D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D₂-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D₂-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D₂DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D₂DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D₂DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D₂DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease

Domain decomposition for implicit solvation models

International audienceThis article is the first of a series of papers dealing with domain decomposition algorithms for implicit solvent models. We show that, in the framework of the COSMO model, with van der Waals molecular cavities and classical charge distributions, the electrostatic energy contribution to the solvation energy, usually computed by solving an integral equation on the whole surface of the molecular cavity, can be computed more efficiently by using an integral equation formulation of Schwarz's domain decomposition method for boundary value problems. In addition, the so-obtained potential energy surface is smooth, which is a critical property to perform geometry optimization and molecular dynamics simulations. The purpose of this first article is to detail the methodology, set up the theoretical foundations of the approach, and study the accuracies and convergence rates of the resulting algorithms. The full efficiency of the method and its applicability to large molecular systems of biological interest is demonstrated elsewhere

D₂ Dopamine Receptors Colocalize Regulator of G-Protein Signaling 9-2 (RGS9-2) via the RGS9 DEP Domain, and RGS9 Knock-Out Mice Develop Dyskinesias Associated with Dopamine Pathways

Regulator of G-protein signaling 9-2 (RGS9-2), a member of the RGS family of Gα GTPase accelerating proteins, is expressed specifically in the striatum, which participates in antipsychotic-induced tardive dyskinesia and in levodopa-induced dyskinesia. We report that RGS9 knock-out mice develop abnormal involuntary movements when inhibition of dopaminergic transmission is followed by activation of D₂-like dopamine receptors (DRs). These abnormal movements resemble drug-induced dyskinesia more closely than other rodent models. Recordings from striatal neurons of these mice establish that activation of D₂-like DRs abnormally inhibits glutamate-elicited currents. We show that RGS9-2, via its DEP domain (for Disheveled, EGL-10, Pleckstrin homology), colocalizes with D₂DRs when coexpressed in mammalian cells. Recordings from oocytes coexpressing D₂DR or the m2 muscarinic receptor and G-protein-gated inward rectifier potassium channels show that RGS9-2, via its DEP domain, preferentially accelerates the termination of D₂DR signals. Thus, alterations in RGS9-2 may be a key factor in the pathway leading from D₂DRs to the side effects associated with the treatment both of psychoses and Parkinson's disease

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD). GNE-0723 use dependently potentiates synaptic NMDA receptor currents and reduces brain oscillation power with a predominant effect on low-frequency (12-20 Hz) oscillations. Interestingly, DS and AD mouse models display aberrant low-frequency oscillatory power that is tightly correlated with network hypersynchrony. GNE-0723 treatment reduces aberrant low-frequency oscillations and epileptiform discharges and improves cognitive functions in DS and AD mouse models. GluN2A-subunit-containing NMDAR enhancers may have therapeutic benefits in brain disorders with network hypersynchrony and cognitive impairments

Accessible Content and Accessibility Experiences: The Interplay of Declarative and Experiential Information in Judgment

Recall tasks render 2 distinct sources of information available: the recalled content and the experienced ease or difficulty with which it can be brought to mind. Because retrieving many pieces of information is more difficult than retrieving only a few, reliance on accessible content and subjective accessibility experiences leads to opposite judgmental outcomes. People are likely to base judgments on accessibility experiences when they adopt a heuristic processing strategy and the informational value of the experience is not called into question. When the experience is considered nondiagnostic, or when a systematic processing strategy is adopted, people rely on accessible content. Implications for the operation of the availability heuristic and the emergence of knowledge accessibility effects are discussed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68686/2/10.1207_s15327957pspr0202_2.pd

Kinematics of the outer pseudorings and the spiral structure of the Galaxy

The kinematics of the outer rings and pseudorings is determined by two processes: the resonance tuning and the gas outflow. The resonance kinematics is clearly observed in the pure rings, while the kinematics of the gas outflow is manifested itself in the pseudorings. The direction of systematical motions in the pure rings depends on the position angle of a point with respect to the bar major axis and on the class of the outer ring. The direction of the radial and azimuthal components of the residual velocities of young stars in the Perseus, Carina, and Sagittarius regions can be explained by the presence of the outer pseudoring of class R1R2' in the Galaxy. We present models, which reproduce the directions and values of the residual velocities of OB-associations in the Perseus and Sagittarius regions, and also model reproducing the directions of the residual velocities in the Perseus, Sagittarius, and Carina regions. The kinematics of the Sagittarius region accurately defines the solar position angle with respect to the bar elongation, theta_b=45 (+/-5) deg.Comment: 16 pages, 10 figures, accepted for publication in Astronomy Letter

Kassiopeia: A Modern, Extensible C++ Particle Tracking Package

The Kassiopeia particle tracking framework is an object-oriented software package using modern C++ techniques, written originally to meet the needs of the KATRIN collaboration. Kassiopeia features a new algorithmic paradigm for particle tracking simulations which targets experiments containing complex geometries and electromagnetic fields, with high priority put on calculation efficiency, customizability, extensibility, and ease of use for novice programmers. To solve Kassiopeia's target physics problem the software is capable of simulating particle trajectories governed by arbitrarily complex differential equations of motion, continuous physics processes that may in part be modeled as terms perturbing that equation of motion, stochastic processes that occur in flight such as bulk scattering and decay, and stochastic surface processes occuring at interfaces, including transmission and reflection effects. This entire set of computations takes place against the backdrop of a rich geometry package which serves a variety of roles, including initialization of electromagnetic field simulations and the support of state-dependent algorithm-swapping and behavioral changes as a particle's state evolves. Thanks to the very general approach taken by Kassiopeia it can be used by other experiments facing similar challenges when calculating particle trajectories in electromagnetic fields. It is publicly available at https://github.com/KATRIN-Experiment/Kassiopei

The Disk and Dark Halo Mass of the Barred Galaxy NGC 4123. I. Observations

The non-circular streaming motions in barred galaxies are sensitive to the mass of the bar and can be used to lift the degeneracy between disk and dark matter halo encountered when fitting axisymmetric rotation curves of disk galaxies. In this paper, we present photometric and kinematic observations of NGC 4123, a barred galaxy of modest size (V_rot = 130 km/sec, L = 0.7 L_*), which reveal strong non-circular motions. The bar has straight dust lanes and an inner Lindblad resonance. The disk of NGC 4123 has no sign of truncation out to 10 scale lengths, and star-forming regions are found well outside R_25. A Fabry-Perot H-alpha velocity field shows velocity jumps of >100 km/sec at the location of the dust lanes within the bar, indicating shocks in the gas flow. VLA observations yield the velocity field of the H I disk. Axisymmetric mass models yield good fits to the rotation curve outside the bar regionfor disk I-band M/L of 2.25 or less, and dark halos with either isothermal or power-law profiles can fit the data well. In a companion paper, we model the full 2-D velocity field, including non-circular motions, to determine the stellar M/L and the mass of the dark halo.Comment: accepted by ApJ, 16 pages, 9 figures (1 color), uses emulateapj.sty, onecolfloat.st

N-body simulations in reconstruction of the kinematics of young stars in the Galaxy

We try to determine the Galactic structure by comparing the observed and modeled velocities of OB-associations in the 3 kpc solar neighborhood. We made N-body simulations with a rotating stellar bar. The galactic disk in our model includes gas and stellar subsystems. The velocities of gas particles averaged over large time intervals ($\sim 8$ bar rotation periods) are compared with the observed velocities of the OB-associations. Our models reproduce the directions of the radial and azimuthal components of the observed residual velocities in the Perseus and Sagittarius regions and in the Local system. The mean difference between the model and observed velocities is $\Delta V=3.3$ km s$^{-1}$. The optimal value of the solar position angle $\theta_b$ providing the best agreement between the model and observed velocities is $\theta_b=45\pm5^\circ$, in good accordance with several recent estimates. The self-gravitating stellar subsystem forms a bar, an outer ring of subclass $R_1$, and slower spiral modes. Their combined gravitational perturbation leads to time-dependent morphology in the gas subsystem, which forms outer rings with elements of the $R_1$- and $R_2$-morphology. The success of N-body simulations in the Local System is likely due to the gravity of the stellar $R_1$-ring, which is omitted in models with analytical bars.Comment: 13 pages, 13 figures, accepted to Astronomy and Astrophysic