Zinc Inhibition of t -[ 3 H]Butylbicycloorthobenzoate Binding to the GABA A Receptor Complex

The effect of Zn 2+ on t -[ 3 H]butylbicycloorthobenzoate ([ 3 H]TBOB) binding to the GABA A receptor complex was studied autoradiographically in rat brain. Zn 2+ inhibited [ 3 H]TBOB binding in a dose-dependent manner at physiological concentrations. Saturation analysis revealed noncompetitive inhibition in various brain regions. The inhibitory effect of Zn 2+ had regional heterogeneity; regions showing the greatest inhibition of [ 3 H]TBOB binding were cortical laminae I–III, most areas of hippocampus, striatum, septum, and cerebellar cortex. Regions with relatively less inhibition of [ 3 H]TBOB binding included cortical laminae V–VI, thalamus, superior colliculus, inferior colliculus, and central gray matter. The effect of Zn 2+ and those of other GABA A ligands, such as benzodiazepines, bicuculline, isoguvacine, and picrotoxin, on [ 3 H]TBOB binding seemed to be additive. Ni 2+ , Cd 2+ , and Cu 2+ also inhibited [ 3 H]TBOB binding with a regional heterogeneity similar to that produced by Zn 2+ . These results are consistent with Zn 2+ acting at the previously detected recognition site on the GABA A receptor complex, distinct from the picrotoxin, GABA, and benzodiazepine sites. The regional heterogeneity of the Zn 2+ effect may reflect differential regional distribution of GABA A receptor subtypes among brain regions. Other divalent cations probably act at the Zn 2+ binding site.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66304/1/j.1471-4159.1994.62020602.x.pd

Quantitative autoradiography of 4'-ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate binding to the GABAA receptor complex

4'-Ethynyl-4-n-[2,3-3H2]propylbicycloorthobenzoate ([3H]EBOB) binding to the GABAA receptor complex was characterized autoradiographically in rat brain and then its binding in human brain was investigated. [3H]EBOB binding was saturable, specific and identified a single population of binding sites. The Kd obtained from saturation was 4.59 nM. Picrotoxin produced dose-dependent inhibition of [3H]EBOB binding and saturation analysis indicated a competetitive interaction. Isoguvacine inhibited [3H]EBOB binding with regionally different effects. Bicuculline increased [3H]EBOB binding only in the cerebellar granule cell layer. In human cerebellum, a high level of [3H]EBOB binding sites was seen in the granule cell layer. These results suggest that [3H]EBOB binds to the picrotoxin binding site associated with the GABAA receptor complex, that regional differences in GABAA agonist and antagonist modulation of [3H]EBOB binding reflect underlying regional differences in GABAA receptor subunit composition, and that there is a species difference in GABAA receptor distribution between human and rat cerebellum.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/31320/1/0000229.pd

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M>70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0<e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Testosterone Reduction Prevents Phenotypic Expression in a Transgenic Mouse Model of Spinal and Bulbar Muscular Atrophy

AbstractSpinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse nuclear staining and nuclear inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA