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.