Position of the Third Na+ Site in the Aspartate Transporter GltPh and the Human Glutamate Transporter, EAAT1

Glutamate transport via the human excitatory amino acid transporters is coupled to the co-transport of three Na+ ions, one H+ and the counter-transport of one K+ ion. Transport by an archaeal homologue of the human glutamate transporters, GltPh, whose three dimensional structure is known is also coupled to three Na+ ions but only two Na+ ion binding sites have been observed in the crystal structure of GltPh. In order to fully utilize the GltPh structure in functional studies of the human glutamate transporters, it is essential to understand the transport mechanism of GltPh and accurately determine the number and location of Na+ ions coupled to transport. Several sites have been proposed for the binding of a third Na+ ion from electrostatic calculations and molecular dynamics simulations. In this study, we have performed detailed free energy simulations for GltPh and reveal a new site for the third Na+ ion involving the side chains of Threonine 92, Serine 93, Asparagine 310, Aspartate 312, and the backbone of Tyrosine 89. We have also studied the transport properties of alanine mutants of the coordinating residues Threonine 92 and Serine 93 in GltPh, and the corresponding residues in a human glutamate transporter, EAAT1. The mutant transporters have reduced affinity for Na+ compared to their wild type counterparts. These results confirm that Threonine 92 and Serine 93 are involved in the coordination of the third Na+ ion in GltPh and EAAT1

GAP waveguides

The coming years will show new applications of wireless communications at higher frequencies (30 GHz and above). Modern wireless technologies like massive MIMO and gigabit transmission will become a reality. The industrial winners will be the companies that can provide the hardware at the lowest cost. This requires new waveguide and mmWave packaging technologies that are more cost-effective than normal rectangular waveguide technology and are more power efficient (lower losses) than PCB-based microstrip and coplanar waveguides. The gap waveguide has this potential. The present chapter gives the historical background of gap waveguide technology until its invention in 2008 and how it has evolved since then to include many different kinds of gap waveguide types. Several useful waveguide components have been developed for integration in complete RF front ends. Passive gap waveguide parts and components like filters, couplers, and transitions have been realized very successfully, and active microwave electronics have been packaged. The chapter contains also an overview of the gap waveguide antennas that have been developed during the last years

Molecular Mechanisms of Action and In Vivo Validation of an M4 Muscarinic Acetylcholine Receptor Allosteric Modulator with Potential Antipsychotic Properties

We recently identified LY2033298 as a novel allosteric potentiator of acetylcholine (ACh) at the M4 muscarinic acetylcholine receptor (mAChR). This study characterized the molecular mode of action of this modulator in both recombinant and native systems. Radioligand-binding studies revealed that LY2033298 displayed a preference for the active state of the M4 mAChR, manifested as a potentiation in the binding affinity of ACh (but not antagonists) and an increase in the proportion of high-affinity agonist–receptor complexes. This property accounted for the robust allosteric agonism displayed by the modulator in recombinant cells in assays of [35S]GTPγS binding, extracellular regulated kinase 1/2 phosphorylation, glycogen synthase kinase 3β phosphorylation, and receptor internalization. We also found that the extent of modulation by LY2033298 differed depending on the signaling pathway, indicating that LY2033298 engenders functional selectivity in the actions of ACh. This property was retained in NG108-15 cells, which natively express rodent M4 mAChRs. Functional interaction studies between LY2033298 and various orthosteric and allosteric ligands revealed that its site of action overlaps with the allosteric site used by prototypical mAChR modulators. Importantly, LY2033298 reduced [3H]ACh release from rat striatal slices, indicating retention of its ability to allosterically potentiate endogenous ACh in situ. Moreover, its ability to potentiate oxotremorine-mediated inhibition of condition avoidance responding in rodents was significantly attenuated in M4 mAChR knockout mice, validating the M4 mAChR as a key target of action of this novel allosteric ligand

Disentangling flow and signals of Chiral Magnetic Effect in U plus U, Au plus Au and p plus Au collisions

We present STAR measurements of the charge-dependent three-particle correlator gamma(a,b) = /v(2){2} and elliptic flow v(2){2} in U+U, Au+Au and p+Au collisions at RHIC. The difference Delta gamma = gamma(opposite sign)-gamma(same sign) measures charge separation across the reaction plane, a predicted signal of the Chiral Magnetic Effect (CME). Although charge separation has been observed, it has been argued that the measured separation can also be explained by elliptic flow related backgrounds. In order to separate the two effects we perform measurements of the gamma-correlator where background expectations differ from magnetic field driven effects. A differential measurement of gamma with the relative pseudorapidity (Delta eta)) between the first and second particles indicate that Delta gamma in peripheral A+A and p+A collisions are dominated by short-range correlations in A. However, a relatively wider component of the correlation in Delta eta tends to vanish the same way as projected magnetic field as predicted by MC-Glauber simulations

Charge-Dependent Directed Flow in Cu plus Au Collisions at root S-NN=200 GeV

We present the first measurement of charge-dependent directed flow in Cu + Au collisions at root S-NN = 200 GeV. The results are presented as a function of the particle transverse momentum and pseudorapidity for different centralities. A finite difference between the directed flow of positive and negative charged particles is observed that qualitatively agrees with the expectations from the effects of the initial strong electric field between two colliding ions with different nuclear charges. The measured difference in directed flow is much smaller than that obtained from the parton-hadron-string-dynamics model, which suggests that most of the electric charges, i.e., quarks and antiquarks, have not yet been created during the lifetime of the strong electric field, which is of the order of, or less than, 1 fm/c