Canonical transient receptor potential (TRPC) channels control influxes of Ca 2؉ and other cations that induce diverse cellular processes upon stimulation of plasma membrane receptors coupled to phospholipase C (PLC). Invention of subtype-specific inhibitors for TRPCs is crucial for distinction of respective TRPC channels that play particular physiological roles in native systems. Here, we identify a pyrazole compound (Pyr3), which selectively inhibits TRPC3 channels. Structure-function relationship studies of pyrazole compounds showed that the trichloroacrylic amide group is important for the TRPC3 selectivity of Pyr3. Electrophysiological and photoaffinity labeling experiments reveal a direct action of Pyr3 on the TRPC3 protein. In DT40 B lymphocytes, Pyr3 potently eliminated the Ca 2؉ influx-dependent PLC translocation to the plasma membrane and late oscillatory phase of B cell receptorinduced Ca 2؉ response. Moreover, Pyr3 attenuated activation of nuclear factor of activated T cells, a Ca 2؉ -dependent transcription factor, and hypertrophic growth in rat neonatal cardiomyocytes, and in vivo pressure overload-induced cardiac hypertrophy in mice. These findings on important roles of native TRPC3 channels are strikingly consistent with previous genetic studies. Thus, the TRPC3-selective inhibitor Pyr3 is a powerful tool to study in vivo function of TRPC3, suggesting a pharmaceutical potential of Pyr3 in treatments of TRPC3-related diseases such as cardiac hypertrophy.Ca 2ϩ signaling ͉ pyrazole compounds ͉ TRPC channels ͉ TRPC3

Skilled movements of the tongue in speech articulation reflect complex formation of the tongue musculature, although its description in the anatomical literature is rather limited for developing a realistic computational model of the tongue. This study presents detailed descriptions of the muscular structure of the human tongue based on macroscopic and microscopic observations and provides three-dimensional schemata of the tongue musculature. Histologic examination revealed that the tongue consists of five strata, stacked along the courses of the fibers of the genioglossus muscle in proximal-distal directions. This stratum structure exists in the entire tongue tissue, indicating that the lingual musculature can be divided into the inner and outer regions. The former consisted of the "stem" and "core," and the latter of the "cover" and "fringe." In gross dissection, the tongue was cut into wedge-like blocks along the course of the genioglossus muscle to examine muscle fiber arrangement. Using this approach, it was determined that serial repetitions of "structural units" composed the inner musculature of the tongue. Each unit consisted of a pair of thin muscle fiber laminae; one was composed of the genioglossus and vertical muscles, and the other of the transverse muscle. In the apex, the laminae lacked the fibers of the genioglossus. These findings have been incorporated in three-dimensional schemata of the tongue musculature.

An acoustic simulator based on the finite-difference time-domain (FDTD) method was evaluated by acoustic measurements on solid models of the vocal tract. Three-dimensional vocal tract (3D VT) shapes for a male subject during production of the five Japanese vowels were measured by magnetic resonance imaging. Transfer functions of the 3D VT shapes were computed by the acoustic simulator. The accuracy of the finite-difference algorithm was second-order in time and fourth-order in space. From the same 3D VT shapes, solid models were made of epoxide resin by a stereo-lithographic technique, and their acoustic transfer functions were measured using a time-stretched pulse signal. The calculated and measured spectra were compared up to 8 kHz. Although locations of major poles and zeros were common between calculated and measured spectra, the calculated spectra showed a larger number of small zeros, possibly caused by underestimation of VT acoustic losses in the simulation. However, the lower four formants were simulated remarkably accurately, with a mean absolute error of only 2.2 % compared with the acoustic measurements. These facts indicated that the acoustic simulator can reasonably account for acoustic phenomena within the VT.

A 3D cine-MRI technique was developed based on a synchronized sampling method [Masaki et al., J. Acoust. Soc. Jpn. E 20, 375-379 (1999)] to measure the temporal changes in the vocal tract area function during a short utterance /aiueo/ in Japanese. A time series of head-neck volumes was obtained after 640 repetitions of the utterance produced by a male speaker, from which area functions were extracted frame-by-frame. A region-based analysis showed that the volumes of the front and back cavities tend to change reciprocally and that the areas near the larynx and posterior edge of the hard palate were almost constant throughout the utterance. The lower four formants were calculated from all the area functions and compared with those of natural speech sounds. The mean absolute percent error between calculated and measured formants among all the frames was 4.5%. The comparison of vocal tract shapes for the five vowels with those from the static MRI method suggested a problem of MRI observation of the vocal tract: data from static MRI tend to result in a deviation from natural vocal tract geometry because of the gravity effect.

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