ALBERT

Description: Disruption of protein:protein interactions (PPIs) that regulate the function of voltage-gated Na+ (Nav) channels leads to neural circuitry aberrations that have been implicated in numerous channelopathies. One example of this pathophysiology is mediated by dysfunction of the PPI between Nav1.6 and its regulatory protein fibroblast growth factor 14 (FGF14). Thus, peptides derived from FGF14 might exert modulatory actions on the FGF14:Nav1.6 complex that are functionally relevant. The tetrapeptide Glu-Tyr-Tyr-Val (EYYV) mimics surface residues of FGF14 at the β8–β9 loop, a structural region previously implicated in its binding to Nav1.6. Here, peptidomimetics derived from EYYV (6) were designed, synthesized, and pharmacologically evaluated to develop probes with improved potency. Addition of hydrophobic protective groups to 6 and truncation to a tripeptide (12) produced a potent inhibitor of FGF14:Nav1.6 complex assembly. Conversely, addition of hydrophobic protective groups to 6 followed by addition of an N-terminal benzoyl substituent (19) produced a potentiator of FGF14:Nav1.6 complex assembly. Subsequent functional evaluation using whole-cell patch-clamp electrophysiology confirmed their inverse activities, with 12 and 19 reducing and increasing Nav1.6-mediated transient current densities, respectively. Overall, we have identified a negative and positive allosteric modulator of Nav1.6, both of which could serve as scaffolds for the development of target-selective neurotherapeutics.

Description: Electrospray thruster life and mission performance are strongly influenced by grid impingement, the extent of which can be correlated with emission modes that occur at steady-state extraction voltages, and thruster command transients. Most notably, we experimentally observed skewed cone-jet emission during steady-state electrospray thruster operation, which leads to the definition of an additional grid impingement mechanism that we termed “tilted emission”. Long distance microscopy was used in conjunction with high speed videography to observe the emission site of an electrospray thruster operating with an ionic liquid propellant (EMI-Im). During steady-state thruster operation, no unsteady electrohydrodynamic emission modes were observed, though the conical meniscus exhibited steady off-axis tilt of up to 15°. Cone tilt angle was independent over a wide range of flow rates but proved strongly dependent on extraction voltage. For the geometry and propellant used, the optimal extraction voltage was near 1.6 kV. A second experiment characterized transient emission behavior by observing startup and shutdown of the thruster via flow or voltage. Three of the four possible startup and shutdown procedures transition to quiescence within ∼475 μs, with no observed unsteady modes. However, during voltage-induced thruster startup, unsteady electrohydrodynamic modes were observed.