Context-Dependent Pharmacology Exhibited by Negative Allosteric Modulators of Metabotropic Glutamate Receptor 7

Phenotypic studies of mice lacking metabotropic glutamate receptor subtype 7 (mGluR7) suggest that antagonists of this receptor may be promising for the treatment of central nervous system disorders such as anxiety and depression. Suzuki et al. (J Pharmacol Exp Ther 323: 147-156, 2007) recently reported the in vitro characterization of a novel mGluR7 antagonist called 6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP), which noncompetitively inhibited the activity of orthosteric and allosteric agonists at mGluR7. We describe that MMPIP acts as a noncompetitive antagonist in calcium mobilization assays in cells coexpressing mGluR7 and the promiscuous G protein G alpha(15). Assessment of the activity of a small library of MMPIP-derived compounds using this assay reveals that, despite similar potencies, compounds exhibit differences in negative co-operativity for agonist-mediated calcium mobilization. Examination of the inhibitory activity of MMPIP and analogs using endogenous G(i/o)-coupled assay readouts indicates that the pharmacology of these ligands seems to be context-dependent, and MMPIP exhibits differences in negative cooperativity in certain cellular backgrounds. Electrophysiological studies reveal that, in contrast to the orthosteric antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxyclycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (LY341495), MMPIP is unable to block agonist-mediated responses at the Schaffer collateral-CA1 synapse, a location at which neurotransmission has been shown to be modulated by mGluR7 activity. Thus, MMPIP and related compounds differentially inhibit coupling of mGluR7 in different cellular backgrounds and may not antagonize the coupling of this receptor to native G(i/o) signaling pathways in all cellular contexts. The pharmacology of this compound represents a striking example of the potential for context-dependent blockade of receptor responses by negative allosteric modulators.

MeV negative ion source from ultra-intense laser-matter interaction

Experimental demonstration of negative ion acceleration to MeV energies from sub-micron size droplets of water spray irradiated by ultra-intense laser pulses is presented. Thanks to the specific target configuration and laser parameters, more than 109 negative ions per steradian solid angle in 5% energy bandwidth are accelerated in a stable and reliable manner. To our knowledge, by virtue of the ultra-short duration of the emission, this is by far the brightest negative ion source reported. The data also indicate the existence of beams of neutrals with at least similar numbers and energies.

Negative ion enhancement in caesium-seeded hydrogen discharges - a volume or surface effect?

Measurements of plasma parameters, including H- ion densities, made in conjunction with wall temperature, visible and vacuum ultraviolet emission spectroscopy verify that there is little caesium in the plasma volume of the H- ion source. Surface work function measurements indicate that there is significant caesium coverage of the inner walls of the ion source. It is found that, as the work function of a test surface decreases due to caesium seeding, the H- ion fraction in the discharge volume increases. These observations combine to indicate that, in the present source, the H- ion enhancement mechanism is a surface dominated effect. (C) 1999 American Institute of Physics. [S0003- 6951(99)04744-0].

Measurements of negative ion densities by absorption spectroscopy

A novel diagnostic technique for the measurement of negative ions is presented. The absorption of a cw-laser beam with a wavelength close to the maximum of the photodetachment cross section is measured. The laser beam undergoes multiple reflections through the discharge volume using a multipass cell there a Herriott arrangement). Proof-of-principle measurements of negative hydrogen ions in a hybrid volume source are presented. The measured H- density is in agreement with results of conventional, Langmuir probe-based photodetachment measurements. (C) 1998 American Institute of Physics. [S0003-6951(98)02119-6].

ELECTRON-ENERGY DISTRIBUTION-FUNCTIONS AND NEGATIVE-ION CONCENTRATIONS IN TANDEM AND HYBRID MULTICUSP NEGATIVE HYDROGEN-ION SOURCES

The second derivative of a Langmuir probe characteristic is used to establish the electron energy distribution function (EEDF) in both a tandem and hybrid multicusp H- ion source. Moveable probes are used to establish the spatial variation of the EEDF. The negative ion density is measured by laser induced photo-detachment. In the case of the hybrid source the EEDF consists of a cold Maxwellian in the central region of the source; the electron temperature increases with increasing discharge current (rising from 0.3 eV at 1 A to 1.2 eV at 50 A when the pressure is 0.4 Pa). A hot-electron tail exists in the EEDF of the driver region adjacent to each filament which is shown to consist of a distinct group of primary electrons at low pressure (0.08 Pa) but becomes degraded mainly through inelastic collisions at higher pressures (0.27 Pa). The tandem source, on the other hand, has a single driver region which extends throughout the central region. The primary electron confinement times are much longer so that even at the lowest pressure considered (0.07 Pa) the primaries are degraded. In both cases the measured EEDF at specific locations and values of discharge operating parameters are used to establish the rate coefficients for the processes of importance in H- production and destruction.

ENHANCED VOLUME PRODUCTION OF NEGATIVE-IONS IN THE POST DISCHARGE OF A MULTICUSP HYDROGEN DISCHARGE

In this paper we demonstrate a new concept in the production of negative hydrogen ions in a low-pressure multicusp discharge. The discharge voltage is modulated to produce a non-Maxwellian, hot-electron plasma during the current pulse, followed by a cool Maxwellian electron plasma in the post discharge. This procedure, of separating in time the required hot and cold electron plasmas required for volume H- production, is called a temporal filter. The time evolution of the electron energy distribution function is measured using the time-resolved second derivative of a Langmuir probe characteristic. Time-resolved measurements of the negative ion density are made using laser photodetachment. The measurements show that the negative ion density in the center of the source, at a gas pressure of 0.07 Pa, increases by a factor of 2 when the discharge is switched off. At this low pressure the average H- beam current extracted from the source, when operated with a discharge current of 1 A in the pulse modulated mode exceeds the H- beam current from a 5 A continuously operated source. The increase in efficiency of the pulsed source is explained in terms of a two-step H- production mechanism.

Evaluation of induction of porcine dermatitis and nephropathy syndrome in gnotobiotic pigs with negative results for porcine circovirus type 2

Objective-To determine whether porcine dermatitis and nephropathy syndrome (PDNS) could be experimentally induced in gnotobiotic swine.