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Speech recognition with dynamic range reduction: (1) deaf and normal subjects in laboratory conditions.

Processing to reduce the dynamic range of speech should increase intelligibility and protect the impaired ear from overloading. There are theoretical and practical objections to using AGC devices to reduce dynamic range. These are overcome by using recently available signal processing employing high frequency carrier clipping. An increase in intelligibility of speech with this HFCC has been demonstrated, for normal subjects with simulated deafness, and for most partially hearing patients. Intelligibility is not improved for some patients; possibly due to their having learned to extract features which are lost. These patients may also benefit after training.

Acoustics

Simultaneous quantitative detection of multiple low-frequency variants by high-dynamic-range capillary electrophoresis.

Sensitive and quantitative detection of low-frequency variants across multiple loci is critical for nucleic acid-based diagnostics, yet clinical implementation requires a balance among sensitivity, multiplexing capacity, cost, and operational simplicity. We previously developed a high-dynamic-range capillary electrophoresis system capable of detecting variants at allele frequencies below 1%; however, its application was limited to single-locus analysis. Here, we expanded this platform to multiplex detection by incorporating mobility-shift strategies into the assay design. This approach enabled simultaneous analysis of 15 hotspot variants across three clinically relevant loci: KRAS codons 12 and 13 and GNAS codon 201. Validation using synthetic oligonucleotides, formalin-fixed paraffin-embedded tissue, and liquid specimens demonstrated high quantitative accuracy over clinically relevant variant allele frequency ranges, with measured values closely matching expected values (R2 > 0.97). The assay showed high concordance with targeted amplicon sequencing and digital polymerase chain reaction for all variants at variant allele frequencies ≥1%, while also detecting selected variants below this threshold. Collectively, these results establish a multiplexed high-dynamic-range capillary electrophoresis assay for simultaneous, quantitative detection of low-frequency variants, offering a scalable and cost-effective approach for disease-focused gene panels in clinical laboratory settings.

HiDy

[Dynamic range of acoustic reflex and its importance for hearing aid evaluation (author's transl)].

It is reported on the dynamic range of acoustic reflex in the case of normal hearing. Stimulation is carried out with speech noise under free field conditions. The sensitivity of impedance measurement is increased by using an averager, which enables acoustic reflex measurements at sound pressure levels of about 70 dB. Further an exact evaluation of input-output-characteristics becomes possible by this procedure. Basing on this consideration the possibility of objective hearing aid evaluation is discussed. The fundamental point of this technique should be the compensation of pathological input-output-characteristics by suitable hearing aids.

Ear, Middle

[Loss of hearing in cerebral palsy (author's transl)].

The hearing threshold level was examined in 75 cerebral palsied children (3--15 yrs.). In the case of 5 patients, we were unable to get an audiogram. 50 children had a normal audiogram on both ears. 13 patients had a bilateral, one a unilateral sensoneural loss of hearing. The rate of conductive loss of hearing was unexpectedly high: 4 patients with a bilateral pure conductive loss of hearing, 3 with a bilateral sensoneural loss of hearing and a bilateral additional airborne gap, and 2 with a monaural conductive loss of hearing. The treatment of the conductive deficiency is of primary importance in cases of a super-imposed senso-neural loss of hearing losses. 7 of our patients have been fitted with a hearing aid. The threshold of the stapedius reflex could be estimated in the case of 10 patients suffering from a sensoneural loss of hearing. All had a reduced dynamic range. Reduction of the dynamic range is not a specific trait of cerebral palsy as our cerebral palsied children with normal hearing had a normal dynamic range. No correlation could be found between asphyxia, underweight and hyperbilirubinaemia as single factors in the newborn period and sensoneural loss of hearing nor between athetosis and sensoneural loss of hearing.

Adolescent

Accommodation dynamics I. Range nonlinearity.

We show the presence of a new nonlinearity in accommodation dynamics. Positive accommodation is slower when the eye is operating in the near range; conversely, relaxation of accommodation is apparently slower during work in the far range. Latency of accommodation is unaffected by working range. This new dynamic range nonlinearity has been defined in connection with a continuing research study of accommodation responses in normal subjects and in clinic patients. Instrumentation and analysis procedures are described.

Accommodation, Ocular

Responses of primate spinothalamic neurons to graded and to repeated noxious heat stimuli.

1. The responses of primate spinothalamic tract cells innervating the glabrous skin of the foot to noxious thermal stimuli have been examined. 2. Of the 41 cells studied, 98% responded to noxious thermal stimuli. Heating the cutaneous receptive field with a series of stimuli from 35 to 43, 47, and 50 degrees C produced a graded increase in discharge rate. The responses were characterized by an onset, which occurred after the temperature change had either slowed or stopped, an acceleration in the discharge up to a peak, and then an adaptation to a new base-line level. The time constants of adaptation were faster than those reported for C polymodal nociceptors. 3. No systematic differences were found in the responses to noxious thermal stimuli of cells with wide dynamic range receptive fields and of cells with narrow dynamic range, high-threshold receptive fields. There were also no differences in the responses of cells located in the marginal zone and of cells located in the neck of the dorsal horn. 4. The relationship between peak frequency and final skin temperature with a 30 s stimulus duration can best be described by a power function with an exponent of 2.1. An increase in the stimulus duration to 120 s resulted in an increase in the exponent of the power function to 3.2. 5. Repetition of the series of 30-s heat stimuli resulted in an increase in peak frequency, total impulse count, and background activity. Repetition of stimuli having a duration of 120 s produced an increase in the peak frequency at 43 and 45 degrees C, a smaller increase at 47 degrees C, and a decrease at 50 degrees C. Background activity was increased by the lower temperature stimuli, but was decreased following higher temperature stimuli. 6. In six additional cells, the skin was heated with three consecutive presentations at each temperature level (43, 45, 47, and 50 degrees C) for 30 s. No change was observed in the peak frequencies of the responses to successive stimuli of the same intensity. However, the exponent of the power function relating the average peak frequency for the six cells to changes in skin temperature was 3.9. This exponent was larger than that seen when two series of graded heat stimuli of 120 s duration were used, indicating more sensitization despite the fact the total time of exposure to noxious heat was less. 7. A role for both high-threshold and wide dynamic range spinothalamic cells in transmitting nociceptive information to the diencephalon is postulated.

Adaptation, Physiological

Inhibition of spinal cord interneurons by narcotic microinjection and focal electrical stimulation in the periaqueductal central gray matter.

Single cell evoked activity was recorded from spinal cord interneurons in rats prepared with microinjection cannulae or stimulating electrodes in the periaqueductal central gray matter (PAG). Morphine microinjections (4-16 microgram) inhibited the response evoked by a noxious stimulus in 55% of the wide dynamic range neurons tested. Microinjections of etorphine (0.25-0.5 microgram) inhibited 82% of the nociceptive neurons tested. Neither drug inhibited neurons which responded only to innocuous mechanical stimulation. The inhibition of wide dynamic range neurons produced by narcotic microinjection was antagonized by naloxone (1 mg/kg, i.p.) in 7 of 11 cases. Control experiments indicated that the effects obtained with microinjections could not be attributed to the drugs' diffusion to the spinal cord. Focal electrical stimulation of the PAG inhibited the responses to noxious stimuli of 60% of wide dynamic range neurons but was without effect on the responses of neurons that were activated only by innocuous stimuli. These experiments directly demonstrate that narcotic analgesics restricted to an intracerebral site of action activate a neural system which preferentially inhibits the responses of spinal cord wide dynamic range neurons to noxious stimuli. The system has a specificity for nociceptive input since non-nociceptive neurons were unaffected. Directly comparable results were produced by electrical stimulation of the PAG, supporting the concept that stimulation and narcotics modulate the transmission of nociceptive information by similar mechanisms.

Animals

Radio frequency clipping in hearing aids.

For those patients with reduced dynamic range of hearing, accomodation of normal dynamic range of speech has always presented a problem. This paper describes a method of overcoming the problem, a method which has the added benefit of offering improved speech discrimination as well as limiting the output from a hearing aid system. The principle employed is the presentation of taped speech material processed through clipping of a radio frequency single side side band suppressed carrier signal, which is filtered to remove the Fourier components and demodulated to obtain the modified speech material. Groups of normally hearing and hearing impaired subjects undergo speech audiometry testing to assess what improvement can be effected by this system. The majority of subjects tested both normal and hearing impaired achieve improved speech discrimination when using the system described. Further once the output was set no increase in the input signal could produce a level in excess of that set by the output control.

Adult

White noise analysis of Phycomyces light growth response system. II. Extended intensity ranges.

By means of white gaussian noise stimulation, the Wiener kernels are derived for the Phycomyces light growth response for a variety of intensity conditions. In one experiment the intensity I, rather than log I, is used as the input variable. Under the very limited dynamic range of that experiment, the response is fairly linear. To examine the dependence of the kernels on dynamic range, a series of experiments were performed in which the range of log I was halved and doubled relative to normal. The amplitude of the kernels, but not the time course, is affected strongly by the choice of dynamic range, and the dependence reveals large-scale nonlinearities not evident in the kernels themselves. In addition kernels are evaluated for experiments at a number of absolute intensity levels ranging from 10(-12) to 10(-3) W/cm2. The kernel amplitudes are maximal at about 10(-6) W/cm2. At 10(-12) W/cm2, just above the absolute threshold, the respond is very small. The falloff at high intensity, attributable to inactivation of the photoreceptor, is analyzed in the framework of a first-order pigment kinetics model, yielding estimates for the partial extinction coefficient for inactivation epsilonI455 = (1.5 +/- 0.2) X 10(4) liter/mol-cm and a regeneration time constant of tau = (2.7 +/- 0.6) min. A model is introduced which associates the processes of adaptation and photoreceptor inactivation. The model predicts that the time constants for adaptation and pigment should be identical. This prediction is consistent with values in this and the preceding paper. The effects of pigment inactivation are simulated by a linear electronic analog circuit element, which may be cascaded with the linear simulator circuit in the preceding paper.

Adaptation, Physiological

Reframing Proteomics Measurement: Super Mass Spectrometry Framework and the Role of Delayed Electrospray Ionization Technique.

Dynamic range, repeatability, and reproducibility remain the central limitations of data-independent acquisition (DIA) proteomics. Current workflows emphasize protein group identification counts and throughput, but these metrics mask the fundamental measurement challenge: generating a repeatable, reproducible, high-fidelity, and relatively complete digital representation of complex proteomes. In particular, plasma proteomics spans more than 10 orders of magnitude in protein abundance, far exceeding the capacity and dynamic range of any single mass spectrometer. Incremental advances have not closed this gap. In this Perspectives article, I introduce the Super Mass Spectrometry framework and then highlight the Delayed Electrospray Ionization (Delayed-ESI) technique, as a practical approach to address these limitations. By producing compositionally identical but temporally staggered ion beams, the Delayed-ESI technique enables deterministic remeasurement of the same analyte profile, supporting various novel strategies to improve analytical figures of merit. While recent implementations of the Delayed-ESI technique have emphasized throughput, I argue that the broader value of the Delayed-ESI technique lies in extending dynamic range and improving repeatability and reproducibility─objectives that should take precedence if proteomics is to evolve into a robust measurement science capable of supporting population-scale proteomics studies.

Proteomics

Evaluation and Optimization of Different Digestion Strategies for In-Depth Proteomic Characterization of Residual Host Cell Proteins in rAAV-Based Gene Therapy Products.

Recombinant adeno-associated virus vectors (rAAVs) are the most important vectors for in vivo gene therapies, yet their safety relies on low levels of residual host cell proteins (HCPs). While mass spectrometry-based proteomics enables sensitive and untargeted HCP profiling, it faces challenges with matrix interferences from purification buffers and the high dynamic range between abundant viral capsids and trace HCPs. Although sample preparation methods that address these challenges are well-established for antibody products, their adaptation to rAAV purification stages and products remains largely unexplored. In this study, we systematically evaluated three widely used proteomic sample preparation workflows─In-Solution, FASP, and SP3─across different stages of rAAV purification. In addition, each workflow was tested under both standard denatured digestion conditions and a "native" digestion strategy designed to reduce dynamic range by preserving capsid integrity while selectively digesting HCPs. This comparison identified the native FASP protocol as the most effective sample preparation method for overcoming matrix interference and dynamic range challenges, consistently outperforming other workflows in HCP identification across purification stages. Further optimization of the native FASP workflow enhanced its performance, achieving the highest host cell (HC) proteome depth, particularly in highly purified drug substance samples. This optimized sample preparation strategy provides a robust and easy-to-use framework for deep characterization of the host cell proteome in rAAV samples. By enabling deeper insights into the HCP profile, this approach supports improved understanding of the rAAV purification process and facilitates the development of targeted strategies to enhance product quality and safety.

Dependovirus

Physiology of peripheral neurons innervating otolith organs of the squirrel monkey. II. Directional selectivity and force-response relations.

1. The directional selectivity of peripheral otolith neurons was studied in the barbiturate-anesthetized squirrel monkey (Saimiri sciureus). Each unit's most sensitive axis was characterized by a functional polarization vector. The direction of a centrifugal force was varied with respect to the vector and to the macular plane. The neurons respond in an excitatory manner to shearing forces orthogonally disposed to the vector. The sensitivity to orthogonal shears was usually 10-15% of the sensitivity to parallel shearing forces. There was no significant response to orthogonal compressions, nor did compressions modify the response to shearing forces. 2. Force-response functions were obtained in the stimulus range of +/- 4.92 g. Forces were directed parallel to each unit's polarization vector. The functions are sigmoid shaped and possess both inhibitory and excitatory plateaus. The presumed physiological range of +/-1 g is represented in the lower (concave upward) portion of the function and has a dynamic range, expressed in terms of response magnitude, amounting to 20-40% of the potential dynamic range of the neuron. 3. There was considerable variation among units in their +/- 4.92 g force-response curves. The salient features of the functions are described by three factors, tentatively identified as a transduction gain, a receptor bias, and a mechanical gain. Both the resting discharge (do) and the +/-1 g sensitivity (so) vary in the same direction with changes in the factors related to transduction gain and receptor bias. It is shown that this covariation provides a quantitatively precise explanation for the positive relation between do and so.

Animals

[Stapedial reflexes in presbyacusis and occupational deafness].

Acoustic reflex thresholds were measured on 251 subjects (418 ears) with varying degrees of sensorineural hearing loss. The subjects are divided in three groups according to the pathology involved: presbyacusis and noise-induced hearing loss and combined hearing loss caused by both presbyacusis and noise exposure. The dynamic range of hearing was found to be reduced for all cases and at all frequencies. The decrease in dynamic range was proportional to the severity of the hearing loss. The sensation levels of the acoustic reflex thresholds seem to be dependent on the degree of hearing loss and not on the aetiology. Practical conclusions are drawn concerning the prediction of thresholds of hearing and the diagnosis of recruitment based on reflex measurements.

Adult

Neural transduction in Xenopus laevis lateral line system.

1. The process of neural excitation in hair cell systems was studied in an in vitro preparation of the Xenopus laevis (African clawed toad) lateral line organ. A specially designed stimulus chamber was used to apply accurately controlled pressure, water movement, or electrical stimuli, and to record the neural responses of the two afferent fibers innervating each organ or stitch. The objective of the study was to determine the characteristics of the neural responses to these stimuli, and thus gain insight into the transduction process. 2. A sustained deflection of the hair cell cilia due to a constant flow of water past the capula resulted in a maintained change in the mean firing rate (MFR) of the afferent fibers. The data also demonstrated that the neural response was proportional to the velocity of the water flow and indicated that both deflection and movement of the cilia were the effective physiological stimuli for this hair cell system. 3. The preparations responded to sinusoidal water movements (past the capula) over the entire frequency range of the stimulus chamber, 0.1-130 Hz, and were most sensitive between 10 and 40 Hz. The variation of the MFR and the percent modulation indicated that the average dynamic range of each organ was 23.5 dB. 4. The thresholds, if any, for sustained pressure changes and for sinusoidal pressure variations in the absence of water movements were very high. Due to the limitations of the stimulus chamber it was not possible to generate pressure stimuli of sufficient magnitude to elicit a neural response without also generating suprathreshold water-movement stimuli. Sustained pressures had no detectable effect on the neural response to water-movement stimuli. 5. The preparations were very sensitive to electrical potentials applied across the toad skin on which the hair cells were located. Potentials which made the ciliated surfaces of the hair cells positive with respect to their bases increased the MFR of the fibers, whereas negative potentials decreased it. The responses to sinusoidal electrical stimuli were similar to responses to water-movement stimuli with respect to frequency and dynamic ranges. Thresholds as low as 100 muV peak to peak (p-p) for 16-Hz stimuli were found. 6. The characteristics of the neural responses to electrical stimulation as well as supporting data obtained from the studies of the effects of anoxia on the evoked responses indicate that the electrical stimulus acts on the hair cells or on the synapses, rather than directly on the nerve fibers. This finding suggests that receptor potentials or their associated currents play an important role in the process of neural excitation in hair cell systems.

Animals