate turnover, cAMP-responsive element (CRE), and serum-responsive element (SRE) controlled transcription, as well as arrestin mobilization. MK-677 acted as a simple agonist having an affinity of 6.5 nm and activated all signal transduction systems with similar high potency (0.2-1.4 nm). L-692,429 also displayed a very similar potency in all signaling assays (25-60 nm) but competed with a 1000-fold lower apparent affinity for ghrelin binding and surprisingly acted as a positive allosteric receptor modulator by increasing ghrelin's potency 4- to 10-fold. In contrast, the potency of GHRP-6 varied 600-fold (0.1-61 nm) depending on the signal transduction assay, and it acted as a negative allosteric modulator of ghrelin signaling. Unexpectedly, the maximal signaling efficacy for ghrelin was increased above what was observed with the hormone itself during coadministration with the nonendogenous agonists. It is concluded that agonists for the ghrelin receptor vary both in respect of their intrinsic agonist properties and in their ability to modulate ghrelin signaling. A receptor model is presented wherein ghrelin normally only activates one receptor subunit in a dimer and where the smaller nonendogenous agonists bind in the other subunit to act both as coagonists and as either neutral (MK-677), positive (L-692,429), or negative (GHRP-6) modulators of ghrelin function. It is suggested that an optimal drug candidate could be an agonist that also is a positive modulator of ghrelin signaling.

Allosteric Regulation↗
PubMed2002

Phase-modulation scatterometry.

Phase-modulation scatterometry is a metrology technique for determining, by means of a phase modulator as a key device, the parameters of gratings. The main source of error to be dealt with are the fluctuations of the phase-modulation amplitude. The grating zeroth-order reflectance modulated by the phase modulator is converted into a signal by the photodetector. The measurables are the direct term and the first two harmonics of the signal. For experimental data fitting, we used the ratio of the harmonics over the direct term because it significantly improves the accuracy. A sensitivity analysis was performed for two samples, one real and one theoretical, to find the measurement configuration that insures optimum determination precision for the grating parameters. For the real sample, comparison of the theoretical predictions for sensitivity with the actual values showed a good agreement. For both samples the sensitivity analysis indicated subnanometric precision for the critical dimension (grating linewidth).

Journal Article↗
PubMed2004

Signal dependence and noise source in ultrasound-modulated optical tomography.

A Monte Carlo modeling technique was used to simulate ultrasound-modulated optical tomography in inhomogeneous scattering media. The contributions from two different modulation mechanisms were included in the simulation. Results indicate that ultrasound-modulated optical signals are much more sensitive to small embedded objects than unmodulated intensity signals. The differences between embedded absorption and scattering objects in the ultrasound-modulated optical signals were compared. The effects of neighboring inhomogeneity and background optical properties on the ultrasound-modulated optical signals were also studied. We analyzed the signal-to-noise ratio in the experiment and found that the major noise source is the speckle noise caused by small particle movement within the biological tissue sample. We studied this effect by incorporating a Brownian motion factor in the simulation.

Animals↗
PubMed2005

Improvement to human-face recognition in a volume holographic correlator by use of speckle modulation.

We show that a speckle-modulation technique can improve the parallelism and the recognition accuracy of volume holographic correlators. The object patterns are modulated by a speckle pattern generated by a diffuser. These modulated patterns are stored as Fourier holograms by use of angular-fractal multiplexing. With the speckle modulation the sidelobes are completely suppressed, the cross talk is negligible, and the correlation peak becomes a bright sharp spot. Thus higher recognition accuracy is achieved. The angular separation between adjacent patterns in the multiplexing could be much smaller, resulting in larger capacity and higher parallelism of the correlator. Also, this technique can be combined with other methods such as wavelet filtering to achieve a large invariant tolerance range. Theoretical analysis, numerical evaluation, and experimental results are presented to confirm that sidelobes and cross talk are sharply suppressed by the speckle modulation.

Journal Article↗
PubMed2006

Optimally tuned spatial light modulators for digital holography.

Digital holography and comparative digital holography are applications that require computer-addressable modulators for the optical reconstruction of digital holograms. The quality of the reconstructed holograms depends on the modulator's properties. Therefore a characterization of the modulators is required. We show the result of a modulator characterization and the modulator's influence on the quality of the reconstructed hologram. We then compare qualitatively and quantitatively the optical reconstruction of phase and amplitude holograms by considering their level of detail and their diffraction efficiency.

Journal Article↗
PubMed2006

Near-lossless continuous phase modulation using the analog switching mode (V-shaped switching) in ferroelectric liquid crystals.

The analog switching mode in ferroelectric liquid crystals, sometimes referred to as 'V-shaped switching,' has, thanks to its submillisecond switching capability, attracted much interest for future fast electro-optic displays where it is to be used for amplitude modulation. We have studied this mode for analog phase-only modulation. As V-shaped switching is based on a conical motion of the index ellipsoid this presents a challenging problem since both the orientation of the slow and fast axes, as well as the amount of birefringence varies in the switching process. We show theoretically, partly by means of Poincaré sphere analysis, that it is in fact possible to obtain near-lossless analog phase modulation between zero and pi radians in an ideal V-shaped switching cell through careful tuning of the polarization state of the input light. Furthermore, we were able to demonstrate this experimentally in a fabricated cell. Although this cell deviated slightly from the ideal conditions, e.g., the tilt cone half-angle was 38 degrees instead of the desired 45 degrees , we still obtained a continuous phase modulation between zero and 0.78pi rad with less than 2% modulation of the amplitude; the measured values agree very well with our numerical simulations of the real device.

Journal Article↗
PubMed2003

Vertical-cavity saturable-absorber intensity modulator.

We propose and demonstrate a reflection-type optical modulator, with surface-normal architecture, that exploits the optical saturation of absorption in semiconductor quantum wells. The modulation section of the modulator, which is composed of quantum wells placed within a Fabry-Perot cavity, is optically controlled by an intensity-modulated beam generated by an in-plane laser integrated monolithically on the same wafer and grown in a single epitaxial step. The modulation section and the in-plane laser share the same medium; therefore, efficient coupling between the control beam and the signal beam is achieved. The device was successfully used for active mode locking of an erbium-doped fiber laser.

Journal Article↗
PubMed2004

Wideband frequency modulation of a mode-locked fiber laser.

We have demonstrated wideband frequency modulation of the frequency comb lines of a high-repetition-rate fiber laser. With a modulation frequency of only approximately 10 kHz, we have generated modulation indices in excess of 250. Although internally modulated, the laser remains stable with 2-kHz linewidths, and thus the 10-kHz modulation sidebands are still clearly resolved even after propagation over several hundred kilometers. This unique characteristic is used for simultaneous measurement of propagation distances to 1-m resolution and velocities of less than 3 mm/s over a distance of greater than 50 km.

Journal Article↗
PubMed2006

Electro-optic transparent frequency conversion of a continuous light wave based on multistage phase modulation.

Frequency conversion of a continuous light wave based on multistage phase modulation has been investigated both analytically and numerically. The proposed frequency-conversion process consists of three stages: (i) phase modulation and chirp compression to generate a pulse train, (ii) Doppler shift of the pulse center frequency in a second phase modulation, and (iii) demodulation of the pulse train. By controlling the modulation power we can select the destination frequency from an equally spaced grid separated by the modulation frequency. A conversion efficiency of approximately 40% has been numerically confirmed with respect to a destination frequency of +/- 50 channels. Carrier frequency conversion of an analog data stream is numerically demonstrated.

Journal Article↗
PubMed2006

All-optical broadband phase modulation of a subcarrier in a radio over fiber system.

An optical modulator that provides broadband phase modulation of microwave subcarriers directly in the photonic domain has been proposed. This modulator, which involves no millimeter-wave device, can provide a dispersion-tolerant output signal with arbitrary phase shift. Therefore it has wide applications in high-frequency radio over fiber systems employing complex constellation modulation. Simulations and a proof-of-concept experiment demonstrate the feasibility of the modulator.

Journal Article↗
PubMed2000

Oxygen supplementation and cardiac-autonomic modulation in COPD.

STUDY OBJECTIVES: Patients with COPD have an increased sympathetic modulation and reduced baroreflex sensitivity (BRS). Therefore, we studied the effects of breathing 31% supplemental oxygen (SuppO(2)) on autonomic modulation in a group of COPD patients. DESIGN: We measured autonomic modulation before and during the administration of SuppO(2) on 51 patients with COPD using time-frequency analysis of R-R intervals and BP before and after intervention. This was done via a counterbalanced crossover design. The BRS index was determined using the sequence method. RESULTS: Significant differences were seen in oxygen saturation levels following breathing with SuppO(2) ([mean +/- SD] 96.4+/-1.5%) when compared to those seen after breathing with compressed air (CA) (92.8+/-2.9%; p<0.0001). Significant increases were seen in the natural log-transformed high-frequency modulation (HFln) (SuppO(2), 10.8+/-1.3 natural logarithm [ln] ms(2)/Hz; CA, 10.6+/-1.3 ln ms(2)/Hz; p<0.028) and BRS (SuppO(2), 3.3+/-2.2 ms/mm Hg; CA, 2.8+/-1.8 ms/mm Hg) following the supplemental oxygen treatment (p<0.015). The low-frequency/high-frequency ratio of heart rate variability revealed significant differences between the two treatments (SuppO(2), 2.7 +/-1.2; CA, 3.1+/-1.3; p<0.008). The analysis of BP variability data revealed significant decreases in the HFln (CA, 6.9+/-1.0 mm Hg(2)/Hz; SuppO(2), 6.5+/-1.2 mm Hg(2)/Hz; p<0.0001). Hemodynamic data also revealed a decrease in mean heart rate after breathing SuppO(2) compared with that after breathing CA (CA, 87.3+/-13.3 beats/min; SuppO(2), 85.0+/-12.4 beats/min; p<0.0004). The arterial pulse pressure significantly decreased when breathing SuppO(2) compared with that when breathing CA (CA, 57.2+/-13.5 mm Hg; SuppO(2), 53.3+/-13.0 mm Hg; p<0.0023). CONCLUSION: Oxygen supplementation in COPD patients significantly and favorably alters autonomic modulation.

Autonomic Nervous System↗
PubMed2004

Direct and remote modulation of L-channels in chromaffin cells: distinct actions on alpha1C and alpha1D subunits?

Understanding precisely the functioning of voltage-gated Ca2+ channels and their modulation by signaling molecules will help clarifying the Ca(2+)-dependent mechanisms controlling exocytosis in chromaffin cells. In recent years, we have learned more about the various pathways through which Ca2+ channels can be up- or down-modulated by hormones and neurotransmitters and how these changes may condition chromaffin cell activity and catecolamine release. Recently, the attention has been focused on the modulation of L-channels (CaV 1), which represent the major Ca2+ current component in rat and human chromaffin cells. L-channels are effectively inhibited by the released content of secretory granules or by applying mixtures of exogenous ATP, opioids, and adrenaline through the activation of receptor-coupled G proteins. This unusual inhibition persists in a wide range of potentials and results from a direct (membrane-delimited) interaction of G protein subunits with the L-channels co-localized in membrane microareas. Inhibition of L-channels can be reversed when the cAMP/PKA pathway is activated by membrane permeable cAMP analog or when cells are exposed to isoprenaline (remote action), suggesting the existence of parallel and opposite effects on L-channel gating by distinctly activated membrane autoreceptors. Here, the authors review the molecular components underlying these two opposing signaling pathways and present new evidence supporting the presence of two L-channel types in rat chromaffin cells (alpha1C and alpha1D), which open new interesting issues concerning Ca(2+)-channel modulation. In light of recent findings on the regulation of exocytosis by Ca(2+)-channel modulation, the authors explore the possible role of L-channels in the autocontrol of catecholamine release.

Animals↗
PubMed2006

A new module for on-line manipulation and display of molecular information in the brain architecture management system.

A new "Molecules" module of the Brain Architecture Management System (BAMS; http://brancusi.usc.edu/bkms) is described. With this module, BAMS becomes the first online knowledge management system to handle central nervous system (CNS) region and celltype chemoarchitectonic data in the context of axonal connections between regions and cell types, in multiple species. The "Molecules" module implements a general knowledge representation schema for data and metadata collated from published and unpublished material, and allows insertion of complex reports about the presence of molecules collated from the literature. For different CNS neural regions and cell types, the module's database structure includes representation of molecule expression revealed by various techniques including in situ hybridization and immunohistochemistry, molecule coexpression and time-dependent level changes, and physiological state of subjects. The metadata representation allows online comparison and evaluation of inserted experiments, and "Molecules"structure allows rapid development of data transfer protocols enabling neuroinformatics visualization tools to display gene expression patterns residing in BAMS, in terms of levels of expressed molecules and in situ hybridization data. The module's web interface allows users to construct lists of CNS regions containing a molecule (depending on physiological state), retrieve further details about inserted records, compare time-dependent data within and across experiments, reconstruct gene expression patterns, and construct complex reports from individual experiments.

Animals↗
PubMed1998

Ion channel modulators that enhance acetylcholine release: potential therapies for Alzheimer's disease.

Enhancing the release of acetylcholine (ACh) in the brain is one approach to increasing neuronal activity, restoring central cholinergic tone and improving attention and cognition. ACh release is modulated by both ligand-gated (gamma-amino butyric acid A receptors/benzodiazepine [GABA(A)/BDZ], nicotinic-acetylcholine and serotonin, 5-HT3) and voltage-gated (calcium and potassium) ion channels. Of the ligand-gated channel modulators, the BDZ receptor (BDZR) inverse agonists (beta-CCM, ZK 93426) enhance activity-dependent release in animals, whereas S-8510, a partial inverse agonist, and the BDZR antagonist, flumazenil, show enhancement regardless of the behavioural state of the animal. Some of these agents have undergone limited clinical evaluation for Alzheimer's disease (AD) (ZK 93426, flumazenil, S-8510), but their potential anxiogenic liability makes their therapeutic use uncertain until more clinical data are available. Within the group of nicotinic agonists, ABT-418, though less potent than nicotine and epibatidine in promoting ACh release in vitro, was clinically evaluated based on its in vivo profile. Its lack of oral bioavailability has limited its acceptability, though transdermal administration has been used to circumvent this deficiency. Serotonin 5-HT3 receptor modulators have not been advanced for clinical evaluation for the treatment of AD. Among the voltage-gated ion channel modulators affecting L- or N-type calcium channels, nefiracetam, a nootropic agent, also increased ACh release in animal studies. It is currently undergoing clinical evaluation for AD, though a need for more potent and brain selective calcium channel blockers exists. Potassium channel modulators have been the most studied ACh release enhancing agents and several of these compounds (4-AP, 3,4-DAP, linopirdine) have been clinically evaluated. In AD patients, 4-AP, an A-type K+ channel blocker, elicited inconsistent and unremarkable effects. Linopirdine, whose enhancement of ACh release correlates with its ability to block M-type K+ channels, also produced disappointing clinical results, which may have been related to its suboptimal pharmacokinetic profile. Further work in this series has provided a compound (DMP 543) that should be a more reliable indicator of whether a blocker of this ion channel can activate the cholinergic system in man. This agent is currently undergoing clinical evaluation for AD.

Journal Article↗
PubMed2000

Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease.

Excitatory neurotransmission in the CNS depends heavily upon alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)-type glutamate receptors. Derangements in AMPA receptor mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention. Recently, drugs that positively modulate AMPA receptors have been identified, having differential effects upon certain AMPA receptor subunits and different effects upon physiological properties of AMPA receptors. These drugs facilitate AMPA receptor mediated processes and may have beneficial therapeutic effects. For example, certain AMPA modulators facilitate long-term potentiation, which is considered a cellular mechanism that may be important for memory storage and they also facilitate memory encoding in behavioural experiments. Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease (AD). However, AMPA receptor mediated excitotoxicity may occur with excessive AMPA receptor activation which occurs in seizures or ischaemia and positive AMPA modulators could promote neuronal injury in those conditions. Ultimately, the clinical utility of positive AMPA modulators will be dependent upon understanding the role of AMPA receptors in certain neurological disorders, identifying receptor subtypes involved in specific neurological disorders and developing drugs with selective actions upon specific AMPA receptor properties that also possess receptor subtype specificity. Currently available drugs have provided significant insight into the physiology and structural determinants of important AMPA receptor properties and some insight into potential clinical uses as well as potential dangers of such drugs.

Animals↗
PubMed2004

Responses of dorsal cochlear nucleus neurons to signals in the presence of modulated maskers.

The detection of a signal in noise is enhanced when the masking noise is coherently modulated over a wide range of frequencies. This phenomenon, known as comodulation masking release (CMR), has been attributed to across-channel processing; however, the relative contribution of different stages in the auditory system to such across-channel processing is unknown. It has been hypothesized that wideband or lateral inhibition may underlie a physiological correlate of CMR. To further test this hypothesis, we have measured the responses of single units from the dorsal cochlear nucleus in which wideband inhibition is particularly pronounced. Using a sinusoidally amplitude-modulated tone at the best frequency of each unit as a masker, a pure-tone signal was added in the dips of the masker modulation. Flanking bands (FBs, also amplitude-modulated pure tones) were positioned to fall within the inhibitory sidebands of the receptive field of the unit. The FBs were either in phase (comodulated) or out of phase (codeviant) with the on-frequency masker. For the majority of units, the addition of the comodulated FBs produced a strong reduction in the response to the masker modulation, making the signal more salient in the post stimulus time histograms. The change in spike rate in response to the signal between the masker and signal-plus-masker conditions was greatest for the comodulated condition for 29 of 45 units. These results are consistent with the hypothesis that wideband inhibition may play a role in across-channel processing at an early stage in the auditory pathway.

Acoustic Stimulation↗

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