The Nudix homology clan encompasses over 80,000 protein domains from all three domains of life, defined by homology to each other. Proteins with a domain from this clan fall into four general functional classes: pyrophosphohydrolases, isopentenyl diphosphate isomerases (IDIs), adenine/guanine mismatch-specific adenine glycosylases (A/G-specific adenine glycosylases), and non-enzymatic activities such as protein/protein interaction and transcriptional regulation. The largest group, pyrophosphohydrolases, encompasses more than 100 distinct hydrolase specificities. To understand the evolution of this vast number of activities, we assembled and analyzed experimental and structural data for 205 Nudix proteins collected from the literature. We corrected erroneous functions or provided more appropriate descriptions for 53 annotations described in the Gene Ontology Annotation database in this family, and propose 275 new experimentally-based annotations. We manually constructed a structure-guided sequence alignment of 78 Nudix proteins. Using the structural alignment as a seed, we then made an alignment of 347 “select” Nudix homology domains, curated from structurally determined, functionally characterized, or phylogenetically important Nudix domains. Based on our review of Nudix pyrophosphohydrolase structures and specificities, we further analyzed a loop region downstream of the Nudix hydrolase motif previously shown to contact the substrate molecule and possess known functional motifs. This loop region provides a potential structural basis for the functional radiation and evolution of substrate specificity within the hydrolase family. Finally, phylogenetic analyses of the 347 select protein domains and of the complete Nudix homology clan revealed general monophyly with regard to function and a few instances of probable homoplasy.

The very large G protein coupled receptor (Vlgr1) is a member of adhesion receptors or large N-terminal family B-7 transmembrane helixes (LNB7TM) receptors within the seven trans-membrane receptor superfamily. Vlgr1 is the largest GPCR identified to date; its mRNA spans 19 kb and encodes 6,300 amino acids. Vlgr1 is a core component of ankle-link complex in inner ear hair cells. Knock-out and mutation mouse models show that loss of Vlgr1 function leads to abnormal stereociliary development and hearing loss, indicating crucial roles of Vlgr1 in hearing transduction or auditory system development. Over the past 10 or so years, human genetics data suggested that Vlgr1 mutations cause Usher syndromes and seizures. Although significant progresses have been made, the details of Vlgr1's function in hair cells, its signaling cascade, and the mechanisms underlying causative effects of Vlgr1 mutations in human diseases remain elusive and ask for further investigation.

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Objective Most studies have evaluated cochlear implant (CI) performance using “clear” speech materials, which are highly intelligible and well-articulated. CI users may encounter much greater variability in speech patterns in the “real-world,” including synthetic speech. In this study, we measured normal-hearing (NH) and CI listeners’ sentence recognition with multiple talkers and speaking rates, and with naturally produced and synthetic speech. Design NH and CI subjects were asked to recognize naturally produced or synthetic sentences, presented at a slow, normal, or fast speaking rate. Natural speech was produced by one male and one female talker; synthetic speech was generated to simulate a male and female talker. For natural speech, the speaking rate was time-scaled while preserving voice pitch and formant frequency information. For synthetic speech, the speaking rate was adjusted within the speech synthesis engine. NH subjects were tested while listening to unprocessed speech or to an 8-channel acoustic CI simulation. CI subjects were tested while listening with their clinical processors and the recommended microphone sensitivity and volume settings. Results The NH group performed significantly better than the CI simulation group, and the CI simulation group performed significantly better than the CI group. For all subject groups, sentence recognition was significantly better with natural than with synthetic speech. The performance deficit with synthetic speech was relatively small for NH subjects listening to unprocessed speech. However, the performance deficit with synthetic speech was much greater for CI subjects and for CI simulation subjects. There was significant effect of talker gender, with slightly better performance with the female talker for CI subjects and slightly better performance with the male talker for the CI simulations. For all subject groups, sentence recognition was significantly poorer only at the fast rate. CI performance was very poor (~10% correct) at the fast rate. Conclusions CI listeners are susceptible to variability in speech patterns due to speaking rate and/or production style (natural vs. synthetic). CI performance with clear speech materials may over-estimate performance in real-world listening conditions. The poorer CI performance may be due to other factors besides reduced spectro-temporal resolution, such the quality of electric stimulation, duration of deafness, or cortical processing. Optimizing the input and/or training may improve CI users’ tolerance for variability in speech patterns.

Purpose The aim of this study was to evaluate normal-hearing (NH) and cochlear implant (CI) listeners' understanding of English sentences produced by native (English) and non-native (Spanish) talkers. Method Sentence recognition in noise was measured in adult CI and NH subjects who were native talkers of American English. Test sentences were from the Hearing-in-Noise Test (HINT) database and were produced in English by 4 native and 8 non-native talkers. Subjects also rated the intelligibility and accent for each talker. Results CI and NH subjects' speech recognition thresholds in noise were 4.23-dB and 1.32-dB poorer with non-native talkers than with native talkers, respectively. Performance was significantly correlated with talker intelligibility and accent ratings for CI subjects but only correlated with talker intelligibility ratings for NH subjects. For all subjects, performance with individual non-native talkers was significantly correlated with talkers' number of years of residence in the United States. Conclusion CI users exhibited a larger deficit in speech understanding with non-native talkers than did NH subjects, relative to native talkers. Non-native talkers' experience with native culture contributed strongly to CI and NH listeners' speech understanding in noise, intelligibility ratings, and accent ratings.