Cyclic AMP promotes EPAC1 and EPAC2 activation through direct binding to a specific cyclic nucleotide-binding domain (CNBD) within each protein, leading to activation of Rap GTPases, which control multiple cell responses, including cell proliferation, adhesion, morphology, exocytosis, and gene expression. As a result, it has become apparent that directed activation of EPAC1 and EPAC2 with synthetic agonists may also be useful for the future treatment of diabetes and cardiovascular diseases. To identify new EPAC agonists we have developed a fluorescent-based, ultra-high-throughput screening (uHTS) assay that measures the displacement of binding of the fluorescent cAMP analogue, 8-NBD-cAMP to the EPAC1 CNBD. Triage of the output of an approximately 350,000 compound screens using this assay identified a benzofuran oxaloacetic acid EPAC1 binder (SY000) that displayed moderate potency using orthogonal assays (competition binding and microscale thermophoresis). We next generated a limited library of 91 analogues of SY000 and identified SY009, with modifications to the benzofuran ring associated with a 10-fold increase in potency towards EPAC1 over SY000 in binding assays. In vitro EPAC1 activity assays confirmed the agonist potential of these molecules in comparison with the known EPAC1 non-cyclic nucleotide (NCN) partial agonist, I942. Rap1 GTPase activation assays further demonstrated that SY009 selectively activates EPAC1 over EPAC2 in cells. SY009 therefore represents a novel class of NCN EPAC1 activators that selectively activate EPAC1 in cellulae.

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The ambient noise model CANARY calculates noise coherence and array noise response by treating the noise sources as surface distributions rather than points. This assumption leads to simplification of the propagation, even in range-dependent environments, and by allowing variations in the source density one can represent distant storms or groups of ships. Included is a description of the numerical algorithms used to calculate coherence. Some recently developed analytical solutions for uniform source distributions and uniformly sloping seabed3 are used as test cases for CANARY. Some additional examples demonstrate CANARY's performance in more realistic environments and conditions including wind and shipping sources, and comparisons are made with the noise model RANDI.

Subjective and/or objective measurements of speech quality are important in benchmarking speech enhancement algorithms. Subjective measures include ratings of speech quality by listeners, whereas objective measures compute a metric based on the clean and enhanced speech samples. While subjective quality ratings are the “gold-standard,” they are also time- and resource-consuming. An objective metric that correlates highly with subjective data is attractive, as it can act as a substitute for benchmarking and fine-tuning the noise reduction algorithms. In this paper, the performance of several noise reduction algorithms for wideband (50–7000 Hz) telephony application was evaluated both subjectively and objectively. A custom wideband noise reduction database was created that contained speech samples corrupted by different background noises at different signal to noise ratios and processed by seven different noise reduction algorithms. Speech samples in the database were subsequently rated by a group of 32 listeners with normal hearing capabilities. Several objective metrics including log-likelihood ratio, weighted spectral slope, PESQ, and the loudness pattern distortion (LPD) measure based on the Moore–Glasberg auditory model were used to predict the subjective ratings. Results showed that the subjective ratings were highly reliable and the LPD metric correlated the best with subjective ratings of enhanced wideband speech.