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Quasi-phasematched mixing processes of acoustic waves via second-order nonlinearity are analyzed with two perfectly guided waves generating a leaky wave. The efficiency of such processes is quantified by an acoustic nonlinearity parameter (ANP), defined as the linear growth rate of the leaky wave's amplitude in the initial stage of its spatial evolution. Two approximate ways of estimating the ANP of such processes are suggested. The first starts from a stationary solution of the equation of motion and boundary conditions for the displacement field, obtained within perturbation theory. This approach requires the solution of a near-singular linear system of equations. The second is based on the resonant state expansion of the displacement field generated in the mixing process. It allows to express the ANP in the form of an overlap integral, requiring normalization of the displacement field associated with the leaky wave. For leaky output waves with a high degree of localization at the waveguide, both methods yield results in good agreement, as demonstrated for an example system with generalized (2D) plate modes. The first approach has also been applied to finite element calculations of the ANP for nonlinear mixing processes of (1D) edge waves in an elastic plate with rigid faces., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Hypertension remains a leading cause of cardiovascular and kidney diseases. Failure to control blood pressure with ≥ 3 medications or control requiring ≥ 4 medications is classified as resistant hypertension (rHTN) and new therapies are needed to reduce the resulting increased risk of morbidity and mortality. Here, we report genetic evidence that relaxin family peptide receptor 2 (RXFP2) is associated with rHTN in men, but not in women. This study shows that adrenal gland gene expression of RXFP2 is increased in men with hypertension and the RXFP2 natural ligand, INSL3, increases adrenal steroidogenesis and corticosteroid secretion in human adrenal cells. To address the hypothesis that RXFP2 activation is an important mechanism in rHTN, we discovered and characterized small molecule and monoclonal antibody (mAb) blockers of RXFP2. The novel chemical entities and mAbs show potent, selective inhibition of RXFP2 and reduce aldosterone and cortisol synthesis and release. The RXFP2 mAbs have suitable rat pharmacokinetic profiles to evaluate the role of RXFP2 in the development and maintenance of rHTN. Overall, we identified RXFP2 activity as a potential new mechanism in rHTN and discovered RXFP2 antagonists for the future interrogation of RXFP2 in cardiovascular and renal diseases., (© 2024. The Author(s).)

The excitation of acoustic waves by a unidirectional transducer, integrated in a piezoelectric cylindrical tube or disk, can lead to a time-independent torque. This phenomenon, demonstrated earlier in experiments and analyzed with coupling-of mode theory, is explained in detail, starting on the level of lattice dynamics of a piezoelectric crystal. Expressions are derived for the stationary torque in the form of integrals over the volume or surface of the piezoelectric, involving the electric potential and displacement field associated with the acoustic waves generated by the transducer. Simulations have been carried out with the help of the finite element method for a tube made of PZT for two cases: A pre-defined potential on the surface of the tube and metal electrodes buried in the piezoelectric. The displacement field and electric potential of the high-frequency acoustic waves (between 200 and 300 kHz) were computed and used in the evaluation of the integrals. The attenuation due to various loss channels of the acoustic waves in the system has been analyzed in detail, as this plays a crucial role for the efficiency of torque generation. It is conjectured that time-reversal symmetry, present in the absence of attenuation, prohibits the generation of a static torque at least in the linear limit. A qualitative comparison is made between the simulations and earlier experiments. Discrepancies are attributed to lack of knowledge of the relevant material constants of the piezoelectric and to a simplified modeling of the electrode geometry in the cylindrical tube, which was necessary for reasons of numerical accuracy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Non-neutralizing anti-idiotype antibodies against a therapeutic monoclonal antibody (mAb) play a crucial role in the creation of total pharmacokinetic (PK) assays and total target engagement (TE) assays during both pre-clinical and clinical development. The development of these anti-idiotype antibodies is challenging. In this study, we utilized a hybridoma platform to produce a variety of anti-idiotype antibodies against GSK2857914, a humanized IgG1 anti-BCMA monoclonal antibody. The candidate clones were evaluated using surface plasmon resonance (SPR) and bio-layer interferometry (BLI) for binding affinity, binding profiling, matrix interference, and antibody pairing determination. We discovered that three anti-idiotype antibodies did not prevent BCMA from binding to GSK2857914. All three candidates demonstrated high binding affinities. One of the three exhibited minimal matrix inference and could pair with the other two candidates. Additionally, one of the three clones was biotinylated as a capture reagent for the total PK assay, and another was labeled with ruthenium as a detection reagent for both the total PK assay and total TE assay. The assay results clearly show that these reagents are genuine non-neutralizing anti-idiotypic antibodies and are suitable for total PK and TE assay development. Based on this and similar studies, we conclude that the hybridoma platform has a high success rate for generating non-neutralizing anti-idiotype antibodies. Our methodology for developing and characterizing non-neutralizing anti-idiotype antibodies to therapeutic antibodies can be generally applied to any antibody-based drug candidate's total PK and total TE assay development., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)