Identification of a ß-arrestin-biased negative allosteric modulator for the ß2-adrenergic receptor.

Catecholamine-stimulated ß2-adrenergic receptor (ß2AR) signaling via the canonical Gs-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous ß-agonists in the treatment of airway disease. ß2AR signaling is tightly regulated by GRKs and ß-arrestins, which together promote ß2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias ß2AR signaling toward the Gs pathway while avoiding ß-arrestin-mediated effects may provide a strategy to improve the functional consequences of ß2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the ß2AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit ß-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of ß-arrestin recruitment to the ß2AR while having no effect on ß2AR coupling to Gs. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the ß2AR and protects against the functional desensitization of ß-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the ß2AR with minimal effects on the ß1AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the ß2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the ß2AR.

Trans-dimensional inversion for seafloor properties for three mud depocenters on the New England shelf under dynamical oceanographic conditionsa).

This paper presents inversion results for three datasets collected on three spatially separated mud depocenters (hereafter called mud ponds) during the 2022 Seabed Characterization Experiment (SBCEX). The data considered here represent modal time-frequency (TF) dispersion as estimated from a single hydrophone. Inversion is performed using a trans-dimensional (trans-D) Bayesian inference method that jointly estimates water-column and seabed properties along with associated uncertainties. This enables successful estimation of the seafloor properties, consistent with in situ acoustic core measurements, even when the water column is dynamical and mostly unknown. A quantitative analysis is performed to (1) compare results with previous modal TF trans-D studies for one mud pond but under different oceanographic condition, and (2) inter-compare the new SBCEX22 results for the three mud ponds. Overall, the estimated mud geoacoustic properties show no significant temporal variability. Further, no significant spatial variability is found between two of the mud ponds while the estimated geoacoustic properties of the third are different. Two hypotheses, considered to be equally likely, are explored to explain this apparent spatial variability: it may be the result of actual differences in the mud properties, or the mud properties may be similar but the inversion results are driven by difference in data information content.

Incubator-based active noise control device: comparison to ear covers and noise reduction zone quantification.

BACKGROUND: Noise exposure in the neonatal intensive care unit (NICU) is consistently higher than current recommendations. This may adversely affect neonatal sleep, weight gain, and overall health. We sought to evaluate the effect of a novel active noise control (ANC) system. METHODS: An ANC device's noise reduction performance was compared to that of adhesively affixed foam ear covers in response to alarm and voice sounds in a simulated NICU environment. The zone of noise reduction of the ANC device was quantified with the same set of alarm and voice sounds. RESULTS: The ANC device provided greater noise reduction than the ear covers in seven of the eight sound sequences tested in which a noise reduction greater than the just noticeable difference was achieved. For noise in the 500 Hz octave band, the ANC device exhibited consistent noise reduction throughout expected patient positions. It provided better performance for noise below 1000 Hz than above 1000 Hz. CONCLUSIONS: The ANC device provided generally superior noise reduction to the ear covers and provided a zone of noise reduction throughout the range where an infant would be placed within an incubator. Implications for patient sleep and weight gain are discussed. IMPACT: Active noise control device can effectively reduce noise inside an infant incubator due to bedside device alarms. This is the first analysis of an incubator-based active noise control device and comparison to adhesively affixed silicone ear covers. A non-contact noise reduction device may be an appropriate means of reducing noise exposure of the hospitalized preterm infant.

Characterizing the acoustic response of Thalassia testudinum leaves using resonator measurements and finite element modeling.

Seagrasses play an important role in coastal ecosystems and serve as important marine carbon stores. Acoustic monitoring techniques exploit the sensitivity of underwater sound to bubbles, which are produced as a byproduct of photosynthesis and present within the seagrass tissue. To make accurate assessments of seagrass biomass and productivity, a model is needed to describe acoustic propagation through the seagrass meadow that includes the effects of gas contained within the seagrass leaves. For this purpose, a new seagrass leaf model is described for Thalassia testudinum that consists of a comparatively rigid epidermis that composes the outer shell of the leaf and comparatively compliant aerenchyma that surrounds the gas channels on the interior of the leaf. With the bulk modulus and density of the seagrass tissue determined by previous work, this study focused on characterizing the shear moduli of the epidermis and aerenchyma. These properties were determined through a combination of dynamic mechanical analysis and acoustic resonator measurements coupled with microscopic imagery and finite element modeling. The shear moduli varied as a function of length along the leaves with values of 100 and 1.8 MPa at the basal end and 900 and 3.7 MPa at the apical end for the epidermis and aerenchyma, respectively.

Introduction to the special issue on education in acoustics.

A substantial fraction of the membership of the Acoustical Society of America are faculty at various types of educational institutions and are actively engaged in educational activities. However, papers focusing on aspects of teaching, pedagogy, demonstrations, student learning, and other education topics are not often published in JASA, even though the Education in Acoustics Committee regularly offers special sessions on these topics at every ASA meeting. This special issue of JASA dedicated to Education in Acoustics includes 41 papers from authors all over the world. This introduction to the special issue briefly describes each of the papers, which have been organized into several broad categories: teaching methods and exercises; project-based learning; use of experiments, demos, and experiential learning; adapting to teaching during COVID-19; circuit models and impedance concepts; software apps and online resources; teaching musical acoustics; and descriptions of acoustics programs at a variety of institutions.

Ray tracing and finite element modeling of sound propagation in a compartment fire.

A compartment fire (a fire in a room or building) creates temperature gradients and inhomogeneous time-varying temperature, density, and flow fields. This work compared experimental measurements of the room acoustic impulse/frequency response in a room with a fire to numerically modeled responses. The fire is modeled using a Fire Dynamics Simulator (FDS). Acoustic modeling was performed using the temperature field computed by FDS. Room acoustics were modeled using two-dimensional ray and finite element modeling. A three-dimensional model was used to simulate an open flame. COMSOLTM Multiphysics was used for finite element acoustic modeling and BELLHOPTM for ray trace acoustics modeling. The results show that the fire causes wave-fronts to arrive earlier (due to the higher sound speed) and with more variation in the delay times (due to the sound speed perturbations). The resonance frequencies of low-frequency modes were shifted upwards. Model results are compared with data and show good agreement in observed trends.

Head-related transfer function measurements in a compartment fire.

The Personal Alert Safety System (PASS) is an alarm signal device carried by firefighters to help rescuers locate and extricate downed firefighters. A fire creates temperature gradients and inhomogeneous time-varying temperature, density, and flow fields that modify the acoustic properties of a room. To understand the effect of the fire on an alarm signal, experimental measurements of head-related transfer functions (HRTF) in a room with fire are presented in time and frequency domains. The results show that low-frequency (<1000 Hz) modes in the HRTF increase in frequency and higher-frequency modal structure weakens and becomes unstable in time. In the time domain, the time difference of arrival between the ears changes and becomes unstable over time. Both of these effects could impact alarm signal detection and localization. The receive level of narrowband tones is presented that shows that the fire makes the receive level of a source vary by > 10 dB. All of these effects could impact the detection and localization of the PASS alarm and have life safety consequences.

Model-data comparison of sound propagation in a glacierized fjord with a simulated brash ice surface.

Glacier ice loss impacts sound propagation within Arctic fjords. Regular calving events contribute to a collection of floating ice fragments, known as brash ice, at the ocean surface that obstruct the natural and anthropogenic acoustic signals, yet are difficult to characterize. Transmission loss measurements using a maximum length sequence (m-sequence) signal were conducted in September 2017 near Hansbreen glacier in Hornsund Fjord, Svalbard with dense brash ice present at the water surface. An acoustic model of the brash ice surface was inferred through consideration of the experimental geometry, arrival amplitude, and travel time difference between the direct and surface reflected arrivals from the source to two receivers. The inferred surface was then incorporated into a forward simulation of the environment using sound speed profiles measured during the experiment. BELLHOP ([Porter and Bucker (1987). J. Acoust. Soc. Am. 82(4), 1349-1359],), a ray tracing code available in the Acoustics Toolbox (HLS Inc., San Diego, CA), was used to track the time difference of arrivals and amplitudes of the modeled direct and surface reflected rays. Comparisons between the measured and simulated results provide insight into the geometric shape and reflection characteristics of the brash ice surface within this and similar environments.

Design and characterization of a three-dimensional anisotropic additively manufactured pentamode material.

A metamaterial of particular interest for underwater applications is the three-dimensional (3D) anisotropic pentamode (PM), i.e., a structure designed to support a single longitudinal wave with a sound speed that depends on the propagation direction. The present work attempts to experimentally verify anisotropic sound speeds predicted by finite element simulations using additively manufactured anisotropic 3D PM samples made of titanium. The samples were suspended in front of a plane wave source emitting a broadband chirp in a water tank to measure time of flight for wavefronts with and without the PM present. The measurement utilizes a deconvolution method that extracts the band limited impulse response of data gathered by a scanning hydrophone in a plane of constant depth behind the samples. Supporting material takes the form of finite element simulations developed to model the response of a semi-infinite PM medium to an incident normal plane wave. A technique to extract the longitudinal PM wave speed for frequency domain simulations based on Fourier series expansions is given.

Impacts of infauna, worm tubes, and shell hash on sediment acoustic variability and deviation from the viscous grain shearing model.

Infauna influence geoacoustic parameters in surficial marine sediments. To investigate these effects, an experiment was conducted in natural sand-silt sediment in the northern Gulf of Mexico. In situ acoustic measurements of sediment sound speed, attenuation, and shear speed were performed, and sediment cores were collected from the upper 20 cm of the seabed. Laboratory measurements of sound speed and attenuation in the cores were conducted, after which the core contents were analyzed for biological and physical properties. Since no model currently accounts for the effects of infauna, a deviation from model predictions is expected. To assess the extent of this, acoustic measurements were compared with the viscous grain shearing model from Buckingham [J. Acoust. Soc. Am. 122, 1486 (2007); J. Acoust. Soc. Am. 148, 962 (2020)], for which depth-dependent profiles of sediment porosity and mean grain size measured from the cores were used as input parameters. Comparison of acoustic results with distributions of infauna, worm tubes, and shell hash suggests biogenic impacts on acoustic variability and model accuracy are important in surficial marine sediments. The presence of infauna and worm tubes were correlated with higher variability in both sound speed and attenuation and greater deviation from the model near the sediment-water interface.

Comparative evaluation of different molecular methods for DNA extraction from individual Teladorsagia circumcincta nematodes.

BACKGROUND: The purpose of this study was to develop a reliable DNA extraction protocol to use on individual Teladorsagia circumcincta nematode specimens to produce high quality DNA for genome sequencing and phylogenetic analysis. Pooled samples have been critical in providing the groundwork for T. circumcincta genome construction, but there is currently no standard method for extracting high-quality DNA from individual nematodes. 11 extraction kits were compared based on DNA quality, yield, and processing time. RESULTS: 11 extraction protocols were compared, and the concentration and purity of the extracted DNA was quantified. Median DNA concentration among all methods measured on NanoDrop 2000™ ranged between 0.45-11.5 ng/µL, and on Qubit™ ranged between undetectable - 0.962 ng/µL. Median A260/280 ranged between 0.505-3.925, and median A260/230 ranged - 0.005 - 1.545. Larval exsheathment to remove the nematode cuticle negatively impacted DNA concentration and purity. CONCLUSIONS: A Schistosoma sp. DNA extraction method was determined as most suitable for individual T. circumcincta nematode specimens due to its resulting DNA concentration, purity, and relatively fast processing time.

Parallel Sequencing Reveals Campylobacter spp. in Commercial Meat Chickens Less than 8 Days Old.

Campylobacter from contaminated poultry meat is a major source of human gastroenteritis worldwide. To date, attempts to control this zoonotic infection with on-farm biosecurity measures have been inconsistent in outcome. A cornerstone of these efforts has been the detection of chicken infection with microbiological culture, where Campylobacter is generally not detectable until birds are at least 21 days old. Using parallel sequence-based bacterial 16S profiling analysis and targeted sequencing of the porA gene, Campylobacter was identified at very low levels in all commercial flocks at less than 8 days old that were tested from the United Kingdom, Switzerland, and France. These young chicks exhibited a much greater diversity of porA types than older birds testing positive for Campylobacter by culture or quantitative PCR (qPCR). This suggests that as the bacteria multiply sufficiently to be detected by culture methods, one or two variants, as indicated by porA type, dominate the infection. The findings that (i) most young chicks carry some Campylobacter and (ii) not all flocks become Campylobacter positive by culture suggest that efforts to control infection, and therefore avoid contamination of poultry meat, should concentrate on how to limit Campylobacter to low levels by the prevention of the overgrowth of single strains. IMPORTANCE Our results demonstrate the presence of Campylobacter DNA among fecal samples from a range of commercially reared meat chicks that are less than 8 days of age, consistent across 3 European countries. The recently developed, sensitive detection method indicates that infection occurs on commercial farms much earlier and more widely than previously thought, which opens up new opportunities to control Campylobacter contamination at the start of the food chain and reduce the unacceptably high levels of human disease.

Systematic review on reporting of components and outcomes in randomized clinical trials of paraoesophageal hernia mesh repair.

BACKGROUND: Surgical interventions, such as paraoesophageal hernia (POH) repair, are complex with multiple components that require consideration in the reporting of clinical trials. Many aspects of POH repair, including mesh hiatal reinforcement and fundoplication type, are contentious. This review summarizes the reporting of components and outcomes in RCTs of POH repair. METHODS: Systematic searches identified RCTs of POH repair published from 1995 to 2020. The patient selection criteria for RCT involvement were noted. The components of the surgical interventions in these RCTs were recorded using the CONSORT guidelines for non-pharmacological treatments, Template for Intervention Description and Replication (TIDieR) and Blencowe frameworks. The outcomes were summarized and definitions sought for critical variables, including recurrence. RESULTS: Of 1918 abstracts and 21 screened full-text articles, 12 full papers reporting on six RCTs were included in the review. The patient selection criteria and definitions of POH between trials varied considerably. Although some description of trial interventions was provided in all RCTs, this varied in depth and detail. Four RCTs described efforts to standardize the trial intervention. Outcomes were reported inconsistently, were rarely defined fully, and overall trial conclusions varied during follow-up. CONCLUSION: This lack of detail on the surgical intervention in POH repair RCTs prevents full understanding of what exact procedure was evaluated and how it should be delivered in clinical practice to gain the desired treatment effects. Improved focus on the definitions, descriptions and reporting of surgical interventions in POH repair is required for better future RCTs.

Covariation among multimodal components in the courtship display of the túngara frog.

Communication systems often include a variety of components, including those that span modalities, which may facilitate detection and decision-making. For example, female túngara frogs and fringe-lipped bats generally rely on acoustic mating signals to find male túngara frogs in a mating or foraging context, respectively. However, two additional cues (vocal sac inflation and water ripples) can enhance detection and choice behavior. To date, we do not know the natural variation and covariation of these three components. To address this, we made detailed recordings of calling males, including call amplitude, vocal sac volume and water ripple height, in 54 frogs (2430 calls). We found that all three measures correlated, with the strongest association between the vocal sac volume and call amplitude. We also found that multimodal models predicted the mass of calling males better than unimodal models. These results demonstrate how multimodal components of a communication system relate to each other and provide an important foundation for future studies on how receivers integrate and compare complex displays.

Influence of seabed on very low frequency sound recorded during passage of merchant ships on the New England shelf.

An examination of the received spectrogram levels of about twenty merchant ship recordings on two vertical line arrays deployed on the New England continental shelf during the Seabed Characterization Experiment 2017 has identified an acoustic feature that can be attributed to the group velocities of modes 1 and 2 being equal at a frequency f=F. The observation of such a feature is a result of ßnm(2πF)=∞, where ßnm is the waveguide invariant for modes n and m. For the New England Mudpatch, the average value of F is about 24.5 Hz. An effective seabed model is inferred from a feature inversion method that has a deep sediment layer which lies between 190 m and 290 m beneath the seafloor with sound speeds on the order of 1810 m/s. This effective sediment model appears to be consistent with a previous seismic survey on the New England shelf that identified a deep low speed layer about 250 m beneath the water sediment interface.

Characterization of an underwater metamaterial made of aluminum honeycomb panels at low frequencies.

This paper presents a method to characterize the effective properties of inertial acoustic metamaterial unit cells for underwater operation. The method is manifested by a fast and reliable parameter retrieval procedure utilizing both numerical simulations and measurements. The effectiveness of the method was proved to be self-consistent by a metamaterial unit cell composed of aluminum honeycomb panels with soft rubber spacers. Simulated results agree well with the measured responses of this metamaterial in a water-filled resonator tube. A sub-unity density ratio and an anisotropic mass density are simultaneously achieved by the metamaterial unit cell, making it useful in implementations of transformation acoustics. The metamaterial, together with the approach for its characterization, are expected to be useful for underwater acoustic devices.

Change in acoustic impulse response of a room due to a fire.

A room fire creates temperature gradients and inhomogeneous time varying temperature, density, and flow fields. Experimental measurements of the room acoustic impulse/frequency response are presented and compared with a ray traced model. The results show that the fire causes wave-fronts to arrive earlier (due to the higher sound speed) and with more variation in the delay times (due to the sound speed perturbations). The frequency response shows that the modes are shifted up in frequency and high frequency (>2500 Hz) modes are significantly attenuated. Model results are compared with data and show good agreement in observed trends.

Experimental observations of a rupture induced underwater sound source.

A rupture induced underwater sound source (RIUSS) is being developed as an alternative to other impulsive sound sources commonly utilized in underwater acoustics experiments and surveys. The device is comprised of a graphite rupture disk mounted over an evacuated chamber. After the disk breaks, an inrush of water creates a high amplitude acoustic pulse. A field test was conducted to measure the acoustic output as a function of depth for a given source configuration, and high speed underwater video was simultaneously captured with an acoustic recording system to correlate the features of the acoustic output to the ensuing bubble activity.

Impacts of simulated infaunal activities on acoustic wave propagation in marine sediments.

The activities of infaunal organisms, including feeding, locomotion, and home building, alter sediment physical properties including grain size and sorting, porosity, bulk density, permeability, packing, tortuosity, and consolidation behavior. These activities are also known to affect the acoustic properties of marine sediments, although previous studies have demonstrated complicated relationships between infaunal activities and geoacoustic properties. To avoid difficulties associated with real animals, whose exact locations and activities are unknown, this work uses artificial burrows and simulates infaunal activities such as irrigation, compaction, and tube building in controlled laboratory experiments. The results show statistically significant changes in sound speed and attenuation over a frequency range of 100-400 kHz, corresponding to wavelengths on the order of the burrow diameter. The greatest effects were observed for tubes constructed of hard shells which increased the attenuation by ∼30 dB m-1 across the measurement band. These results highlight the importance of biogenic hard structures such as tubes on sound attenuation and suggest that organisms that create hard structures may be good targets for acoustic mapping of infaunal abundance and distribution.

Application of acoustical remote sensing techniques for ecosystem monitoring of a seagrass meadow.

Seagrasses provide a multitude of ecosystem services and serve as important organic carbon stores. However, seagrass habitats are declining worldwide, threatened by global climate change and regional shifts in water quality. Acoustical methods have been applied to assess changes in oxygen production of seagrass meadows since sound propagation is sensitive to the presence of bubbles, which exist both within the plant tissue and freely floating the water as byproducts of photosynthesis. This work applies acoustic remote sensing techniques to characterize two different regions of a seagrass meadow: a densely vegetated meadow of Thalassia testudinum and a sandy region sparsely populated by isolated stands of T. testudinum. A Bayesian approach is applied to estimate the posterior probability distributions of the unknown model parameters. The sensitivity of sound to the void fraction of gas present in the seagrass meadow was established by the narrow marginal probability distributions that provided distinct estimates of the void fraction between the two sites. The absolute values of the estimated void fractions are biased by limitations in the forward model, which does not capture the full complexity of the seagrass environment. Nevertheless, the results demonstrate the potential use of acoustical methods to remotely sense seagrass health and density.