Antibodies have enormous therapeutic and biotechnology potential. G protein-coupled receptors (GPCRs), the main targets in drug development, are of major interest in antibody development programs. Metabotropic glutamate receptors are dimeric GPCRs that can control synaptic activity in a multitude of ways. Here we identify llama nanobodies that specifically recognize mGlu2 receptors, among the eight subtypes of mGluR subunits. Among these nanobodies, DN10 and 13 are positive allosteric modulators (PAM) on homodimeric mGlu2, while DN10 displays also a significant partial agonist activity. DN10 and DN13 have no effect on mGlu2-3 and mGlu2-4 heterodimers. These PAMs enhance the inhibitory action of the orthosteric mGlu2/mGlu3 agonist, DCG-IV, at mossy fiber terminals in the CA3 region of hippocampal slices. DN13 also impairs contextual fear memory when injected in the CA3 region of hippocampal region. These data highlight the potential of developing antibodies with allosteric actions on GPCRs to better define their roles in vivo.
A time-domain numerical modeling of Biot poroelastic waves is presented. The viscous dissipation occurring in the pores is described using the dynamic permeability model developed by Johnson-Koplik-Dashen (JKD). Some of the coefficients in the Biot-JKD model are proportional to the square root of the frequency: in the time-domain, these coefficients introduce order 1/2 shifted fractional derivatives involving a convolution product. Based on a diffusive representation, the convolution kernel is replaced by a finite number of memory variables that satisfy local-in-time ordinary differential equations. Thanks to the dispersion relation, the coefficients in the diffusive representation are obtained by performing an optimization procedure in the frequency range of interest. A splitting strategy is then applied numerically: the propagative part of Biot-JKD equations is discretized using a fourth-order ADER scheme on a Cartesian grid, whereas the diffusive part is solved exactly. Comparisons with analytical solutions show the efficiency and the accuracy of this approach.
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