Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.

Carollia perspicillata (Phyllostomidae) is a frugivorous bat that emits low-intensity, broadband, frequency-modulated echolocation pulses through nostrils surrounded by a noseleaf. The emission pattern of this bat is of interest because the ratio between the nostril spacing and the emitted wavelength varies during the pulse, causing complex interference patterns in the horizontal dimension. Sound pressures around the bat were measured using a movable microphone and were referenced to those at a stationary microphone positioned directly in front of the animal. Interference between the nostrils was confirmed by blocking one nostril, which eliminated sidelobes and minima in the emission pattern, and by comparison of real emission patterns with simple computer models. The positions of minima in the patterns indicate effective nostril spacings of over a half-wavelength. Displacement of the dorsal lancet of the noseleaf demonstrated that this structure directs sound in the vertical dimension.

The emission pattern of Eptesicus fuscus was found to be consistent with those of the other frequency-modulating (FM) bats studied in similar detail in that there is a mainlobe aimed forward of the animal together with a prominent −6-dB ventral lobe. This ventral lobe cannot be explained as the first sidelobe of a piston source mounted in an infinite baffle and must be formed by some other acoustic means. Nevertheless, a piston source with a radius comparable to that of the open mouth can nicely explain the changes in the width of the mainlobe with frequency, so that the open mouth alone can explain the observed directionality. At wavelengths greater than the mouth dimensions, however, some additional sound ‘‘focusing’’ may occur, presumably due to diffraction by the head.

Big brown bats, Eptesicus fuscus, can be trained to use echolocation to track a small microphone with a food reward attached when it is moved rapidly toward them. This situation mimics prey interception in the wild while allowing very precise recording of the sonar pulses emitted during tracking behavior. The results show that E. fuscus intensity compensates, reducing emitted intensity by 6 dB per halving of target range so that the intensity incident upon the target is constant and echo intensity increases by 6 dB per halving of range. This increase in echo intensity is effectively canceled by the reduction in auditory sensitivity due to automatic gain control (AGC) of 6 to 7 dB per halving of range. Intensity compensation behavior and AGC therefore form a dual-component, symmetrical system that stabilizes perceived echo amplitudes during target approach. The same system is present in the fishing bat, Noctilio leporinus, suggesting that it may be widespread in echolocating bats. Correlation analysis shows that, despite large changes in the duration of the pulses emitted by E. fuscus during an approach, the pulse frequency structure is such that the spatial image of the target perceived along the range axis is highly stable. Pulse duration is not reduced in the manner theoretically necessary to eliminate potential echo distortion effects due to AGC, but is reduced in such a way that this distortion is insignificant. During the terminal buzz, a high degree of temporal overlap (relative to pulse duration) occurs between emitted pulse and returning echo.

Previous research on echo detection in bats has suggested that the effective threshold is a function of the acoustic clutter in the experimental environment, as might be expected given the low ambient noise levels typical of such psychophysical research. This paper demonstrates that theory of signal detectability (TSD) methodology is applicable to bats and uses it to show that an important element of clutter limiting in Eptesicusfuscus and Noctilio leporinus is backward masking of phantom targets by the real echo from the loudspeakers used to generate them. This information suggests that a previous estimate of the magnitude of automatic gain control (AGC) is too high, due to variable backward masking inherent in the experimental method used. A re-examination of gain control using a masking-free method shows that it reduces auditory sensitivity by 6 to 7 dB per halving of target range, rather than 11 dB as previously thought.

Many bats change the acoustic parameters of their echolocation calls in a deliberate manner during prey capture. Attempts to quantify these changes have been either of limited scope or subject to potentially severe errors due to an inadequate consideration of the directionality of both the bat and the recording microphone. Therefore, the echolocation pulses emitted by two N. leporinus have been recorded as they approached and captured stationary prey, with the microphone positioned in such a way that the structure of the pulses incident upon the target could be determined. The results of this study show that: (1) during the last 1.5 m of the approach, N. leporinus reduces the intensity of emitted pulses by 6 dB per halving of distance, so that the intensity incident upon the target is constant; (2) at a point in the pulse train that corresponds to the position of the hypothesized tracking phase of echolocation, N. leporinus selectively reduces the intensity of the frequency-modulated (FM) fundamental so that the FM pulse component is predominantly second harmonic; and (3) a high degree of temporal overlap occurs between the FM component of emitted pulse and echo when N. leporinus is within 0.4 m of its prey.

The acoustic role of the enlarged, bony, nasal cavities and rigid tracheal chambers in the horseshoe bat, Rhinolophus hildebrandti (Fig. 2) was investigated by determining the effect of their selective filling on the nasally emitted sonar pulse and on the sound traveling backwards down the trachea. Normal sonar signals of this bat contain a long constant frequency component with most energy in the second harmonic at about 48 kHz. The fundamental is typically suppressed 20 to 30 dB below the level of the second harmonic (Fig. 1). None of the experimental manipulations described affected the frequency of the sonar signal fundamental. Filling the dorsal and both lateral tracheal chambers had little effect on the emitted vocalization, but caused the level of the fundamental component in the trachea to increase 15 to 19 dB in most bats (Table 2). When only the dorsal chamber or only the two lateral chambers were filled, the effect was less striking and more variable (Tables 3 and 4), suggesting that the tracheal fundamental is normally suppressed by acoustic interaction between these three cavities. Filling the enlarged dorsal nasal cavities had no effect on the tracheal sound. The effect of this treatment on the nasally emitted sonar pulse was inconsistent. Sometimes the fundamental increased 10 to 12 dB, other times the intensity of all harmonics decreased; in still other cases the second, third or fourth harmonic increased, but the fundamental remained unchanged (Tables 5, 6, and 7). When bats were forced to vocalize through the mouth, by sealing the nostrils, there was a prominent increase in the level of the emitted fundamental (10 to 21 dB) and in the fourth harmonic (6 to 17 dB). In one instance there was also a significant increase in the level of the third harmonic (Tables 8 and 9). The supraglottal tract thus filters the fundamental from the nasally emitted sonar signal, although the role of the inflated nasal cavities in this process is unclear. We conclude that a high glottal impedance acoustically isolates the subglottal from the supraglottal vocal tract. The tracheal chambers do not affect the emitted sonar signal, but may attenuate the fundamental in the trachea and prevent it from being reflected from the lungs back towards the cochlea. It may be important to prevent the reflected fundamental from stimulating the cochlea, via tissue conduction, along multiple indirect pathways which would temporally smear cochlear stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

The transfer function of the supraglottal vocal tract of the horseshoe bat, Rhinolophus hildebrandti, was obtained by a noninvasive technique, based on incremental variations in the helium content of inspired gas, which also allowed the source spectrum to be determined. The acoustic role of the vocal tract chambers was examined by obtaining the transfer function before and after filling the chambers. Simultaneous recording of sound pressures in the trachea during these experiments allowed some analysis of subglottal acoustics. With the vocal tract intact, the transfer function was found to show sharp transmission minima at the fundamental and third harmonic and a broad transmission maximum at the emitted second harmonic. This transfer function shape, along with the source spectrum obtained, demonstrates that the second harmonic dominance in the emitted pulse is achieved by vocal tract filtering, although the source spectrum is different from that typical of man in that it does not show an f−2 harmonic decay. Changes in the transfer function caused by filling the nasal chambers suggest that these structures may play an impedance matching role at the second harmonic. Filling of the tracheal chambers did not affect the transfer function but changed the tracheal acoustics in a manner which suggests that these chambers may return backward-propagated sound to the larynx with a phase shift. The possible interactive role of the nasal and tracheal chambers in increasing vocal efficiency at the second harmonic is discussed.