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Inositol 1,4,5-trisphosphate (InsP3) and calcium interact to increase the dynamic range of InsP3 receptor-dependent calcium signaling.

The inositol 1,4,5-trisphosphate (InsP3)-gated Ca channel in cerebellum is tightly regulated by Ca (Bezprozvanny, I., J. Watras, and B.E. Ehrlich. 1991. Nature (Lond.). 351:751-754; Finch, E.A., T. J. Turner, and S.M. Goldin. 1991. Science (Wash. DC). 252:443-446; Hannaert-Merah, Z., J.F. Coquil, L. Combettes, M. Claret, J.P. Mauger, and P. Champeil. 1994. J. Biol. Chem. 269:29642-29649; Iino, M. 1990. J. Gen. Physiol. 95:1103-1122; Marshall, I., and C. Taylor. 1994. Biochem. J. 301:591-598). In previous single channel studies, the Ca dependence of channel activity, monitored at 2 microM InsP3, was described by a bell-shaped curve (Bezprozvanny, I., J. Watras, and B.E. Ehrlich. 1991. Nature (Lond.). 351:751-754). We report here that, when we used lower InsP3 concentrations, the peak of the Ca-dependence curve shifted to lower Ca concentrations. Unexpectedly, when we used high InsP3 concentrations, channel activity persisted at Ca concentrations as high as 30 microM. To explore this unexpected response of the channel, we measured InsP3 binding over a broad range of InsP3 concentrations. We found the well-characterized high affinity InsP3 binding sites (with Kd < 1 and 50 nM) (Maeda, N., M. Niinobe, and K. Mikoshiba. 1990. EMBO (Eur. Mol. Biol. Organ.) J. 9:61-67; Mignery, G., T.C. Sudhof, K. Takei, and P. De Camilli. 1989. Nature (Lond.). 342:192-195; Ross, C.A., J. Meldolesi, T.A. Milner, T. Satoh, S. Supattapone, and S.H. Snyder. 1989. Nature (Lond.). 339:468-470) and a low affinity InsP3 binding site (Kd = 10 microM). Using these InsP3 binding sites, we developed a new model that accounts for the shift in the Ca-dependence curve at low InsP3 levels and the maintained channel activity at high Ca and InsP3 levels. The observed Ca dependence of the InsP3-gated Ca channel allows the cell to abbreviate the rise of intracellular Ca in the presence of low levels of InsP3, but also provides a means of maintaining high intracellular Ca during periods of prolonged stimulation.

Animals↗

A wide dynamic range, high-spatial-resolution scanning system for radiochromic dye films.

This paper describes the evaluation of an inexpensive, commercially available 35 mm transparency slide scanner as a potential alternative scanning device for GafChromic HD-810 radiochromic dye film. Besides its low cost, the principal advantages of this type of scanner are high spatial resolution and high speed (a typical scan taking less than 1 min). With broad-band illumination the useful dose range using grey-scale imaging of GafChromic HD-810 is limited to about 50-800 Gy. By using the colour-scale imaging capability of the scanner we have been able to achieve a significant extension covering a similar range (15-2000 Gy) to that attainable using monochromatic illumination. The short-term reproducibility of the system is good, with a coefficient of variation of doses estimated from repeat scanning of uniformly exposed calibration films of less than 2%. Long-term stability is ensured by the scanning of a manufacturer-supplied test slide. The slide scanner system has been used in the determination of depth dose distributions from a model 'hot particle' source containing 106Ru/Rh. GafChromic dye film stacks irradiated by the source were read out on both the slide scanner and a conventional Joyce Loebl MDM6 scanning stage microdensitometer. The overall agreement between the dose estimates provided by the two systems was within 10%.

Beta Particles↗

Client preferences for compression threshold in single-channel wide dynamic range compression hearing aids.

OBJECTIVE: Compression in hearing aids can be applied with low compression ratios over a wide range of input levels, but reverts to linear amplification below the compression threshold (CT). In this study, we aimed to determine which of two CTs was preferred by subjects as they used their hearing aids in their own environments, and whether they would prefer to have no low ratio compression at all. DESIGN: Subjects were fitted with a multimemory hearing aid incorporating input controlled compression with a 2:1 compression ratio and output controlled compression limiting. The two memories contained identical programs except that they differed in CT. Sixteen mild to moderately sensorineurally hearing-impaired subjects compared low (approximately 40 dB SPL) and moderate (approximately 65 dB SPL) CTs over 2 mo of field trials using hand held remote controls to switch between the alternatives. In a third month's trial, the preferred option (which also included output controlled compression limiting) was compared with compression limiting alone. RESULTS: The higher CT was preferred by 14 of the subjects. The combination of input compression and output compression limiting was preferred to compression limiting alone by 14 of the subjects. CONCLUSIONS: Several real world advantages of frequency independent 2:1 compression with a CT of about 65 dB SPL were demonstrated over linear amplification. Extending the compression to much lower input levels appears to carry more disadvantages than advantages, at least for clients with mild and moderate hearing losses, when fitted with single-channel compression aids with a 2:1 compression ratio.

Aged↗

The preferred number of channels (one, two, or four) in NAL-NL1 prescribed wide dynamic range compression (WDRC) devices.

OBJECTIVE: The recently introduced NAL-NL1 rationale for fitting WDRC devices prescribes a relatively high compression threshold and prescribes compression ratios lower than those prescribed by loudness normalization rationales. The aim of this study was to investigate whether the compression characteristic prescribed by NAL-NL1 is most effective in a single-channel scheme or in a multi-channel scheme. DESIGN: Twenty-four subjects with flat or steeply sloping hearing loss participated in the study. One, two, and four channels were implemented digitally in the laboratory and evaluated on the basis of a paired-comparison test and a speech recognition test. The test stimuli consisted of speech and noise presented at average input levels, and speech and noise alternating every 3 sec among different input levels. The single-channel and 2-channel NAL-NL1 prescriptions were also evaluated in individually selected everyday situations in the field using a digital 2-memory device. RESULTS: The three compression schemes produced no significant difference in speech recognition scores. Most subjects showed no preference for either scheme in the paired-comparison test. Those who did mainly selected the single-channel scheme. These preferences can be explained on the basis on audibility and quality. In the field all subjects with a steeply sloping loss, but one, preferred the 2-channel scheme. Among the subjects with a flat loss more preferred the single-channel scheme than preferred the 2-channel scheme. Statistical analyses showed that those who preferred the 2-channel scheme were fitted with significantly greater differences in the compression ratio in the high frequencies, and those who preferred the single-channel scheme were fitted with significantly greater differences in the high-frequency gain for a 65 dB input. CONCLUSIONS: Multi-channel compression prescribed according to NAL-NL1 in up to four channels showed no adverse effects on speech recognition relative to a single-channel scheme. The paired-comparison test showed a small, but explainable preference for the single-channel scheme. The field test revealed a preference for the 2-channel scheme by subjects with steeply sloping loss. When using the NAL-NL1 rationale it is recommended to use at

Acoustic Stimulation↗

The dynamic range of neonatal heart rate variability.

INTRODUCTION: Although it is generally appreciated that heart rate variability is low during severe illness, the extent, time course, and mathematical characteristics of heart rate variability during transitions between health and illness have not been systematically examined. The purpose of this study was to analyze heart rate variability in newborn infants during a rapid recovery from severe respiratory and circulatory failure. METHODS AND RESULTS: From prolonged ECG recordings, we evaluated heart rate variability in the time domain (mean, relative change, and coefficient of variation of RR intervals), in the frequency domain (using power spectra of the time series of RR intervals), and using a neural network. Qualitatively, RR interval plots showed little heart rate variability during severe illness but became "noisier" during recovery. Quantitatively, recovery was marked by twofold to threefold increases in time-domain parameters, by eightfold increases in frequency-domain parameters, and by more than 20-fold increases in a neural network measure. Time-domain and frequency-domain measures were correlated, but not strongly. Heart rate variability reached stable levels by 4 to 5 days. Heart rate did not change dramatically. CONCLUSION: Recovery from severe neonatal illness is accompanied by large and rapid increases in heart rate variability, but not by large changes in heart rate. This increase can be effectively assessed in the time domain, in the frequency domain, and by using a neural network.

Cardiovascular Diseases↗

Contrast enhancement of noisy images by windowing: limitations due to the finite dynamic range of the display system.

A theoretical model has been developed to explain the effects of simple linear windowing on the apparent contrasts of signals in displayed digital images. The model predicts, and experimental results demonstrate, that the effective displayed contrast of a digital radiographic signal depends in a complex way upon interactions among the endpoints of the display scale, the signal contrast and noise level of the original data, the window center and display center selected, and the contrast enhancement factor applied. The results obtained from this work apply quantitatively to the highly idealized situation in which (i) a uniform signal is superimposed on a uniform background containing Gaussian pixel-value noise, and (ii) a linear (or exponential) relationship exists between the optical density of a film display (or the light intensity of a luminous display) and pixel value in some finite range. However, the qualitative effects demonstrated here may be expected to arise in a broad variety of situations involving strong digital contrast enhancement.

Computer Simulation↗

Side effects of fast-acting dynamic range compression that affect intelligibility in a competing speech task.

Using a cochlear implant simulator, Stone and Moore [J. Acoust. Soc. Am. 114, 1023-1034 (2003)] reported that wideband fast-acting compression led to poorer intelligibility than slow-acting compression in a competing speech task. Compression speed was varied by using different pairs of attack and release times. In the first experiment reported here, it is shown that attack times less than about 2 ms in a wideband compressor are deleterious to intelligibility. In experiment 2, fast wideband compression was applied to the target and background either before or after mixing. The former reduced the modulation depth of each signal but maintained the independence between the two signals, while the latter introduced "comodulation." Using simulations with 6 and 11 channels, intelligibility was higher when compression was applied before mixing. In experiment 3, wideband compression was compared with multichannel compression; the latter led to reduced comodulation effects. For 6 channels, the position of the compressor, either wideband or within each channel, had no effect on intelligibility. For 11 channels, channel compression severely degraded intelligibility compared to wideband compression, presumably because of the greater reduction of across-channel contrasts. Overall, caution appears necessary in the use of fast-acting compression in cochlear implants, so as to preserve intelligibility.

Adult↗

Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage.

Expression of the constitutively activated TEL/PDGFbetaR fusion protein is associated with the t(5;12)(q33;p13) chromosomal translocation found in a subset of patients with chronic myelomonocytic leukemia. TEL/PDGFbetaR activates multiple signal transduction pathways in cell-culture systems, and expression of the TEL-PDGFRB fusion gene induces myeloproliferative disease (MPD) in mice. We used gene-targeted mice to characterize the contribution of signal transducer and activator of transcription (Stat) and Src family genes to TEL-PDGFRB-mediated transformation in methylcellulose colony and murine bone marrow transduction/transplantation assays. Fetal liver hematopoietic stem and progenitor cells harboring targeted deletion of both Stat5a and Stat5b (Stat5ab(null/null)) genes were refractory to transformation by TEL-PDGFRB in methylcellulose colony assays. Notably, these cell populations were maintained in Stat5ab(null/null) fetal livers and succumbed to transformation by c-Myc. Surprisingly, targeted disruption of either Stat5a or Stat5b alone also impaired TEL-PDGFRB-mediated transformation. Survival of TPiGFP-->Stat5a(-/-) and TPiGFP-->Stat5a(+/-) mice was significantly prolonged, demonstrating significant sensitivity of TEL-PDGFRB-induced MPD to the dosage of Stat5a. TEL-PDGFRB-mediated MPD was incompletely penetrant in TPiGFP-->Stat5b(-/-) mice. In contrast, Src family kinases Lyn, Hck, and Fgr and the Stat family member Stat1 were dispensable for TEL-PDGFRB disease. Together, these data demonstrate that Stat5a and Stat5b are dose-limiting mediators of TEL-PDGFRB-induced myeloproliferation.

Animals↗