Sound attenuation enhancement of acoustic meta-atoms via coupling.

Arrangements of acoustic meta-atoms, better known as acoustic metamaterials, are commonly applied in acoustic cloaking, for the attenuation of acoustic fields or for acoustic focusing. A precise design of single meta-atoms is required for these purposes. Understanding the details of their interaction allows improvement of the collective performance of the meta-atoms as a system, for example, in sound attenuation. Destructive interference of their scattered fields, for example, can be mitigated by adjusting the coupling or tuning of individual meta-atoms. Comprehensive numerical studies of various configurations of a resonator pair show that the coupling can lead to degenerate modes at periodic distances between the resonators. We show how the resonators' separation and relative orientation influence the coupling and thereby tunes the sound attenuation. The simulation results are supported by experiments using a two-dimensional parallel-plate waveguide. It is shown that coupling parameters like distance, orientation, detuning, and radiation loss provide additional degrees of freedom for efficient acoustic meta-atom tuning to achieve unprecedented interactions with excellent sound attenuation properties.

Willis Coupling-Induced Acoustic Radiation Force and Torque Reversal.

Acoustic meta-atoms serve as the building blocks of metamaterials, with linear properties designed to achieve functions such as beam steering, cloaking, and focusing. They have also been used to shape the characteristics of incident acoustic fields, which led to the manipulation of acoustic radiation force and torque for development of acoustic tweezers with improved spatial resolution. However, acoustic radiation force and torque also depend on the shape of the object, which strongly affects its scattering properties. We show that by designing linear properties of an object using metamaterial concepts, the nonlinear acoustic effects of radiation force and torque can be controlled. Trapped objects are typically small compared with the wavelength, and are described as particles, inducing monopole and dipole scattering. We extend such models to a polarizability tensor including Willis coupling terms, as a measure of asymmetry, capturing the significance of geometrical features. We apply our model to a three-dimensional, subwavelength meta-atom with maximal Willis coupling, demonstrating that the force and the torque can be reversed relative to an equivalent symmetrical particle. By considering shape asymmetry in the acoustic radiation force and torque, Gorkov's fundamental theory of acoustophoresis is thereby extended. Asymmetrical shapes influence the acoustic fields by shifting the stable trapping location, highlighting a potential for tunable, shape-dependent particle sorting.

Bandwidth and size limits of achromatic printed-circuit metasurfaces.

Metasurfaces can implement a wide variety of wave-manipulation functions with sub-wavelength layers. They are typically created from resonant elements, thus their refraction properties depend strongly on frequency. The resulting chromatic aberration is undesirable for most applications, motivating recent efforts in the development of achromatic metasurfaces. However, it remains unclear whether there are any physical limits on the achievable operating bandwidth of achromatic metasurfaces. Here we address this question, considering a common microwave metasurface geometry based on three metallic layers, separated by dielectric substrates. Since each of these metallic layers is modeled as an impedance, we apply Foster's reactance theorem to determine the bandwidth over which they are physically realizable using passive, causal and lossless structures. We derive limits for the bandwidth and total size of the metasurface, showing that there is a trade-off between these two parameters. A higher angle of refraction, corresponding to a larger numerical aperture for a lens, further limits the realizable bandwidth. We consider both Huygens' and Omega-bianisotropic metasurface types, and show that the limit is more severe for bianisotropic metasurfaces, making them less suitable for broadband achromatic designs.

Discovery and optimization of 2-pyridinone aminal integrase strand transfer inhibitors for the treatment of HIV.

HIV integrase strand transfer inhibitors (InSTIs) represent an important class of antiviral therapeutics with proven efficacy and excellent tolerability for the treatment of HIV infections. In 2007, Raltegravir became the first marketed strand transfer inhibitor pioneering the way to a first-line therapy for treatment-naïve patients. Challenges with this class of therapeutics remain, including frequency of the dosing regimen and the genetic barrier to resistance. To address these issues, research towards next-generation integrase inhibitors has focused on imparting potency against RAL-resistent mutants and improving pharmacokinetic profiles. Herein, we detail medicinal chemistry efforts on a novel class of 2-pyridinone aminal InSTIs, inpsired by MK-0536, which led to the discovery of important lead molecules for our program. Systematic optimization carried out at the amide and aminal positions on the periphery of the core provided the necessary balance of antiviral activity and physiochemical properties. These efforts led to a novel aminal lead compound with the desired virological profile and preclinical pharmacokinetic profile to support a once-daily human dose prediction.

Strong terahertz absorption in all-dielectric Huygens' metasurfaces.

We propose an all dielectric metamaterial that acts as a perfect terahertz absorber without a ground plane. The unit cell consists of a dielectric cylinder embedded in a low index material. In order to achieve near-perfect terahertz absorption (99.5%) we employ impedance matching of the electric and magnetic resonances within the cylinders of the Huygens' metasurface. The impedance matching is controlled by changing the aspect ratio between the height and diameter of the cylinder. We show that the absorption resonance can be tuned to particular frequencies from 0.3 to 1.9 THz via changing the geometry of the structure while keeping a nearly constant aspect ratio of the cylinders.

Realistic prediction and engineering of high-Q modes to implement stable Fano resonances in acoustic devices.

Quasi-bound states in the continuum (QBICs) coupling into the propagating spectrum manifest themselves as high-quality factor (Q) modes susceptible to perturbations. This poses a challenge in predicting stable Fano resonances for realistic applications. Besides, where and when the maximum field enhancement occurs in real acoustic devices remains elusive. In this work, we theoretically predict and experimentally demonstrate the existence of a Friedrich-Wintgen BIC in an open acoustic cavity. We provide direct evidence for a QBIC by mapping the pressure field inside the cavity using a Laser Doppler Vibrometer (LDV), which provides the missing field enhancement data. Furthermore, we design a symmetry-reduced BIC and achieve field enhancement by a factor of about three compared to the original cavity. LDV measurements are a promising technique for obtaining high-Q modes' missing field enhancement data. The presented results facilitate the future applications of BICs in acoustics as high-intensity sound sources, filters, and sensors.

Magnetoelastic metamaterials.

The study of advanced artificial electromagnetic materials, known as metamaterials, provides a link from material science to theoretical and applied electrodynamics, as well as to electrical engineering. Being initially intended mainly to achieve negative refraction, the concept of metamaterials quickly covered a much broader range of applications, from microwaves to optics and even acoustics. In particular, nonlinear metamaterials established a new research direction giving rise to fruitful ideas for tunable and active artificial materials. Here we introduce the concept of magnetoelastic metamaterials, where a new type of nonlinear response emerges from mutual interaction. This is achieved by providing a mechanical degree of freedom so that the electromagnetic interaction in the metamaterial lattice is coupled to elastic interaction. This enables the electromagnetically induced forces to change the metamaterial structure, dynamically tuning its effective properties. This concept leads to a new generation of metamaterials, and can be compared to such fundamental concepts of modern physics as optomechanics of photonic structures or magnetoelasticity in magnetic materials.

Spatial dispersion of multilayer fishnet metamaterials.

We study the anisotropic properties of multilayer fishnet optical metamaterials and describe topological transitions between the elliptic and hyperbolic dispersion regimes. In contrast to other hyperbolic media, multilayer fishnet metamaterials may have negative components not only in the effective permittivity tensor but also in the effective permeability tensor, thus allowing the realization of magnetic hyperbolic and generalized indefinite media.

Discovery of potent and liver-targeted stearoyl-CoA desaturase (SCD) inhibitors in a bispyrrolidine series.

Inhibition of stearoyl-CoA desaturase (SCD) activity represents a potential novel mechanism for the treatment of metabolic disorders including obesity and type II diabetes. To circumvent skin and eye adverse events observed in rodents with systemically-distributed SCD inhibitors, our research efforts have been focused on the search for new and structurally diverse liver-targeted SCD inhibitors. This work has led to the discovery of novel, potent and structurally diverse liver-targeted bispyrrolidine SCD inhibitors. These compounds possess suitable cellular activity and pharmacokinetic properties to inhibit liver SCD activity in a mouse pharmacodynamic model.

Microacoustic Metagratings at Ultra-High Frequencies Fabricated by Two-Photon Lithography.

The recently proposed bianisotropic acoustic metagratings offer promising opportunities for passive acoustic wavefront manipulation, which is of particular interest in flat acoustic lenses and ultrasound imaging at ultra-high frequency ultrasound. Despite this fact, acoustic metagratings have never been scaled to MHz frequencies that are common in ultrasound imaging. One of the greatest challenges is the production of complex microscopic structures. Owing to two-photon polymerization, a novel fabrication technique from the view of acoustic metamaterials, it is now possible to precisely manufacture sub-wavelength structures in this frequency range. However, shrinking in size poses another challenge; the increasing thermoviscous effects lead to a drop in efficiency and a frequency downshift of the transmission peak and must therefore be taken into account in the design. In this work three microacoustic metagrating designs refracting a normally incident wave toward -35° at 2 MHz are proposed. In order to develop meta-atoms insensitive to thermoviscous effects shape optimization techniques incorporating the linearized Navier-Stokes equations discretized with finite element method are used. The authors report for the first time microscopic acoustic metamaterials manufactured using two-photon polymerization and, subsequently, experimentally verify their effectiveness using an optical microphone as a detector in a range from 1.8 to 2.2 MHz.

Acoustofluidics 24: theory and experimental measurements of acoustic interaction force.

The motion of small objects in acoustophoresis depends on the acoustic radiation force and torque. These are nonlinear phenomena originating from wave scattering, and consist of primary and secondary components. The primary radiation force is the force acting on an object due to the incident field, in the absence of other objects. The secondary component, known as acoustic interaction force, accounts for the interaction among objects, and contributes to the clustering patterns of objects, as commonly observed in experiments. In this tutorial, the theory of acoustic interaction forces is presented using the force potential and partial-wave expansion approaches, and the distinguishing features of these forces such as rotational coupling and non-reciprocity are described. Theoretical results are compared to experimental measurements of interaction forces using a glass micro-capillary setup to explain the practical challenges. Finally, the phenomenon of clustering patterns induced by the close-range interaction of objects is demonstrated to point out the considerations about multiple collision and the predicted clustering patterns entirely due to the interaction force. Understanding the principles of acoustic interaction enables us to develop novel acoustofluidic applications beyond the typical processing of large populations of particles and with focus on the controlled manipulation of small clusters.

Topological Supercavity Resonances in the Finite System.

Acoustic resonant cavities play a vital role in modern acoustical systems. The ultrahigh quality-factor resonances are highly desired for some applications such as high-resolution acoustic sensors and acoustic lasers. Here, a class of supercavity resonances is theoretically proposed and experimentally demonstrated in a coupled acoustic resonator system, arising from the merged bound states in the continuum (BICs) in geometry space. Their topological origin is demonstrated by explicitly calculating their topological charges before and after BIC merging, accompanied by charges annihilation. Compared with other types of BICs, they are robust to the perturbation brought by fabrication imperfection. Moreover, it is found that such supercavity modes can be linked with the Friedrich-Wintgen BICs supported by an entire rectangular (cuboid) resonator sandwiched between two rectangular (or circular) waveguides and thus more supercavity modes are constructed. Then, these coupled resonators are fabricated and such a unique phenomenon-moving, merging, and vanishing of BICs-is experimentally confirmed by measuring their reflection spectra, which show good agreement with the numerical simulation and theoretical prediction of mode evolution. The results may find exciting applications in acoustic and photonics, such as enhanced acoustic emission, filtering, and sensing.

Discrete dissipative localized modes in nonlinear magnetic metamaterials.

We analyze the existence, stability, and propagation of dissipative discrete localized modes in one- and two-dimensional nonlinear lattices composed of weakly coupled split-ring resonators (SRRs) excited by an external electromagnetic field. We employ the near-field interaction approach for describing quasi-static electric and magnetic interaction between the resonators, and demonstrate the crucial importance of the electric coupling, which can completely reverse the sign of the overall interaction between the resonators. We derive the effective nonlinear model and analyze the properties of nonlinear localized modes excited in one-and two-dimensional lattices. In particular, we study nonlinear magnetic domain walls (the so-called switching waves) separating two different states of nonlinear magnetization, and reveal the bistable dependence of the domain wall velocity on the external field. Then, we study two-dimensional localized modes in nonlinear lattices of SRRs and demonstrate that larger domains may experience modulational instability and splitting.

Biological activity and preclinical efficacy of azetidinyl pyridazines as potent systemically-distributed stearoyl-CoA desaturase inhibitors.

Potent and orally bioavailable SCD inhibitors built on an azetidinyl pyridazine scaffold were identified. In a one-month gDIO mouse model of obesity, we demonstrated that there was no therapeutic index even at low doses; efficacy in preventing weight gain tracked closely with skin and eye adverse events. This was attributed to the local SCD inhibition in these tissues as a consequence of the broad tissue distribution observed in mice for this class of compounds. The search for new structural scaffolds which may display a different tissue distribution was initiated. In preparation for an HTS campaign, a radiolabeled azetidinyl pyridazine displaying low non-specific binding in the scintillation proximity assay was prepared.

Nicotinic acids: liver-targeted SCD inhibitors with preclinical anti-diabetic efficacy.

An in vitro screening protocol was used to transform a systemically-distributed SCD inhibitor into a liver-targeted compound. Incorporation of a key nicotinic acid moiety enables molecular recognition by OATP transporters, as demonstrated by uptake studies in transfected cell lines, and likely serves as a critical component of the observed liver-targeted tissue distribution profile. Preclinical anti-diabetic oGTT efficacy is demonstrated with nicotinic acid-based, liver-targeting SCD inhibitor 10, and studies with a close-structural analog devoid of SCD1 activity, suggest this efficacy is a result of on-target activity.

Deformations and end effects in isolated blood vessel testing.

Blood vessels are commonly studied in isolation to define their mechanical and biological properties under controlled conditions. While sections of the wall are sometimes tested, vessels are most often attached to needles and examined in their natural cylindrical configuration where combinations of internal pressure and axial force can be applied to mimic in vivo conditions. Attachments to needles, however, constrain natural vessel response, resulting in a complex state of deformation that is not easily determined. As a result, measurements are usually limited to the midsection of a specimen where end effects do not extend and the deformation is homogeneous. To our knowledge, however, the boundaries of this uninfluenced midsection region have not been explored. The objective of this study was to define the extent of these end effects as a function of vessel geometry and material properties, loading conditions, and needle diameter. A computational fiber framework was used to model the response of a nonlinear anisotropic cylindrical tube, constrained radially at its ends, under conditions of axial extension and internal pressure. Individual fiber constitutive response was defined using a Fung-type strain energy function. While quantitative results depend on specific parameter values, simulations demonstrate that axial stretch is always highest near the constraint and reduces to a minimum in the uninfluenced midsection region. Circumferential stretch displays the opposite behavior. As a general rule, the length of the region disturbed by a needle constraint increases with the difference between the diameter of the needle and the equilibrium diameter of the blood vessel for the imposed loading conditions. The reported findings increase the understanding of specimen deformation in isolated vessel experiments, specifically defining considerations important to identifying a midsection region appropriate for measurement.

Sound trapping in an open resonator.

The ability of sound energy confinement with high-quality factor resonance is of vital importance for acoustic devices requiring high intensity and hypersensitivity in biological ultrasonics, enhanced collimated sound emission (i.e. sound laser) and high-resolution sensing. However, structures reported so far have been experimentally demonstrated with a limited quality factor of acoustic resonances, up to several tens in an open resonator. The emergence of bound states in the continuum makes it possible to realize high quality factor acoustic modes. Here, we report the theoretical design and experimental demonstration of acoustic bound states in the continuum supported by a single open resonator. We predicted that such an open acoustic resonator could simultaneously support three types of bound states in the continuum, including symmetry protected bound states in the continuum, Friedrich-Wintgen bound states in the continuum induced by mode interference, as well as a new type-mirror symmetry induced bound states in the continuum. We also experimentally demonstrated their existence with quality factor up to one order of magnitude greater than the highest quality factor reported in an open resonator.

Dual Glycolate Oxidase/Lactate Dehydrogenase A Inhibitors for Primary Hyperoxaluria.

Both glycolate oxidase (GO) and lactate dehydrogenase A (LDHA) influence the endogenous synthesis of oxalate and are clinically validated targets for treatment of primary hyperoxaluria (PH). We investigated whether dual inhibition of GO and LDHA may provide advantage over single agents in treating PH. Utilizing a structure-based drug design (SBDD) approach, we developed a series of novel, potent, dual GO/LDHA inhibitors. X-ray crystal structures of compound 15 bound to individual GO and LDHA proteins validated our SBDD strategy. Dual inhibitor 7 demonstrated an IC50 of 88 nM for oxalate reduction in an Agxt-knockdown mouse hepatocyte assay. Limited by poor liver exposure, this series of dual inhibitors failed to demonstrate significant PD modulation in an in vivo mouse model. This work highlights the challenges in optimizing in vivo liver exposures for diacid containing compounds and limited benefit seen with dual GO/LDHA inhibitors over single agents alone in an in vitro setting.

Reducing the Toxicity of Designer Aminoglycosides as Nonsense Mutation Readthrough Agents for Therapeutic Targets.

A significant proportion of genetic disease cases arise from truncation of proteins caused by premature termination codons. In eukaryotic cells some aminoglycosides cause readthrough of premature termination codons during protein translation. Inducing readthrough of these codons can potentially be of therapeutic value in the treatment of numerous genetic diseases. A significant drawback to the repeated use of aminoglycosides as treatments is the lack of balance between their readthrough efficacy and toxicity. The synthesis and biological testing of designer aminoglycoside compounds is documented herein. We disclose the implementation of a strategy to reduce cellular toxicity and maintain readthrough activity of a library of compounds by modification of the overall cationic charge of the aminoglycoside scaffold through ring I modifications.

Redefining the Histone Deacetylase Inhibitor Pharmacophore: High Potency with No Zinc Cofactor Interaction.

A novel series of histone deacetylase (HDAC) inhibitors lacking a zinc-binding moiety has been developed and described herein. HDAC isozyme profiling and kinetic studies indicate that these inhibitors display a selectivity preference for HDACs 1, 2, 3, 10, and 11 via a rapid equilibrium mechanism, and crystal structures with HDAC2 confirm that these inhibitors do not interact with the catalytic zinc. The compounds are nonmutagenic and devoid of electrophilic and mutagenic structural elements and exhibit off-target profiles that are promising for further optimization. The efficacy of this new class in biochemical and cell-based assays is comparable to the marketed HDAC inhibitors belinostat and vorinostat. These results demonstrate that the long-standing pharmacophore model of HDAC inhibitors requiring a metal binding motif should be revised and offers a distinct class of HDAC inhibitors.